NZ609052B2

NZ609052B2 - Methods for treating HCV

Info

Publication number: NZ609052B2
Application number: NZ609052A
Authority: NZ
Inventors: Khatri Amit; M Bernstein Barry; E Klein Cheri; E Cohen Daniel; Sandeep Dutta; O Dumas Emily; M Menon Rajeev; C Brun Scott; Mensing Sven; J Podsadecki Thomas
Original assignee: Abbvie Inc
Priority date: 2011-10-21
Filing date: 2012-10-19
Publication date: 2016-09-27

Abstract

Provided are therapeutic regimens for the treatment of hepatitis C virus (HCV). The regimens comprise the administration of at least two direct acting antiviral agents (DAAs) and ribavirin, wherein the regimens exclude interferon and last for 6, 7, 8, 9, 10, 11 or 12 weeks. In one embodiment a regimen includes the use of ribavirin, PSI-7977 (sofosbuvir), and GS-5885 (ledipasvir). en includes the use of ribavirin, PSI-7977 (sofosbuvir), and GS-5885 (ledipasvir).

Description

METHODS FOR TREATING HCV This application claims the benefit of U.S. Provisional ation No. 61/550,352 filed October 21, 2011, U.S. Provisional Application No. 61/562,181 filed er 21, 2011, U.S.

Provisional ation No. 61/587,225 filed y 17, 2012, U.S. Provisional Application No. 61/600,276 filed February 17, 2012, U.S. Provisional Application No. 61/619,870 filed April 3, 2012, U.S. Provisional Application No. 61/656,251 filed June 6, 2012, and U.S. Provisional ation No. 61/711,830 filed October 10, 2012.

FIELD OF THE INVENTION The present invention s to interferon-free treatment for hepatitis C virus (HCV).

BACKGROUND OF THE INVENTION The HCV is an RNA virus belonging to the virus genus in the Flaviviridae family.

The enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises imately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins E1 and E2, a membrane bound protein p7, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

Chronic HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often incomplete. Therefore, there is a need for new therapies to treat HCV infection.

BRIEF Y OF THE INVENTION As one aspect of the present invention, methods for treating HCV ion in a subject are provided. The methods comprise administering at least two direct acting antiviral agents (DAAs) and ribavirin for a duration of no more than twelve weeks, or for another on as set forth .

Preferably, the duration of the treatment is twelve weeks. The duration of the treatment can also be no more than eight weeks. Preferably, the two or more direct acting antiviral agents (DAAs) and ribavirin are stered in amounts effective to provide a sustained virological response (SVR) or achieve another desired measure of effectiveness in a subject. The subject is not administered interferon during 6273790_1 (GHMatters) P99395.NZ LAURAW the treatment regimen. Put another way, the methods exclude the administration of interferon to the subject, thereby avoiding the side effects associated with eron. In some embodiments, the methods r comprise administering an inhibitor of cytochrome P-450 (such as ritonavir) to the subject to improve the pharmacokinetics or bioavailability of one or more of the DAAs.

As another aspect, methods for treating HCV infection in a subject are provided. The methods comprise administering (a) therapeutic agent 1, (b) at least one polymerase inhibitor selected from the group consisting of therapeutic agent 2, therapeutic agent 3, and combinations thereof, (0) ribavirin and (d) an inhibitor of cytochrome P-450 to the subject for a duration of no more than twelve weeks, or for another duration as set forth herein (e.g., the treatment regimen can last a duration of for no more than 8 weeks). Preferably, therapeutic agent 1, the polymerase inhibitor(s), ribavirin and the inhibitor of rome P-450 are administered in amounts effective to provide high rates of SVR or another measure of effectiveness in the subject. As non-limiting examples, therapeutic agent 1 and the inhibitor of cytochrome P-450 can be mulated and administered once daily, and the polymerase inhibitor(s) can be administered once daily or twice daily, and the treatment regimen preferably lasts for twelve weeks (the treatment regimen can also last, for example, for eight weeks).

As still another aspect, methods for treating a population of subjects having HCV infection are provided. The methods comprise administering at least two DAAs, together with ribavirin, to the subjects for a duration of no more than 12 weeks. Preferably, the at least two DAAs are administered to the subjects in amounts effective to result in SVR or r measure of effectiveness in at least about 50% of the population, preferably at least about 70% of the population.

In the foregoing methods as well as methods described hereinbelow, the DAAs can be selected from the group consisting of protease tors, side or tide polymerase inhibitors, cleoside polymerase inhibitors, NS3B inhibitors, NS4A inhibitors, NSSA inhibitors, NSSB tors, cyclophilin tors, and ations of any of the foregoing. For example, in some ments, the DAAs used in the t methods comprise or consist of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. The HCV polymerase inhibitor can be a nucleotide or nucleoside rase inhibitor or a non-nucleoside polymerase inhibitor. The HCV rase inhibitor can also be a non-nucleotide rase inhibitor.

In some ments, the HCV protease inhibitor is therapeutic agent 1 (described below) and the HCV polymerase inhibitor is therapeutic agent 2 and/or therapeutic agent 3 (also described below). By way of example, therapeutic agent 1 can be administered a total daily dose of from about 100 mg to about 250 mg, or administered at least once daily at a dose of from about 150 mg to about 250 mg, and therapeutic agent 2 is administered in a total daily dose of from about 300 mg to about 1800 mg or administered at least twice daily at doses from about 200 mg to about 400 mg. For some SUBSTITUTE SHEET (RULE 26) embodiments, the HCV protease inhibitor is eutic agent 1 and the non-nucleoside HCV polymerase inhibitor is therapeutic agent 3. By way of example, therapeutic agent 1 can be stered at a total daily dose of about lOO mg, atively about 200 mg, or alternatively about 250 mg; and therapeutic agent 3 is administered at a total daily dose of about 400 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) can be inistered with therapeutic agent 1 to improve the pharmacokinetics and bioavailability of therapeutic agent 1.

In some embodiments, the at least two DAAs se at least one HCV protease inhibitor and at least one NSSA inhibitor. Preferably, the HCV protease inhibitor is therapeutic agent 1 and the NSSA inhibitor is therapeutic agent 4. By way of e, therapeutic agent 1 can be administered at a total daily dosage from about 100 mg to about 250 mg, and therapeutic agent 4 can be administered in a total daily dose from about 25 mg to about 200 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) can be co-administered with therapeutic agent 1 to improve the pharmacokinetics and bioavailability of therapeutic agent 1.

In the foregoing methods as well as methods described herein, the DAAs and ribavirin can be stered in any ive dosing schemes andjor frequencies, for example, they can each be administered daily. Each DAA can be stered either separately or in combination, and each DAA can be administered at least once a day, at least twice a day, or at least three times a day. Likewise, the ribavirin can be administered at least once a day, at least twice a day, or at least three times a day, either separately or in combination with one or more of the DAAs. In some preferred embodiments, therapeutic agent 3 is administered once daily (QD) or twice daily (BID), and therapeutic agent 1 is administered once daily.

In some aspects, the present technology provides a method for treating HCV infection comprising administering to a subject in need thereof at least two DAAs and ribavirin for a on of no more than twelve weeks, wherein the subject is not administered with interferon during said duration. In some aspects, the at least two DAAs and ribavirin are administered in an amount effective to result in SVR. Some methods further comprise stering an inhibitor of cytochrome P450 to the subject. In some aspects, the duration is no more than eight weeks.

In some aspects of the present technology, the at least two direct acting antiviral agents comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, which is co-administered or co- formulated with ritonavir, and (ii) Compound 2 or a ceutically acceptable salt thereof.

In other aspects, the at least two direct acting antiviral agents se (i) Compound 1 or a pharmaceutically acceptable salt thereof, which is co-administered or co-formulated with vir, and (ii) Compound 3 or a pharmaceutically acceptable salt thereof.

SUBSTITUTE SHEET (RULE 26) 2012/061075 In yet another aspect, the at least two direct acting antiviral agents comprise (i) nd 1 or a pharmaceutically acceptable salt thereof, which is co-administered or co-formulated with ritonavir, and (ii) compound 4 or a pharmaceutically acceptable salt thereof.

In yet a further aspect, the at least two direct acting ral agents comprise (i) Compound 1 or a pharmaceutically able salt thereof, which is co-administered or co-formulated with ritonavir, (ii) Compound 2 or a pharmaceutically able salt thereof, and (iii) compound 4 or a pharmaceutically acceptable salt thereof.

In yet another aspect, the at least two direct acting antiviral agents comprises a drug combination selected from the group consisting of: a combination of PSI-7977 and PSI-938, a combination of BMS-790052 and BMS-650032, a combination of GS-5885 and GS-9451, a combination of GS-5885, O and GS-9451, a combination of BI-201335 and BI-27127, a combination of telaprevir and VX-222, a combination of PSI-7977 and TMC-435, and a combination of danoprevir and R7128. In yet another aspect, the at least two direct acting antiviral agents comprises a ation of PSI-7977 and BMS-790052 (daclatasvir). In yet another aspect, the at least two direct acting antiviral agents ses a combination of PSI-7977 and BMS-650032 (asunaprevir). In still another aspect, the at least two direct acting antiviral agents comprises a combination of PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another aspect, the at least two direct acting antiviral agents comprises a ation ofTMC-435 and daclatasvir.

In other aspects, the present technology provides a method for treating HCV infection in a subject comprising administering (a) therapeutic agent 1, (b) at least one polymerase inhibitor selected from the group consisting of therapeutic agent 2, therapeutic agent 3 and ations thereof, (c) ribavirin and (d) an inhibitor of cytochrome P450 to the subject and for a duration of no more than twelve weeks, wherein the eutic agent 1, the at least one polymerase inhibitor, the ribavirin and the inhibitor of cytochrome P450 are administered in amounts effective to result in sustained virological response (SVR) in the t.

In yet another aspect, the present technology es a method for treating a population of subjects having HCV infection, the method comprising administering at least two DAAs to the subjects for a duration of no more than 12 weeks, n the at least two DAAs are administered to the ts in amounts and for a duration effective to provide a SVR in at least about 70% of the population.

In another aspect, the t technology features a combination of at least two DAAs for use in treating HCV infection, wherein the duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). The treatment comprises administering the at least two DAAs to a subject infected with HCV. Preferably, the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for SUBSTITUTE SHEET (RULE 26) example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering ribavirin but does not include administering interferon.

The ent may also include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires cokinetic enhancement. The at least two DAAs can be administered concurrently or sequentially. For example, one DAA can be administered once daily, and another DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered concurrently (e. g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV- treatrnent naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder, a partial der or a relapser), or not a candidate for interferon treatment.

In another aspect, the present technology features a combination of Compound 1 (or a ceutically able salt thereof) and nd 2 (or a pharmaceutically acceptable salt thereof) for use in treating HCV infection. The treatment comprises administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). ably, the on of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment es administering ribavirin but does not include stering interferon; and ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) is administered with Compound 1 (or the salt thereof) to improve the cokinetics of the latter. Compound 1 (or the salt thereof) and nd 2 (or the salt thereof) can be administered concurrently or sequentially. For example, Compound 1 (or the salt thereof) can be administered once daily, together with ritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and Compound 2 (or the salt f) can be stered twice daily. For yet another example, Compound 1 (or the salt thereof) and ritonavir (or r CYP3A4 inhibitor, e. g., cobicistat) are co-formulated in a single composition and administered rently (e.g., once daily). For yet another example, Compound 1 (or the salt thereof), co-formulated with ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), is administered once daily, and Compound 2 (or the salt thereof) is administered twice daily. As a non- limiting example, the patient being treated can be infected with HCV genotype 1, such as pe la or lb. As another miting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive SUBSTITUTE SHEET (RULE 26) patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet r example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the ent lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In r e, the treatment lasts for 11 weeks, and the subject being d is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In yet another example, the ent lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient ed with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) ed with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being d is a non- responder (e. g., a null responder) infected with HCV pe 1. In still another example, the treatment lasts for 10 weeks, and the subject being d is a non-responder (e. g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a non-responder infected (e.g., a null responder) with HCV genotype 1.

In another aspect, the present technology features a ation of Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 3 (or a pharmaceutically acceptable salt thereof) for use in ng HCV infection. The ent comprises administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e.g., the on being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of the ent regimen is twelve weeks. The on of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The SUBSTITUTE SHEET (RULE 26) treatment es administering rin but does not include administering interferon; and ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) is administered with nd 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) can be administered concurrently or sequentially. For example, Compound 1 (or the salt f) can be administered once daily, together with ritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and Compound 3 (or the salt thereof) can be administered twice daily. For another example, Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) are administered once daily. For yet another e, Compound 1 (or the salt thereof) and ritonavir (or another CYP3A4 inhibitor, e. g., cobicistat) are co-formulated in a single composition and administered concurrently (e.g., once daily). For yet another example, Compound 1 (or the salt thereof), ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), and Compound 3 (or the salt thereof) are co-formulated in a single ition and stered concurrently (e. g., once daily). As a non-limiting example, the patient being treated can be ed with HCV genotype 1, such as genotype 1a or lb. As another non-limiting example, the patient can be infected with HCV pe 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive t, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for eron treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still r example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being d is a naive patient infected with HCV genotype 1. In yet another example, the ent lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1.

In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being d is a naive patient infected with HCV genotype 2. In still another e, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another e, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient ed with HCV genotype 3. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive t infected with HCV genotype 3. In yet another example, the ent lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, SUBSTITUTE SHEET (RULE 26) the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a sponder (e. g., a null responder) infected with HCV genotype 1. In still another e, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet r example, the ent lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null der) ed with HCV genotype 1. In yet r e, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) ed with HCV genotype 1.

In another aspect, the t technology features a combination of Compound 1 (or a ceutically acceptable salt thereof) and compound 4 (or a pharmaceutically acceptable salt thereof) for use in treating HCV infection. The treatment comprises administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering ribavirin but does not include administering interferon; and ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) is administered with Compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof) and compound 4 (or the salt thereof) can be administered concurrently or sequentially. For example, Compound 1 (or the salt thereof) can be administered once daily, together with ritonavir or another CYP3A4 inhibitor (e.g., stat), and compound 4 (or the salt thereof) can be administered twice daily. For another example, Compound 1 (or the salt f) and nd 4 (or the salt thereof) are administered once daily. For yet another example, Compound 1 (or the salt thereof) and ritonavir (or r CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a single composition and administered concurrently (e.g., once daily). For yet another example, Compound 1 (or the salt thereof), ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), and nd 4 (or the salt thereof) are co-formulated in a single composition and stered concurrently (e.g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the t can be ed with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment na'ive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another e, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV SUBSTITUTE SHEET (RULE 26) genotype 1. In still another example, the ent lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another e, the treatment lasts for 9 weeks, and the subject being d is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being d is a naive patient infected with HCV genotype 1.

In yet another example, the ent lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In r example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV pe 2. In yet r example, the treatment lasts for 8 weeks, and the t being treated is a naive patient infected with HCV pe 2. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive t infected with HCV genotype 3. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the ent lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In yet another e, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the ent lasts for 8 weeks, and the subject being treated is a sponder (e.g., a null responder) infected with HCV genotype 1.

In another aspect, the present technology features a combination of nd 1 (or a pharmaceutically able salt thereof), Compound 2 (or a pharmaceutically acceptable salt thereof), and compound 4 (or a pharmaceutically acceptable salt thereof) for use in treating HCV infection. The treatment comprises administering the DAAs to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e. g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 . Preferably, the duration of the treatment regimen is twelve weeks.

The duration of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering ribavirin but does not include administering interferon; and ritonavir or another CYP3A4 inhibitor (e. g., SUBSTITUTE SHEET (RULE 26) cobicistat) is administered with Compound 1 (or the salt thereof) to improve the pharmacokinetics of the latter. Compound 1 (or the salt thereof), Compound 2 (or the salt thereof), and compound 4 (or the salt thereof) can be administered concurrently or sequentially. For example, nd 1 (or the salt f) can be administered once daily, together with ritonavir or another CYP3A4 inhibitor (e.g., cobicistat), and compound 4 (or the salt thereof) can be administered once daily, and nd 2 (or the salt thereof) can be administered twice daily. For yet another example, Compound 1 (or the salt thereof), compound 4 (or the salt f), and ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat) are co-formulated in a single composition and stered concurrently (e.g., once . For yet another e, Compound 1 (or the salt thereof), ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), and compound 4 (or the salt thereof) are co-formulated in a single composition and administered concurrently (e.g., once , and Compound 2 (or the salt thereof) are administered twice daily. As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive t, a HCV-treatment experienced patient, an interferon non- responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the t being treated is a naive t infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another e, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet r e, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In still another example, the treatment lasts for 10 weeks, and the subject being d is a naive patient infected with HCV pe 2. In yet another example, the ent lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the subject being d is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient ed with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the ent lasts for 8 weeks, and the subject being treated is a naive patient infected with SUBSTITUTE SHEET (RULE 26) WO 59630 HCV pe 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In r example, the treatment lasts for 11 weeks, and the subject being treated is a sponder (e.g., a null responder) infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) ed with HCV pe 1.

In another aspect, the present technology features a ation of at least two DAAs for use in treating HCV infection, wherein said combination comprises a combination selected from: a combination of PSI-7977 and PSI-938, a combination of BMS-790052 and EMS-650032, a ation of GS-5885 and GS-9451, a ation of GS-5885, GS-9190 and GS-9451, a combination of BI-201335 and BI-27127, a combination of telaprevir and VX-222, a combination of PSI-7977 and TMC-435, and a combination of danopreVir and R7128.

The ent comprises stering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e. g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering rin but does not include administering interferon. The treatment may also include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The at least two DAAs can be administered concurrently or sequentially.

For example, one DAA can be administered once daily, and r DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and stered concurrently (e.g., once daily). As a non-limiting e, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a eatment na'ive patient, a HCV-treatment experienced patient, an eron non-responder (e.g., a null responder), or not a candidate for interferon treatment.

SUBSTITUTE SHEET (RULE 26) In yet r aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein said combination comprises a combination selected from: a combination of PSI-7977 and BMS-790052 a combination of PSI-7977 and BMS-650032, a combination of PSI-7977, BMS-790052 and BMS-650032, a combination of INX-l 89 and 0052 a combination of INX-l 89 and 0032, or a combination of INX-l89 BMS-790052 and BMS-650032.

The treatment comprises administering the DAA combination to a subject infected with HCV. The on of the ent regimen is no more than twelve weeks (e. g., the duration being 12 weeks; or the duration being ll, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the on of the treatment n is twelve weeks. The duration of the ent can also last, for example, no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering ribavirin but does not include administering interferon. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The at least two DAAs can be administered concurrently or sequentially.

For example, one DAA can be administered once daily, and another DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered rently (e.g., once daily). As a non-limiting example, the t being treated can be infected with HCV genotype 1, such as pe la or 1b. As r non-limiting example, the patient can be infected with HCV genotype 2 0r 3. As yet another non-limiting example, the patient can be a HCV-treatment naive patient, a HCV-treatment experienced patient, an eron non-responder (e.g., a null responder), or not a candidate for interferon treatment.

In still another aspect, the present technology features PSI-7977, or a combination of at least two DAAs, for use in treating HCV infection, wherein said combination compiises a ation selected from: a combination of mericitabine and danoprevir, a combination of INX-l 89, daclatasvir and BMS-79l325, and a combination of PSI-7977 and GS-S 885.

The treatment comprises administering 77 or the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e. g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). For example, the duration of the SUBSTITUTE SHEET (RULE 26) treatment regimen is no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 . The treatment includes administering ribavirin but does not include administering interferon. The treatment may include administering ritonavir or another CYP3A4 tor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The at least two DAAs can be stered concurrently or sequentially. For example, one DAA can be stered once daily, and another DAA can be administered twice daily. For another e, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered concurrently (e. g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as pe la or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null der), or not a candidate for interferon treatment.

In still another aspect, the present technology features PSI-7977, or a combination of at least two DAAs, for use in treating HCV infection, wherein said combination complises a combination ed from: a combination of mericitabine and danoprevir, a combination of INX-l 89, daclatasvir and BMS-79l325, and a combination of PSI-7977 and GS-S 885.

The treatment comprises administering PSI-7977 or the DAA combination to a subject infected with HCV. The duration of the treatment n is no more than twelve weeks (e. g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5,4, or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e.g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The ent es administering rin but does not include stering interferon. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The at least two DAAs can be administered concurrently or sequentially.

For example, one DAA can be administered once daily, and another DAA can be administered twice daily. For another e, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and stered concurrently (e.g., once daily). As a non-limiting example, the patient being treated can be ed with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment na'ive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment.

SUBSTITUTE SHEET (RULE 26) In still another aspect, the present technology features a combination of at least two DAAs, for use in treating HCV infection, n said combination comprises a combination selected from: a combination of tegobuvir and GS-925 6, a combination of BMS-79l325, asunaprevir and daclatasvir, and a combination of TMC—435 and daclatasvir.

The treatment comprises administering the DAA ation to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e. g., the duration being 12 weeks; or the duration being ll, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the on of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering ribavirin but does not include stering interferon. The treatment may include administering ritonavir or r CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The at least two DAAs can be administered rently or sequentially.

For example, one DAA can be administered once daily, and another DAA can be administered twice daily. For r example, the two DAAs are administered once daily. For yet another e, the two DAAs are co-formulated in a single composition and administered concurrently (e.g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive t, a HCV-treatment experienced patient, an eron non-responder (e.g., a null responder), or not a candidate for eron treatment.

In yet another aspect, the present logy features a ation of PSI-7977 and EMS-790052 for use in treating HCV infection. The treatment comprises administering the DAA combination to a subject infected with HCV. The duration of the treatment can last, for e, no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). Preferably, the duration of the treatment regimen is twelve weeks. The on of the treatment can also last, for example, no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment includes administering ribavirin but does not include administering interferon. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires cokinetic enhancement. The two DAAs can be administered concurrently or sequentially. For example, one DAA can be administered once daily, and the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and SUBSTITUTE SHEET (RULE 26) stered concurrently (e. g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype la or lb. As r miting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the t can be a HCV-treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV pe 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet r example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the t being treated is a naive patient infected with HCV genotype 1.

In yet another example, the treatment lasts for 12 weeks, and the t being treated is a naive patient infected with HCV genotype 2. In r example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV pe 2. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient ed with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being d is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the t being treated is a naive patient ed with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another e, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another e, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive t infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a sponder (e. g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a sponder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology features a combination of PSI-7977 and TMC—435 for use in ng HCV infection. The treatment comprises administering the DAA SUBSTITUTE SHEET (RULE 26) combination to a subject infected with HCV. The duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 .

Preferably, the duration of the treatment n is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The treatment es administering rin but does not include administering interferon. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The two DAAs can be administered concurrently or sequentially. For example, one DAA can be stered once daily, and the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered rently (e. g., once daily). As a non-limiting example, the patient being d can be infected with HCV genotype 1, such as genotype 1a or lb. As another non-limiting example, the t can be infected with HCV pe 2 or 3. As yet another non-limiting example, the patient can be a eatment naive patient, a HCV-treatment enced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being d is a naive t infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive t infected with HCV genotype 1.

In yet another example, the treatment lasts for 12 weeks, and the t being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the t being treated is a naive patient infected with HCV genotype 2. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the t being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the ent lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 8 weeks, and the t being treated is a naive patient infected with HCV SUBSTITUTE SHEET (RULE 26) genotype 3. In yet another example, the ent lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e.g., a null responder) ed with HCV genotype 1. In yet r example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being d is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In yet another aspect, the t technology es a combination of danoprevir and mercitabine for use in treating HCV infection. The treatment comprises administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than sixteen weeks (e.g., the duration being 16 weeks; or the duration being 14, 12 or 10 . The duration of the treatment regimen may also be less than 10 weeks. The treatment includes administering ribavirin but does not include administering interferon. The treatment also includes co-administering vir or another CYP3A4 inhibitor (e.g., cobicistat) with danoprevir to improve the pharmacokinetics of danoprevir. The two DAAs can be administered concurrently or sequentially. For e, one DAA can be administered once daily, and the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet r example, the two DAAs are co-formulated in a single composition and administered concurrently (e.g., once daily). As a non-limiting example, the t being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non- limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive patient, a HCV-treatment enced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 16 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks, and the t being treated is a naive t infected with HCV genotype 1. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a naive patient ed with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the ent lasts for 12 weeks, and the t being treated is a naive t infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In still r example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet r example, the treatment lasts for 9 weeks, and the SUBSTITUTE SHEET (RULE 26) subject being treated is a naive patient ed with HCV genotype 2. In yet another example, the ent lasts for 8 weeks, and the subject being d is a naive patient infected with HCV genotype 2.

In yet another e, the treatment lasts for 16 weeks, and the subject being d is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 13 weeks, and the subject being d is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being d is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 16 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In r example, the treatment lasts for 15 weeks, and the subject being treated is a non- responder (e. g., a null responder) ed with HCV pe 1. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a non-responder (e. g., a null der) ed with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a non-responder (e.g., a null der) infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In yet another aspect, the present technology features a ation of INX-189, daclatasvir and BMS-791325 for use in treating HCV infection. The treatment comprises administering the DAA ation to a subject infected with HCV. The duration of the treatment regimen is no more than sixteen weeks (e.g., the duration being 16 weeks; or the duration being 14, 12 or 10 weeks). The duration of the treatment regimen may also be less than 10 weeks. The ent includes administering ribavirin but does not include stering interferon. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires pharmacokinetic enhancement. The two DAAs can be administered concurrently or sequentially. For example, one DAA can be administered once daily, and the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered concurrently (e.g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non- ng example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 16 weeks, and the subject being treated is a naive patient ed with HCV genotype 1. In another example, the treatment lasts for 15 weeks, and the subject being treated is a SUBSTITUTE SHEET (RULE 26) naive patient infected with HCV genotype 1. In still another e, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the t being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient ed with HCV genotype 2. In another e, the ent lasts for 11 weeks, and the subject being treated is a naive t ed with HCV genotype 2. In still another example, the treatment lasts for 10 weeks, and the t being treated is a naive patient ed with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 2.

In yet another example, the treatment lasts for 16 weeks, and the subject being treated is a naive patient ed with HCV genotype 3. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV pe 3. In yet another example, the ent lasts for 16 weeks, and the subject being treated is a non-responder (e. g., a null responder) ed with HCV pe 1. In another example, the treatment lasts for 15 weeks, and the subject being treated is a non- responder (e. g., a null responder) infected with HCV genotype 1. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV pe 1. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the t being treated is a non-responder (e.g., a null responder) ed with HCV genotype 1.

In yet another aspect, the present technology features a combination of PSI-7977 and GS- 5885 for use in treating HCV infection. The treatment comprises administering the DAA combination to a subject infected with HCV. The duration of the treatment regimen is no more than sixteen weeks (e.g., the duration being 16 weeks; or the duration being 14, 12 or 10 weeks). The duration of the treatment regimen may also be less than 10 weeks. The treatment includes stering ribavirin but does not include administering eron. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e. g., cobicistat) if one of the DAAs es pharmacokinetic enhancement. The two DAAs can be administered concurrently or sequentially. For example, one DAA can be administered once daily, and SUBSTITUTE SHEET (RULE 26) the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are mulated in a single composition and administered concurrently (e.g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype la or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting e, the patient can be a eatment naive patient, a HCV-treatment experienced t, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment. In one example, the treatment lasts for 16 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a naive patient ed with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient ed with HCV pe 2. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient ed with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the t being treated is a naive patient infected with HCV genotype 2. In yet another example, the ent lasts for 16 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In still another example, the treatment lasts for 14 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a naive t infected with HCV genotype 3. In yet another example, the ent lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another e, the treatment lasts for 16 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In r example, the treatment lasts for 15 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In still another example, the ent lasts for 14 weeks, and the subject being treated is a sponder (e. g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 13 weeks, and the subject being treated is a non-responder (e.g., a null responder) ed with HCV genotype 1. In yet r example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

SUBSTITUTE SHEET (RULE 26) In yet r , the t technology features a combination of TMC-435 and daclatasvir for use in ng HCV infection. The treatment comprises administering the DAA combination to a subject ed with HCV. The duration of the treatment regimen is no more than twelve weeks (e.g., the duration being 12 weeks; or the duration being 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks).

