NZ625539B2

NZ625539B2 - Combination treatment of daas for use in treating hcv

Info

Publication number: NZ625539B2
Application number: NZ625539A
Authority: NZ
Inventors: Walid M Awni; Barry M Bernstein; Scott C Brun; Daniel E Cohen; Emily O Dumas; Sandeep Dutta; Amit Khatri; Cheri E Klein; Rajeev M Menon; Sven Mensing
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 PSI-7977 (sofosbuvir) and a HCV NS5A inhibitor, such as GS-5885 (ledipasvir), wherein the regimens do not include administration of either interferon or ribavirin, and last for 6-12 weeks. last for 6-12 weeks.

Description

COMBINATION TREATMENT OF DAAS FOR USE IN TREATING HCV The application claims the benefit of U.S. Provisional Application No. 61/550,360 filed October 21, 2011, U.S. Provisional Application No. 61/562,176 filed November 21, 2011, U.S.

Provisional Application No. 61/587,197 filed January 17, 2012, U.S. Provisional Application No. 61/600,468 filed February 17, 2012, U.S. Provisional Application No. 61/619,883 filed April 3, 2012, U.S. Provisional Application No. ,253 filed June 6, 2012, and U.S. Provisional Application No. 61/711,793 filed October 10, 2012.

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

BACKGROUND OF THE INVENTION The HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae . The enveloped HCV virion contains a positive stranded RNA genome ng all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 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 non-structural 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 cy and tolerability remain as many users suffer from side effects, and viral ation from the body is often incomplete. Therefore, there is a need for new ies to treat HCV infection.

BRIEF SUMMARY OF THE INVENTION As one aspect of the present invention, methods for treating HCV infection in a t are ed. The methods comprise administering at least two direct acting antiviral agents (DAAs) for a duration of no more than twelve weeks, or for another duration as set forth herein.

Preferably, the duration of the ent is twelve weeks. The duration of the treatment can also be no more than eight weeks. Preferably, the two or more direct acting ral agents (DAAs) are administered in amounts effective to provide a sustained virological se (SVR) or achieve another desired measure of effectiveness in a subject. The t is not administered ribavirin during the duration of administering 6837291_1 (GHMatters) P99394.NZ the at least two DAAs. Put another way, the methods exclude the administration of ribavirin to the subject during the treatment n. The subject is also not administered interferon during the treatment regimen. Put another way, the methods exclude the administration of interferon to the subject, y avoiding the side effects associated with interferon. In some embodiments, the methods further 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 t 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 ations thereof, and (c) an inhibitor of cytochrome P-450 to the t for a on of no more than twelve weeks, or for another duration as set forth herein (e.g., the treatment regimen can last for a on of no more than 8 weeks).

Preferably, therapeutic agent 1, the rase inhibitor(s), and the tor of cytochrome P-450 are administered in amounts effective to provide high rates of SVR or another measure of effectiveness in the subject. As miting examples, therapeutic agent 1 and the inhibitor of cytochrome P-450 can be co- formulated 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 ts having HCV infection are provided. The methods se administering at least two DAAs 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 another measure of effectiveness in at least about 50% of the population, preferably at least about 70% of the population.

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

In some embodiments, 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 is 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 embodiments, the HCV protease inhibitor is therapeutic agent 1 and the non-nucleoside HCV polymerase inhibitor is therapeutic agent 3. By way of example, therapeutic agent 1 can be administered at a total daily dose of about 100 mg, alternatively 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 co-administered with therapeutic agent 1 to improve the pharmacokinetics and bioavailability of therapeutic agent 1.

In some embodiments, the at least two DAAs comprise at least one HCV protease inhibitor and at least one NSSA inhibitor. ably, the HCV protease tor is therapeutic agent 1 and the NSSA inhibitor is therapeutic agent 4. By way of example, 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 rome 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 can be administered in any effective dosing schemes and/or 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. 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 logy provides a method for treating HCV infection comprising administering to a subject in need thereof at least two DAAs for a duration of no more than twelve weeks, wherein the subject is not administered with either interferon or ribavirin during said duration. In some s, the at least two DAAs are administered in an amount ive to result in SVR. Some methods further comprise administering an inhibitor of cytochrome P450 to the subject. In some aspects, the on 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 ceutically 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 ral agents comprise (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.

In yet another aspect, 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) nd 4 or a pharmaceutically acceptable salt thereof.

In yet a further aspect, 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, (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and (iii) nd 4 or a pharmaceutically acceptable salt thereof.

In yet another , the at least two direct acting ral agents comprises a drug ation selected from the group consisting of: a combination of PSI-7977 and PSI-93 8, a combination of BMS-790052 and BMS-650032, a combination of GS—5885 and GS—9451, a combination of GS-5885, GS-919O 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 combination of PSI-7977 and EMS-790052 (daclatasvir). In yet another , the at least two direct acting antiviral agents comprises a ation 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, EMS-650032 (asunaprevir) and EMS-790052 (daclatasvir). In yet r aspect, the at least two direct acting ral agents comprises a combination of TMC-435 and daclatasvir.

In other aspects, the present technology provides a method for ng 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 combinations thereof, and (c) an inhibitor of cytochrome P450 to the subject and for a duration of no more than twelve weeks, wherein the therapeutic agent 1, the at least one polymerase inhibitor, and the inhibitor of cytochrome P450 are administered in s effective to result in SVR in the t.

In yet r aspect, the present technology provides 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, wherein the at least two DAAs are administered to the subjects in s and for a duration effective to provide a SVR in at least about 70% of the population.

In another aspect, the present technology es 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). 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 ses administering the at least two DAAs to a t infected with HCV.

The treatment does not include administering interferon or ribavirin. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e. g., stat) if one of the DAAs requires pharmacokinetic enhancement. The at least two DAAs can be administered concurrently or tially.

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 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 d 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 patient, a HCV-treatment enced t, an interferon non-responder (e.g., a null responder, a partial responder, or a relapser), or not a candidate for eron treatment.

In another aspect, the present technology features a combination of Compound 1 (or a pharmaceutically able salt f) and Compound 2 (or a pharmaceutically acceptable salt f) 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 does not include administering eron or ribavirin. 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 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 thereof) can be administered twice daily. For yet r example, Compound 1 (or the salt thereof) and vir (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), co-formulated with ritonavir (or r 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 genotype 1a or 1b. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet r non-limiting example, the patient can be a HCV-treatment na'1've patient, a HCV-treatment experienced patient, an interferon non- responder (e.g., a null der), or not a candidate for interferon treatment. In one example, the treatment lasts for 12 weeks, and the subject being d 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 pe 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient ed with HCV genotype 1. In yet another example, the treatment lasts for 9 weeks, and the t 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 d is a naive patient infected with HCV genotype 1. In yet another 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 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 pe 2. In yet another e, 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 r example, the treatment lasts for 10 weeks, and the t being treated is a naive patient ed 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, 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) ed with HCV genotype 1. In r 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 der) 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) ed with HCV pe 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 technology features a combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 3 (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 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 treatment does not include administering interferon or ribavirin. Ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) is administered with Compound 1 (or the salt thereof) to improve the pharmacokinetics 2012/061085 of the latter. nd 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 thereof) can be administered once daily, together with vir or another CYP3A4 inhibitor (e. g., cobicistat), and Compound 3 (or the salt thereof) can be administered twice daily. For r example, Compound 1 (or the salt thereof) and Compound 3 (or the salt thereof) are administered once daily. For yet another example, Compound 1 (or the salt thereof) and ritonavir (or another 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), ritonavir (or another CYP3A4 inhibitor, e.g., cobicistat), and Compound 3 (or the salt f) 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 eatment 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 t 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 treated is a naive patient infected with HCV genotype 1. In yet r example, the treatment lasts for 9 weeks, and the t being treated 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 r example, the treatment lasts for 12 weeks, and the subject being d is a naive patient infected with HCV genotype 2. In r example, the ent 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 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 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 treatment lasts for 10 weeks, and the subject being treated is a naive t infected with HCV genotype 3. In yet r 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, 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 WO 59638 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 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 another example, the treatment lasts for 9 weeks, and the subject being treated is a non-responder (e.g., a null der) infected with HCV genotype 1. In yet another e, 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 r aspect, the present technology features a combination of Compound 1 (or a pharmaceutically acceptable salt thereof) and Compound 4 (or a pharmaceutically acceptable salt thereof) for use in ng HCV infection. The treatment ses stering 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 does not include stering eron or ribavirin. Ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) is administered with Compound 1 (or the salt thereof) to e the pharmacokinetics of the latter. nd 1 (or the salt thereof) and Compound 4 (or the salt thereof) can be administered rently 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 4 (or the salt thereof) can be administered twice daily. For another example, Compound 1 (or the salt thereof) and Compound 4 (or the salt thereof) are administered once daily. For yet another example, 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, nd 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 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 t can be a eatment na'1've patient, a HCV-treatment experienced patient, an eron 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 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 pe 1. In yet another example, the treatment lasts for 8 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 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 pe 2. In still another example, the ent 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 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) infected with HCV pe 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) infected with HCV genotype 1.