Preferably, the duration of the treatment regimen is twelve weeks. The duration of the treatment can also last, for example, no more than eight weeks (e. g., the duration being 8 weeks; or the duration being 7, 6, 5, 4, or 3 weeks). The ent includes administering ribavirin but does not include administering interferon. The treatment may include administering vir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs requires cokinetic enhancement. The two DAAs can be administered concurrently or sequentially. For example, one DAA can be administered once daily, and the other DAA can be administered twice daily. For another example, the two DAAs are administered once daily. For yet another example, the two DAAs are co-formulated in a single composition and administered concurrently (e.g., once daily). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be a HCV-treatment naive patient, a eatment experienced patient, an interferon non-responder (e.g., a null responder), or not a ate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient ed with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the t being d is a naive patient infected with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient ed with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 1.

In yet r example, the treatment lasts for 12 weeks, and the subject being treated is a naive t infected with HCV genotype 2. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another example, the treatment lasts for 8 weeks, and the subject being d is a naive patient infected with HCV genotype 2. In yet another example, the ent lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient ed with HCV genotype 3. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 9 weeks, SUBSTITUTE SHEET (RULE 26) and the t being treated is a naive patient infected with HCV genotype 3. In yet another e, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another example, the treatment lasts for 12 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a non-responder (e. g., a null responder) infected with HCV genotype 1. In still r example, the treatment lasts for 10 weeks, and the subject being treated is a non-responder (e. g., a null responder) ed with HCV genotype 1. In yet r example, the treatment lasts for 9 weeks, and the t being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a non-responder (e.g., a null responder) infected with HCV genotype 1.

In another aspect, the present invention features methods for treatment of HCV infection, n the methods comprise administering to a subject in need f at least two direct acting antiviral agents (DAAs) and ribavirin, and the treatment does not include administration of interferon to the subject. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive t. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e. g., HCV genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In one embodiment of this aspect of the invention, the at least two DAAs comprise (i) Compound 1 or a pharmaceutically able salt thereof, and (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and said method further ses administering ritonavir to the subject.

Ritonavir es the pharmacokinetics or drug exposure of Compound 1. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The ent can also last for 8 weeks. The subject being treated can be, for example, a ent-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g., a null responder). ably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example, the t being treatment is ed with HCV genotype 3.

In another embodiment of this aspect of the invention, the at least two DAAs comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, and (ii) Compound 4 or a pharmaceutically acceptable salt thereof, and the method further comprises stering ritonavir to the subject to improve the pharmacokinetics or drug exposure of nd 1. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for SUBSTITUTE SHEET (RULE 26) 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a ent-experienced patient, or an interferon non- responder (e.g., a null responder). Preferably, the subject being treated is ed with HCV genotype 1, e. g., HCV genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In another embodiment of this aspect of the invention, the at least two DAAs comprise (i) Compound 1 or a pharmaceutically acceptable salt thereof, (ii) Compound 2 or a pharmaceutically able salt thereof, and (iii) Compound 4 or a pharmaceutically acceptable salt thereof, and the method further comprises administering ritonavir to the subject to improve the acokinetics or drug exposure of Compound 1. The treatment can last, for example and t limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g., a null responder).

Preferably, the t being treated is ed with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example, the t being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise a HCV protease inhibitor and a HCV polymerase tor. The treatment can last, for example and without tion, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e.g., a null responder). Preferably, the subject being d is infected with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting e, the subject being treatment is infected with HCV genotype 3.

In yet r embodiment of this aspect of the invention, the at least two DAAs comprise a HCV protease inhibitor and a non-nucleoside or non-nucleotide HCV polymerase inhibitor.

The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. ably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks.

The subject being treated can be, for e, a treatment-naive patient. The t can also be a treatrnent—experienced patient, or an interferon non-responder (e.g., a null responder). Preferably, the t being treated is infected with HCV genotype 1, e. g., HCV genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise a HCV protease inhibitor and a nucleoside or nucleotide HCV polymerase inhibitor. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or SUBSTITUTE SHEET (RULE 26) 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for e, a treatment-naive patient. The subject can also be a treatment- experienced patient, or an interferon non-responder (e.g., a null responder). Preferably, the subject being treated is ed with HCV genotype 1, e. g., HCV pe 1a. As another non-limiting example, the t being treatment is infected with HCV pe 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise a HCV protease inhibitor and a HCV NSSA inhibitor. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive t. The subject can also be a treatment-experienced patient, or an interferon non- responder (e.g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e. g., HCV genotype 1a. As r non-limiting example, the t being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise a HCV polymerase inhibitor and a HCV NSSA inhibitor. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced t, or an interferon non-responder (e.g., a null der). ably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example, the t being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise a HCV non-nucleoside or non-nucleotide polymerase inhibitor and a HCV NSSA inhibitor. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The ent can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment- experienced t, or an interferon non-responder (e.g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e. g., HCV genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise a HCV nucleoside or nucleotide polymerase inhibitor and a HCV NSSA inhibitor. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. ably, the ent lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being d can be, for example, a treatment-naive patient. The subject can also be a treatment- SUBSTITUTE SHEET (RULE 26) experienced patient, or an interferon sponder (e.g., a null responder). ably, the subject being treated is infected with HCV genotype 1, e. g., HCV genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and TMC-435. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e. g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet another ment of this aspect of the invention, the at least two DAAs comprise TMC—435 and asvir. The treatment can last, for example and without tion, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for e, a treatment-naive patient. The t can also be a treatment-experienced patient, or an interferon non-responder (e. g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As another miting example, the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and daclatasvir. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. ably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e. g., a null responder). Preferably, the subject being treated is ed with HCV genotype 1, e.g., HCV pe 1a. As another non-limiting example, the t being treatment is infected with HCV genotype 3.

In yet another ment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and GS-S885. The ent can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e. g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV SUBSTITUTE SHEET (RULE 26) WO 59630 genotype 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise tabine and danoprevir. The ent can last, for e and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a ent-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e. g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV pe 1a. As another non-limiting example, the subject being treatment is ed with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise EMS-790052 and EMS-650032. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks.

The treatment can also last for 8 weeks. The subject being treated can be, for example, a ent-naive patient. The subject can also be a treatment-experienced patient, or an interferon non-responder (e. g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1b. As a non-limiting example, the subject being treatment is infected with HCV genotype 1a.

As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise 9, daclatasvir and BMS-791325. The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being d can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced t, or an interferon non- responder (e.g., a null responder). Preferably, the subject being treated is infected with HCV genotype 1, e. g., HCV genotype 1a. As another non-limiting e, the subject being treatment is infected with HCV genotype 3.

In yet another aspect, the present invention features methods for treatment of a treatment- naive subject with HCV pe 1 infection, wherein the method comprises administering to said patient PSI-7977 and ribavi1in, and the treatment does not include administration of interferon to the subject.

The treatment can last, for example and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks.

Preferably, the subject being treated is ed with pe 1a. More preferably, the subject being treated is a naive patient infected with genotype 1. The subject being treated can also be a treatment- enced patient or an interferon non-responder (e.g., a null responder), and/or is infected with HCV SUBSTITUTE SHEET (RULE 26) WO 59630 genotype 3. In one e, the treatment lasts for 12 weeks, and the subject being treated is a naive t ed with genotype 1. In another example, the ent lasts for 11 weeks, and the subject being treated is a naive patient infected with genotype 1. In still r example, the ent lasts for weeks, and the subject being treated is a naive patient infected with genotype 1. In yet another example, the ent lasts for 9 weeks, and the subject being treated is a naive patient infected with genotype 1. In yet another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with genotype 1. The present invention also features PSI-7977 or a pharmaceutical acceptable salt thereof for use in any treatment described in this aspect of the invention.

In still another aspect, the present invention features methods for treatment of HCV infection, wherein the methods comprise administering to a subject in need thereof at least two DAAs and ribavirin for a duration sufﬁcient to achieve a sustained virologic response. The treatment does not include administration of interferon. Any DAA combination described herein can be used. The duration can be, for example no more than 8 weeks or ably, no more than 12 weeks.

A treatment regimen of the t technology lly tutes a complete treatment regimen, i.e., no subsequent interferon-containing regimen is intended. Thus, a treatment or use described herein generally does not include any subsequent interferon-containing treatment.

Other features, objects, and advantages of the present invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while ting preferred embodiments of the invention, are given by way of illustration only, not tion.

Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a 3-D surface plot illustrating deviations from expected inhibitory effects from varying trations of Compound 1 and Compound 2 in a genotype 1b HCV replicon assay.

Figure 2 is a contour plot g concentrations at which Compound 1 and Compound 2 exhibited syngeristic, additive, or antagonistic ctions in the genotype 1b HCV replicon assay.

Figure 3 is a 3-D surface plot illustrating deviations from ed inhibitory effects from varying concentrations of Compound 1 and compound 4 in a genotype 1b HCV replicon assay.

Figure 4 is a r plot showing concentrations at which Compound 1 and compound 4 exhibited syngeristic, additive, or antagonistic interactions in the genotype 1b HCV replicon assay.

Figure 5A is a bar graph showing the percentage of cells containing HCV genotype 1a replicon constructs surviving after three weeks of exposure to therapeutic agent 1, therapeutic agent 2, therapeutic agent 4, or a combination of some or all of those therapeutic agents in the presence of G418.

SUBSTITUTE SHEET (RULE 26) WO 59630 2012/061075 Figure 5B is another bar graph g the percentage of surviving la-H77 on cells grown in the presence of G418, and two or three DAA combinations, for approximately three weeks.

Figure 5C depicts the effect of Compound 1, Compound 4 and a ation thereof in long-term HCV RNA reduction assays in la-H77 replicon cell lines.

Figure 5D demonstrates the effect of Compound 1, Compound 4 and a combination thereof in long-term HCV RNA reduction assays in lb-Conl replicon cell lines.

Figure 6A shows the predicted median and 90% nce interval of SVR percentage for different treatment durations of a 2-DAA regimen without ribavirin; the 2 DAAs include Compound 1 (in combination with ritonavir, i.e., Compound l/r) and Compound 2.

Figure 6B rates the predicted median and 90% conﬁdence intelval of SVR percentage for different treatment durations of a 2-DAA regimen without ribavirin; the 2 DAAs include Compound 1 (in combination with vir, i.e., Compound 1/r) and Compound 4.

Figure 6C depicts the predicted median and 90% conﬁdence interval of SVR percentage for different treatment durations of a 3-DAA regimen t ribavirin; the 3 DAAs include (i) Compound 1 (in combination with ritonavir, i.e., Compound l/r), (ii) nd 2 and (iii) Compound 4.

Figure 7 shows the exposure-response model ted versus observed tage of subjects with HCV RNA less than LOD over time in the clinical study described in Example 1.

Figure 8 demonstrates the exposure-response model predicted versus observed percentage of subjects with SVR12 in the clinical study described in Example 2A.

Figure 9 shows the predicted median and 90% conﬁdence interval of SVR rates for different treatment durations of a 2-DAA regimen containing BMS-790052 and 0032.

Figure 10 shows the predicted median of SVR rates for different ent durations of a 3-DAA regimen containing Compound l/r, Compound 4 and PSI-7977.

Figure 11 shows the predicted median and 90% conﬁdence interval of SVR percentage for different treatment durations of a l-DAA regimen containing PSI-7977 and ribavirin.

Figure 12 depicts the predicted median and 90% nce interval of SVR percentage for different treatment durations of a 2-DAA regimen containing daclatasvir (BMS-790052) 60 mg QD and PSI-7977 400 mg QD.

Figure 13 shows the predicted median and 90% conﬁdence interval of SVR percentage for different treatment durations of a 2-DAA regimen containing TMC-435 150 mg QD and PSI-7977 400 mg QD.

Figure 14 illustrates the predicted median and 90% conﬁdence interval of SVR percentage for different treatment durations of a 2-DAA regimen containing danoprevir 100 mg BID and mercitabine 750 mg BID.

SUBSTITUTE SHEET (RULE 26) Figure 15 depicts the predicted median and 90% nce interval of SVR percentage for different treatment durations of a 2-DAA regimen ning GS-9190 (tegobuvir) 30 mg BID + GS- 9451 200 mg QD + GS-5885 90 mg QD.

Figure 16 shows the ted median and 90% conﬁdence interval of SVR percentage for different treatment durations of the following DAA combo regimens: (1) GS-9451 200 mg QD + GS- 7977 (PSI-7977) 400 mg QD; (2) GS-5885 90 mg QD + GS-7977 (PSI-7977) 400 mg QD; and (3) GS- 9451 200 mg QD + GS-5885 90 mg QD + GS-7977 (PSI-7977) 400 mg QD.

Figure 17 shows the ted median and 90% conﬁdence interval of SVR tage for different treatment durations of a 2-DAA regimen containing TMC-435 150 mg QD and daclatasvir (BMS-790052) 60 mg QD.

DETAILED PTION OF THE INVENTION The present methods can include administering therapeutic agent 1 to a subject.

Therapeutic agent 1 is Compound 1 ( ) or a pharmaceutically acceptable salt thereof. Compound 1 is also known as (2R,6S,13aS,14aR,16aS,Z)—N- (cyclopropylsulfonyl)(5-methylpyrazinecarboxamido)-5 , 16-dioxo(phenanthridinyloxy)— 1,2,3,5,6,7,8,9,10,1 1,13a,14,14a,l5,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2- a][1,4]diazacyclopentadecine-14a-carboxamide. Compound 1 is a potent HCV protease inhibitor. The synthesis and formulation of Compound 1 are described in U.S. Patent Application Publication No. 144608, U.S. Provisional Application Serial No. 61/339,964 ﬁled on March 10, 2010, and U.S.

Patent Application Publication No. 312973 ﬁled on March 8, 2011. All of these applications are incorporated herein by reference in their entireties. Therapeutic agent 1 includes various salts of nd 1. Therapeutic agent 1 may be administered in any suitable amount such as, for example, in doses of from about 0.01 to about 50 mg/kg body weight, alternatively from about 0.1 to about 25 mg/kg body weight. As non-limiting examples, therapeutic agent 1 may be administered in a total daily dose amount of from about 50 mg to about 250 mg, preferably from about 100 mg to about 250 mg, and SUBSTITUTE SHEET (RULE 26) includes, but is not limited to, for example, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg and suitable amounts there between.

RitonaVir or another inhibitor of cytochrome P-450 ably is co-administered with therapeutic agent 1 to e the pharmacokinetics of Compound 1.

The present methods can include administering therapeutic agent 2 to a subject.

Therapeutic agent 2 is Compound 2 or a salt thereof.

LNNYO OONHSOZCHg O 0/ Compound 2 Compound 2 is also known N—(6-(3-tert-butyl(2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methoxyphenyl)naphthalenyl)methanesulfonamide. As described in, for example, International Publication No. WO2009/039127, therapeutic agent 2 es various salts of nd 2, such as sodium salts, ium salts, and choline salts. Therapeutic agent 2 also includes crystalline forms of Compound 2 and its salts such as solvate, hydrate, and t-free crystalline forms of Compound 2 and its salts. Compositions comprising therapeutic agent 2 can be prepared as described in, for example, International Publication No. /039127 which is incorporated by reference herein.

Therapeutic agent 2 may be administered as a free acid, salt or particular crystalline form of Compound 2. In some embodiments, therapeutic agent 2 is administered as a sodium salt. Therapeutic agent 2 may be stered in any suitable amount such as, for example, in doses of from about 5 mg/kg to about 30 mg/kg. As non-limiting examples, therapeutic agent 2 may be administered in a total daily dose amount of from about 300 mg to about 1800 mg, or from about 400 mg to about 1600 mg, or from about 600 mg to about 1800 mg, or from about 800 mg to about 1600 mg or any amounts there between.

In some ments, the total daily dosage amount for therapeutic agent 2 is about 600 mg. In some embodiments, the total daily dosage amount for therapeutic agent 2 is about 800 mg. In some embodiments, the total daily dosage amount for therapeutic agent 2 is about 1200 mg. In some embodiments, the total daily dosage amount for therapeutic agent 2 is about 1600 mg.

The present methods can include administering therapeutic agent 3 or a salt thereof to a subject. Therapeutic agent 3 is Compound 3 or a salt thereof.

SUBSTITUTE SHEET (RULE 26) Compound 3 Compound 3 is also known as (E)-N-(4-(3-tert-butyl(2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)methoxystyryl)phenyl)methanesulfonamide. As described in, for example, International Publication No. W02009/039127, therapeutic agent 3 includes various salts of Compound 3, such as sodium salts, ium salts, and choline salts. Therapeutic agent 3 also includes crystalline forms of Compound 3 and its salts such as solvate, hydrate, and solvent-free crystalline forms of Compound 3 and its salts. Compositions comprising therapeutic agent 3 can be prepared as described in, for example, ational Publication No. W02009/039127 which is incorporated by nce herein.

Therapeutic agent 3 may be administered as a free acid, salt or particular crystalline form of Compound 3. In some embodiments, Compound 3 is administered as a potassium salt. Therapeutic agent 3 may be administered in any suitable amount such as, for example, in doses of from about 0.5 mg/ g to about 15 mg/kg or from about 1 mg/kg to about 10 mg/kg. As non-limiting examples, eutic agent 3 may be administered in a total daily dose amount of from about 100 mg to about 600 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is about 300 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is about 320 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is about 400 mg. In some embodiments, the total daily dosage amount for therapeutic agent 3 is about 600 mg.

The present s can include administering eutic agent 4 or a salt thereof to a subject. Therapeutic agent 4 is compound 4 or a salt thereof.

ZI & SUBSTITUTE SHEET (RULE 26) Compound 4 Compound 4 is also known as yl (2S,2’S)-1,1’-((2S,2’S)—2,2’-(4,4’-((2S,5S)(4- tert-butylphenyl)pyrrolidine-2,5 bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine- 2,1-diyl)bis(3-methyloxobutane-2,1-diyl)dicarbamate. Compound 4 can be prepared as bed in, for example, US. Publication No. 2010/03 17568, which is incorporated herein by reference.

Therapeutic agent 4 may be administered as a free acid, or a salt form. Therapeutic agent 4 may be administered in any suitable amount such as, for example, in doses of from about 0.1 mg/kg to about 200 mg/kg body weight, or from about 0.25 mg/kg to about 100 mg/kg, or from about 0.3 mg/kg to about 30 mg/kg. As non-limiting examples, therapeutic agent 4 may be administered in a total daily dose amount of from about 5 mg to about 300 mg, or from about 25 mg to about 200 mg, or from about 25 mg to about 50 mg or any amounts there between. In some embodiments, the total daily dosage amount for therapeutic agent 4 is about 25 mg.

The at least two DAAs may also be co-administered with ribavirin, or a pro-drug thereof, in the same or separate pharmaceutical compositions. Ribavirin may include any suitable form or formulation of ribavirin. Exemplary formulations of ribavirin include COPEGUS®, REBETOL® and RIBASPHERE®. An exemplary pro-drug of ribavirin is virin having the chemical name of 1-[3—D- ribofuranosyl-1,2,4-triazolecarboxamidine. Ribavirin and taribavirin may be administered in accordance with ribavirin and taribavirin administration well known in the art. In some embodiments, COPEGUS® or REBETOL® is administered in a daily dosage amount of from about 500 mg to about 1500 mg in one dose or in divided doses. In some embodiments, COPEGUS® or REBETOL® is administered in a daily dosage amount of about 800 mg. In some embodiments, L® is administered in a daily dosage amount of about 1000 mg. In some embodiments, COPEGUS® or REBETOL® is administered in a daily dosage amount of about 1200 mg. In some embodiments, REBETOL® is administered in a daily dosage amount of about 1400 mg. Suitable dosages of ribavirin are dependent on the weight of the subject, for example about 1000-1200 mg. Suitable total daily dosages of rin include, but are not limited to about 400 mg to about 1400 mg a day, alternatively about 800 mg to about 1400 mg per day, alternatively about 400 mg to about 1200 mg, atively about 800 mg to about 1200 mg.

The current standard of care (SOC) for the ent of HCV includes a course of treatment of interferon, e. g. pegylated interferon (e.g., ted interferon-alpha-2a or pegylated interferon-alpha-2b, such as PEGASYS by Roche, or PEG-INTRON by Schering-Plough) and the antiviral drug ribavirin (e.g., COPEGUS by Roche, L by Schering-Plough, or HERE by Three Rivers ceuticals). The treatment often lasts for 24-48 weeks, depending on hepatitis C virus genotype.

Other interferons include, but are not limited to, interferon-alpha-2a (e.g., Roferon-A by Roche), SUBSTITUTE SHEET (RULE 26) interferon-alpha-Zb (e. g., Intron-A by Schering-Plough), and interferon alfacon—l nsus interferon) (e.g., Infergen by Valeant). Less than 50% of patients with chronic HCV infection with genotype 1 virus respond to this therapy. Further, interferon therapy has many side effects that hinder patient compliance and results in premature discontinuation of the treatment.

The interferon/ribavirin—based treatment may be physically demanding, and can lead to ary disability in some cases. A substantial proportion of patients will experience a panoply of side effects ranging from a “ﬂu-like” syndrome (the most common, experienced for a few days after the weekly injection of interferon) to severe adverse events including anemia, cardiovascular events and psychiatric problems such as suicide or suicidal ideation. The latter are exacerbated by the general physiological stress experienced by the patients. Ribavirin also has a number of side effects, including, anemia, high pill burden (e.g. 5-6 pills a day split BID) and teratogenicity restricting use in women of childbearing age.

The t methods provide effective treatment of HCV infection without the use of interferon and for a shorter period of time, such as a treatment on of no more than twelve weeks, alternatively no more than eleven weeks, alternatively no more than ten weeks, alternatively no more than nine weeks, atively no more than eight weeks, alternatively no more than seven weeks, alternatively no more than six weeks, alternatively no more than five weeks, alternatively no more than four weeks, or alternatively, no more than three weeks.

In some embodiments, the present technology provides s for treating HCV infection in a subject comprising administering at least two DAAs with ribavirin in the e of interferon for a duration of no more than twelve weeks, alternatively no more than eight weeks. Put another way, the present methods exclude interferon, or the subject does not receive interferon for the duration of the treatment. The at least two DAAs can be co-administered or can be administered independently (with the same or different dosing ncies) and can be administered once a day, alternatively twice a day, alternatively three times a day.

In some embodiments, the methods of treatment comprise daily administration of two or more DAAs, wherein a first DAA may be administered once a day, twice a day, or three times a day, and a second DAA may be stered once a day, twice a day, or three times a day. In some embodiments, a third DAA may be administered once a day, twice a day, or three times a day. The DAAs may be co- stered or administered at different times or frequencies. Preferably, in the methods, at least two DAAs and ribavirin are stered in effective amounts to provide a desired e of effectiveness in the t. Preferably, the treatment has reduced side effects as ed with eron-containing treatments.

SUBSTITUTE SHEET (RULE 26) Various measures may be used to express the effectiveness of the present methods of HCV treatment. One such measure is rapid virological response (RVR), meaning that HCV is undetectable in the subject after 4 weeks of treatment, for example, after 4 weeks of administration of two or more of DAAs and ribavirin. Another measure is early virological response (EVR), meaning that the subject has >2log10 reduction in viral load after 12 weeks of treatment. Another e is complete EVR (cEVR), meaning the HCV is undetectable in the se1um of the subject after 12 weeks of treatment.

Another measure is extended RVR (eRVR), meaning achievement of RVR and cEVR, that is, HCV is undetectable at week 4 and 12. Another measure is the presence or absence of detectable virus at the end of y (EOT). Another measure is (SVR), which, as used herein, means that the virus is undetectable at the end of therapy and for at least 8 weeks after the end of y (SVRS); preferably, the virus is undetectable at the end of therapy and for at least 12 weeks after the end of therapy (SVR12); more preferably, the virus is undetectable at the end of therapy and for at least 16 weeks after the end of therapy (SVR16); and highly preferably, the virus is undetectable at the end of therapy and for at least 24 weeks after the end of therapy (SVR24). SVR24 is often considered as a functional tion of cure; and a high rate of SVR at less than 24 week post-treatment (e.g., SVR8 or SVR12) can be predictive of a high rate of SVR24. se, a high rate of SVR at less than 12 week post-treatment (e.g., SVR4 or SVR8) can be tive of a high rate of SVR12. A high rate of EOT (e.g., at week 8 or week 12) can also be indicative of a significant rate of SVR12 or SVR24.

In some embodiments, the amounts of the two or more DAAs and ribavirin, and/or the duration of the treatment regimen of the two or more DAAs and ribavirin, are effective to provide an RVR in a subject, or an EVR in a subject, or a cEVR in a subject, or an eRVR in a subject, or an absence of detectable virus at EOT in a subject. In some embodiments, the present methods comprise treating a population of subjects having HCV infection (e.g. ent na'1've subjects), and the methods se administering at least two DAAs and ribavirin to the subjects for a duration of no more than 12 weeks, or for another on disclosed herein, wherein the at least two DAAs and ribavirin are administered to the subjects in amounts effective to provide an SVR (e. g., SVR after 8 weeks post-treatment, or SVR after 24 weeks post-treatment) in at least about 70% of the population, alternatively at least about 75% of the population, alternatively at least about 80% of the population, alternatively at least about 85% of the tion, alternatively at least about 90% of the population, alternatively at least about 95% of the population, alternatively about 100% of the population. In some embodiments, the present methods comprise ng a population of IFN experienced ts (e. g., interferon non-responders) having HCV infection, and the methods se administering at least two DAAs and ribavirin to the ts for a duration of no more than 12 weeks, or for another duration disclosed herein, wherein the at least two DAAs and ribavirin are stered to the subjects in amounts effective to provide an SVR (e.g., SVR SUBSTITUTE SHEET (RULE 26) 2012/061075 after 8 weeks post-treatment, or SVR after 24 weeks post-treatment) in at least about 50% of the population, alternatively at least about 55% of the population, alternatively at least about 60% of the population, alternatively at least about 65% of the population. In other embodiments, the amount of DAAs and ribavirin and the on of the treatment are effective to provide one or more of an SVR (e.g., SVR after 8 weeks post-treatment, or SVR after 24 weeks post-treatment), an RVR, an EVR, a cEVR, an eRVR, or an absence of detectable virus at EOT, in at least about 50% of the population, alternatively at least about 55%, in at least about 60% of the population, alternatively at least about 65% of the population, alternatively at least about 70% of the population, alternatively at least about 75% of the tion, alternatively at least about 80% of the population, alternatively at least about 85% of the population, altematively at least about 90% of the population, atively at least about 95% of the population, alternatively about 100% of the population. For example, the present methods se administering at least two DAAs and ribavirin in amounts and for durations ive to provide an SVR (e.g., SVR after 8 weeks post-treatment, or SVR after 24 weeks post-treatment) in a t. In some embodiments, the present technology provides for an SVR (e.g., SVR after 8 weeks reatment, or SVR after 24 weeks post-treatment) in at least about 50% of the population, alternatively at least about 55% of the population, in at least about 60% of the population, preferably in at least about 65% of the population, preferably in at least about 70% of the population, preferably at least about 75% of the patients treated by such methods herein described, more preferably in at least 80% of the tion, and highly preferably in at least about 90% of the patients being treated. In some embodiments, a treatment of the present technology provides an RVR or undetectable level of HCV RNA in the bloodstream at four (4) weeks of treatment (preferably in on to a SVR).

A DAA of the present technology includes, but is not limited to, a protease inhibitor, a HCV polymerase inhibitor, an HCV NSSA inhibitor, an HCV NS3B inhibitor, an HCV NS4A inhibitor, an HCV NSSB inhibitor, an HCV entry inhibitor, a cyclophilin inhibitor, a CD81 inhibitor, or an internal ribosome entry site inhibitor. The HCV polymerase inhibitor may be a side polymerase tor or a non-nucleoside polymerase inhibitor. The HCV polymerase inhibitor may be a nucleotide polymerase inhibitor or a non-nucleotide polymerase inhibitor.

In yet another e of this aspect of the technology, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and 5. In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs comprises 5, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-20l335 and BI—207127. In yet another example, the combination of two or more DAAs comprises telaprevir and VX-222. In another e, the combination of two or more SUBSTITUTE SHEET (RULE 26) 2012/061075 DAAs ses GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes evir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs es PSI-7977 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes 77, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs includes 9 and BMS- 790052 (daclatasvir). In yet r example, the combination of two or more DAAs es INX-189 and EMS-650032 previr). In still another example, the combination of two or more DAAs includes INX-189, BMS-650032 (asunaprevir) and EMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs comprises 5 and daclatasvir.

It was unexpectedly discovered that an interferon-free ent using a combination of two or more DAAs, together with ribavirin, and for a duration of no more than 12 weeks, could achieve signiﬁcant SVR. In many cases, such a treatment can achieve an SVR in at least about 75% of patients, and in some cases, such a treatment can e an SVR in at least about 85% of patients, and in n cases, such a treatment can achieve an SVR in at least about 90% of patients. It was also surprising that such a treatment could achieve signiﬁcant viral suppression even at 4 weeks of the treatment. In some embodiments, the interferon-free treatment using a combination of two or more DAAs, together with ribavirin, and for a duration of no more than 12 weeks, could achieve signiﬁcant SVR in interferon non- responders, for example, treatment can achieve an SVR in at least about 50% of patients in the interferon non-responder population, preferably at least about 60% of patients in the interferon non-responder population, more preferably at least about 65% of patients in the interferon non-responder tion.

Accordingly, in one aspect, the present technology features a method of treating HCV infection, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, er with an effective amount of rin. The treatment lasts 8 weeks and does not e administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive t, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient may be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or HCV genotype lb; or HCV genotype 2 or 3. The treatment according to this aspect of the technology may also be effective t other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV SUBSTITUTE SHEET (RULE 26) protease inhibitor and at least one HCV polymerase inhibitor (e. g., a combination of at least one HCV se inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV se inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside tor). For another instance, the combination of two or more DAAs can be a combination of at least one HCV protease tor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a ation of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a ation of at least two HCV polymerase inhibitors (e.g., a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside or nucleotide rase tor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one side or tide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt f). Compound 1 (or a salt thereof) can be co-formulated with Vir.

In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co- formulated with ritonaVir. In a further example, the combination of two or more DAAs is a combination of nd 1 (or a salt f), Compound 2 (or a salt thereof) and Compound 4 (or a salt f).

Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 can be co-f01mulated with ritonaVir. In yet another example, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs ses PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In SUBSTITUTE SHEET (RULE 26) yet another example, the ation of two or more DAAs ses GS-5885, GS-9190, and GS-9451.

In yet another example, the combination of two or more DAAs comprises BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs comprises telaprevir and . In another example, the ation of two or more DAAs comprises GS-5885 and GS-9451. In yet another example, the ation of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In yet another example, the ation of two or more DAAs includes 77 and EMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-790052 (daclatasvir). In yet r example, the combination of two or more DAAs includes INK-189 and EMS-650032 (asunaprevir). In still r example, the combination of two or more DAAs includes INK-189, EMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danoprevir. In still another example, the combination of two or more DAAs includes 9, daclatasvir and BMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5 885 . In yet another example, the combination of two or more DAAs ses TMC-435 and daclatasvir. In still another example, the combination of two or more DAAs includes PSI-7977, Compound 1 (with ritonavir), and Compound 4. In still another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still another example, the method comprises administering 100 or 200 mg nd 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet another example, the method ses stering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another e, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen ing to this aspect of the logy. In any aspect, embodiment, and example of this application, 250 mg BID can be used for Compound 2 in lieu of 400 mg BID; it was unexpectedly discovered that by SUBSTITUTE SHEET (RULE 26) increasing the amount of the binder (e.g., copovidone) in a solid formulation of Compound 2 (or a ceutically acceptable salt thereof), the bioavailability of Compound 2 (or said salt) can be signiﬁcantly improved such that 250 mg Compound 2 (or said salt) in the improved formulation was bioequivalent to 400 mg Compound 2 (or said salt) in the original formulation.

In another aspect, the present technology features a method of treating HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 7 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing ncy. The patient being treated can be a ent naive patient, a ent experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non- responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for e and without limitation, HCV genotype 1, such as HCV genotype 1a or HCV pe lb; or HCV genotype 2 or 3. The treatment according to this aspect of the technology can also be effective against other HCV pes. The DAAs can be administered around the same time or at ent times, and can be co-formulated in a single ation or formulated in different itions. Each DAA can be selected from HCV se inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e.g., a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least one HCV protease tor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). For another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase tor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e. g., a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase tor and at least one non- nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase tors).

For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease tors. For another instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase tor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside polymerase inhibitor, or SUBSTITUTE SHEET (RULE 26) a combination of at least one HCV NSSA inhibitor and at least one nucleoside or tide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and nd 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and Compound 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In a r example, the combination of two or more DAAs is a combination of nd 1 (or a salt thereof), Compound 2 (or a salt f) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), nd 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt f) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs comprises BMS-790052 and 0032. In yet another example, the combination of two or more DAAs comprises GS-S 885, 0, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs comprises telapreVir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danopreVir (with ritonaVir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasvir). In yet another e, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunapreVir). In still r example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunapreVir) and BMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INX-189 and 0052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs es INK-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and evir. In still another example, the combination of two or more DAAs includes INK-189, daclatasvir and BMS-79l325. In still another example, the combination of two or more DAAs es PSI-7977 and GS-S 885 . In still another example, the combination of two or more SUBSTITUTE SHEET (RULE 26) DAAs es PSI-7977, Compound 1 (with ritonavir), and Compound 4. In still another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still another example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg vir once daily, and 25 mg compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 er with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 er with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of treating HCV, comprising stering to a patient in need f an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 6 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being treated can be a treatment na'ive patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take eron. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or HCV genotype lb; or HCV genotype 2 or 3. The ent according to this aspect of the logy can also be effective against other HCV pes. The DAAs can be administered around the same time or at ent times, and can be co-formulated in a single formulation or ated in different compositions.

Each DAA can be selected from HCV protease inhibitors, HCV rase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e. g., a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). For r instance, the combination of two or more DAAs can be a SUBSTITUTE SHEET (RULE 26) combination of at least one HCV se inhibitor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e. g., a combination of at least two side or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase tor and at least one non- nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors).

For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the ation of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a ation of at least one HCV NSSA inhibitor, at least one side or nucleotide polymerase inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and Compound 2 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In another e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be mulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt f) can be co-formulated with ritonaVir. In a further e, the combination of two or more DAAs is a combination of nd 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-f01mulated with ritonaVir. In yet another example, the combination of two or more DAAs ses PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises 77 and TMC-435. In yet another example, the combination of two or more DAAs comprises TMC-435 and daclatasVir. In yet another example, the combination of two or more DAAs comprises BMS-790052 and 0032. In yet another example, the combination of two or more DAAs comprises GS-5885, GS-9l90, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-20l335 and BI—207127. In yet another example, the combination of two or more DAAs comprises telapreVir and VX-222. In another example, the combination of two or more SUBSTITUTE SHEET (RULE 26) 2012/061075 DAAs comprises GS-5885 and GS-9451. In yet r example, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and 0052 (daclatasvir). In yet another e, the combination of two or more DAAs includes INK-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INX-189, EMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still r example, the combination of two or more DAAs includes mericitabine and danoprevir. In still another example, the combination of two or more DAAs includes INK-189, daclatasvir and EMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another example, the combination of two or more DAAs includes PSI-7977, Compound 1 (with ritonavir), and Compound 4. In still another example, the method ses administering to a patient in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still another example, the method ses administering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg nd 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In r example, the method comprises administering 150 mg Compound 1 together with 100 mg vir once daily, and 400 mg nd 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 er with 100 mg ritonavir once daily, mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg nd 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the logy.

In yet another aspect, the present logy features a method of treating HCV, comprising stering to a t in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 5 weeks and does not e administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being treated can be a treatment naive patient, a ent experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon SUBSTITUTE SHEET (RULE 26) non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for e and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease tor and at least one HCV polymerase tor (e. g., a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least one HCV protease inhibitor and at least one side or nucleotide rase inhibitor, or a ation of at least one HCV protease tor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). For r instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a combination of at least one HCV protease tor, at least one HCV rase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e.g., a ation of at least two side polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the ation of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside or nucleotide rase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt f). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir.

In another e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co- formulated with ritonavir. In a further example, the combination of two or more DAAs is a combination SUBSTITUTE SHEET (RULE 26) of Compound 1 (or a salt thereof), nd 2 (or a salt thereof) and Compound 4 (or a salt thereof).

Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet r example, the combination of two or more DAAs is a ation of Compound 1 (or a salt thereof), Compound 3 (or a salt f) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with vir. In yet another example, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet r example, the combination of two or more DAAs comprises PSI-7977 and TMC- 435. In yet another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir.

In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS- 650032. In yet another example, the ation of two or more DAAs comprises GS-5885, GS-9190, and GS-9451. In yet r example, the combination of two or more DAAs comprises BI-201335 and BI-207127. In yet another example, the ation of two or more DAAs comprises telaprevir and VX- 222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet another e, the combination of two or more DAAs includes danoprevir (with ritonaVir) and R7128. In yet another e, the combination of two or more DAAs includes PSI-7977 and BMS- 790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS- 650032 (asunapreVir). In still another example, the ation of two or more DAAs includes PSI- 7977, BMS-650032 previr) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-l89 and 0052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunapreVir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes tabine and danopreVir. In still another example, the combination of two or more DAAs includes INK-189, daclatasvir and BMS-79l325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another example, the method comprises administering to a t in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, er with an effective amount of ribaVirin. In still another example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonaVir once daily, and 25 mg compound 4 once daily. In yet another example, the method ses administering 150 mg or 250 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonaVir once daily, 25 mg compound 4 once daily, and 400 mg SUBSTITUTE SHEET (RULE 26) 2012/061075 Compound 2 twice daily. In r example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of treating HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 4 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being treated can be a treatment na'1've patient, a treatment enced patient, including, but not d to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV pe 1a or HCV genotype lb; or HCV genotype 2 or 3. The treatment according to this aspect of the technology can also be effective against other HCV pes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV rase inhibitor (e. g., a combination of at least one HCV se inhibitor and at least one non-nucleoside rase inhibitor, or a combination of at least one HCV protease inhibitor and at least one side or nucleotide rase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase tor and at least one non-nucleoside inhibitor). For another instance, the ation of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. For still r instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e. g., a combination of at least two nucleoside or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non- side polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors).

For another instance, the ation of two or more DAAs can be a combination of at least two HCV protease inhibitors. For r instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a SUBSTITUTE SHEET (RULE 26) combination of at least one HCV NSSA inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one side or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase tor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt f). Compound 1 (or a salt thereof) can be co-formulated with vir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt f). Compound 1 (or a salt thereof) can be mulated with ritonaVir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt f). Compound 1 (or a salt thereof) can be mulated with ritonaVir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt f) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be mulated with ritonaVir. In yet another example, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises 77 and TMC-435. In yet another e, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In yet another example, the ation of two or more DAAs comprises BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs comprises GS-S 885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs comprises telapreVir and VX-222. In another example, the combination of two or more DAAs ses GS-5885 and 1. In yet another example, the combination of two or more DAAs includes danopreVir (with Vir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 preVir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- 650032 (asunapreVir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danopreVir. In still another example, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In still r example, the combination of two or more DAAs es SUBSTITUTE SHEET (RULE 26) PSI-7977 and GS-5885. In still another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still another example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet another e, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg nd 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of ng HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 3 weeks (or even less, depending on the patient’s condition) and does not include stration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being treated can be a treatment na'ive patient, a treatment experienced patient, including, but not limited to, a relapser, an eron partial responder, an interferon non-responder (e.g., a null der), or a patient unable to take interferon. The patient can be infected with, for example and without tion, HCV genotype 1, such as HCV genotype 1a or HCV genotype lb; or HCV genotype 2 or 3. The treatment ing to this aspect of the technology can also be effective against other HCV pes. The DAAs can be stered around the same time or at different times, and can be co-formulated in a single ation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NS5A tors. For instance, the ation of two or more DAAs can be a ation of at least one HCV protease inhibitor and at least one HCV polymerase tor (e.g., a combination of at least one HCV protease inhibitor and at least one non-nucleoside rase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease tor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). For another instance, the combination of two or more DAAs can be a combination of at least one HCV se SUBSTITUTE SHEET (RULE 26) inhibitor and at least one HCV NSSA tor. For still another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e.g., a combination of at least two nucleoside rase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e. g., a combination of at least one HCV NSSA inhibitor and at least one non- side polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a ation of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of nd 1 (or a salt thereof) and nd 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In a r example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs is a combination of nd 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-f01mulated with ritonaVir. In yet another example, the ation of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and TMC-435. In yet r example, the combination of two or more DAAs comprises TMC-435 and daclatasVir. In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In yet r example, the combination of two or more DAAs ses GS-5885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-201335 and BI—207127. In yet another example, the combination of two or more DAAs comprises telapreVir and VX-222. In another example, the ation of two or more DAAs ses GS-S885 and GS-9451. In yet another example, the combination of two or more DAAs SUBSTITUTE SHEET (RULE 26) 2012/061075 includes evir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and 0052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INX-189, EMS-650032 previr) and EMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danoprevir. In still another e, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another e, the method ses administering to a patient in need thereof an effective amount of PSI- 7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still r example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg nd 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg nd 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg nd 4 once daily, and 400 mg nd 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg d twice daily. Other DAA(s) can also be ed in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of ng HCV, comprising stering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 24 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being d can be a treatment na'i've patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV pe 1a or HCV genotype SUBSTITUTE SHEET (RULE 26) lb; or HCV genotype 2 or 3. The treatment ing to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at ent times, and can be co-formulated in a single formulation or ated in different compositions.

Each DAA can be ed from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e. g., a combination of at least one HCV protease tor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a ation of at least one HCV se inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one cleoside inhibitor). For another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. For still another instance, the ation of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase tor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e.g., a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV se inhibitors. For r instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside or nucleotide rase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one side or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the ation of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir.

In r example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and nd 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co- formulated with ritonavir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof).

Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the SUBSTITUTE SHEET (RULE 26) ation of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt f) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs ses PSI-7977 and PSI-938. In yet another e, the combination of two or more DAAs comprises PSI-7977 and TMC- 435. In yet another example, the combination of two or more DAAs ses TMC-435 and daclatasVir.

In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS- 650032. In yet another example, the combination of two or more DAAs comprises GS-5885, GS-9190, and GS-9451. In yet another example, the ation of two or more DAAs comprises BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs comprises telaprevir and VX- 222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet r e, the combination of two or more DAAs includes danoprevir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS- 790052. In yet another example, the ation of two or more DAAs includes PSI-7977 and BMS- 650032 (asunaprevir). In still another e, the combination of two or more DAAs includes PSI- 7977, BMS-650032 previr) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-l89 and 0052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still r example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunapreVir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danopreVir. In still another example, the combination of two or more DAAs includes INK-189, asyir and BMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, er with an effective amount of rin. In still another e, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonaVir once daily, and 25 mg compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonaVir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonaVir once daily, 25 mg compound 4 once daily, and 400 mg SUBSTITUTE SHEET (RULE 26) Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of treating HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts from 13 to 23 weeks (e.g., the duration ofthe ent is selected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being treated can be a treatment naive patient, a ent expelienced patient, including, but not limited to, a er, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV pe 2 or 3. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different itions.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For ce, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e. g., a combination of at least one HCV se inhibitor and at least one non-nucleoside polymerase inhibitor, or a ation of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside tor). For another instance, the combination of two or more DAAs can be a ation of at least one HCV se inhibitor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a ation of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e.g., a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or tide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside rase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For r ce, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside or tide SUBSTITUTE SHEET (RULE 26) polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one side or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside rase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and Compound 2 (or a salt thereof). Compound 1 (or a salt f) can be co-formulated with ritonaVir.

In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and nd 4 (or a salt f). Compound 1 (or a salt thereof) can be co- formulated with 1itonaVir. In a further e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof).

Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another e, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and TMC- 435. In yet another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir.

In yet another e, the combination of two or more DAAs comprises 0052 and BMS- 650032. In yet another example, the combination of two or more DAAs comprises GS-5885, GS-9190, and GS-9451. In yet another example, the ation of two or more DAAs ses BI-20l335 and l27. In yet another e, the combination of two or more DAAs comprises telapreVir and VX- 222. In r e, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet r example, the combination of two or more DAAs includes danopreVir (with ritonaVir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS- 790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS- 650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI- 7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and BMS-790052 (daclatasvir). In yet another example, the ation of two or more DAAs includes INK-189 and BMS-650032 previr). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danoprevir. In still another example, the combination of two or more DAAs includes INK-189, daclatasvir and BMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another example, the method comprises SUBSTITUTE SHEET (RULE 26) stering to a patient in need thereof an ive amount of PSI-7977 as the sole DAA in lieu of a ation of two or more DAAs, together with an ive amount of ribavirin. In still another example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 er with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg vir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet r aspect, the present technology es a method of treating HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an ive amount of ribavirin. The treatment lasts 12 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The t being treated can be a treatment na'1've patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or HCV genotype lb; or HCV genotype 2 or 3. The treatment according to this aspect of the technology can also be effective against other HCV pes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.

Each DAA can be selected from HCV se inhibitors, HCV polymerase inhibitors, or HCV NS5A inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e. g., a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV se inhibitor and at least one nucleoside or nucleotide rase tor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). For another instance, the combination of two or more DAAs can be a ation of at least one HCV protease tor and at least one HCV NSSA inhibitor. For still SUBSTITUTE SHEET (RULE 26) another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e.g., a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one side or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a ation of at least two HCV protease tors. For another instance, the combination of two or more DAAs can be a ation of at least two HCV NSSA inhibitors. For another ce, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a ation of at least one HCV NSSA tor and at least one non-nucleoside rase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA tor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor). In one e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof).

Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In still another example, the combination oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) and nd 4 (or a salt thereof). Compound 1 (or a salt thereof) can be mulated with ritonaVir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and nd 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with 1itonaVir. In yet another example, the combination of two or more DAAs comprises 77 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and 5. In yet another e, the combination of two or more DAAs ses TMC-435 and daclatasVir. In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs ses GS-5885, GS-9l90, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-201335 and BI-207127. In yet another example, the combination of two or more DAAs comprises telapreVir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danopreVir (with Vir) and R7128. In yet another SUBSTITUTE SHEET (RULE 26) example, the combination of two or more DAAs includes 77 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes PSI-7977 and 0032 (asunaprevir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-790052 tasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunaprevir) and 0052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danoprevir. In still r example, the combination of two or more DAAs includes INK-189, daclatasvir and BMS-791325. In still another example, the combination of two or more DAAS includes 77 and GS-5885. In still another example, the method comprises administering to a t in need thereof an effective amount of 77 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still another example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet r example, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In r example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg nd 3 once daily. In another e, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg vir once daily, 25 mg nd 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of treating HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts 11 weeks and does not include administration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing ncy. The patient being treated can be a treatment naive patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an eron non-responder (e.g., a null responder), or a t unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or HCV genotype lb; or HCV pe 2 or 3. The ent according to this aspect of the technology can also be SUBSTITUTE SHEET (RULE 26) effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease tor and at least one HCV polymerase tor (e. g., a combination of at least one HCV protease tor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide rase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one cleoside inhibitor). For r instance, the combination of two or more DAAs can be a combination of at least one HCV se inhibitor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV rase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a ation of at least two HCV polymerase inhibitors (e.g., a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another ce, the combination of two or more DAAs can be a combination of at least two HCV NSSA tors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV NSSA tor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and nd 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In a r example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another e, the combination of two or more DAAs is a combination of nd 1 (or a salt f), Compound 3 (or a salt thereof) and Compound SUBSTITUTE SHEET (RULE 26) 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the ation of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs comprises TMC-435 and daclatasvir. In yet another e, the combination of two or more DAAs comprises 0052 and 0032. In yet another example, the combination of two or more DAAs comprises GS-S 885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-201335 and BI-207l27. In yet another example, the combination of two or more DAAs comprises telaprevir and VX-222. In another example, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danopreVir (with ritonaVir) and R7128. In yet r example, the combination of two or more DAAs es PSI-7977 and EMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- 650032 (asunaprevir) and BMS-790052 (daclatasvir). In yet r example, the combination of two or more DAAs includes INK-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danopreVir. In still another example, the combination of two or more DAAs includes 9, daclatasVir and BMS-79l325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still r example, the method comprises administering to a t in need thereof an effective amount of 77 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribaVirin. In still r example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonaVir once daily, and 25 mg compound 4 once daily. In yet another e, the method comprises stering 150 mg or 250 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg Vir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg Vir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonaVir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonaVir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. rin can be SUBSTITUTE SHEET (RULE 26) administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present technology features a method of treating HCV, comprising administering to a patient in need thereof an effective amount of a combination of two or more DAAs, er with an effective amount of ribavirin. The treatment lasts 10 weeks and does not include stration of any interferon. The DAAs and ribavirin can be administered at the same or different dosing frequency. The patient being treated can be a treatment na'1've patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype la or HCV genotype lb; or HCV genotype 2 or 3. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in ent itions.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV rase tor (e. g., a ation of at least one HCV protease inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one cleoside inhibitor). For r instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. For still r instance, the ation of two or more DAAs can be a combination of at least one HCV se inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another ce, the combination of two or more DAAs can be a combination of at least two HCV polymerase inhibitors (e.g., a combination of at least two side polymerase inhibitors, or a combination of at least one side or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA inhibitor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor, at least one nucleoside or nucleotide SUBSTITUTE SHEET (RULE 26) polymerase inhibitor and at least one cleoside polymerase inhibitor). In one e, the combination of two or more DAAs is a ation of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonavir. In a further e, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs is a combination of nd 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs comprises PSI-7977 and TMC-435. In yet r example, the combination of two or more DAAs ses TMC-435 and daclatasvir. In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs comprises GS-S 885, GS-9190, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-201335 and 127. In yet r example, the combination of two or more DAAs comprises telapreVir and VX-222. In another example, the combination of two or more DAAs ses GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes danopreVir (with ritonaVir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- 650032 preVir) and BMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and 0032 (asunaprevir). In still another example, the ation of two or more DAAs includes INK-189, BMS-650032 preVir) and BMS-790052 (daclatasVir). In still another example, the combination of two or more DAAs includes tabine and danopreVir. In still another example, the combination of two or more DAAs includes 9, asvir and BMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another example, the method comprises administering to a patient in need f an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribaVirin. In still r example, the method comprises SUBSTITUTE SHEET (RULE 26) stering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg Compound 1 er with 100 mg ritonavir once daily, and 400 mg Compound 2 twice daily. In r example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method ses administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the t technology features a method of treating HCV, comprising stering to a t in need thereof an effective amount of a combination of two or more DAAs, er with an effective amount of ribavirin. The treatment lasts 9 weeks and does not include administration of any interferon. The DAAs and rin can be administered at the same or different dosing frequency. The patient being treated can be an interferon naive patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The t can be infected with, for example and without limitation, HCV genotype 1, such as HCV genotype 1a or HCV genotype lb; or HCV genotype 2 or 3. The ent according to this aspect of the technology can also be effective against other HCV genotypes. The DAAs can be administered around the same time or at different times, and can be co-formulated in a single formulation or formulated in different compositions.

Each DAA can be selected from HCV se tors, HCV rase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a combination of at least one HCV protease tor and at least one HCV polymerase inhibitor (e. g., a combination of at least one HCV se inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or tide polymerase inhibitor and at least one non-nucleoside inhibitor). For another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. For still another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. For another instance, the combination of two or more DAAs can be a combination of at least two HCV SUBSTITUTE SHEET (RULE 26) polymerase inhibitors (e.g., a combination of at least two nucleoside polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside or nucleotide polymerase inhibitor, or a combination of at least two non-nucleoside polymerase inhibitors). For another instance, the combination of two or more DAAs can be a combination of at least two HCV protease inhibitors. For another instance, the combination of two or more DAAs can be a ation of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a combination of at least one HCV polymerase inhibitor and at least one NSSA tor (e.g., a combination of at least one HCV NSSA inhibitor and at least one non-nucleoside rase inhibitor, or a combination of at least one HCV NSSA tor and at least one nucleoside or nucleotide polymerase tor, or a combination of at least one HCV NSSA tor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase inhibitor). In one example, the ation oftwo or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 2 (or a salt thereof). Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In another example, the combination of two or more DAAs is a ation of Compound 1 (or a salt thereof) and Compound 3 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and Compound 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 2 (or a salt thereof) and Compound 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet r example, the ation of two or more DAAs is a combination of Compound 1 (or a salt thereof), Compound 3 (or a salt thereof) and Compound 4 (or a salt thereof). nd 1 (or a salt thereof) can be co-formulated with ritonaVir. In yet another example, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet another example, the combination of two or more DAAs ses PSI-7977 and TMC-435. In yet another example, the combination of two or more DAAs comprises TMC-435 and asvir. In yet another example, the combination of two or more DAAs comprises BMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs comprises GS-S 885, GS-9l90, and GS-9451. In yet another example, the combination of two or more DAAs comprises BI-20l335 and BI-207l27. In yet another example, the combination of two or more DAAs comprises telapreVir and VX-222. In another e, the combination of two or more DAAs comprises GS-5885 and GS-9451. In yet another example, the combination of two or more DAAs includes evir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- SUBSTITUTE SHEET (RULE 26) 650032 (asunaprevir) and BMS-790052 tasvir). In yet another example, the ation of two or more DAAs includes INK-189 and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and BMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INK-189, 0032 (asunaprevir) and BMS-790052 (daclatasvir). In still another example, the combination of two or more DAAs includes mericitabine and danoprevir. In still another example, the combination of two or more DAAs includes INX-189, daclatasvir and BMS-791325. In still another example, the ation of two or more DAAs includes 77 and GS-5885. In still another example, the method comprises administering to a patient in need thereof an effective amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs, together with an effective amount of ribavirin. In still another example, the method comprises administering 100 or 200 mg Compound 1 together with 100 mg ritonavir once daily, and 25 mg compound 4 once daily. In yet another example, the method comprises administering 150 mg or 250 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg nd 2 twice daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg nd 3 once daily. In another example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg Compound 3 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 er with 100 mg vir once daily, 25 mg nd 4 once daily, and 400 mg Compound 2 twice daily. In another example, the method comprises administering 100 or 150 mg Compound 1 together with 100 mg ritonavir once daily, 25 mg compound 4 once daily, and 400 mg Compound 3 twice daily. Ribavirin can be administered based on patient weight, and in many cases, 1000 to 1200 mg divided twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In another ment, the present technology es interferon-free treatment comprising administering daily two DAAs with ribavirin, where the two DAAs e a HCV polymerase inhibitor, for e PSI-7977 and a NSSA inhibitor, for example BMS-790052 for a duration of no more than twelve weeks (e.g., no more than eleven weeks), preferably no more than eight weeks.