In r aspect, the present technology features a combination of nd 1 (or a ceutically acceptable 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 on 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 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 does not include administering interferon or ribavirin. Ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) is administered with Compound 1 (or the salt f) to e the pharmacokinetic of the latter. Compound 1 (or the salt thereof), nd 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 thereof) 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 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 administered concurrently (e. g., once daily). For yet another example, Compound 1 (or the salt f), 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 daily); and Compound 2 (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 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 sponder (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 t infected with HCV genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient ed 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 pe 1. In yet another example, the treatment lasts for 8 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 2. In another 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 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 d is a naive patient infected with HCV genotype 2. In yet another example, the ent lasts for 12 weeks, and the t 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 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 genotype 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 d is a non-responder (e.g., a null responder) infected with HCV pe 1. In another example, the treatment lasts for 11 weeks, and the t being treated 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 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 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. 2012/061085 In another aspect, the t 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 PSI-938, a combination of EMS-790052 and EMS-650032, a combination of GS-5885 and GS-9451, a combination of GS-5885, GS—919O 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 treatment comprises administering 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). ably, the on 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 . The treatment does not include administering interferon or ribavirin. The treatment may include administering vir 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 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 non- limiting example, the t 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 yet another , the present technology features a ation of at least two DAAs for use in treating HCV infection, wherein said combination comprises a combination ed from: a combination of PSI-7977 and EMS-790052 a combination ofPSI-7977 and EMS-650032, a combination ofPSI-7977, 0052 and 0032, a combination ofINX-l89 and EMS-790052 a combination ofINX-l89 and EMS-650032, or a combination ofINX-l89 EMS-790052 and EMS-650032.

The treatment comprises administering 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 on of the ent 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 does not include administering interferon or ribavirin. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., stat) 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 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 lb. As another non- limiting example, the t 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 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 comprises a combination selected from: a combination of mericitabine and danoprevir, a combination of INK-189, asvir and EMS-791325, and a combination of PSI-7977 and GS-5885.

The treatment comprises stering 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 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 does not include administering either interferon or ribavirin. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e. g., cobicistat) if one of the DAAs requires cokinetic ement. 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 administered 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 lb. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet r non-limiting example, the patient can be a eatment na'1've 2012/061085 patient, a HCV-treatment experienced patient, an interferon sponder (e. g., a null responder), or not a candidate for interferon ent.

In still another aspect, the present technology features 77, or a combination of at least two DAAs, for use in treating HCV infection, wherein said combination comprises a combination selected from: a combination of mericitabine and danoprevir, a combination of INK-189, asvir and EMS-791325, and a combination of PSI-7977 and 5.

The treatment comprises administering PSI-7977 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). 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 does not include stering either interferon or ribavirin. The treatment may include administering ritonavir or r CYP3A4 inhibitor (e. g., cobicistat) if one of the DAAs es 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 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-treatment naive patient, a eatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon treatment.

In still another 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 tegobuvir and 6, a combination of EMS-791325, asunaprevir and daclatasvir, and a ation of TMC—435 and asvir.

The treatment comprises administering 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 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 treatment does not include WO 59638 administering either interferon or ribavirin. The treatment may e stering ritonavir or another CYP3A4 inhibitor (e.g., stat) 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 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 ed 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 yet another aspect, the present technology features a combination 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 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 does not include administering either interferon or ribavirin. The ent may include administering ritonavir or another CYP3A4 inhibitor (e. g., cobicistat) if one of the DAAs es cokinetic enhancement. The two DAAs can be stered concurrently or tially.

For example, one DAA can be administered once daily, and the other DAA can be administered twice daily. For r 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 miting example, the patient can be infected with HCV genotype 2 or 3. As yet another miting example, the patient can be a HCV-treatment na'1've 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 d 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 e, 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 another example, the treatment lasts for 8 weeks, and the subject being treated is a naive patient infected with HCV pe 1. In yet another 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 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 treated is a naive t infected with HCV genotype 2. In yet another example, the treatment lasts for 12 weeks, and the t 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 infected with HCV genotype 3. In still another example, the treatment lasts for 10 weeks, and the t being d is a naive patient infected with HCV genotype 3. In yet r example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another e, the treatment lasts for 8 weeks, and the t 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 d 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 der) 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 genotype 1.