In some embodiments, the present technology provides a method of treating Hepatitis C virus infection in a subject comprising administering daily a HCV protease inhibitor and a HCV polymerase inhibitor to the subject in the absence of interferon for a duration of no more than twelve weeks, preferably no more than eight weeks. In some embodiments, ritonavir (or an equivalent thereof) is co-administered with one or more protease inhibitors to improve the pharmacokinetics of the protease inhibitor(s). The treatment further ses administering ribavirin to the patient. In some ments, the HCV polymerase inhibitor is at least one nucleoside or nucleotide polymerase inhibitor SUBSTITUTE SHEET (RULE 26) or at least one non-nucleoside rase inhibitor. In some embodiments, both a nucleoside or nucleotide polymerase tors and a cleoside polymerase inhibitor may be administered.

The methods of the present technology as described herein may be used to treat a naive patient or a treatment experienced patient. Treatment experienced patients include interferon non- responders, partial responders nts whose HCV RNA levels declined but never became ctable), and relapsers (patients who achieved undetectable levels of HCV RNA during therapy but rebound). Methods of the present technology may also be used to treat patients who are not ates for interferon ent. Patients who are not ates for interferon treatment include, but are not limited to, one or more of the following groups: patients intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions which preclude them from taking interferon, and patients who have an increased risk of side effects or infection by taking interferon.

In some embodiments, a cytochrome P-450 inhibitor, e. g. ritonavir, is administered either in the same or separate pharmaceutical composition with the protease inhibitor (e. g. Compound 1 (or a pharmaceutically acceptable salt thereof)) to improve the pharmacokinetics. A cytochrome P450 inhibitor reduces the metabolism of some protease inhibitors, such as Compound 1, thereby improving the pharmacokinetics and bioavailability of the protease inhibitor, for example Compound 1. More preferably, Compound 1 (or a pharmaceutically able salt thereof) is co-formulated with ritonavir in the same dosage form. Other cytochrome P450 inhibitors, such as cobicistat, may also be administered in lieu of ritonavir, to enhance the pharmacokinetics of Compound 1 (or a pharmaceutically acceptable salt thereof).

Inhibitors of rome P450, such as ritonavir, may be co-administered with the DAAs, either sequentially or simultaneously, in the same or different compositions. In some embodiments, the cytochrome P450 inhibitors are administered in order to improve the pharmacokinetics of at least one of the DAAs. Not to be bound by any theory, but a cytochrome P450 inhibitor may also reduce the development of resistant s ofHCV when co-administered with a DAA, thus providing the effectiveness in a r treatment. In some embodiments, ritonavir is co-administered with eutic agent 1. In some embodiments, ritonavir is co-administered with therapeutic agent 1 in the same compositions.

In some embodiments, the present technology provides a method of treating HCV infection comprising administering at least one se inhibitor and at least one HCV polymerase inhibitor with ribavirin in a course of treatment of no more than, or less than, eight weeks in the absence of interferon. In some embodiments, the HCV rase inhibitor is nd 1 (or a pharmaceutically acceptable salt f).

SUBSTITUTE SHEET (RULE 26) In some embodiments, the present technology provides a method of treating HCV infection without using interferon, the method comprising administering at least two DAAs and ribavirin to a patient in need of such treatment, wherein the at least two DAAs include at least one protease inhibitor and at least one HCV polymerase inhibitor. In some ments, the at least two DAAs es therapeutic agent 1 with at least one HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor is at least one non-nucleoside polymerase inhibitor. In some embodiments, the non-nucleoside rase tor is therapeutic agent 2 or therapeutic agent 3 or a combination thereof.

In some embodiments, the t technology provides a method of treating HCV infection without using interferon, the method sing administering a HCV protease inhibitor, preferably therapeutic agent 1, with at least one HCV NSSA inhibitor to a patient in need of such treatment. In some embodiments, the NSSA inhibitor is therapeutic agent 4.

In some embodiments of the present technology, a method of treating HCV infection without using interferon, the method comprises administering at least three DAAs and ribavirin to a subject for no more than 8 weeks without administering eron. The at least three DAAs can be at least one se inhibitor, at least one HCV polymerase inhibitor, and at least one NSSA inhibitors. In a preferred embodiment, the at least one protease inhibitor is therapeutic agent 1, the at least one rase inhibitor is therapeutic agent 2 or therapeutic agent 3, and the at least one NSSA inhibitor is therapeutic agent 4.

Preferred HCV protease inhibitors include, but are not limited to, therapeutic agent 1, telaprevir (Vertex), boceprevir (Merck), BI-201335 (Boehringer Ingelheim), GS-9451 (Gilead), and BMS-650032 (BMS). Other suitable protease inhibitors include, but are not limited to, ACH-1095 (Achillion), ACH-l625 (Achillion), 84 (Achillion), AVL-l8l (Avila), AVL-l92 (Avila), BMS- 650032 (BMS), danoprevir (RG7227/ITMN—l9l, , GS-9l32 (Gilead), GS-9256 (Gilead), IDX-l36 x), IDX-3l6 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir (Schering-Plough Corp), PHX-l766 (Phenomix), 5 ec), vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-SOO (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a ation thereof.

Preferred cleoside HCV polymerase tors for use in the present technology include, but are not limited to, eutic agent 2, therapeutic agent 3, GS-9l90 (Gilead), BI-207127 (Boehringer Ingelheim), and VX-222 (VCH-222) (Ve1tex & ViraChem). Preferred nucleotide HCV polymerase inhibitors include, but are not limited to, PSI-7977 (Pharmasset), and PSI-938 (Pharmasset).

Other suitable and non-limiting examples of suitable HCV polymerase inhibitors include ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-l94l (Boehringer Ingelheim), BMS-79l325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 d), IDX-375 (Idenix), MK-328l ), SUBSTITUTE SHEET (RULE 26) tegobuvir, TMC—647055 (Tibotec), VCH-759 Wertex & ViraChem), VCH-916 (ViraChem), VX-759 (Vertex), GS-6620 (Gilead), 2 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), RG7128 (Roche), TMC64912 (MediVir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), ALS-22OO (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination f. A polymerase inhibitor may be a nucleoside polymerase inhibitor, such as GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (ldenix), INK-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination therefore. A polymerase inhibitor may also be a non-nucleoside polymerase inhibitor, such as PF-00868554 (Pﬁzer), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 inger Ingelheim), BMS-791325 (BMS), ﬁlibuVir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 d), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC—647055 (Tibotec), VCH—759 Wertex & em), VCH—916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combination thereof.

Preferred NSSA inhibitors include, but are not limited to, therapeutic agent 4, BMS- 790052 (BMS) and GS-5885 (Gilead). Non-limiting examples of suitable NSSA tors include 36805 (GlaxoSmithKline), ACH—2928 (Achillion), AZD2836 (Astra-Zeneca), 5 (Astra- Zeneca), BMS-790052 (BMS), BMS-824393 (BMS), GS-5885 d), PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or a combination thereof.

Non-limiting examples of suitable cyclophilin inhibitors include alisporovir (Novartis & Debiopharm), NM-8ll (Novartis), SCY-635 (Scynexis), or a ation thereof.

Non-limiting examples of suitable HCV entry inhibitors include ITX-4520 (iTherx), ITX- 5061 x), or a combination thereof.

Speciﬁc examples of other DAA agents that are suitable for the present methods include, but are not limited to, AP-HOOS, A-831 (Arrow Therapeutics) (NSSA inhibitor), A-689 (Arrow Therapeutics) (NS5A tor), INX08189 (Inhibitex) (polymerase inhibitor), ITMN—191 (Intermune/Roche) A se inhibitor), VBY-376 (Protease Inhibitor) (Virobay), ACH-1625 (Achillion, Protease inhibitor), IDX136 x, Protease Inhibitor), IDX316 (Idenix, se inhibitor), VX-813 (Vertex), SCH 900518 (Schering-Plough), TMC-435 ec), ITMN—191 (Intermune, Roche), MK-7009 (Merck), IDX-PI (Novartis), R7128 (Roche), PF-868554 (Pﬁzer) (non-nucleoside polymerase inhibitor), PF-4878691 ), 4 (Idenix), 5 (Idenix, NSSB polymerase inhibitor), PPI- 461 (Presidio), BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), CTS-1027 (Conatus), 0 (Gilead), PF-4878691 ), ROS303253 (Roche), ALS-2200 (Alios BioPharma/Vertex), 58 (Alios BioPharma/Vertex), GSK62336805 SmithKline), or any combinations thereof.

SUBSTITUTE SHEET (RULE 26) In some embodiments, the t technology features methods for treating patients with pe 1, such as la or lb, HCV infection. The methods comprise administering to such a t a combination of at least 2 DAAs and ribavirin for no more than 12 weeks, preferably no more than 8 weeks, wherein the treatment does not include administration of interferon. Patients with genotype 1, such as la or lb, ion can be treated with a combination of at least 2 DAAs t interferon where the at least two DAAs include therapeutic agent 1 and therapeutic agent 2 with ribavirin. Therapeutic agent 1 and therapeutic agent 2 with ribavirin can be administered in therapeutically effective amounts to provide a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) after a treatment duration of no more than 12 weeks (e. g., the duration being 12 , preferably no more than 8 weeks (e.g., the duration being 8 weeks). The ts may be treatment naive patients or treatment experienced HCV patients.

The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than t 4 weeks, or no more than 3 weeks, e. g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 2 can be administered with therapeutic agent 1 in any of the dosages of eutic agent 1 described above. The total daily dosage of eutic agent 2 can be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or 1800 mg. Suitably, ribavirin may be administered in connection with therapeutic agent 1 and therapeutic agent 2 at any of the dosages described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 2 75 kg. In some ments, ritonavir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, but are not limited to, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology features methods for treating patients with genotype 2 or 3 HCV infection. The methods comprise stering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 , wherein the treatment does not include administration of interferon. Patients with genotype 2 or 3 HCV infection can be treated with a combination of at least 2 DAAs without eron where the at least two DAAs include therapeutic agent SUBSTITUTE SHEET (RULE 26) 1 and therapeutic agent 2 with ribavirin. eutic agent 1 and therapeutic agent 2 can be administered in therapeutically effective amounts to provide a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) with a treatment duration of no more than 12 weeks, preferably no more than 8 weeks. The patients may be treatment naive HCV patients or treatment experienced HCV ts. The treatment duration can be no more than 12 weeks, including but not d to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e. g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 300 mg.

Therapeutic agent 2 can be administered in connection with eutic agent 1 in any of the dosages bed above. The total daily dosage of therapeutic agent 2 can be, but is not d to, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or 1800 mg. Suitably, ribavirin may be stered in tion with therapeutic agent 1 and therapeutic agent 2 in any combination of suitable dosages described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and e, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg. In some embodiments, ritonavir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology features methods for treating patients with HCV infection. The s comprise administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The ation comprises therapeutic agent 1, therapeutic agent 2 and ribavirin. Suitably, the patient may be a treatment nai've patient, a treatment experienced patient or an interferon nonresponder. In some ments, the patient is infected with HCV pe 1, such as genotype 1a.

In some embodiments, the patient is infected with HCV genotype 1b. In some embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The treatment duration can be for no more than 12 weeks, preferably no more than 8 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than SUBSTITUTE SHEET (RULE 26) 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e. g., the duration being 12 weeks, or the duration being 8 weeks. Therapeutic agent 1 and eutic agent 2 can be administered in therapeutically effective amounts to provide a SVR (for example, a SVR8, SVR12, SVR 16, or SVR 24) after treatment duration of no more than 12 weeks, ably no more than 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not d to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 2 can be administered with therapeutic agent 1 in any of the dosages described above. The total daily dosage of therapeutic agent 2 can be, but is not d to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg. Suitably, ribavirin may be administered in connection with therapeutic agent 1 and therapeutic agent 2 at any combination of the dosages described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg.

In some embodiments, the t technology features s for ng patients with HCV infection who are not candidates for interferon treatment. The s comprise administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. Patients who are not candidates for interferon treatment include, but are not limited to, one or more of the following groups: patients intolerant to interferon, patients who refuse to take interferon ent, patients with medical conditions which preclude them from taking interferon, and ts who have an increased risk of side effects or infection by taking interferon. A non-candidate for interferon treatment can be infected with HCV pe 1 or 2, for example, genotype 1a or 1b. A non-candidate for interferon treatment can be ed with HCV genotype 2, for example, genotype 2a or 2b. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. In some embodiments, non-candidate for interferon treatment patients can be treated with a combination of at least 2 DAAs without eron and with ribavirin for a treatment duration of no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e. g., the duration being 12 weeks, or the duration being 8 weeks. The at least two DAAs include at least one HCV protease inhibitor and at least one HCV polymerase inhibitor. Suitably, the at least one HCV protease inhibitor can be therapeutic agent 1 and the at least one HCV polymerase inhibitor can be SUBSTITUTE SHEET (RULE 26) therapeutic agent 2. Therapeutic agent 1 and therapeutic agent 2 can be administered in eutically effective amounts to e a SVR after a ent duration of no more than 12 weeks, preferably no more than 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.

Therapeutic agent 2 can be administered with therapeutic agent 1 with therapeutic agent 1 administered at any of the dosages described above. The total daily dosage of therapeutic agent 2 can be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. Suitably, ribavirin may be administered in connection with therapeutic agent 1 and therapeutic agent 2 at any of the dosages described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a t < 75 kg or about 1200 mg per day for a patient 3 75 kg.

In another aspect, the present logy es methods for treating patients with HCV infection. The methods se administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e. g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), n the treatment does not include administration of interferon.

The combination comprises therapeutic agent 1, therapeutic agent 2, therapeutic agent 4 and ribavirin. In some embodiments, the patient is infected with HCV genotype 1, such as pe 1a. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The ent duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks or the duration being 8 weeks. Therapeutic agent 1, therapeutic agent 2, and therapeutic agent 3 can be provided in effective amounts to e a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) after a treatment duration of no more than 12 weeks, preferably no more than 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 300 mg. Therapeutic agent 2 can be administered with therapeutic agent 1 with therapeutic agent 1 being administered in any of the dosages described above. The total daily dosage of therapeutic agent 2 can be, but is not limited to, for example, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or SUBSTITUTE SHEET (RULE 26) WO 59630 about 1000 mg. Therapeutic agent 4 can be provided in combination with therapeutic agent 1 and therapeutic agent 2 in which eutic agent 1 and therapeutic agent 2 are administered in any combination of the dosages for therapeutic agent 1 and therapeutic agent 2 described above. Therapeutic agent 4 can be provided in ation with therapeutic agent 1 and therapeutic agent 2 in a total daily dose of therapeutic agent 4 of an amount from about 5 mg to about 350 mg, preferably about 5 mg to about 300 mg, more preferably about 25 mg to about 200 mg. The total daily dosage of therapeutic agent 4 can be, but are not limited to, for example, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, ritonavir can be either co-administered or stered separately with therapeutic agent 1.

Suitable s of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. Suitably, ribavirin may be administered in connection with therapeutic agent 1, therapeutic agent 2, and therapeutic agent 4 in which therapeutic agent 1, therapeutic agent 2, and therapeutic agent 4 are stered in any combination of the dosages described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg. Suitably, in some embodiments, the patient may be a treatment na'ive patient, a treatment enced patient, or an interferon nonresponder.

In some embodiments, the present technology features methods for ng patients with genotype 1, such as pe 1a or 1b, HCV infection. The methods se administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e. g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The combination comprises therapeutic agent 1, therapeutic agent 3 and ribavirin. The treatment duration may be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 3 can be administered in connection with therapeutic agent 1 with therapeutic agent 1 being administered at any of the dosages of described above. Therapeutic agent 3 can be provided in combination with therapeutic agent 1. The total daily dosage of therapeutic agent 3 can be, but is not limited to, for e, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about SUBSTITUTE SHEET (RULE 26) 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be administered either at the same time or at a separate time than therapeutic agent 1 and therapeutic agent 3; and therapeutic agent 1 and therapeutic agent 3 can be administered in any of the suitable dosages of therapeutic agent 1 or therapeutic agent 3 recited above. Suitable total daily dosages of ribavirin can be based on the weight of the t and include, but are not limited to, from about 800 mg to about 1200 mg, ing, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg. In some ments, ritonavir can be either co-administered or stered separately with therapeutic agent 1. le dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology features methods for treating patients with genotype 2 or 3, such as genotype 2a, 2b or 321, HCV infection. The s comprise administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 , preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The combination comprises therapeutic agent 1, therapeutic agent 3 and ribavirin. The treatment duration can be no more than 12 weeks, ing but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks.

Therapeutic agent 1 and therapeutic agent 3 and rin can be administered in therapeutically effective amounts to provide a SVR (for example, a SVR8, SVR12, SVR16 or SVR24) in a treatment duration of no more than 12 weeks, preferably no more than 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for e, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 3 can be administered with therapeutic agent 1 with therapeutic agent 1 being administered at any of the dosages described above. Therapeutic agent 3 can be provided in combination with therapeutic agent 1. The total daily dosage of therapeutic agent 3 can be, but is not limited to, for example, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 SUBSTITUTE SHEET (RULE 26) mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be administered either at the same time or at a separate time than therapeutic agent 1 and therapeutic agent 3; and therapeutic agent 1 and therapeutic agent 3 can be administered in any combination of dosage of therapeutic agent 1 or therapeutic agent 3 recited above. Suitable total daily dosages of ribavirin can be based on the weight of the t and e, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg. In some embodiments, vir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the t technology features methods for treating patients with HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The combination comprises therapeutic agent 1, therapeutic agent 3 and ribavirin. Suitably, the patient may be a treatment naive patient, a treatment experienced patient or an eron ponder. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a.

In some embodiments, the patient is infected with HCV pe 1b. In some other embodiments, the t is ed with HCV pe 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 3 can be administered in tion with therapeutic agent 1 with therapeutic agent 1 being stered at any of the dosages described above. Therapeutic agent 3 can be provided in combination with therapeutic agent 1. The total daily dosage of therapeutic agent 3 can be, but is not limited to, for example, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, SUBSTITUTE SHEET (RULE 26) about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be administered either at the same time or at a separate time than therapeutic agent 1 and therapeutic agent 3; and therapeutic agent 1 and eutic agent 3 can be administered in any combination of the suitable dosages recited above. Suitable total daily s of ribavirin can be based on the weight of the t and include, but are not limited to, from about 800 mg to about 1200 mg, ing, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg. In some embodiments, ritonaVir can be either co-administered or administered separately with therapeutic agent 1.

Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day.

In some embodiments, the present technology features methods for treating patients with HCV infection who are not candidates for interferon treatment. The methods comprise administering to such a patient a combination of at least 2 DAAs and ribaVirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), n the treatment does not include stration of eron. The combination comprises therapeutic agent 1, therapeutic agent 3 and ribaVirin. Patients who are not candidates for interferon treatment include, but are not d to, one or more of the following groups: patients intolerant to interferon, patients who refuse to take interferon treatment, ts with l conditions which preclude them from taking interferon, and patients who have an increased risk of side effects or infection by taking interferon. In some embodiments, the patient is infected with HCV genotype 1, such as genotype 1a. In some embodiments, the patient is infected with HCV genotype 1b. In some other embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other ments, the patient is infected with HCV genotype 3a. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably patients who are more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e. g., the duration being 12 week, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 3 can be stered with therapeutic agent 1 with therapeutic agent 1 being administered at any of the SUBSTITUTE SHEET (RULE 26) dosages described above. eutic agent 3 can be provided in combination with therapeutic agent 1.

The total daily dosage of therapeutic agent 3 can be, but is not limited to, for example, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. Ribavirin can be administered either at the same time or at a separate time than eutic agent 1 and therapeutic agent 3; and therapeutic agent 1 and therapeutic agent 3 can be administered in any combination of dosages of therapeutic agent 1 and eutic agent 3 recited above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg. In some ments, ritonavir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir e, from about 50 mg to about 400 mg per day, ably about 100 mg per day.

In some ments, the t technology features methods for treating patients with HCV genotype 1, such as 1a or 1b, infection. The methods comprise administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The combination comprises therapeutic agent 1, therapeutic agent 4 and ribavirin. ts with genotype 1a or 1b infection can be treated with a combination of at least 2 DAAs without interferon in which the at least two DAAs include therapeutic agent 1 and therapeutic agent 4 with ribavirin. Therapeutic agent 1 and therapeutic agent 4 can be administered in therapeutically effective amounts to e a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) in a ent duration of no more than 12 weeks, preferably no more than 8 weeks. The patients may be treatment nai've patients or treatment experienced patients. The treatment duration can be no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.

SUBSTITUTE SHEET (RULE 26) Therapeutic agent 4 can be administered in connection with therapeutic agent 1 where therapeutic agent 1 is administered in any of the dosages described above. Therapeutic agent 4 can be provided in combination with therapeutic agent 1 in a total daily dose of therapeutic agent 4 of from about 25 mg to about 200 mg. The total daily dosage of therapeutic agent 4 can be, but is not limited to, for example, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can be either co-administered or administered separately with eutic agent 1. Suitable dosages of ritonaVir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, therapeutic agent 1 and therapeutic agent 4 are administered once a day. Suitably, ribaVirin may be administered in connection with therapeutic agent 1 and therapeutic agent 4 where therapeutic agent 1 and therapeutic agent 4 are administered in any combination of the suitable dosages detailed above. Suitable total daily dosages of ribaVirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for e, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg.

In some embodiments the present technology features methods for treating patients with HCV infection. The methods comprise administering to such a patient a ation of at least 2 DAAs and ribaVirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The ation comprises therapeutic agent 1, eutic agent 4 and ribavirin. The patients may be treatment na'ive patients or treatment experienced patients. The treatment can be administered for a duration of no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e. g., the on being 12 weeks, or the duration being 8 weeks. The patient can have HCV genotype 1, such as HCV genotype 1a or 1b. In other embodiments, the t may have HCV pe 1b. In some embodiments, it is plated to treat other HCV genotypes. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can be administered in connection with SUBSTITUTE SHEET (RULE 26) WO 59630 2012/061075 therapeutic agent 1 in any of the dosages described above. Therapeutic agent 4 can be provided alone or in combination with therapeutic agent 1. The total daily dosage of eutic agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some ments, ritonavir can be either co- administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, therapeutic agent 1 and therapeutic agent 4 are administered once a day. In some embodiments, therapeutic agent 1 and eutic agent 4 are administered with ribavirin. Suitable total daily dosages of rin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg.

In some embodiments, the present technology features methods for treating patients with HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon. The combination ses therapeutic agent 1, therapeutic agent 4 and ribavirin. The patients may be treatment na'ive patients or treatment experienced patients. The treatment can be administered for a duration of no more than 12 weeks, including but not limited to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but ably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the on being 8 weeks. The patient can have HCV genotype 2 or 3, such as HCV genotype 2a. In some embodiments, the patient may have HCV genotype 2b. In other embodiments the patient may have HCV genotype 3a. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. Therapeutic agent 4 can be administered in connection with therapeutic agent 1 in which therapeutic agent 1 is administered in any of the dosages described above. eutic agent 4 can be provided in combination with eutic agent 1. The total daily dosage of therapeutic agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 SUBSTITUTE SHEET (RULE 26) mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, therapeutic agent 1 and therapeutic agent 4 are administered once a day.

In some embodiments, therapeutic agent 1 and therapeutic agent 4 are administered with ribavirin.

Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a t 3 75 kg.

In some ments, the present technology features methods for ng patients with HCV infection who are not candidates for interferon treatment. The methods se administering to such a t a combination of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not e administration of interferon. The combination comprises therapeutic agent 1, therapeutic agent 4 and ribavirin. Patients who are not candidates for interferon treatment include, but are not limited to one or more of the following : patients intolerant to interferon, patients who refuse to take interferon treatment, patients with medical conditions which preclude them from taking interferon, and patients who have an increased risk of side effects or infection by taking interferon. In some embodiments, the t is infected with HCV genotype 1, such as genotype 1a. In some embodiments, the patient is infected with HCV pe 1b. In some other embodiments, the patient is infected with HCV genotype 2 or 3, such as 2a or 2b. In some other embodiments, the patient is infected with HCV genotype 3a. The ent according to this aspect of the technology can also be effective against other HCV genotypes. Therapeutic agent 1 and therapeutic agent 4 can be administered in eutically effective amounts to provide a SVR (for example, a SVR8, SVR12, SVR16 or SVR24) after treatment of no more than 12 weeks, ably no more than 8 weeks. The interferon non- responder patients include partial interferon responders and interferon rebound patients. See GUIDANCE FOR INDUSTRY — CHRONIC HEPATITIS C VIRUS INFECTION: DEVELOPING DIRECT-ACTING ANTIVIRAL AGENTS FOR TREATMENT (FDA, September 2010, draft guidance) for the definitions of naive, partial responder, der relapser (i.e., rebound), and null responder ts. The interferon non-responder ts also include null responder patients. The treatment can be administered for a duration of no more than 12 weeks, including but not d to, no more than 11 weeks, no more than 10 weeks, no more than SUBSTITUTE SHEET (RULE 26) WO 59630 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.

Therapeutic agent 4 can be administered with therapeutic agent 1 where therapeutic agent 1 is administered in any of the dosages described above. Therapeutic agent 4 can be provided in combination with therapeutic agent 1. The total daily dosage of eutic agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, ritonavir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable embodiments, therapeutic agent 1 and therapeutic agent 4 are administered once a day. Suitably, ribavirin may be administered in connection with therapeutic agent 1 and therapeutic agent 4 where therapeutic agent 1 and therapeutic agent 4 are administered in any combination of suitable s as described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, including, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 2 75 kg.

In some embodiments, the present technology features methods for treating patients with HCV infection who are interferon sponders (e. g., null responders). The methods comprise administering to such a t a ation of at least 2 DAAs and ribavirin for no more than 12 weeks (e.g., the on being 12 weeks), ably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of eron. Interferon nonresponder patients can be treated with a combination of at least 2 DAAs without interferon with rin wherein the two DAAs include therapeutic agent 1 and therapeutic agent 4 with ribavi1in. Therapeutic agent 1 and therapeutic agent 4 can be administered in therapeutically effective amounts to provide a SVR (for example, a SVR8, SVR12, SVR16 or SVR24) after treatment duration of no more than 12 weeks, preferably no more than 8 weeks. The interferon non-responder patients include partial interferon ders and interferon rebound patients. The interferon nonresponder patient may have HCV pe 1, such as 1a. The SUBSTITUTE SHEET (RULE 26) eron ponder patient may have HCV genotype 1b. The interferon nonresponder patient can have HCV genotype 2 or 3, such as HCV genotype 2a. In some ments, the patient may have HCV genotype 2b. In other embodiments the patient may have HCV genotype 3a. In some embodiments, it is contemplated to treat other HCV genotypes. The ent can be administered for a duration of no more than 12 weeks, including but not d to, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, but preferably no more than 8 weeks, no more than 7 weeks, no more than 6 weeks, no more than 5 weeks, no more than 4 weeks, or no more than 3 weeks, e.g., the duration being 12 weeks, or the duration being 8 weeks. The total daily dosage of therapeutic agent 1 can be, but is not limited to, for example, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg.

Therapeutic agent 4 can be stered with therapeutic agent 1 wherein therapeutic agent 1 is administered in any of the dosages described above. Therapeutic agent 4 can be provided in combination with therapeutic agent 1. The total daily dosage of therapeutic agent 4 can be, but is not limited to, for example, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In some embodiments, vir can be either co-administered or administered separately with therapeutic agent 1. Suitable dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In suitable ments, therapeutic agent 1 and therapeutic agent 4 are administered once a day. Suitably, ribavirin may be administered in connection with therapeutic agent 1 and therapeutic agent 4 wherein therapeutic agent 1 and therapeutic agent 4 are administered in any combination of suitable dosages as described above. Suitable total daily dosages of ribavirin can be based on the weight of the patient and include, but are not limited to, from about 800 mg to about 1200 mg, ing, for example, about 1000 mg per day for a patient < 75 kg or about 1200 mg per day for a patient 3 75 kg.

Accordingly, in some embodiments, the present technology features a method of treating HCV infection, comprising stering to a patient in need thereof an effective amount of a combination of two or more DAAs, together with an effective amount of ribavirin. The treatment lasts no more than 12 weeks, alternatively no more than 11 weeks, altematively no more than 10 weeks, alternatively no more than 9 weeks, ably no more than 8 weeks, alternatively no more than 7 weeks, alternatively no more than 6 weeks, alternatively no more than 5 weeks, alternatively no more than 4 SUBSTITUTE SHEET (RULE 26) weeks, alternatively no more than 3 weeks and does not include administration of any eron. The DAAs and ribavirin can be administered at the same or different dosing frequencies. The patient being treated can be an HCV-treatment naive patient or HCV-treatment experienced t, including, interferon non-responders, interferon partial responders (patients whose HCV RNA levels declined but never became undetectable when treated with interferon), or relapsers (patients who achieved undetectable levels of HCV RNA during therapy but rebound) or a patient unable to take interferon. The patient can be infected with, for example and without limitation, HCV genotypes l or 2. In some embodiments are preferably genotypes 1a or 1b. In other embodiments, the HCV genotype is 2 or 3.

Each DAA can be selected from HCV protease inhibitors, HCV polymerase tors, or HCV NSSA inhibitors.

For instance, the ation of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor (e.g., a combination of at least one HCV protease inhibitor and at least one non-nucleoside polymerase inhibitor, or a combination of at least one HCV protease inhibitor and at least one nucleoside or nucleotide polymerase tor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside inhibitor).

For another instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor and at least one HCV NSSA inhibitor. In an example, the ation of two or more DAAs comprises 5 (an NSSA tor), and GS-9451 (a protease inhibitor or an NS3 protease inhibitor). In some examples, GS-5885 is provided in a daily dose from about 3 mg to about 200 mg, alternatively from about 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, including, but not limited to, for e, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. GS-9451 can be administered in combination with any of the daily dosages of GS-S 885 described above. GS-9451 can be administered in a total daily dose from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including, but not limited to, for example, about 100 mg, about l50 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. Suitably examples include total daily dosages of about 30 mg GS-5885 and about 200 mg GS-9451; alternatively about 60 mg GS-5885 and about 200 mg GS-9451; alternatively about 90 mg GS-5885 and about 200 mg GS-9451.

In another ce, the t technology provides the at least two DAAs comprise at least two HCV polymerase inhibitors. In some embodiments, the at least two HCV polymerase inhibitors comprise at least one nucleoside or tide analog polymerase inhibitor. In some embodiments, the at SUBSTITUTE SHEET (RULE 26) least two HCV polymerase inhibitors comprise at least two nucleoside or nucleotide analog polymerase inhibitors. Suitable nucleotide analog polymerase inhibitors include PSI-7977 asset) and PSI-938 (Pharmasset). Suitable daily s of the at least one nucleoside or nucleotide analog polymerase inhibitor e from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including, but not d to, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. For example, a suitable combination es a total daily dose of PSI-7977 of about 400 mg and a total daily of PSI-938 of about 300 mg, alternatively a total daily dose of about 200 mg PSI-7977 and a total daily dose of about 300 mg PSI-938. Suitably, ribavirin can be administered with the at least two DAAs, preferably in an amount based on weight of the t, in a total daily dose of from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, a suitable ribavirin daily treatment is weight based, for example, 1000 mg/day < 75 kg and 1200 mg/day 3 75 kg, divided twice daily (BID). In yet another ce, the combination of two or more DAAs comprises at least one HCV protease tor and at least one HCV polymerase inhibitor. In some embodiments, the at least one protease inhibitor is TMC—435 and the at least one polymerase inhibitor is a nucleotide/nucleoside analog polymerase inhibitor, for example PSI-7977, or for example TMC-647055. Suitably, the at least one protease inhibitor, e.g. TMC-435, is provided in a total daily dosage from about 25 mg to about 250 mg, alternatively from about 25 mg to about 200 mg, alternatively from about 50 mg to about 200 mg, alternatively from about 75 mg to about 150 mg, for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg; and the at least one polymerase inhibitor (e. g. PSI-7977) is provided in a total daily dose from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including, but not limited to, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. For example, a combination can be a total daily dosage of about 75 mg TMC-435 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg PSI-7977, alternatively about 150 mg TMC—435 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg PSI-7977, alternatively about 75 mg TMC-435 and about 200 mg PSI-7977, alternatively about 150 mg TMC—435 and about 200 mg PSI-7977, atively about 100 mg TMC-435 and about 200 mg PSI-7977, alternatively about 75 mg TMC-435 and about 100 mg PSI-7977, alternatively about 100 mg 5 and about 100 mg PSI-7977, alternatively about 150 mg TMC-435 and about 100 mg PSI-7977, and can include other suitable combinations. ly, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, suitably in an amount from about 100 mg to about 400 mg per day, preferably about 100 mg per day. Suitable rin can be administered with the at least two DAAs, preferably in SUBSTITUTE SHEET (RULE 26) an amount based on weight of the subject, suitably about 1000 mg or about 1200 mg per day. For example, a suitable ribavirin daily treatment is weight based, for example, 1000 mg/day < 75 kg and 1200 mg/day 3 75 kg, divided twice daily (BID). In alternative embodiments, the at least one protease is BI- 201335 (NS3/4A protease tor) and the at least one HCV rase inhibitor is a non-nucleoside polymerase inhibitor, e. g. BI-207127. In some examples, the BI-201335 is ed in a total daily dose from about 100 mg to about 400 mg, atively from about 120 mg to about 240 mg, including about 100 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 275 mg, about 300 mg, about 320 mg, about 330 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, or about 400 mg; and 127 can be administered in a total daily dose from about 300 mg to about 3600 mg, preferably from about 1200 mg to about 2100 mg, including, but not limited to, for example, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 3000 mg, about 3200 mg, about 3400 mg, or about 3600 mg.

Suitable examples, include, but are not limited to, a combination of a total daily dose of about 120 mg BI- 201335 and about 1200 mg 127, alternatively about 120 mg BI-201335 and about 1500 mg BI- 207127, alternatively about 120 mg BI-201335 and about 1800 mg BI-207127, alternatively about 120 mg 335 and about 2100 mg BI-207127, alternatively about 240 mg BI-201335 and about 1200 mg BI-207127, alternatively about 240 mg BI-201335 and about 1500 mg BI-207127, alternatively about 240 mg BI-201335 and about 1800 mg BI-207127, alternatively about 240 mg BI-201335 and about 2100 mg BI-207127. ly, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, suitably in an amount of about 100 mg per day. ly, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, suitable in an amount from about 100 mg to about 400 mg per day, preferably about 100 mg per day. Suitable ribavirin can be administered with the at least two DAAs, ably in an amount based on weight of the subject, suitably from about 400 mg to about 1400 mg per day, for example, about 1000 mg or about 1200 mg per day. For example, a suitable ribavirin daily treatment is weight based, for example, from 400 mg to about 1400 mg, preferably about 1000 mg/day < 75 kg and 1200 mg/day 3 75 kg, divided twice daily (BID). In yet another example, the combination of two or more DAAs comprises telaprevir (VX-950, protease inhibitor) and VX-222 (non-nucleoside polymerase inhibitor). In some examples, the evir is provided in total daily doses from about 1000 mg to about 2500 mg, alternatively from about 2000 mg to about 2500 mg, including, but not limited to, SUBSTITUTE SHEET (RULE 26) for example, about 1000 mg, about 1200 mg, about 1300 mg, about 1500 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2400 mg, about 2500 mg. VX-222 can be administered with telaprevir in any ation with the dosage amounts of telaprevir provided above. VX-222 can be provided in a total daily dosage from about 100 mg to about 1000 mg, alternatively from about 200 mg to about 800 mg, including, but not limited to, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some examples, telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 100 mg, alternatively telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 200 mg, alternatively telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 400 mg, atively telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 600 mg, alternatively telaprevir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 800 mg, alternatively telaprevir can be a total daily dose of about 1500 mg and VX-222 can be a total daily dose of about 200 mg, alternatively telaprevir can be a total daily dose of about 1500 mg and VX-222 can be a total daily dose of about 400 mg, alternatively telaprevir can be a total daily dose of about 1500 mg and VX-222 can be a total daily dose of about 800 mg. Suitably, telaprevir can be administered three times a day (TID), for example 3 times a day with 750 mg per dose. Other suitable daily dosage of telaprevir is 1125 mg twice a day (BID). Suitably, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease tor, suitably in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. le ribavirin can be administered with the at least two DAAs, preferably in an amount based on weight of the subject, from about 400 mg to about 1400 mg, ly about 1000 mg or about 1200 mg per day. For example, a suitable ribavirin daily treatment is weight based, for example, 1000 mg/day < 75 kg and 1200 mg/day 2 75 kg, divided twice daily (BID).

In yet another example, the combination of two or more DAAs includes danoprevir (protease inhibitor) and R7128 (nucleoside polymerase inhibitor). In some embodiments, danoprevir can be administered in a total daily dosage from about 100 mg to about 2000 mg, alternatively from about 200 mg to about 1800 mg, alternatively from about 400 mg to about 1800 mg, including, but not d to, for e, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, and other amounts therebetween. R7128 can be administered in a total daily dose from about 100 mg to about 2000 mg, alternatively from about 200 mg to about 2000 mg, alternatively from about 1000 mg to about 2000 mg, ing, but not limited to, for example, about 150 mg, about 200 mg, about 400 mg, about 500 mg, SUBSTITUTE SHEET (RULE 26) about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In some examples, the total daily dose of the danoprevir is about 200 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily doses of the danoprevir is about 400 mg and the total daily dose of R7128 is about 200 mg, alternatively, the total daily dose of the danoprevir is about 1000 mg and the total daily dose of R7128 at about 200 mg, alternatively the total daily dose of the danoprevir is about 1800 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of the danoprevir is about 2000 mg and the total daily dose of R7128 is about 200 mg, alternatively the total daily dose of the danoprevir is about 400 mg and the total daily dose of R7128 is about 400 mg, alternatively, the total daily dose of the danoprevir is about 1000 mg and the total daily dose of R7128 is about 400 mg, altematively the total daily dose of the danoprevir is about 2000 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose of the danoprevir is about 1800 mg and the total daily dose of R7128 is about 400 mg, alternatively the total daily dose of the danoprevir is about 400 mg and the total daily dose of R7128 is about 1000 mg, alternatively, the total daily dose of the danoprevir is about 1000 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of the danoprevir is about 2000 mg and the total daily dose of R7128 is about 1000 mg, atively the total daily dose of the danoprevir is about 1800 mg and the total daily dose of R7128 is about 1000 mg, alternatively the total daily dose of the danoprevir is about 400 mg and the total daily dose of R7128 is about 2000 mg, alternatively, the total daily dose of the evir is about 1000 mg and the total daily dose of R7128 is about 2000 mg, atively the total daily dose of the danoprevir is about 2000 mg and the total daily dose of R7128 is about 2000 mg, alternatively the total daily dose of the danoprevir is about 1800 mg and the total daily dose of R7128 is about 2000 mg. ln suitable embodiments, danoprevir and R7128 can be administered with ritonavir, ly in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. Suitable ribavirin can be administered with the at least two DAAs, preferably in an amount based on weight of the subject, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, a suitable ribavirin daily treatment is weight based, for example, 1000 mg/day < 75 kg and 1200 mg/day Z 75 kg, divided twice daily (BID).

In some other instances of the present technology, the combinations of two or more DAAs may be at least one protease inhibitor and at least one NS5A tor. In some examples, the at least one protease inhibitor is an NS3 protease inhibitor. In some ments, the at least one protease tor and at least one NSSA inhibitor comprises BMS-650032 (EMS) and BMS-790052 (BMS) respectively. In suitable embodiments, BMS-650032 can be administered in a total daily dose from about 300 mg to about 1500 mg, alternatively from about 500 mg to about 1500 mg, including, but not limited SUBSTITUTE SHEET (RULE 26) to, for example, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg, and BMS-790052 (BMS) can have a total daily dose from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, including, but not d to, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In suitable examples, BMS-650032 (BMS) total daily dose is about 1200 mg and BMS-790052 (BMS) total daily dose is about 60 mg, alternatively BMS-650032 (BMS) total daily dose is about 300 mg and BMS-790052 (BMS) total daily dose is about 60 mg.

Suitable ribavirin can be administered with the at least two DAAs, preferably in an amount based on weight of the t, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For example, a le ribavirin daily treatment is weight based, for e, 1000 mg/day < 75 kg and 1200 mg/day 3 75 kg, divided twice daily (BID).

In some other instances of the present technology, the combinations of two or more DAAs may be at least one nucleoside or nucleotide polymerase inhibitor, at least one protease inhibitor, and at least one NS5A inhibitor. In some examples, the at least one se inhibitor is an NS3 se inhibitor. In some embodiments, the at least one nucleoside or nucleotide polymerase tor is INX- 189, the at least one protease inhibitor is 0032 (asunaprevir), and the at least one NSSA inhibitor comprises is BMS-790052 (daclatasvir). Such embodiments are especially contemplated for treating a patient infected with HCV genotype 1, such as genotype 1a or 1b (particularly genotype 1a), as well as patients infected with other HCV genotypes, such as genotypes 2 or 3. In suitable embodiments, INX- 189 can be administered in a total daily dose from about 5 mg to about 400 mg, alternatively from about mg to about 200 mg, including but not limited to, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, or about 300 mg. In suitable embodiments, BMS-650032 can be administered in a total daily dose from about 300 mg to about 1500 mg, alternatively from about 500 mg to about 1500 mg, including, but not limited to, for e, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, and about 1500 mg, and BMS-790052 (BMS) can have a total daily dose from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, including, but not limited to, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In suitable examples, BMS-650032 (BMS) total daily dose is SUBSTITUTE SHEET (RULE 26) about 1200 mg and BMS-790052 (BMS) total daily dose is about 60 mg, alternatively BMS-650032 (BMS) total daily dose is about 300 mg and BMS-790052 (BMS) total daily dose is about 60 mg.

Suitable ribavirin can be administered with the at least two DAAs, preferably in an amount based on weight of the subject, from about 400 mg to about 1400 mg, suitably about 1000 mg or about 1200 mg per day. For e, a suitable ribavirin daily treatment is weight based, for example, 1000 mg/day < 75 kg and 1200 mg/day 3 75 kg, divided twice daily (BID).

For still r instance, the combination of two or more DAAs can be a combination of at least one HCV protease inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor. In an example, the combination of two or more DAAs comprises GS-S885 (an NSSA inhibitor), GS-9190 (tegobuvir, a non-nucleoside rase tor), and GS-9451 (a protease inhibitor or a NS3 protease inhibitor). In some examples, GS-5885 is provided in a daily dose from about 3 mg to about 200 mg, alternatively from about 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, including, but not limited to, for example, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg, and GS-9190 is provided in a daily dose from about 10 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, including, but not limited to, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; and GS-9451 can be administered in a daily dose from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, including, but not limited to, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. Suitably examples include about daily s of about mg GS-5885, about 60 mg GS-9190 and about 200 mg GS-9451; atively about 60 mg GS-5885, about 60 mg GS-9190, and about 200 mg GS-9451; alternatively about 90 mg GS-5885, about 60 mg GS- 9190, and about 200 mg GS-9451. In some embodiments the GS-9190, GS-9451, and GS-5885 is administered with vir or a suitable equivalent, suitably in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. le ribavirin can be administered with the at least two DAAs, preferably in an amount based on weight of the subject, from 400 mg to about 1400 mg, ly about 1000 mg or about 1200 mg per day. For example, a suitable ribavirin daily treatment is weight based, for example, 1000 mg/day < 75 kg and 1200 mg/day 3 75 kg, d twice daily (BID). For still another instance, the combination of two or more DAAs can be a combination of at least one HCV se inhibitor, at least one HCV polymerase inhibitor, and at least one HCV NSSA inhibitor.

In another embodiment, the present technology provides interferon-free treatment comprising administering daily two DAAs with ribavirin, where the two DAAs include a HCV SUBSTITUTE SHEET (RULE 26) 2012/061075 polymerase inhibitor, for example PSI-7977 and a NSSA inhibitor, for example BMS-790052 for a duration of no more than eleven weeks, preferably no more than eight weeks. PSI-7977 and BMS- 790052 are administered in an ive amount to provide an SVR (for example, an SVR8, SVR12, SVRl6, or SVR24) with a treatment duration of no more than eleven weeks, no more than ten weeks, no more than nine weeks, no more than eight weeks, no more than seven weeks, no more than six weeks, no more than ﬁve weeks, no more than four weeks or no more than three weeks. The patients can be treatment naive patients or treatment enced patients. In some embodiments, the patients can have HCV genotype 1, such as 1a or 1b. In some embodiments, the patients can have genotype 2 or 3, such as 2a, 2b or 3a. PSI-7977 can be provided in a total daily dose of from about 100 mg to about 500 mg, alternatively from about 200 mg to about 400 mg, ing, but not limited to, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg. 0052 can be administered in combination with PSI-7977 at any daily dose of PSI-7977 provided above. BMS-790052 (BMS) can have a total daily dose of from about 10 mg to about 200 mg, alternatively from about 50 mg to about 100 mg, including, but not limited to, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In one suitable example, PSI-7977 is administered in a total daily dose of 400 mg and BMS-790052 is administered in a total daily dose of 60 mg.

The al structures of some of these HCV inhibitors as reported by numerous sources are provided below: midi/195W O a W o Telaprevir SUBSTITUTE SHEET (RULE 26) WO 59630 BI—201335 _.~. 1') "x, If““a“ TMC—435 (TMC-435350) Vaniprevir, MK-7009 SUBSTITUTE SHEET (RULE 26) WO 59630 _.- a“ N w, \J Mrs“ “a“, -\ $11. H \ x - \ xix-”x. _ "a l4 f \ 6" \{g’ \‘x L)\ ,l » ‘ 15,) \ _ \ ..

Q ..

K. - \ 0-» ‘ 1‘“ “_-‘““‘-"\5 '" V“ F! u .‘ I A“ N NJ. >6 N “I" 4‘“ ~_.‘ S“>6 ~ x! 6; :$ L C r; mm”? -—«.

MK-5172 SUBSTITUTE SHEET (RULE 26) ANM900 a bW.W.) ..\\\\\\\\\v, Sit. . ts.

GS633u6 /|\w 1w M maswHV01r.) VYAAAAS SUBSTITUTE SHEET (RULE 26) N, z 3 I}\ A ” V \f‘ g; ,N \ x.\ ‘V ’3' .4! p a; “H \“ 1“ n" E 3 \\ \ ‘ w-5\-\ xgiﬁx """ “H \ x 99' “f ‘N NH \x‘s \ I," E; 1 b (x F' .4" \\ ‘\ ’\ I .-'- u i \M r x \w‘ {"1 “\f- F I. \f». ‘ x ,- «H S é‘xx HQ {1-H IDX-184 ﬁlibuvir (PF-00868554) SUBSTITUTE SHEET (RULE 26) ,a', ”In” ilwiamtsviik mchiicdde ‘2,y/. s BIT-225 SUBSTITUTE SHEET (RULE 26) 2012/061075 GS—9256 SUBSTITUTE SHEET (RULE 26) 2012/061075 GS-5885 TMC-647055 SUBSTITUTE SHEET (RULE 26) BMS-791325 preferably is As used herein, BMS- ‘C: affix ‘ in. -~'. fax-x ~ [\ i‘\ 55>“wa $1 é; ““ “x HON ,x- {Max 791325 0 may also be “w" . See also publications at http://wwwl .easl.eu/ealeOl l/prograrru’Posters/Abstract680.htm; and http://clinicaltrials.gov/show/NCTOO664625. For GS-5885, see publications at http://www.natap.org/201 lﬂEASL/EASL_68.htm; http://wwwl .easl.eu/ealeOl 1/program/Posters/Abstractl 097.htm; and /clinicaltrials.gov/ct2/show/NCTO 1 353248.

Any HCV inhibitor or DAA described herein encompasses its suitable salt forms when it is used in therapeutic treatments or pharmaceutical formulations.

The following table lists non-limiting examples of the treatment ns of the present technology. In each treatment regimen, the at least two DAA with or without ritonavir, are administered daily to an HCV patient under such treatment. Each treatment is eron-free. Administration of rin is included in each regimen. Each treatment regimen may also optionally comprise administering one or more other onal DAAs to the patient. The duration of each ent regimen may last, for example and without limitation, no more than 12 weeks, no more than 11 weeks, no more than 10 weeks, no more than 9 weeks, no more than 8 weeks, alternatively no more than 7 weeks, alternatively no more than 6 weeks, alternatively no more than 5 weeks, alternatively no more than 4 weeks and may depend on the patient’s response. In any given regimen bed below, the drugs can be, for example and without limitation, co-formulated in a single solid dosage form when each has the same dosing frequency.

For instance, two or more drugs in a regimen can be co-formulated in amorphous forms or molecularly dispersed in a matrix comprising a water-soluble polymer and optionally a surfactant; for another instance, therapeutic agent 1 and ritonavir (RTV) are ated in an amorphous f01m or molecularly dispersed in a matrix comprising a water-soluble polymer and ally a surfactant, and eutic agent 3 is combined with amorphous Compound 1 and RTV in a single solid dosage form.

SUBSTITUTE SHEET (RULE 26) For yet another instance, Compound 1 and RTV are formulated in a different dosage form than that of therapeutic agent 3.

Table 1 miting Examples of Interferon-free Treatment Regimens with two or more DAAs (with ribavirin“ and with or t ritonavir) Drugs Used in Suitable total daily dosages Treatment Therapeutic Agent 1* + 150 to 250 mg (pref 150, 200, 250 mg) Therapeutic Agent 4 5 mg to 300 mg (pref. 25 mg) 2 Therapeutic Agent 1* + 150 to 250 mg (pref. 150, 200, 250 mg) Therapeutic Agent 4 + 5 mg to 300 mg (pref. 25 to 200 mg) Therapeutic Agent 2 300 to 1800 mg (pref. 400 mg or 800 mg) 3 Therapeutic Agent 1* + 150-250 mg (pref. 150 mg or 250 mg) Therapeutic Agent 3 + 50 mg-1000 mg (pref. 400 mg) Therapeutic Agent 4 5 mg-300 mg (pref. 25 mg-200 mg, more pref 25 mg) Therapeutic Agent 1* + 150-250 mg (150 mg, 200 mg or 250 mg) Therapeutic Agent 2 300-1800 mg (pref. 200 mg, 800 mg) Therapeutic Agent 1* + 50 mg to 250 mg (pref. 50 mg or 250 mg) Therapeutic Agent 3 50 mg to 1000 mg (pref 400 mg to 800 mg) 6 PSI-7977 + 100 mg to 500 mg (pref 200, 400 mg) 8 100 mg to 500 mg (pref. 300 mg) 7 BMS-790052 + 10 mg to 200 mg (pref. 60 mg) BMS-650032 300 mg to 1500 mg (pref. 1200 mg) GS- 3 mg to 200 mg (pref. 30 mg to 90 mg) GS- 30 mg to 90 mg (pref 60 mg) GS-9451 100 mg to 500 mg (pref. 200 mg) GS-S885+ 3 mg to 200 mg (pref. 30 to 90 mg) 1 100 mg to 500 mg (pref. 200 mg) Bl-201335 + 100 mg to 400 mg (pref. 120 mg or 240 mg) Bl-207127 300 mg to 3600 mg (pref 1200 mg to 2100 PSI-7977+ 100 mg to 500 mg (pref. 400 mg) SUBSTITUTE SHEET (RULE 26) Drugs Used in Suitable total daily dosages Reglmen Treatment TMC—435 25 mg to 200 mg (pref. 75 mg to 150 mg) te1aprevir + 1000 mg to 2500 mg (pref. 2250 mg) VX-222 200 mg to 800 mg evir* + 100 mg to 2000 mg (pref. 200 mg or 400 R7128 100 mg to 2000 mg (pref. 200 mg, 400 mg, 1000 mg or 2000 mg) Danoprevir + 100 mg to 2000 mg (pref 800 mg or 1000 mg, or 1800 mg or 2000 mg) R7128 100 mg to 2000 mg (pref. 200 mg, 400 mg, 1000 mg or 2000 mg) PSI-7977 -- 100 mg to 500 mg (pref. 400 mg) daclatasvir (BVIS- 10-200 mg (pref. 60 mg) 790052) 16 PSI-7977 - 100 mg to 2000 mg (pref. 1800 mg or 2000 revir (BMS- 300-1500 mg (pref 1200 mg) 650032) 17 77 + 100 mg to 500 mg (pref. 400 mg) daclatasvir (BMS- 10-200 mg (pref. 60 mg) 790052) asunaprevir (BMS- 300-1500 mg (pref. 1200 mg) 650032) * ritonavir or a suitable equivalent can be added to any one of these treatments as described and may be added to any of these ents at a daily total dosage as described in the present technology; preferably ritonavir is co-formulated with therapeutic agent 1 or danoprevir; the dose of ritonavir preferably is 100 mg. Pref. = preferred ** in each regimen, ribavirin preferably is used in a weight based amount from 400 mg to 1400 mg (pref. 1000 to 1200 mg) Additional miting examples of interferon-free ent regimens with two or more DAAs, with ribavirin and with or without ritonavir or a suitable equivalent, including the following: (a) Therapeutic Agent 1 at a total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, or 100 mg) with ritonavir or a suitable equivalent, and Therapeutic Agent 4 at a total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, or 100 mg); (b) Therapeutic Agent 1 at a total daily dose of 5 mg to 200 mg (pref. 5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or a suitable equivalent, Therapeutic Agent 4 at a total daily SUBSTITUTE SHEET (RULE 26) dose of 5 mg to 200 mg (pref 25 mg or 100 mg), and Therapeutic Agent 2 at a total daily dose of 200 mg to 800 mg (pref. 400 mg or 800 mg); (c) Therapeutic Agent 1 at a total daily dose of 5 mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, or 100 mg) with ritonavir or a suitable equivalent, Therapeutic Agent 3 at a total daily dose of 100 mg to 600 mg (pref. 400 mg), and Therapeutic Agent 4 at a total daily dose of 5 mg to 300 mg (pref. 25 mg to 200 mg, more pref. 25 mg); (d) eutic Agent 1 at a total daily dose of mg to 150 mg (pref. 5 mg, 25 mg, 50 mg, 100 mg) with ritonavir or a suitable equivalent, and Therapeutic Agent 2 at a total daily dose of 200-800 mg; (e) GS-5885 at a total daily dose of 3-200 mg (pref. 30-90 mg). GS-9190 at a total daily dose of 30-90 mg (pref. 60 mg), and GS-9451 at a total daily dose of 100-500 mg (pref. 200 mg); (1) GS-5885 at a total daily dose of3 mg to 200 mg (pref. 30 mg, 60 mg, or 90 mg), and 1 at a total daily dose of 100 mg to 500 mg (pref. 200 mg); (g) Bl-201335 at a total daily dose of 100 mg to 400 mg (pref. 120 mg, 240 mg), and Bl-207127 at a total daily dose of 300 mg to 3600 mg (pref. 1200 or 1500 mg, 1800 mg or 2100 mg); (h) PSI-7977 at a total daily dose of 100 mg to-500 mg (pref. 100, 200 mg), and TMC-435 at a total daily dose of 25 mg to 200 mg (pref. 75 mg, 100 mg, or 150 mg); (i) telaprevir at a total daily dose of 1000 mg to 2500 mg (pref. 1500 mg or 2250 mg), and VX-222 at a total daily dose of 100 mg to 800 mg (pref. 100 mg, 200 mg, 400 mg, 600 mg or 800 mg); (j) 9 at a total daily dose of 5 mg to 400 mg (pref. 50 mg, 100 mg or 200 mg), and daclatasvir (BMS-790052) at a total daily dose of 10 mg to 200 mg (pref. 60 mg); (k) INK-189 at a total daily dose of 5 mg to 400 mg (pref. 50 mg, 100 mg or 200 mg), and asunaprevir (BMS-650032) at a total daily dose of300 mg to 1500 mg (pref. 1200 mg); and (l) INK-189 at a total daily dose of5 mg to 400 mg (pref. 50 mg, 100 mg or 200 mg), asvir (BMS-790052) at a total daily dose of 10 mg to 200 mg (pref. 60 mg), and asunaprevir (BMS-650032) at a total daily dose of 300 mg to 1500 mg (pref. 1200 mg). In any of these examples, ritonavir or a suitable equivalent can be added to any one of these treatments as described and may be added to any of these treatments at a daily total dosage as bed in the present technology; ably ritonavir is co-formulated with therapeutic agent 1 or danoprevir; the dose of ritonavir preferably is 100 mg. In these examples, ribavirin preferably is used in a weight based amount from 400 mg to 1400 mg (pref. 1000 to 1200 mg).