In yet another aspect, the t technology features a combination of PSI-7977 and TMC—435 for use in treating HCV infection. The treatment comprises administering the DAA combination to a subject ed with HCV. The on of the treatment regimen is no more than twelve weeks (e.g., the on being 12 weeks; or the on 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 does not include administering either eron or ribavirin. The treatment may include stering 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 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 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 patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null der), 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 d is a naive patient infected with HCV genotype 1. In still another example, the ent lasts for 10 weeks, and the t 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 ed 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 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 ent 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 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 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 genotype 3. In yet another example, the ent lasts for 8 weeks, and the t 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 d is a non-responder (e.g., a null der) 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 example, the treatment lasts for 9 weeks, and the subject being d is a non-responder (e.g., a null responder) 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) infected with HCV pe 1.

In yet another aspect, the present technology features a combination of danoprevir and mercitabine for use in treating 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 sixteen weeks (e. g., the duration being 16 weeks; or the duration being 14, 12 or 10 weeks). The duration of the ent regimen may also be less than 10 weeks. The treatment does not include administering either interferon or ribavirin. The treatment also includes co-administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) with danoprevir to e the pharmacokinetics of danoprevir. 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-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 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 naive t ed with HCV pe 1. In still r 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 d is a naive t 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 1. In yet another e, the ent lasts for 12 weeks, and the subject being treated is a naive patient infected with HCV pe 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 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 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 r e, the treatment lasts for 14 weeks, and the t 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 ed 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 sponder (e.g., a null responder) infected with HCV genotype 1. In another example, the treatment lasts for 15 weeks, and the t 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 r e, 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 subject being d 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 INK-189, asvir and EMS-791325 for use in treating HCV infection. The treatment comprises administering the DAA combination to a subject infected with HCV. The duration of the treatment n 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 does not include administering either eron or ribavirin. The treatment may e 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 stered twice daily. For another example, the two DAAs are stered 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-treatment naive patient, a HCV-treatment experienced patient, an interferon non-responder (e.g., a null responder), or not a candidate for interferon ent. In one example, the ent 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 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 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 t being treated is a naive patient infected with HCV pe 2. In another e, 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 ent lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 2. In yet another e, 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 infected with HCV pe 3. In another example, the treatment lasts for 15 weeks, and the subject being treated is a naive t ed with HCV genotype 3. In still another example, the treatment lasts for 14 weeks, and the subject being d is a naive patient infected with HCV pe 3. In yet another example, the treatment lasts for 13 weeks, and the t 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 genotype 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) infected with HCV genotype 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 genotype 1. In yet r 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 r example, the treatment lasts for 12 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 present technology es a combination of PSI-7977 and GS- 5885 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 n 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 does not include administering either interferon or ribavirin. The treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat) if one of the DAAs es 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 pe 1, such as genotype 1a or 1b. As r non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another miting 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 infected with HCV genotype 1. In r 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 r 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 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 ed with HCV genotype 2. In another example, the ent 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 t being treated is a naive patient infected with HCV genotype 2. In yet r 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 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 e, 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 ed 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 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 another example, the treatment lasts for 15 weeks, and the t being d is a sponder (e. g., a null responder) infected with HCV genotype 1. In still r example, the treatment lasts for 14 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 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 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 TMC—435 and daclatasvir 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 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 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 two DAAs can be administered concurrently or sequentially. For e, one DAA can be administered once daily, and the other DAA can be stered twice daily. For r example, the two DAAs are stered 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 1a or 1b. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another miting example, the patient can be a HCV-treatment na'1've 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 na'1've 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 ent 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 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 ed 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 t 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 another example, the treatment lasts for 11 weeks, and the subject being treated is a naive t infected with HCV genotype 3. In still r example, the ent lasts for 10 weeks, and the subject being treated is a naive patient infected with HCV genotype 3. In yet another e, 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 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) 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 ent 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 non-responder (e.g., a null responder) infected with HCV genotype 1. In yet another example, the treatment lasts for 8 weeks, and the t being treated is a non-responder (e. g., a null responder) ed with HCV genotype 1.