The treatments of the present technology may be effective in treating HCV infection against HCV genotypes l, 2, 3, 4, 5, 6, including subgenotypes, such as 1a, lb, 2a, and 3a.

In general and depending on patients’ conditions, the total daily dose of the DAAs of the present technology may be administered (either as a single or divided dose) in amounts from about 0.001 mg/kg to about 200 mg/kg, or from about 0.001 mg/kg to about 30 mg/kg, or from about 0.001 mg/kg to about 30 mg/kg, or from about 0.01 mg/kg, to about 10 mg/kg (i.e. mg of the nd or salt per kg body weight), and include any amounts or ranges there between, including, but not limited to increments of 0.001 mg/kg, 0.005 mg/kg, 0.01 mg/kg, 0.05 mg/kg, and multiple factors thereof (e.g. 0.25x, 0.5x, 1x, SUBSTITUTE SHEET (RULE 26) 2x, 3x, 5x, 10x, 100x, etc.). Suitable dosages of the DAAs of the present technology include, but are not limited to, from about 25 mg to about 2000 mg, from about 25 mg to about 1500 mg, from about 25 mg to about 1600 mg, from about 25 mg to about 1000 mg, from about 25 mg to about 800 mg, from about 25 mg to about 500 mg, from about 25 mg to about 250 mg, ﬁ‘om about 50 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1600 mg, ﬁ‘om about 50 mg to about 1000 mg, ﬁ‘om about 50 mg to about 800 mg, from about 50 mg to about 500 mg, from about 50 mg to about 250 mg, and include, but are not limited to, for example, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 80 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 165 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 250 mg, and includes any increments there between, including increments of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 10 mg, about 15 mg, about 20 mg, about 25, and multiples thereof (e.g. 0.25x, 0.5x, 1x, 2x, 3x, 5x, 10x, 100x, etc.). It will be understood, however, that the speciﬁc dose level for any particular t will depend upon a y of s ing the activity of the speciﬁc compound employed, the age, body weight, general health, sex, diet, time of stration, route of administration, rate of excretion, drug combination, and the severity of the disease undergoing therapy.

The cytochrome P-450 inhibitor may be administered in any suitable amount such as, for example, in doses of from about 0.3 mg/kg to about 2 mg/kg or from about 0.6 mg/kg to about 1.5 mg/kg.

As non-limiting examples, the cytochrome P-450 inhibitor may be administered in a total daily dose amount of from about 25 mg to about 300 mg, or from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose of about 100 mg to about 400 mg, preferably about 100 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose amount of about 25 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose amount of about 50 mg. In some ments, the cytochrome P-450 inhibitor is administered in a total daily dose amount of about 75 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose amount of about 100 mg. In some embodiments, the cytochrome P-450 inhibitor is administered in a total daily dose amount of about 125 mg.

The one or more DAAs and ribavirin can be administered, for example and without limitation, rently or sequentially, and at the same or different frequencies. For instance, For example, one DAA can be administered immediately before or after the administration of r DAA.

A short delay or time gap may exist n the administration of one DAA and that of another DAA.

The ncy of administration may also be different. For example, a ﬁrst DAA may be administered SUBSTITUTE SHEET (RULE 26) once a day and a second DAA may be administered twice or three times a day. For e, a f1rstDAA with or without ritonavir may be stered once daily, and a second DAA may be administered twice daily.

The DAAs of the present technology can be co-formulated in a single dosage form. Non- limiting examples of suitable dosage forms include liquid or solid dosage forms. For example, a dosage form of Compound 1 as a solid dosage form is described in US. Patent Application Publication No. 2011/0312973, ﬁled March 8, 2011 and entitled ”Solid Compositions", the entire content of which is incorporated herein by reference. More preferably, the dosage form is a solid dosage form in which at least one of the DAAs is in an ous form, or highly preferably larly dispersed, in a matrix which comprises a pharmaceutically acceptable soluble polymer and a pharmaceutically acceptable surfactant. The other DAAs can also be in an amorphous form or molecularly dispersed in the matrix, or formulated in different form(s) (e. g., in a crystalline form).

The DAAs of the present technology can be formulated in different dosage forms. It will be understood that the total daily dosage of the compounds and compositions to be administered will be decided by the attending physician within the scope of sound medical judgment.

In one embodiment, a method for ng a naive subject comprises administering Therapeutic agent 1 at a dose of 150 mg once a day (QD), therapeutic agent 2 at a dose of 400 mg or 800 mg twice a day (BID), ritonavir at a dose of 100 mg once a day (QD), and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the t) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method for treating a naive subject comprises stering Therapeutic agent 1 at a dose of 50 mg QD, eutic agent 2 at a dose of 400 mg or 800 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method for treating a naive subject comprises stering Therapeutic agent 1 at a dose of 250 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In another embodiment, a method for treating a naive subject comprises administering Therapeutic agent 1 at a dose of 150 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an SUBSTITUTE SHEET (RULE 26) amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method for treating a peginterferon + ribavirin (P/RBV) non-responder ses administering Therapeutic agent 1 at a dose of 150 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for e, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method for treating a peginterferon + ribavirin (P/RBV) non-responder comprises administering Therapeutic agent 1 at a dose of 50 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no detectable virus.

In one embodiment, a method for treating a naïve subject ses administering Therapeutic agent 1 at a total daily dose of 150 mg QD, Therapeutic agent 3 at a total daily dose of 400 mg QD, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the subject has no able virus.

In another embodiment, a method for treating a naïve subject comprises administering eutic agent 1 at a total daily dose of 100 mg or 200 mg QD, Therapeutic agent 4 at a total daily dose of 25 mg QD, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks.

At the end of treatment, the subject has no able virus.

In yet another embodiment, a method for treating a naïve subject comprises administering Therapeutic agent 1 at a total daily dose of 100 mg or 150 mg QD, Therapeutic agent 2 at a total daily dose of 400 mg BID, Therapeutic agent 4 at a total daily dose of 25 mg QD, ritonavir at a dose of 100 mg QD, and an effective amount of ribavirin (for example, 1000 mg or 1200 mg, or an amount based on the weight of the subject) QD, for 12 weeks. At the end of treatment, the t has no able virus. [0172A] There is further provided use of PSI-7977 and/or GS-5885 in the manufacture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, n said treatment includes administration of ribavirin but does not include administration of interferon, and wherein said treatment lasts for 8, 9, 10 or 11 weeks, wherein the medicament comprises: (a) PSI-7977 and GS-5885 co-formulated in a single ition; or 5_1 (GHMatters) .NZ NGUYENN (b) PSI-7977, wherein the medicament is for administration in ation with GS- 5885; or (c) GS-5885, wherein the medicament is for administration in combination with PSI- 7977. [0172B] There is further provided the use as described herein, wherein the treatment lasts for 8 weeks. [0172C] There is further provided the use as described herein, wherein said patient is a HCV treatment-naive patient. [0172D] There is further provided the use as described , n said patient is infected with HCV genotype 1a. [0172E] There is further provided the use as described herein, n the two DAAs are administered once daily. [0172F] There is r provided the use as described herein, n the two DAAs are coformulated in a single composition and administered concurrently. [0172G] There is further provided the use as described herein, wherein said treatment comprises administering 90 mg QD of GS-5885 and 400 mg QD of PSI-7977 to a genotype 1 naive patient. [0172H] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype [0172I] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 75% of ts infected with HCV genotype ] There is further provided use of 77 and/or GS-5885 in the manufacture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, wherein said treatment includes administration of ribavirin but does not include stration of interferon, and wherein said treatment lasts for 12 weeks, n the medicament comprises: (a) PSI-7977 and 5 co-formulated in a single composition; or (b) PSI-7977, wherein the medicament is for administration in combination with GS- 5885; or (c) GS-5885, wherein the medicament is for administration in combination with PSI- 7977. 103A 6840625_1 (GHMatters) P99395.NZ NGUYENN [0172K] There is further provided the use as bed herein, wherein said patient is a HCV treatment-naive patient. [0172L] There is r provided the use as described herein, wherein said patient is infected with HCV genotype 1a. [0172M] There is further provided the use as described herein, wherein the two DAAs are administered once daily. [0172N] There is r provided the use as described , wherein the two DAAs are coformulated in a single composition and administered concurrently.

] There is further provided the use as described herein, wherein said treatment comprises administering 90 mg QD of GS-5885 and 400 mg QD of PSI-7977 to a genotype 1 naive patient.

] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype [0172Q] There is further provided the use as described herein, n the treatment of HCV achieves sustained virologic response (SVR) in at least 90% of patients infected with HCV genotype [0172R] There is further provided use of 77 and/or an HCV NS5A inhibitor in the manufacture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, wherein said treatment includes administration of ribavirin but does not include stration of interferon, and wherein said treatment lasts for 8, 9, 10, 11 or 12 weeks, wherein the medicament comprises: (a) PSI-7977 and an HCV NS5A co-formulated in a single composition; or (b) PSI-7977, wherein the medicament is for stration in combination with HCV NS5A tor; or (c) HCV NS5A inhibitor, wherein the medicament is for administration in combination with PSI-7977. [0172S] There is further provided the use as described herein, wherein the treatment lasts for 8 weeks. [0172T] There is further provided the use as described herein, wherein the treatment lasts for 12 weeks. [0172U] There is further provided the use as described herein, wherein said patient is an HCV treatment-naive patient. 103B 6840625_1 ters) P99395.NZ NGUYENN [0172V] There is further provided the use as described herein, wherein said patient is infected with HCV genotype 1a.

] There is further provided the use as described herein, n the two DAAs are administered once daily.

] There is further provided the use as described herein, wherein the two DAAs are coformulated in a single composition and administered concurrently. [0172Y] There is further provided the use as described herein, wherein said treatment ses administering 400 mg QD of PSI-7977 to a genotype 1 naive patient. [0172Z] There is further ed the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype [0172AA] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 75% of patients infected with HCV genotype [0172BB] There is further ed the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 90% of ts infected with HCV genotype 1, wherein said treatment lasts for 12 weeks. [0172CC] There is further provided use of PSI-7977 and/or an HCV NS5A tor in the manufacture of a medicament for the ent of HCV in a patient infected with HCV genotype 1, n said treatment lasts for 6 or 7 weeks and does not include stration of interferon to said patient, wherein the medicament comprises: (a) PSI-7977 and an HCV NS5A inhibitor mulated in a single composition; or (b) PSI-7977, wherein the medicament is for administration in combination with HCV NS5A inhibitor; or (c) HCV NS5A inhibitor, wherein the ment is for administration in combination with PSI-7977; and wherein the medicament further comprises another DAA or is administered in combination with another DAA. 103C 6840625_1 (GHMatters) P99395.NZ NGUYENN [0172DD] There is further provided the use as described herein, wherein said another DAA is Compound 1 ( ), and said HCV NS5A inhibitor is Compound 4 ( ). [0172EE] There is r provided the use as described herein, wherein said PSI-7977 is administered at a dose of 400 mg once daily.

F] There is further provided the use as described herein, n said another DAA is an HCV protease inhibitor.

G] There is further provided the use as described herein, wherein said another DAA is an HCV polymerase inhibitor. [0172HH] There is further provided the use as described herein, wherein said patient is a treatment naive t. [0172II] There is further provided the use as described herein, wherein said patient is an interferon non-responder. [0172JJ] There is further provided the use as bed herein, n the treatment of HCV achieves ned virologic response (SVR) in at least 70% of patients infected with HCV genotype [0172KK] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 75% of patients infected with HCV genotype 103D 6840625_1 (GHMatters) P99395.NZ NGUYENN It should be understood that the described embodiments and the following examples are given by way of illustration, not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the present description.

Example 1 Use of 2-DAA Combination with Ribavirin (RBV) to Treat Treatment-Naïve Subjects Infected with HCV Genotype 1 103E 6840625_1 ters) P99395.NZ NGUYENN Previously untreated subjects having HCV infection were treated with a protease tor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The ent was t eron.

Subjects included 11 treatment naive, non-cirrhotic HCV genotype 1-infected subjects between the ages of 18 and 65. All subjected had IL28B CC genotype. All subjects completed 12 weeks of therapy with Compound 1 and ritonavir (Compound 1/r) dosed in combination with Compound 3 and ribavirin (RBV). Compound 1 (150 mg once daily (QD)) was dosed with 100 mg QD ritonavir, 400 mg QD Compound 3, and weight-based amounts of RBV (LOGO-1,200 mg/day dosed twice daily) in treatment naive subjects infected with genotype (GT) 1 HCV.

HCV RNA levels were measured by TaqMan assay. Five of the eleven subjects had hepatitis C cleic acid (HCV RNA) <25 IU/mL (119., below the limit of fication) at 2 weeks.

Another five subjects had undetectable levels of HCV RNA at 2 weeks. At week 3, three of the eleven subjects had HCV RNA levels of less than 25 IU/mL, and eight subjects had undetectable levels of HCV RNA. Ten of the eleven subjects had undetectable levels of HCV RNA at 4 weeks, and one subject had an HCV RNA level of less than 25 IU/mL. All eleven subjects had undetectable levels of HCV RNA at 5 weeks. HCV RNA levels remained undetectable in all subjects at week 6, 7, 8, 9, 10, 11 and 12. All subjects had undetectable levels of HCV RNA at post-treatment weeks 2 and 4. At post-treatment weeks 8 and 12, a single t had detectable HCV RNA (breakthrough), and the remaining 10 subjects did not have any detectable level of HCV RNA. These remaining ten subjects were further tested at post- ent weeks 16 and 24, and all of them had ctable levels of HCV RNA at both timepoints. One of the remaining ten subjects unexpectedly showed detectable HCV RNA at post-treatment week 36. e 2A Use of 2-DAA Combination with Ribavirin to Treat Treatment-Naive or Non-Responder Subjects Infected with HCV Genotype 1 Group 1. Previously untreated subjects having HCV infection were treated with a se inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon.

Subjects included 19 treatment naive subjects between the ages of 18 and 65. One subject tinued the study at week 3. All of the remaining 18 subjects completed 12 weeks of therapy with Compound 1/r dosed in combination with Compound 2 and RBV. Compound 1 (250 mg QD) was dosed with 100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in treatment naive ts infected with GT1 HCV.

SUBSTITUTE SHEET (RULE 26) Group 2. Previously untreated subjects having HCV infection were treated with a protease inhibitor (in combination with ritonavir), a polymerase inhibitor, and ribavirin. The treatment was without interferon.

Subjects included 14 treatment naive subjects between the ages of 18 and 65. One subject discontinued the study at week 1. Therefore, a total of 13 subjects were under study. All of the thirteen subjects completed 12 weeks of therapy with Compound 1/r dosed in combination with Compound 2 and RBV. nd 1 (150 mg QD) was dosed with 100 mg QD vir, 400 mg BID Compound 2, and RBV in treatment naive ts infected with GT1 HCV.

Group 3. erferon + ribavirin (P/RBV) non-responders were treated with a se inhibitor (in combination with ritonavir), a polymerase inhibitor, and rin. The treatment was without eron.

Subjects included 17 P/RBV non-responders between the ages of 18 and 65. Subjects were treated with Compound 1/r dosed in ation with Compound 2 and RBV for 12 weeks.

Compound 1 (150 mg QD) was dosed with 100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in P/RBV non-responders infected with GT1 HCV. During the treatment, four patients had breakthroughs and discontinued the study before week 7.

The baseline characteristics ofthe patients are shown in the table below.

Table 2 Genotype (la/1b) 17/2 11/3 16/1 Undetermined Median baseline HCV RNA 6.4 [4.1-7.2] 6.9 [3.1-7.5] 6.9 [6.0-7.8] (log IU/mL) Results from Group 1. Ten of the nineteen subjects had HCV RNA <25 IU/mL at 2 weeks. Another eight had undetectable levels of HCV RNA at 2 weeks. At week 3, one subject discontinued, four of the remaining 18 subjects had HCV RNA levels of less than 25 IU/mL, and fourteen SUBSTITUTE SHEET (RULE 26) 2012/061075 of the remaining 18 subjects had undetectable levels of HCV RNA. At week 4, een of the remaining 18 subjects had undetectable levels of HCV RNA; one subject had HCV RNA <25 lU/mL. At week 5, all of the remaining 18 subjects had undetectable levels of HCV RNA. At week 6, seventeen of the remaining 18 subjects had undetectable levels of HCV RNA, and one subject had HCV RNA <25 lU/mL. At weeks 7, 8, 9, 10, 11 and 12, all of the remaining 18 subjects had ctable levels of HCV RNA (one subject was not tested at week 12). At post-treatment weeks 2, 4, 8, and 12 all of the remaining 18 subjects (including the one who was not tested at week 12 during treatment) had undetectable levels of HCV RNA. At post-treatment week 24, seventeen of the ing 18 subjects were tested, and all of the seventeen subjects tested had undetectable levels of HCV RNA. At post- treatment week 24, all of the ing 18 ts were tested and found no detectable levels of HCV RNA.

A larger clinical study using the same drug combination showed about 85-90% SVR4 and SVR12 rates after 12-week treatment regimen in treatment-naive patients. Among these patients, the SVR4 and SVR12 rates irologic failures removed) in genotype 1a patients were about 86 and 82%, respectively. All of these SVR4 and SVR12 rates were based on observed data.

Results from Group 2. Of the thirteen subjects tested, six had HCV RNA <25 lU/mL at 2 weeks. Another six subjects had undetectable levels of HCV RNA at 2 weeks. At week 3, two ts had HCV RNA levels of less than 25 lU/mL, and ten subjects had undetectable levels of HCV RNA.

Eleven of the thilteen subjects had undetectable levels of HCV RNA at 4 weeks and two had HCV RNA <25 lU/mL. At weeks 5, 6, 7, 8, 9 and 10, all thirteen subjects that were tested had undetectable levels of HCV RNA. One subject had detectable levels of HCV RNA at week 11 (the remaining 12 subjects had undetectable levels of HCV RNA at week 11), but HCV RNA levels in that subject, as well as all other subjects, were ctable at week 12. At post-treatment weeks 2, 4, 8 and 12, all thirteen subjects tested (including the one who had detectable levels of HCV RNA at week 11 during treatment) had undetectable levels of HCV RNA. At post-treatment weeks 24, twelve of the thirteen subjects were tested and found no detectable levels of HCV RNA. s from Group 3. Seven of the seventeen subjects tested had HCV RNA <25 lU/mL at 2 weeks. Another seven subjects had undetectable levels of HCV RNA at 2 weeks. Three subjects had detectable levels of HCV RNA at 2 weeks. At week 3, three subjects had HCV RNA levels of less than 25 lU/mL, twelve subjects had undetectable levels of HCV RNA, and two subjects had detectable levels of HCV RNA. At week 4, two subjects had HCV RNA levels of less than 25 lU/mL, thirteen subjects had undetectable levels of HCV RNA, and two subjects had detectable levels of HCV RNA.

Sixteen subjects were tested at 5 weeks; thirteen subjects had undetectable levels of HCV RNA and three ts had detectable levels of HCV RNA. Fifteen subjects were tested at 6 weeks; twelve subjects had SUBSTITUTE SHEET (RULE 26) undetectable levels of HCV RNA and three subjects had detectable levels of HCV RNA. All thirteen subjects that were tested at 7 weeks had ctable levels of HCV RNA. Twelve of the thirteen subjects that were tested at 8 weeks had undetectable levels of HCV RNA; one subject had HCV RNA levels of less than 25 IU/mL. All ten subjects that were tested at 9 weeks had undetectable levels ofHCV RNA. Twelve of the thirteen subjects that were tested at 9 weeks had undetectable levels of HCV RNA; one subject had detectable levels of HCV RNA. Twelve of the thirteen subjects that were tested at 10 weeks had undetectable levels of HCV RNA; one t had detectable levels of HCV RNA. Eleven of the twelve ts that were tested at 11 weeks had undetectable levels of HCV RNA; one t had HCV RNA levels of less than 25 lU/mL. Ten of the twelve subjects that were tested at week-12 of the treatment had undetectable levels of HCV RNA; one subject had HCV RNA levels of less than 25 IU/mL, and another subject had detectable levels of HCV RNA. The one subject that had HCV RNA levels of less than 25 IU/mL at week-12 of the treatment had breakthrough at post-treatment week 2. At post- treatment weeks 2 and 4, ten ts that had undetectable HCV RNA at week-12 of the treatment were tested: eight of the ten subjects had undetectable levels of HCV RNA; and the ing two subjects had detectable HCV RNA (breakthrough). The eight subjects that had undetectable HCV RNA at post- treatment weeks 2 and 4 were further test at post-treatment weeks 8 and 12 and found no detectable HCV RNA.

The seventeen sponder subjects in Group 3 included 6 null responders and 11 partial responders. Three out of the six null responders, and ﬁve out of the eleven partial responders, achieved SVR12.

The study also showed that IL28B host genotype appeared not to have signiﬁcantly impact on SVR12 in this study (including Groups 1, 2 and 3).

Example 2B Use of 2-DAA Combination with Ribavirin to Treat Treatment-Naive ts Infected with pe l, 2 or 3 Genotype I Ten previously untreated subjects infected with HCV genotype 1 were treated with a 2- DAA ation with ribavirin. The treatment was interferon-free and was designed to last l2 weeks.

The 2-DAA combination included Compound l/r (200/100 mg QD) and Compound 4 (25 mg QD). The weight based dosing of ribavirin ranged from l000 to 1200 mg divided twice daily. At weeks 5, 6 and 7 of the treatment, nine of the ten subjects showed no detectable HCV RNA; and the remaining one subject had HCV RNA levels of less than 25 IU/mL. At week 8 of the treatment, ﬁve of the nine subjects were tested and showed no able HCV RNA. At weeks 9 and 10 of the treatment, four of the ﬁve subjects SUBSTITUTE SHEET (RULE 26) were further tested and found no detectable HCV RNA. At week 11, two of the four subjects were tested and found no detectable HCV RNA. onal testing showed that all of the initial ten subjects at weeks 8, 9, 10 and 11 of the treatment had no able HCV RNA. At week 12, nine of the initial ten ts showed undetectable HCV RNA, and one had HCV RNA levels of less than 25 lU/mL. At post-treatment week 2, all of the ten ts were tested (including the one with HCV RNA levels of less than 25 lU/mL at week 12 of the treatment), and all ten subjects showed no detectable HCV RNA. At post-treatment weeks 4, 8 and 12, all of the ten subjects were tested and found no detectable HCV RNA. Eight of the ten subjects were further tested at post-treatment week 24 and found no able HCV RNA.

A larger clinical study using the same drug combination showed about 90% SVR4 rate and about 83% SVR12 rate after 12-week treatment regimen in treatment-naive patients. Among these patients, the SVR4 and SVR12 rates irologic failures removed) in genotype 1a patients were about 92 and 85%, respectively. All of these SVR4 and SVR12 rates were based on observed data.

Genotype 2 Ten previously untreated subjects infected with HCV pe 2 were treated with the same regimen of this Example. At week 4 of the treatment, all of the ten subjects were tested and showed no detectable HCV RNA. At weeks 5 and 6 of the ent, all of the ten subjects were tested and found no detectable HCV RNA. At weeks 9-11 of the treatment, all of the ten subjects were further tested, and nine of them showed no detectable HCV RNA, and one subject showed HCV RNA levels of less than 25 lU/mL. At week 12 of the treatment, nine of the initial ten subjects were tested, eight of the nine subjects found no detectable HCV RNA and one showed detectable HCV RNA.

The subject showing able HCV RNA at week 12 of the treatment was confirmed breakthrough at post-treatment week 2. Eight of the initial ten subjects were also tested at post-treatment week 2 and found no detectable HCV RNA; eight of the initial ten subjects were further tested at post- treatment weeks 4, 8 and 12 and found no detectable HCV RNA; and three of the initial ten subject were further tested at post-treatment week 24 and found no detectable HCV RNA.

Genotype 3 Similarly, ten previously untreated subjects infected with HCV pe 3 were treated with the same regimen of this Example. At week 5 of the treatment, two subjects had viral rebound; seven of the remaining eight ts had no detectable HCV RNA; and one of the remaining eight subjects had HCV RNA levels of less than 25 IU/mL. At week 12 of the treatment, and among the eight SUBSTITUTE SHEET (RULE 26) non-breakthrough subjects, one subject was lost from the study, another showed detectable HCV RNA, and the remaining six found no detectable HCV RNA.

At post-treatment weeks 2, 4 and 8, two more subjects appeared to have breakthrough, and six subjects had no detectable HCV RNA. At post-treatment weeks 12 and 24, ﬁve subjects found no detectable HCV RNA.

One of the two subjects that had viral rebound at week 5 of the treatment was treated with a combination of peginterferon and ribavirin (P/RBV) starting at week 12. After four weeks of the P/RBV treatment, the subject was tested and found no detectable HCV RNA.

Example 2C Use of 2-DAA Combination with Ribavirin to Treat Treatment-Experienced Subjects ed with Genotype 1 Six treatment-experienced subjects with HCV genotype 1 infection were treated with a 2- DAA combination with ribavirin for 12 weeks. The treatment was interferon-free. The 2-DAA combination included nd l/r (200/100 mg QD) and Compound 4 (25 mg QD). The weight based dosing of ribavirin ranged from 1000 to 1200 mg d twice daily. These patients had previously undergone a standard interferon/ribavirin therapy but were not responsive (interferon null responders).

At week 6 of the treatment, all six subjects showed no detectable HCV RNA. At week 8 of the treatment, all six ts were tested and, among them, five showed no detectable HCV RNA and one had HCV RNA levels of less than 25 IU/mL. At weeks 10 and 12 of the treatment, all six ts were tested and found no detectable HCV RNA.

At post-treatment weeks 2 and 4, all six subjects were tested, one had breakthrough and the ing five subjects found no detectable HCV RNA. At post-treatment week 8 and 12, the five non-breakthrough subjects were further tested and found no detectable HCV RNA.

A larger clinical study using the same drug ation showed about 85%-90% SVR4 and SVRl2 rates after l2-week treatment regimen in interferon null ders. Among these patients, the SVR4 and SVRl2 rates (non-virologic failures removed) in genotype la ts were about 80%.

All of these SVR4 and SVRl2 rates were based on observed data.

Example 2D Use of 3-DAA Combination with Ribavirin to Treat Treatment-Naive or Treatment- Experienced Subjects Infected with pe l Treatment-Naive Patients Six previously untreated subjects having HCV genotype 1 infection were d with a 3-DAA combination with ribavirin for 8 weeks. The treatment was interferon-free. The 3-DAA SUBSTITUTE SHEET (RULE 26) combination included Compound l/r (150/100 mg QD), Compound 2 (400 mg BID), and Compound 4 (25 mg QD). The weight based dosing of ribavirin ranged from 1000 to 1200 mg divided twice daily. At week 8 of the treatment, all six subjects had no detectable HCV RNA. At post-treatment weeks 2, 4, 8, 12 and 24, all six subjects had no detectable HCV RNA.

Nine previously untreated subjects having HCV genotype 1 infection were treated with a 3-DAA combination with rin for 12 weeks. The ent was interferon-free. The 3-DAA combination included Compound 1/r (150/ 100 mg QD or 100/100 mg QD), Compound 2 (400 mg BID), and nd 4 (25 mg QD). The weight based dosing of rin ranged from 1000 to 1200 mg divided twice daily. At week 8 of the treatment, all nine subjects had no detectable HCV RNA. At week 12 of the treatment, all nine subjects were tested and found no able HCV RNA. At reatment weeks 2, 4, 8, 12 and 24, all of the nine subjects were further tested and showed no detectable HCV RNA.

A larger clinical study using the same drug combination showed about 95% SVR4 and SVR12 rates after 12-week treatment regimen in treatment-naive patients, and about 85-90% SVR4 and SVR12 rates after 8-week treatment regimen in treatment-naive patients. Among these patients, the SVR4 and SVR12 rates (non-virologic failures removed) in pe 1a patients were about 98% after 12-week treatment regimen, and about 85-90% after 8-week treatment n. All of these SVR4 and SVR12 rates were based on observed data.

Treatment-Experienced Patients Ten ent-experienced subjects with HCV genotype 1 infection were treated with a 3-DAA combination with ribavirin: four subjects were treated for 12-week, one subject was treated for 16-week treatment, and the remaining five subjects were treated for 24-week treatment. The treatment was interferon-free. The 3-DAA ation included Compound l/r (150/ 100 mg QD or 100/100 mg QD), Compound 2 (400 mg BID), and Compound 4 (25 mg QD). The weight based dosing of ribavirin ranged from 1000 to 1200 mg divided twice daily. These patients had previously undergone a standard interferon/ribavirin therapy but were not responsive (interferon null ders).

At weeks 6, 8, 10 and 12 of the treatment, all ten subjects showed no detectable HCV RNA.

At post-treatment weeks 2, 4, 8 and 12, all of the four subjects in the 12-week treatment regimen found no detectable HCV RNA; and two of the four subjects were further tested at post-treatment week 24 and found no detectable HCV RNA. At post-treatment weeks 2, 4, 8 and 12, the one subject in the 16-week treatment regimen found no detectable HCV RNA. All five subjects in the 24-week treatment regimen were tested at post-treatment weeks 2 and 4 and found no detectable HCV RNA; and four of the ﬁve subjects were further tested at post-treatment week 8 and found no detectable HCV RNA; SUBSTITUTE SHEET (RULE 26) and one of the five subjects was further tested at post-treatment week 12 and found no able HCV RNA.

A larger clinical study using the same drug combination showed about 90-95% SVR4 and SVR12 rates after 12-week treatment regimen in interferon null responders. Among these patients, the SVR4 and SVR12 rates (non-virologic failures removed) in genotype 1a patients were about .

All of these SVR4 and SVR12 rates were based on observed data.

Example 3 Synergistic concentrations of Compound 1 and Compound 2 in genotype lb HCV replicon assay.

Examples 3-5 are for illustration and do not limit the scope of this disclosure in any way.

Not to be bound by any theory, the unexpected synergistic effects from combining different classes of HCV inhibitors (e.g., a combination of a protease inhibitor (such as Compound 1) and a polymerase inhibitor (such as Compound 2), or a combination of a protease inhibitor (such as Compound 1) and a NSSA inhibitor (such as compound 4)) may contribute to the effectiveness of the short-duration, interferon-free therapies of the present logy.

Materials: A replicon cell line was derived from the human hepatoma cell line Huh7. It was derived from HCV genotype lb (Conl), and is a bicistronic subgenomic replicon, essentially similar to those described in e 24):110-3 (1999). The ﬁrst cistron of the construct contains a ﬁreﬂy luciferase reporter and a neomycin phosphotransferase selectable marker. Replicon cells were maintained in co’s ed Eagle Media (DMEM) containing 100 IU/ml penicillin, 100 mg/ml streptomycin (lnvitrogen), 200 mg/ml G418, an aminoglycoside antibiotic (lnvitrogen) and 10% fetal bovine serum (FBS) at 37° C and 5% C02.

Replicon Cell Culture: Replicon cells were seeded at a density of 5000 cells per well of a 96-well plate in 100 pl DMEM containing 5% PBS. The following day, Compounds 1 and 2 were diluted in dimethyl ide (DMSO) to te a 200K stock in a series of 6 two-fold dilutions. The dilution series was then further diluted ld in the medium containing 5% PBS. ation Studies: Combination studies were performed to evaluate the interaction s of therapeutic agent 1 and therapeutic agent 2 in the replicon assay described above. The purpose of these studies was to determine whether there are doses or concentrations of each compound where y or antagonism is demonstrated with the other compound. Three experiments with three plates in each experiment were performed on three separate days. Six concentrations of Compound 1 alone and six concentrations of Compound 2 alone were assayed in each plate. In addition, 36 combinations of concentrations of the two compounds were assayed for each plate. The variable ed was the fraction of inhibition of the rase signal.

SUBSTITUTE SHEET (RULE 26) The dilutions of each compound were combined with the ons of the other compound in a checkerboard fashion. The trations tested were chosen to ensure that the EC50 for each compound alone is in the middle of the serial dilution range. Medium with inhibitor(s) was added to the cell culture plates already containing 100 pl of DMEM with 5% FBS. The cells were incubated in a tissue culture incubator at 37° C and 5% C02 for three days. The inhibitor effects of compounds on HCV replication were determined by measuring activity of a luciferase reporter gene using a Luciferase Assay System kit (Promega) ing the manufacturer’s instructions. Passive Lysis buffer (30 ul, Promega) was added to each well, and the plates were incubated for 15 minutes with rocking to lyse the cells.

Luciferin solution (100 pl, Promega) was added to each well and the rase activity was measured using a Victor H luminometer (Perkin-Elmer). To determine the EC50, the luciferase inhibition data were analyzed using GraphPad Prism 4 software. Three experiments were performed with three replicates per experiment. The percent inhibition results were analyzed for synergy, additivity and antagonism ing to the Pritchard and Shipman model (Antiviral Research 14: 181-206 (1990)).

Combination is: Prichard and Shipman proposed a direct approach to solve this drug-drug interaction problem. The method was able to calculate theoretical additive effects directly from the individual dose-response culves determined in the assay. The ated theoretical additivity was then compared to the experimental dose-response surface, and subsequently subtracted to reveal any areas of aberrant interaction. The following equation was used to calculate the theoretical additive effects: Z=X+Y(1—X)=X+Y—XY, where Z is the total inhibition produced by the combination of drugs X and Y, with X and Y representing the inhibition produced by drugs X and Y alone respectively.

A difference between the actual observed fraction of tion and the predicted value was calculated for each concentration combination for each plate in each experiment to determine whether the observed ed effect was greater than the tical ve effect Z calculated from the equation above. For each concentration combination, the replicates s all plates and experiments) were used to calculate a mean difference between ed and predicted fraction of inhibition, its standard error and its two-sided 95% conﬁdence interval.

Synergy or nism for a concentration combination was determined based on the following 2 rules: First, the 95% CI of the mean difference between observed and predicted fraction of inhibition at each concentration combination is calculated. If the lower bound of 95% CI is larger than zero, then the drug combination would be ered having a istic ; if the upper bound of 95% CI is less than zero, then the drug combination would be considered having an antagonistic effect; otherwise, no signiﬁcant antagonism or synergy at this concentration combination.

SUBSTITUTE SHEET (RULE 26) Second, the synergistic or antagonistic effect must have its relative mean difference, the absolute mean difference divided by its corresponding observed mean inhibition, greater than 1%. By doing this, small ences of statistical signiﬁcance caused by very small valiance could be excluded.

Combination of Therapeutic Agent 1 and Therapeutic Agent 2: The inhibitory s on replicons produced by each drug alone or in combination with the other at concentrations up to ten-fold above the EC50 were examined in the genotype lb (Conl) replicon using a checkerboard titration pattern (two-fold serial dilutions) in a standard three-day antiviral assay. The concentrations tested were chosen to ensure that the EC50 values of the compounds were in the middle of the serial dilution range. For Compound 1, concentrations ranged from 0.031 nM to 1.0 nM. For Compound 2, concentrations ranged from 0.125 nM to 4.0 nM. Synergy, vity, and antagonism were evaluated using the Pritchard and Shipman model.

Results: The s of the assay analysis are illustrated in Figures 1 and 2 and Table 3.

In the 3-D surface plot of Figure 1, deviations from expected interactions n Compound 1 and Compound 2 are purely additive at concentrations associated with a horizontal plane at 0%. Synergistic interactions between nd 1 and Compound 2 appear as a peak above the horizontal plane with a height ponding to the percent above ated additivity. Antagonistic ctions between Compound 1 and Compound 2 appear as a pit or trough below the horizontal plane with a negative value signifying the percent below the calculated additivity. Synergistic interactions appear as dark grey, additive ctions appear white, and antagonistic interactions appear as speckled.

As illustrated in the 3-D surface plot of Figure l and the contour plot of Figure 2, an additive or synergistic effect exists at most of the concentrations for nd 1 and Compound 2. In particular, there is a concentration region showing synergy at most concentrations of Compound 1 and at the lower to mid-range dose concentrations of Compound 2.

Table 3 below lists combinations of concentrations of Compound 1 and Compound 2 with statistically significant synergistic or antagonistic effects based on the Prichard and Shipman model analysis. For each combination of concentrations, Table 3 includes the mean difference in the observed and predicted fraction of inhibition, the standard deviation or error of the mean difference, and the upper and lower limits of the 95% confidence interval.

According to Table 3, all of the combinations of nd 1 and Compound 2 listed in the table have tically significant synergistic effects.

The results presented in Figures 1 and 2 and Table 3 trate that the ation of therapeutic agent 1 and eutic agent 2 achieves additivity or synergy at most of the concentration combinations of the two agents. Taken together, these in vitro replicon results suggest that therapeutic SUBSTITUTE SHEET (RULE 26) agent 2 should produce a signiﬁcant antiviral effect in patients when administered in combination with eutic agent 1 in patients infected with HCV.

Table 3 Mean difference in fraction of inhibition: Standard error Lower 95% Compound Compound Observed - of mean conﬁdence Upper 95% 2, nM 1, nM Predicted difference limit conﬁdence limit .125 .12500 0.06176 0.023352 0.007912 0.11561 .125 .25000 0.05321 0.022199 0.002024 0.10440 .125 .50000 0.01176 0.002680 0.005583 0.01794 .250 .250000 0.06626 0.020630 0.018692 0.11384 .250 .50000 0.01061 0.002677 0.004438 0.01679 .500 .06250 0.04373 0.014897 0.009375 0.07808 .500 .12500 0.10416 0.026757 0.042454 0.16586 .500 .25000 0.09327 0.019859 0.047471 0.13906 .500 .50000 0.01422 0.003333 0.006535 1 1.00 .06250 6 0.020488 15 0.11421 1.00 .12500 0.14103 0.021289 0.091939 0.19013 1.00 .25000 0.11027 0.016762 0.071617 0.14892 1.00 .50000 0.01365 0.002312 0.008315 0.01898 2.00 .06250 0.05974 0.007690 0.042004 0.07747 2.00 .12500 0.10032 0.011820 0.073066 8 2.00 .25000 0.07117 0.009428 0.049428 1 4.00 .03125 5 0.003950 0.023236 0.04145 4.00 .06250 0.05141 13 0.041470 6 4.00 .12500 0.06572 0.004692 0.054901 0.07654 4.00 .25000 0.03452 0.004775 0.023509 0.04553 Example4 Synergistic concentrations of Compound 1 and nd 4 in genotype 1b HCV replicon assay.

SUBSTITUTE SHEET (RULE 26) Materials: The replicon cell line was derived from the human hepatoma cell line Huh7.

It was derived from HCV genotype lb (Conl), and is a bicistronic subgenomic replicon, essentially similar to those described in Science 285(5424):110-3 (1999). The ﬁrst cistron of the construct contains a ﬁreﬂy luciferase reporter and a neomycin phosphotransferase selectable marker. Replicon cells were maintained in Dulbecco’s Modified Eagle Media (DMEM) ning 100 lU/ml penicillin, 100 mg/ml streptomycin (lnvitrogen), 200 mg/ml G418 (lnvitrogen) and 10% fetal bovine serum (PBS) at 37° C and % C02.

Replicon Cell e: Replicon cells were seeded at a density of 5000 cells per well of a 96-well plate in 100 pl DMEM containing 5% PBS. The following day, compounds were diluted in dimethyl sulfoxide (DMSO) to te a 200K stock in a series of 6 two-fold dilutions. The dilution series was then r diluted 100-fold in the medium containing 5% PBS. ation Studies: Combination studies were performed to evaluate the interaction effects of therapeutic agent 1 and therapeutic agent 4 in the replicon assay described above. The purpose of these studies was to determine doses or concentrations of each compound where synergy or antagonism is demonstrated with the other compound. Three experiments with three plates in each experiment were performed on three te days. Six concentrations of Compound 1 alone and six concentrations of Compound 2 alone were assayed in each plate. In addition, 36 combinations of concentrations of the two compounds were assayed for each plate. The le analyzed was the fraction of inhibition of the rase signal.

The dilutions of each compound were combined with the dilutions of the other compound in a rboard fashion. The concentrations tested were chosen to ensure that the EC50 for each compound alone is in the middle of the serial dilution range. Medium with inhibitor(s) was added to the cell culture plates already containing 100 pl of DMEM with 5% PBS. The cells were ted in a tissue culture incubator at 37° C and 5% C02 for three days. The inhibitor effects of compounds on HCV replication were determined by measuring activity of a luciferase reporter gene using a Luciferase Assay System kit (Promega) following the manufacturer’s instructions. Passive Lysis buffer (30 ul, a) was added to each well, and the plates were incubated for 15 s with rocking to lyse the cells.

Luciferin solution (100 pl, Promega) was added to each well and the luciferase activity was measured using a Victor ll luminometer (Perkin-Elmer). To determine the EC50, the luciferase tion data were analyzed using GraphPad Prism 4 re. Three experiments were performed with three ates per experiment. The percent inhibition results were analyzed for synergy, additivity and antagonism according to the ard and Shipman model (Antiviral Research 14:181-206 (1990)).

Combination Analysis: The Prichard and Shipman approach to calculating theoretical additive effects (described in Example 3) was used for the present example.

SUBSTITUTE SHEET (RULE 26) The difference between the actual observed fraction of inhibition and the predicted value was calculated for each concentration combination for each plate in each experiment to determine whether the observed combined effect was greater than the theoretical additive effect Z calculated from the Prichard and Shipman equation. For each concentration combination, the replicates (across all plates and experiments) were used to calculate a mean ence n observed and predicted fraction of inhibition, its standard error and its two-sided 95% confidence interval. y or antagonism for a concentration ation was determined based on the same rules set forth in Example 3.

Combination of Therapeutic Agent 1 and Therapeutic Agent 4: The inhibitory effects in on produced by each drug alone or in combination with the other at concentrations up to ten-fold above the EC50 were examined in the genotype lb (Conl) replicon using a checkerboard titration patteln (two-fold serial ons) in the standard three-day antiviral assay. The concentrations tested were chosen to ensure that the EC50 values of the compounds were in the middle of the serial on range.

For compound 4, concentrations ranged from 0.0002 nM to 0.0063 nM, and for Compound 1, concentrations ranged from 0.023 nM to 0.75 nM. Synergy, additivity, and antagonism were evaluated using the Pritchard and Shipman model.

Results: The results of the assay analysis are illustrated in s 3 and 4 and Table 4. In the 3-D surface plot of Figure 3, ions from expected interactions between Compound 1 and compound 4 are purely additive at concentrations associated with a horizontal plane at 0%.

Synergistic interactions between nd 1 and compound 4 appear as a peak above the horizontal plane with a height corresponding to the percent above calculated additivity. Antagonistic interactions between Compound 1 and compound 4 appear as a pit or trough below the horizontal plane with a negative value signifying the percent below the calculated additivity. Synergistic interactions appear as shades of dark grey, additive interactions appear white, and antagonistic interactions appear as speckled.

As illustrated in the 3-D surface plot of Figure 3 and the contour plot of Figure 4, an additive or synergistic effect exists at most of the concentrations for Compound 1 and compound 4. In particular, there is a concentration region showing synergy at the lower dose concentrations of compound 4 and mid-range dose concentrations of Compound 1.

Table 4 below lists combinations of concentrations of nd 1 and nd 4 with statistically significant istic or antagonistic effects based on the Prichard and Shipman Model analysis. For each ation of concentrations, Table 4 includes the mean ence in the observed and predicted fraction of inhibition, the standard deviation or error of the mean difference, and the upper and lower limits of the 95% confidence interval.

SUBSTITUTE SHEET (RULE 26) According to Table 4, most of the combinations of Compound 1 and compound 4 listed in the table have statistically signiﬁcant synergistic effects. A small amount of nism was observed at the lowest concentrations of nd 1.

The results presented in Figures 3 and 4 and Table 4 demonstrate that the combination of therapeutic agent 4 and therapeutic agent 1 achieves additivity at most of the concentration combinations of the two agents and achieves synergy at certain concentration combinations, in particular, at low concentrations of therapeutic agent 4 and mid-range concentrations of therapeutic agent 1. Taken together, these in vitro replicon results suggest that therapeutic agent 4 should e a cant ral effect in ts when administered in combination with therapeutic agent 1 in patients infected with HCV.

Table 4 Mean difference in rd error Lower 95% Upper 95% Compound Compound fraction of inhibition: of mean conﬁdence conﬁdence 4, nM 1, nM Observed - Predicted difference limit limit 0.000197 0.375000 0.09895 0.033975 0.02060 0.17729 0.000394 0.187500 0.16900 0.038934 0.07922 0.25878 0.000394 0.375000 0.11401 0.027710 0.05011 0.17791 0.000788 0.187500 0.15349 0.038860 0.06388 0.24310 0.000788 0.375000 0.09992 0.027266 0.03704 0.16279 0.001575 0.023438 -0.08326 26 82 -0.02071 0.001575 0.046875 -0.11894 0.026099 -0.17913 -0.05876 0.001575 0.187500 0.07958 0.020080 0.03328 0.12588 0.003150 0.023438 -0.10156 0.018406 -0.14401 -0.05912 0.003150 0.046875 -0.08091 0.014615 -0.11462 -0.04721 e 5. Reduction of fected cells with combinations of therapeutic agents 1, 2 and 4 In order to quantify the frequency of resistant replicon colonies selected by therapeutic agent 1, therapeutic agent 2, therapeutic agent 4, or various combinations of these agents, the stable subgenomic replicon cell line derived from HCV pe 1a (H77; Genbank accession number AFOll751) was utilized. The replicon construct was bicistronic and the cell line was generated by introducing the constructs into cell lines d from the human hepatoma cell line Huh-7. The replicon also has a ﬁrefly luciferase reporter and a neomycin phosphotransferase (Neo) able marker. The two coding regions, separated by the FMDV 2a protease, comprise the ﬁrst cistron of the bicistronic SUBSTITUTE SHEET (RULE 26) WO 59630 replicon construct, with the second n containing the HCV NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R, K2040R and S2204l. This HCV on cell line was maintained in Dulbecco’s modiﬁed Eagles medium (DMEM; lnvitrogen) containing 10% (v/v) fetal bovine serum, 100 lU/ml penicillin, 100 ug/ml streptomycin, and 200 ug/ml G418 (all from lnvitrogen). 1a-H77 replicon cells (105-106) were plated in 150 mm cell culture plates and grown in the presence of G418 (400 [Lg/ml) and nd 1, Compound 2, andjor compound 4 at trations that were either 10- fold (10X) or 100-fold (IOOX) above the ECSO value for the HCV genotype 1a replicon cell line. The ECSO values for Compound 1, Compound 2, and compound 4 used for this experiment were 0.9, 7.7, and 0.01 nM, respectively. After three weeks of treatment, the majority of replicon cells were cleared of replicon RNA and, therefore, were unable to survive in the G418-containing medium since the replicon RNA ed the neo marker conferring G418 resistance. The cells containing resistant replicon variants survived and formed colonies, and these colonies were stained with 1% eiystal violet in 10% Protocol SafeFix 11 reagent (Fisher Scientiﬁc), and counted. As shown in Figure 5A, the combination of compound 4 plus either Compound 1 or nd 2 at either 10-fold or 100-fold above their respective ECSO value resulted in signiﬁcantly fewer es than either Compound 1, Compound 2, or compound 4 alone at 10-fold or 100-fold above their respective EC50 value.

Figure 5B illustrates the percentage of colonies surviving two vs. three DAA combinations. In colony sulvival assays, 1a-H77 replicon cells were grown in the ce of a DAA combination and G418 for approximately three weeks, after which time the cells containing resistant on ts had formed colonies. The cells were stained with crystal violet and counted. “Triple Combination” is either a combination of nds 1, 2 and 4 at concentrations of 5-fold (5X) over their respective EC50 , or a combination of Compounds 1, 2 and 4 at trations of 10-fold (10X) over their tive ECSO values.

Figures 5C and 5D show the effect of a combination of Compounds 1 and 4 in long-term HCV RNA reduction assays in genotype 1 replicon cell lines. In long-term replicon RNA reduction assays, 106 replicon cells were plated in the absence of G418. The inhibitors at concentrations of either -fold (10X) or 100-fold ( IOOX) over their respective EC50 values were added, and the cells were grown to approximately 95% conﬂuence (4 days). At each passage, 106 cells were removed and frozen, and an additional 106 cells were passed into another ﬁask with fresh media and inhibitors. RNA was extracted ﬁom 106 cells and HCV RNA was measured in a Real-Time RT-PCR assay. Figures 5C and 5D show that in both 1a and 1b replicon cells, the combination of Compounds 1 and 4, each at 10-fold over EC50, is more effective at clearing cells of replicon than 100-fold over EC50 of either inhibitor alone.

Predominant resistant variants selected by Compound 1, 2, or 4 in genotype 1 replicons were also determined. For Compound 1, the inant resistance variants in 1a-H77 replicons include SUBSTITUTE SHEET (RULE 26) R155K, D168A and D168V with fold resistance of 26, 48 and 128, respectively; and the predominant resistance variants in lb-Conl replicons include R155K, A156T and D168V with fold resistance of 48, 9 and 190, respectively. For Compound 2, the predominant resistance variants in 1a-H77 ons include C316Y, M414T, Y448C and SSS6G with fold resistance of 1600, 36, 980 and 15, respectively; and the inant resistance variants in lb-Conl replicons include C316Y, M414T and D559G with fold resistance of 1400, 26 and 100, tively. For Compound 4, the predominant resistance variants in 1a- H77 replicons include M28T, M28V, Q30R, Y93C and Y93H with fold resistance of 9000, 60, 800, 1700 and 41000, respectively; and the predominant resistance variants in 1b-Con1 replicons e Y93H with fold resistance of 55. These experiments also showed that in genotype 1a, a number of variants selected by Compounds 2 or 4 conferred higher levels of resistance than those selected by nd 1, and that in genotype 1b, one variant (C316Y) selected by Compound 2 red a higher level of resistance than those selected by either Compound 1 or Compound 4.

The above examples show that the ation of two different classes of DAAs (e.g., a combination of a HCV protease inhibitor and a HCV polymerase inhibitor, or a combination of a HCV protease inhibitor and a HCV NSSA inhibitor, or a combination of a HCV polymerase inhibitor and a HCV NSSA inhibitor) can lead to an improved resistance barrier in patients relative to a single DAA alone, while the combination of three different classes of DAAs (e. g., a ation of a HCV protease inhibitor, a HCV polymerase inhibitor, and a HCV NSSA inhibitor) can lead to even more significant barrier to resistance. Improvement in the barrier to ance achieved through co-administration of multiple DAAs of different classes or with ent mechanism of action is expected to ate with enhanced efficacy in patients.

Example 6. Clinical Modeling for Interferon-free DAA Combination Therapies This example describes a novel al model for evaluating optimal doses and durations of interferon-free HCV therapies using combinations of different DAAs. This model reasonably predicted the effectiveness of numerous DAA ations in interferon-free, short-duration therapies.

A mechanistic model was used to model the relationship between DAA exposures and antiviral y in HCV-infected subjects. This model was used to conduct clinical trial simulations of clinical outcomes following administration of various DAA combination regimens (e.g., specific DAA combinations and different doses of DAAs) and durations oftherapy.

Numerous DAAs have been extensively documented to select mutants following short duration of monotherapy (e.g., less than 1 week). The viral dynamic model of this e included single and double mutants. Specifically, the model included 2 single mutants and one double mutant for SUBSTITUTE SHEET (RULE 26) each of the 2-DAA combination regimens. Thus, a 2-DAA combination regimen (e. g., a combination of a protease inhibitor and a NSSA inhibitor) included 2 single mutants and one double mutant. A 3-DAA combination (e. g., a ation of a protease tor, a polymerase inhibitor and a NSSA inhibitor, such as a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor (NNPI) and a NSSA inhibitor) included 3 single and 2 double mutants.