In another aspect, the present invention features methods for treatment of HCV infection, wherein the methods comprise stering to a subject in need thereof at least two direct acting antiViral agents (DAAs), and the treatment does not include administration of either interferon or ribaVirin to the subject. 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 t being d can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient, or an eron non-responder (e.g., a null der).

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 acceptable salt thereof, and (ii) Compound 2 or a pharmaceutically acceptable salt thereof, and said method r comprises administering ritonavir to the t.

Ritonavir improves 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 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 pe 1a. As another non-limiting e, 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 able salt thereof, and (ii) nd 4 or a pharmaceutically acceptable salt thereof, and the method further comprises administering ritonavir to the subject to improve the pharmacokinetics or drug exposure of Compound 1. 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 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 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 acceptable salt thereof, and (iii) Compound 4 or a pharmaceutically acceptable salt thereof, and the method further comprises administering ritonavir to the subject to e the pharmacokinetics or drug exposure of Compound 1. The treatment 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 t 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 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 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 d 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 non-limiting example, the subject being ent 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 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. 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 embodiment of this aspect of the invention, the at least two DAAs comprise a HCV protease inhibitor and a nucleoside or nucleotide HCV rase 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 eron sponder (e.g., a null responder). Preferably, the subject being d is infected with HCV pe 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 a HCV protease inhibitor and a HCV NSSA inhibitor. 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 d 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 ent is ed with HCV genotype 3.

In yet another embodiment of this aspect of the ion, 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 t 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 d 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 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 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 ent is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs se a HCV nucleoside or nucleotide polymerase inhibitor and a HCV NSSA inhibitor. The treatment can last, for e and without limitation, for no more than 12 weeks, such as 8, 9, 10, 11 or 12 weeks.

Preferably, the ent 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 sponder (e.g., a null responder). ably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As r non-limiting example, the subject being treatment is infected with HCV pe 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise PSI-7977 and 5. The treatment 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 d 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).

In yet another embodiment of this aspect of the invention, the at least two DAAs comprise TMC—435 and daclatasvir. 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 der).

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 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. 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 eron 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 PSI-7977 and GS-S885 . 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 t 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 pe 1a. As another non-limiting example, the subject being treatment is infected with HCV genotype 3.

In yet r ment of this aspect of the ion, the at least two DAAs comprise mericitabine and evir. 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 t 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 pe 3.

In yet r ment of this aspect of the invention, the at least two DAAs comprise EMS-790052 and 0032. 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 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 INX-189, daclatasvir and 1325. 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 t 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 e, the subject being treatment is infected with HCV genotype 3.

In yet another , the present invention features methods for treatment of a treatment- na'ive subject with HCV genotype 1 infection, n the method comprises administering an effective amount of PSI-7977 to said patient, and the treatment does not include administration of either interferon or rin to the subject. The treatment 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. Preferably, the subject being treated is infected with genotype 1a. More preferably, the t being treated is a naive patient infected with genotype 1. The t being treated can also be a treatment-experienced patient or an interferon non-responder (e.g., a null responder), and/or is infected with HCV genotype 3. In one example, the treatment lasts for 12 weeks, and the subject being treated is a naive patient infected with genotype 1. In another example, the treatment lasts for 11 weeks, and the subject being treated is a naive patient infected with genotype 1. In still another example, the treatment lasts for 10 weeks, and the subject being treated is a naive patient infected with pe 1. In yet another example, the treatment lasts for 9 weeks, and the subject being treated is a naive patient ed 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 ion 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 , the present invention features methods for treatment of HCV infection, wherein the methods comprise administering to a t in need thereof at least two DAAs for a duration sufficient to achieve a sustained virologic response. The treatment does not include administration of either interferon or ribavirin. Any DAA combination bed herein can be used. The duration can be, for example no more than 8 weeks or preferably, no more than 12 weeks.

A treatment n of the present logy lly constitutes 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. Preferably, a treatment or use described herein does not include any subsequent ribavirin-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 indicating preferred embodiments of the invention, are given by way of illustration only, not limitation. s changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description BRIEF PTION OF THE DRAWINGS Figure 1 is a 3-D surface plot illustrating deviations from ed inhibitory effects from varying concentrations of Compound 1 and Compound 2 in a pe 1b HCV replicon assay.

Figure 2 is a contour plot showing concentrations at which Compound 1 and Compound 2 ted syngeristic, additive, or antagonistic interactions in the genotype lb HCV replicon assay.