The model has 3 ents: hepatocytes (uninfected or target cell), infected cell and Viral dynamics. The differential equations describing the dynamics of the 3 components are as follows: (1) Hepatocytes (Uninfected or Target Cell) Dynamics dT/dt = s - de*T- (1-n)*B*T*(VLWT + VLPoly + VLProt + VLNSSA + VLNSSAProt + VLPolyProt) (2) Infected Cell Dynamics (a) Infected with Wild type Virus d IWT/dt = (l-n)*B *T* VLWT — 5 *IWT (b) Infected with rase Mutant Virus d IPoly/dt = (l-n)*B oly - y (c) Infected with Protease Mutant Virus (1 IProt/dt = (l-n)*l3 *T*VLProt - 8 *IProt (d) ed with NS5A Mutant Virus d lNSSA/dt = (l-n)*B *T*VLNSSA - 8 *lNSSA (e) Infected with Protease-NS5A Double Mutant Virus d INSSAProt/dt = (l-n)*B *T*VLNSSAProt - 5 *lNSSAProt 09 Infected with Protease— Polymerase Double Mutant Virus d IPolyProt/dt = (1-n)*B*T*VLPolyProt - 8 *IPolyProt (3) Viral dynamics SUBSTITUTE SHEET (RULE 26) (a) Wild Type Virus dVLWT/dt=(1-3*u)*p*(1-Eff1)*IWT+ u *(p*(1-Eff2)*Fit1*IPoly + p*(1-Eff3)*Fit2*IProt +p*(1- Eff4)*Fit3*INSSA)- c*VLWT (b) Polymerase Mutant Virus dVLPoly/dt = (1- u -(|))* p*(1-Efi2)*Fit1*IPoly + u * p*(1-Eff1)*IWT + (I) * p*(1-Eff5)*Fit4* IPoly- Prot - c*VLPoly (C) Protease Mutant Virus dVLProt/dt = (1— u — 2*¢)* p*(1-Eff3)*Fit2*IProt + u * p*(1-Eff3)*IWT + ¢ *(p*(1- Eff5)*Fit4*IPolyProt + p*(1-Eff6)*Fit5*INSSAProt) - c*VLProt (a’) NS5A Mutant Virus d VLNSSA/dt = (1— u- ¢)*p*(1-Eff4)*Fit3*INSSA + u Eff1)*IWT + (I) *p*(1- Eff6)*Fit5*INSSAProt — c*VLNSSA (e) NS5A ana’ Protease Double Mutant Virus dVLNSSAProt/dt= 1-2* * p*1-Eff6 *Fit5*INSSAProt+ * p*(1-Eff4 *Fit3*INSSA+p* 1— Eff3)*Fit2*1Prot) — c*VLNSSAProt w Poly ana’ Protease Mutant Double Mutant Virus dVLPol Prot/dt= 1-2* )* * * * 1-Eff2)*Fit1*IPoly+ p* y P l-EffS *Fit4*1Pol Prot+y P 1- Efi3)*Fit2*IProt) - c*VLPolyProt The parameters used in the above equations are described in Table 5.

Table 5. Viral Dynamic Parameters Parameter Description s zero-order tion of hepatocytes T number of Target or cted cytes de rder rate constant for the death of hepatocytes SUBSTITUTE SHEET (RULE 26) Parameter Description B rate-constant for the infection of hepatocytes by virus 8 first-order rate constant for the death of infected hepatocytes n fractional reduction of the rate-constant for the infection of hepatocytes by virus u probability of the formation of single mutants and mutation back to Wild-Type (I) probability of the formation of double mutants and mutation back to single mutant p production rate of the Wild-Type virus c clearance rate of the virus Effl, Eff2, Eff3, inhibition of production of Wild Type, polymerase, protease, Eff4 and NSSA mutant, respectively EffS, Eff6 inhibition of tion of polymerase-protease and NSSA- protease double mutant, respectively Fitl, Fit2, Fit3 ﬁtness of polymerase, protease and NSSA mutant relative to Wild type virus, respectively Fit4, Fit5 fitness of polymerase-protease and NSSA-protease double mutant ve to wild type virus, respectively IWT, IPoly, lprot, number of cells ed with Wild type, polymerase, protease INSSA and NSSA mutants, tively IPoly-Prot, INSSA- number of cells infected with polymerase-protease and NSSA- Prot protease double mutant, respectively VLWT, , viral load for wild type virus, polymerase, protease and NSSA , VLNSSA mutant virus, respectively SUBSTITUTE SHEET (RULE 26) Parameter Description VLPoly-Prot, viral load for polymerase-protease and NSSA-protease double VLNSSA-Prot mutant, respectively As shown in the differential equations for viral dynamics, the effect of DAA is included as an inhibition of viral load production. For example, the effect of DAA(s) on production of wild type virus is given as (l-Effl)* p where Effl is the fraction of viral production that is inhibited. In the absence of drug Effl =0 and in the presence of drug Effl takes a value between 0 and l. Effl is described using an Emax model: Effl = Emax*Conc/(EC50 + Conc) where Emax represents maximum tion, Conc is the plasma DAA concentration and EC50 is the tration that inhibits viral load production by 50%. As the fold-change in EC50 for the mutants ed to wild type virus was based on values obtained from in vitro on studies, EC50 was estimated only for wild type vilus.

For DAA combinations, the effect was assumed to be multiplicative and incorporated as follows: l) = DAA1)*(1-EffDAA2)*(1-EffDAA3) The effect of ribavirin (RBV) was added on infection rate B as an Emax model. In ce of ribavirin, the infection rate decreases by a factor (l-n) where n = ConcRBV /( EC50_RBV + ConcRBV) The model does not include a double mutant to the polymerase + NSSA inhibitors. In a 3-DAA regimens, a polymerase + NSSA double mutant is often wild type for the protease inhibitor.

Hence, this double mutant is not expected to signiﬁcantly affect clinical outcomes for a 3-DAA regimen simulation. On the other hand, the model can be readily adapted to simulate a 2-DAA regimen ning a polymerase inhibitor and a NSSA inhibitor by treating the polymerase inhibitor (e.g., PSI-7977) as a protease inhibitor in the model.

The lowest available limit of detection (LOD) of viral load assays is 10 IU/mL.

Assuming 3 virion particles per 1U, this constitutes about 0.5 million viruses in the body at LOD. Hence, subjects have to be treated for significant period of time after their viral load falls below the LCD to SUBSTITUTE SHEET (RULE 26) achieve cure. This duration depends on the y of the compounds and the individual response to therapy.

In order to predict the duration required for cure, a “threshold” concept was used. For simulations, an HCV-infected subject was assumed to achieve SVR when viral load reaches less than 1 virion in the total plasma and extracellular ﬂuid volume (about 15000 mL), i.e., viral load measurement of <1 copy/15000 mL or <0.33 IU/15000 mL. This translates to about 5 log IU/mL. Cf. Snoeck E et al., CLIN PHARMACOL THER. 87(6):706-13 (2010), wherein based on data from ts treated with peg-IFN and ribavirin, subjects were ted to achieve SVR when the ted number of infected cells fell below 1. While such low viral loads cannot be measured experimentally, they can be simulated using the viral dynamic model.

The model can be used to predict SVR for any ation of DAAs, with or without interferon, and with or without ribavirin.

As non-limiting examples, various interferon-free treatment regimens using different ations of Compound 1, Compound 2 and/or Compound 4, with or without ribavirin, were evaluated using the model of this Example. The following approach was used to include mutants in the model: a. One single mutant per DAA b. One double mutant per DAA combination For a combination of two DAAs, e.g., a combination of Compound 1 and nd 2, the model included one mutant resistant to nd 1, one mutant resistant to nd 2, and one double mutant resistant to both Compound 1 and Compound 2. Compound 1 is coadministered or co- formulated with ritonavir (or another pharmacokinetics enhancer) to improve its drug re.

A double mutant to Compound 2 and Compound 4 was not included in the modeling. In the 3-DAA regimens, a Compound 2/Compound 4 double mutant is likely wild type for Compound 1 due to the high potency and resistant profile of Compound 1. Hence, the Compound ound 4 double mutant is not ed to affect clinical outcomes for treatments containing Compound 1.

Single mutants included in the model were based on mutants observed for the individual DAAs in the Phase 1b and 2a studies (e.g., clinical studies M10-351, Ml2-116, and M11-602). For double mutants with resistance to 2 DAA classes, the sensitivity (EC50) of double mutants to drug was assumed to be a ation of the 2 single mutants. Thus, for Compound 1 and Compound 2, the single mutants were D168V and M414T, respectively, and the double mutant was D168V-M414T. In this scenario, the D168V mutant would be less sensitive to Compound 1 but would be as sensitive to Compound 2 as wild type virus. Similarly, the M414T mutant would be less sensitive to Compound 2 but SUBSTITUTE SHEET (RULE 26) 2012/061075 would be as sensitive to Compound 1 as wild type virus. The double mutant D168V-M414T would be less sensitive to both Compound 1 and Compound 2.

The fold change in EC50 for the mutants ed to wild type virus was based on values obtained from in vitro replicon studies. Since monotherapy data for Compound 4 indicated a variety of mutants with different EC50s, a value of 1000x fold change in EC50 was used for Compound 4 for modeling and simulations.

Baseline prevalence of the mutants was estimated during model ﬁtting, while the mutation rate was based on the literature values. Both baseline prevalence and mutation rate determined mutant ﬁtness.

Pharmacokinetic data and viral load data from 140 treatment-naive HCV-infected subjects were used to construct the model. For modeling, number of target cells at baseline, number of infected cells at ne, death rate of target cells and mutation rates were based on literature values.

See, e.g., Snoeck et a1. supra; Rong el al. SCI TRANSL MED. 2(30):30ra32 (2000); Neal and Pravin, ACOP 2009 (http://2009.go-acop.org/sites/all/assets/webform/Lauren-Neal_ACoP_2009.pdf); Neumann er al. SCIENCE 282(5386):103-7 ( 1998); Shudo er a1. ANTIVIR THER. 13(7):919-26 (2008); and Dahari er al. J THEOR BIOL. 247(2):371-81 (2007). The production rate of virus and infection rate of virus were derived from other parameters in the model. All other ters were estimated. Exposure-antiviral response modeling was performed using NONMEM 7.2. al trial simulations were performed using Trial Simulator version 2.2.1. Fifty subjects and 50 ates were simulated for each treatment. A t drop out rate from the study due to any reason was assumed to be 8% over 24 weeks based on available literature on trials in subjects with HCV. All simulations were conducted assuming 100% compliance. Covariates ed in the simulations were genotype 1a/1b status. Clinical outcomes simulated ed: (1) tage of subjects below limit of ion (LOD) of 101U/mL and (2) percentage of ts achieving SVR.

Clinical trial simulations were conducted to determine optimal dose and duration for SVR. Over 80 scenarios were simulated to predict the percentage of subjects with SVR following administration of various 2- and 3-DAA combinations (e.g., Compound 1 + Compound 2, or Compound 1 + Compound 4, or Compound 1 + Compound 2 + Compound 4), without RBV, at a range of doses for each DAA (e.g., nd 1/ritonavir at 250/100, 150/100 or 100/ 100 mg QD, Compound 4 at 5, 25 or 100 mg QD, and Compound 2 at 400 or 800 mg BID) and across a range of treatment durations (e.g., 2. 4, 6, 8, 10, 12, 16, and 24 weeks).

Optimal dose and duration were predicted based on percentage of subjects with viral load of less than -5log lU/mL old for SVR. Selected and relevant results of simulation for the 2- and 3- DAA combinations of Compounds 1, 2 and/or 4 are shown in Figures 6A, 6B and 6C for two different SUBSTITUTE SHEET (RULE 26) doses of Compound 1. Figure 6A shows the predicted median SVR percentage (“% SVR”) and 90% conﬁdence al (the vertical bar at the top of each SVR percentage column) for different treatment durations using a combination of Compound 1 and Compound 2; Figure 6B shows the predicted median and 90% conﬁdence interval for different treatment durations using a ation of nd 1 and Compound 4; and Figure 6C shows the predicted median and 90% conﬁdence al for different treatment durations using a combination of nd 1, Compound 2 and nd 4. In each simulation, RBV was included, and Compound 1 was used with 100 mg ritonavir, and the subjects are HCV genotype 1, treatment-naive patients. SVR24 is lower than SVR12 in some cases due to drop out; longer durations are not necessarily predicted to improve SVR but could result in more dropouts resulting in lower SVR.

The model predicted that with 8-12 weeks of dosing at least 80 to 90% subjects can achieve SVR with 2 and 3 DAA combinations. The model also predicted that durations shorter than 8 weeks can cure a cant number of subjects. A 2-DAA regimen was predicted to cure over 40% of the ts and a 3-DAA regimen was predicted to cure about 60% of the subjects with only 6 weeks of dosing. Dosing for durations of over 12 weeks was not expected to increase the tage of subjects with SVR significantly. Addition of the 3ml DAA was predicted to shorten treatment duration by 2 to 4 weeks as optimal durations for the 3-DAA combination of Compound 1, Compound 2 and Compound 4 were predicted to be 8-10 weeks.

Figures 6A, 6B and 6C illustrate the predictions for DAA combinations without ribavirin.

The model also predicts similar or comparable SVR percentages for these DAA combinations when used with ribavirin. In addition, the effect of interferon (e.g., pegylated interferon) can also be added by incorporating interferon similar to a DAA but without any resistant mutants.

One of the advantages that the model provides is that it allows examination of various viral parameters and its effect on dose, duration and SVR. For example while experimentally ining the effect of mutants parameters is very difficult if not impossible, they can be examined using the model.

Thus SVR in patient population that have different s can be predicted with the model.

The model was used to simulate the treatment described in Example 1 which included 150/100 mg Compound 1/ritonaVir QD + 400 mg Compound 3 QD + weight-based amounts of RBV BID for 12 weeks, and the percentage of subjects with HCV RNA less than LOD at 2, 4, 8, 10, and 12 weeks was ized in Figure 7. The mean predicted versus observed percentage of subjects with below LOD (“% LOD”) at respective weeks are shown Figure 7. 95% conﬁdence intervals for the predicted data (the vertical bar at the top of each tive ted LOD percentage column) were also indicated.

As shown in Figure 7, the model reasonably predicted the clinical outcome of %LOD.

SUBSTITUTE SHEET (RULE 26) The model was also used to simulate the treatment described in Example 2A. The mean predicted versus observed percentage SVR (“% SVR”) after 12-week treatment are shown Figure 8. 95% conﬁdence intervals for the predicted data (the vertical bar at the top of each respective predicted SVR percentage column) were also ted. As shown in Figure 8, the predicted SVR percentages aligned well with the ed SVR percentages. Simulations also predict that the same treatment regimen as described in Example 2A but without ribavirin has similar or comparable LOD percentages for different treatment durations.

The exposure response viral dynamic model of this Example provided a quantitative method to reasonably predict SVR for s combination of antiviral compounds. Based on the exposure-antiviral response modeling and al trial simulations, it demonstrated that (1) addition of a 3ml DAA to a 2-DAA combination can reduce optimal duration of treatment and/or increase SVR; (2) 8-12 weeks of dosing is the l duration of therapy for 2 and 3 DAA combinations of Compound 1/r, Compound 2 and Compound 4; and (3) durations shorter than 8 weeks of interferon-free treatment have been predicted to cure a signiﬁcant percent of the subjects.

Example 7. Clinical Modeling for Interferon-free DAA Combination Therapies Containing EMS-790052 and EMS-650032 The model described above was also used to predict the SVR percentage of eron- ﬁee ent ns ning BMS-790052 and BMS-650032 without 1ibavirin, based on existing hed clinical data including two Phase 1 and one Phase 2 study of EMS-790052 and one Phase 1 and one Phase 2a study of EMS-650032. Figure 9 shows the predicted median SVR percentage and 90% SVR conﬁdence interval for different treatment durations of a 2-DAA regimen containing BMS-790052 (60 mg QD) and EMS-650032 (600 BID) in genotype 1 naive subjects. The combination of BMS- 790052 (60 mg QD) plus BMS-650032 (600 mg BID) in genotype 1 subjects was predicted to achieve improved SVR for ons of 12 weeks or greater with predicted SVR rates of about 70% for 10 weeks of dosing. r regimens but containing ribavirin, or regimens with r dosings of 0052 and EMS-650032 with or without ribavirin, are expected to achieve similar SVR rates.

Example 8. Clinical Modeling for Interferon-free Therapies Containing PSI-7977 Likewise, a 3-DAA regimen without interferon and ribavirin was modeled for genotype 1 patients based on existing clinical data. The 3-DAA regimen contains 200/100 mg QD nd l/r, 50 mg QD Compound 4, and 400 mg QD PSI-7977. Figure 10 depicts the predicted median SVR rates for different treatment durations of this 3-DAA combination. This 3-DAA ation was predicted to SUBSTITUTE SHEET (RULE 26) have over 60% SVR in 6 weeks and over 80% SVR at duration of 8-week, 10-week, 12-week or longer treatment. Similar regimens but containing ribavirin, or ns with similar dosings of Compound l/r, Compound 4 and PSI-7977 with or without rin, are expected to achieve similar SVR rates.

The model can also be used to predict SVR for regimens containing single DAA or single DAA with ribavirin. For example, the model predictions for PSI-7977 + ribavirin for various durations for treating HCV genotype 1 treatment-naive ts were obtained. Figure 11 depicts the predicted median and 90% conﬁdence interval of SVR percentage for different treatment durations of such a regimen containing PSI-7977 (as the sole DAA; 400 mg QD) and ribavirin (600 mg BID). The 90% conﬁdence interval for the predicted SVR (the vertical bar at the top of each tive predicted SVR percentage column) is also indicated in Figure 11. The prediction was based on the already published clinical data for PSI-7977. SVR rate for PSI-7977 + ribavirin was predicted to be around 75-90% following 12 weeks of , and about 55-75% following 8 weeks , in genotype 1 subjects.

Similar SVR percentages for genotype 1 treatment-naive patients are expected for similar regimens containing similar PSI-7977 QD dosing (e.g., 200-600 mg QD) and weight-based amounts of ribavirin (e.g., 1000 to 1200 mg divided twice daily).

Data from two Phase 1 and one Phase 2 study of Daclatasvir (BMS-790052) and one Phase 1 and one Phase 2 study of PSI-7977 were used for estimating the pharmacokinetic and viral dynamic model parameters. Predictions for a 2-DAA combination with Daclatasvir (BMS-790052) and PSI-7977 in genotype 1 nai've patients are shown in Figure 12. The model predicted that following 10-12 weeks of dosing with the combination of Daclatasvir and PSI-7977 without ribavirin, at least 90% of HCV pe 1 na'ive ts can achieve SVR. Similar or better SVR rates are ted if rin is included in the regimens.

Similarly, data from one Phase 1a study of TMC-435 and one Phase 1 and one Phase 2 study of PSI-7977 were used for estimating the pharmacokinetic and viral dynamic model parameters.

Predictions for a 2-DAA combination with the TMC-435 and PSI-7977 in genotype 1 naive patients are shown in Figure 13. The model ts that following 10-12 weeks of dosing with the combination of TMC-435 and 77 without ribavirin, at least 90% of HCV patients can achieve SVR. r or better SVR rates are predicted if ribavirin is included in the regimens.

Example 9. Clinical ng for Interferon-free DAA Combination Therapies Containing Danoprevir and Mercitabine In addition, data from one Phase 1 and one Phase 2 study of Danoprevir and abine were used for estimating the pharmacokinetic and viral c model parameters. Ritonavir was co- SUBSTITUTE SHEET (RULE 26) administered with evir to improve the pharmacokinetics of Danoprevir. tions for a 2-DAA ation with Danoprevir and Mercitabine in genotype 1 naive patients are shown in Figure 14. The model predicts that following 16 weeks of dosing with the combination of Danoprevir and Mercitabine without ribavirin, at least 90% of HCV patients can achieve SVR. Similar or better SVR rates are predicted if ribavirin is included in the regimens Example 10. al Modeling for Interferon-free DAA Combination Therapies Containing Tegobuvir (GS-9190), GS—9451 and GS-5885 Data from Phase 1 and Phase 2 studies of GS-9190 (tegobuvir), GS-9451 and GS-5885 were used for estimating the pharmacokinetic and viral dynamic model ters. Predictions for the combination with 0 (tegobuvir), GS-9451 and GS-S 885 in genotype 1 naive patients are shown in Figure 15. The model predicts that following 12 weeks of dosing with the combination of 0 uvir) + GS-9451 + GS-S 885 + RBV, about 70% of genotype 1 naive patients can achieve SVR and following 24 weeks of ent > 80% of genotype 1 naive ts can e SVR. Similar or better SVR rates are expected when ribavirin is included in the regimen.

Example 11. Clinical Modeling for Interferon-free DAA Combination Therapies Containing PSI- 7977 (GS-7977) Data from Phase 1 and Phase 2 studies of GS-9451 and GS-7977 (PSI-7977) were used for estimating the pharmacokinetic and viral dynamic model parameters. Predictions for the combination with 1 and 7 (PSI-7977) in genotype 1 naive patients are shown in Figure 16.

Data from Phase 1 and Phase 2 studies of GS-5885 and 7 (PSI-7977) were used for estimating the cokinetic and viral dynamic model parameters. Predictions for the combination with GS-5885 and GS-7977 (PSI-7977) in genotype 1 naive patients are shown in Figure 16.

Data from Phase 1 and Phase 2 studies of GS-9451, GS-5885 and GS-7977 (PSI-7977) were used for estimating the pharmacokinetic and viral dynamic model parameters. Predictions for the combination with GS-9451, GS-S 885 and GS-7977 (PSI-7977) in genotype 1 naive patients are shown in Figure 16.

The model predicts that following 12 weeks of dosing with the combination of GS-9451 and GS-7977 (PSI-7977), or the combination of GS-5885 and GS-7977 (PSI-7977), or the combination of GS-9451, GS-5885 and GS-7977 (PSI-7977), at least 90% of genotype 1 naive patients can achieve SVR.

Similar or better SVR rates are expected when ribavirin is included in these regimens.

SUBSTITUTE SHEET (RULE 26) Example 12. Clinical Modeling for Interferon-free DAA ation Therapies ning TMC-43 and Daclatasvir (EMS-790052) Data from one Phase 1a study of TMC-435 and from two Phase 1 and one Phase 2 study of daclatasvir (BMS-790052) were used for estimating the pharrnacokinetic and viral dynamic model parameters. Predictions for the combination with 5 and daclatasvir in pe 1 naive patients are shown in Figure 17.

The model ts that following 12 weeks of dosing with the combination of TMC-435 and daclatasvir (BMS-790052), about 80% of genotype 1 naive patients can achieve SVR. Similar or better SVR rates are expected when ribavirin is ed in these regimens.

The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modiﬁcations and variations are possible in light of the above teachings or may be acquired from practice of the invention. Thus, it is noted that the scope of the invention is deﬁned by the claims and their equivalents.

SUBSTITUTE SHEET (RULE 26) [Annotation] amandam None set by amandam [Annotation] m MigrationNone set by amandam [Annotation] amandam Unmarked set by amandam

Claims

1. Use of PSI-7977 ( ) and GS-5885 ( ) in the manufacture of a medicament for the treatment of HCV in a t infected with HCV genotype 1, n said treatment includes administration of ribavirin but does not include administration of interferon, and wherein said treatment lasts for 8, 9, 10 or 11 weeks, wherein the medicament comprises PSI-7977 and 5 mulated in a single composition.

2. The use according to claim 1, wherein the treatment lasts for 8 weeks.

3. The use according to claim 1 or claim 2, wherein said patient is a HCV treatmentnaive patient.

4. The use according to any one of claims 1 to 3, wherein said patient is infected with HCV genotype 1a.

5. The use according to any one of claims 1 to 4, wherein the medicament is formulated for the administration of PSI-7977 and GS-5885 once daily.

6. The use ing to any one of claims 1 to 5, wherein said medicament is formulated for the stration of 90 mg QD of GS-5885 and 400 mg QD of PSI-7977 to a genotype 1 naive patient.

7. The use according to any one of claims 1 to 6, wherein the treatment of HCV es sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype 1.

8. The use according to any one of claims 1 to 6, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 75% of patients infected with HCV genotype 1.

9. Use of PSI-7977 ( ) and GS-5885 ( ) in the manufacture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, wherein said treatment includes administration of rin but does not include administration of interferon, and wherein said treatment lasts for 12 weeks and the medicament comprises PSI-7977 and GS- 5885 co-formulated in a single composition.

10. The use according to claim 9, wherein said patient is a HCV treatment-naive patient.

11. The use ing to claim 9 or claim 10, wherein said patient is infected with HCV genotype 1a. [Annotation] amandam None set by amandam [Annotation] amandam MigrationNone set by m [Annotation] amandam Unmarked set by m

12. The use according to any one of claims 9 to 11, wherein the medicament is ated for the administration of PSI-7977 and GS-5885 once daily.

13. The use according to any one of claims 9 to 12, wherein said ment is ated for administration of 90 mg QD of GS-5885 and 400 mg QD of PSI-7977 to a genotype 1 naive patient.

14. The use according to any one of claims 9 to 13, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype 1.

15. The use according to any one of claims 9 to 13, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 90% of patients infected with HCV genotype 1.

16. Use of PSI-7977 ( ) and an HCV NS5A inhibitor in the manufacture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, wherein said treatment includes administration of ribavirin but does not include administration of interferon, and wherein said treatment lasts for 8, 9, 10, 11 or 12 weeks and the medicament comprises PSI-7977 and an HCV NS5A mulated in a single composition.

17. The use ing to claim 16, wherein the treatment lasts for 8 weeks.

18. The use according to claim 16, wherein the treatment lasts for 12 weeks. [Annotation] amandam None set by amandam [Annotation] amandam MigrationNone set by amandam ation] amandam Unmarked set by amandam

19. The use according to any one of claims 16 to 18, wherein said patient is an HCV treatment-naive patient.

20. The use according to any one of claims 16 to 19, wherein said patient is infected with HCV genotype 1a.

21. The use according to any one of claims 16 to 20, wherein the PSI-7977 and the HCV NS5A inhibitor are formulated for administration once daily.

22. The use according to any one of claims 16 to 21, wherein said medicament is formulated for the stration of 400 mg QD of PSI-7977 to a genotype 1 naive patient.

23. The use ing to any one of claims 16 to 22, wherein the treatment of HCV achieves sustained gic response (SVR) in at least 70% of patients infected with HCV genotype 1.

24. The use ing to any one of claims 16 to 22, wherein the ent of HCV achieves ned virologic response (SVR) in at least 75% of patients infected with HCV genotype 1.

25. The use according to any one of claims 18 to 22, wherein the ent of HCV achieves sustained virologic response (SVR) in at least 90% of patients infected with HCV genotype 1, wherein said treatment lasts for 12 weeks.

26. Use of PSI-7977 ( ) and an HCV NS5A inhibitor in the manufacture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, wherein said treatment lasts for 6 or 7 weeks and does not include administration of interferon to said patient [Annotation] amandam None set by amandam [Annotation] amandam ionNone set by amandam [Annotation] amandam Unmarked set by amandam and the medicament comprises PSI-7977 and an HCV NS5A inhibitor co-formulated in a single composition, and wherein the medicament further comprises r direct acting antiviral (DAA) or is administered in combination with r DAA.

27. The use according to claim 26, wherein said another DAA is Compound 1 ( ), and said HCV NS5A inhibitor is Compound 4 ( ).

28. The use according to claim 26 or claim 27, wherein said medicament is formulated for administration of PSI-7977 at a dose of 400 mg once daily.

29. The use according to claim 28, wherein said another DAA is an HCV protease inhibitor.

30. The use according to claim 28, wherein said another DAA is an HCV polymerase inhibitor.

31. The use according to any one of claims 26 to 30, n said patient is a treatment naive t.

32. The use according to any one of claims 26 to 30, wherein said patient is an interferon non-responder. [Annotation] amandam None set by amandam [Annotation] amandam MigrationNone set by amandam [Annotation] amandam Unmarked set by amandam

33. The use according to any one of claims 26 to 32, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 70% of patients ed with HCV genotype 1.

34. The use according to any one of claims 26 to 33, wherein the treatment of HCV achieves ned virologic response (SVR) in at least 75% of patients infected with HCV genotype 1.