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

Figure 4 is a contour plot showing concentrations at which Compound 1 and Compound 4 exhibited syngeristic, ve, 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.

Figure 5B is another bar graph showing the percentage of surviving 1a-H77 replicon cells grown in the ce of G418, and two or three DAA combinations, for approximately three weeks.

Figure 5C depicts the effect of Compound 1, Compound 4 and a combination f in long- term HCV RNA reduction assays in 1a-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 1b-Con1 replicon cell lines.

Figure 6A shows the ted median and 90% conﬁdence interval 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 2.

Figure 6B illustrates the predicted median and 90% conﬁdence al of SVR tage for different treatment durations of a 2-DAA regimen without ribavirin; the 2 DAAs include Compound 1 (in combination with vir, i.e., nd 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 without ribavirin; the 3 DAAs include (i) Compound 1 (in combination with ritonavir, i.e., Compound 1/r), (ii) Compound 2 and (iii) Compound 4.

Figure 7 shows the exposure-response model predicted versus observed percentage of subjects with HCV RNA less than LOD over time in a clinical study.

Figure 8 demonstrates the exposure-response model predicted versus observed tage of subjects with SVR12 in another clinical study.

Figure 9 shows the predicted median and 90% conﬁdence interval of SVR rates for different treatment durations of a 2-DAA regimen containing EMS-790052 and EMS-650032.

Figure 10 shows the predicted median of SVR rates for different treatment durations of a 3- DAA regimen containing nd 1/r, Compound 4 and 77.

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 s the predicted median and 90% nce interval of SVR tage for different treatment durations of a 2-DAA regimen containing daclatasvir (EMS-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 n 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.

Figure 15 depicts the predicted median and 90% conﬁdence al of SVR percentage for different treatment durations of a 2-DAA regimen containing GS-9l90 (tegobuvir) 30 mg BID + GS-9451 200 mg QD + GS-5885 90 mg QD.

Figure 16 shows the predicted median and 90% confidence interval of SVR percentage for different treatment durations of the ing DAA combo regimens: (1) GS-9451 200 mg QD + GS- 7977 977) 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 percentage for different treatment durations of a 2-DAA regimen containing TMC-435 150 mg QD and daclatasvir (BMS—790052) 60 mg QD.

DETAILED DESCRIPTION OF THE ION The present methods can include administering therapeutic agent 1 to a subject. Therapeutic agent 1 is nd 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)- 1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2- a][1,4]diazacyclopentadecine-14a-carboxamide. Compound 1 is a potent HCV se inhibitor. The synthesis and formulation of Compound 1 are described in U.S. Patent Application Publication No. 2010/0144608, U.S. Provisional Application Serial No. 61/339,964 filed on March 10, 2010, and U.S.

Patent Application Publication No. 2011/0312973 ﬁled on March 8, 2011. All of these applications are incorporated herein by reference in their entireties. Therapeutic agent 1 includes various salts of Compound 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 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 Ritonavir or another inhibitor of cytochrome P-450 preferably is co-administered with eutic agent 1 to improve the pharmacokinetics of Compound 1.

The present s can e administering therapeutic agent 2 to a t. Therapeutic agent 2 is Compound 2 or a salt thereof LNYO CCNHSOZCH; Compound 2 Compound 2 is also known 3-tert-butyl(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)- 2-methoxyphenyl)naphthalenyl)methanesulfonamide. As described in, for example, International Publication No. WO2009/O39127, therapeutic agent 2 includes various salts of Compound 2, such as sodium salts, potassium salts, and choline salts. Therapeutic agent 2 also includes crystalline forms of Compound 2 and its salts such as solvate, hydrate, and solvent-free crystalline forms of Compound 2 and its salts. Compositions comprising therapeutic agent 2 can be ed as described in, for example, International Publication No. WO2009/039127 which is orated by reference .

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 administered 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 n.

In some embodiments, the total daily dosage amount for therapeutic agent 2 is about 600 mg. In some embodiments, the total daily dosage amount for eutic 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.

Compound3 Compound 3 is also known as (E)-N—(4-(3-tert-butyl(2,4-dioxo-3,4-dihydropyrimidinl (2H)-yl)methoxystyryl)phenyl)methanesulfonamide. As described in, for example, ational Publication No. W02009/039127, therapeutic agent 3 includes various salts of Compound 3, such as sodium salts, potassium salts, and choline salts. eutic agent 3 also includes lline forms of Compound 3 and its salts such as e, 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, International Publication No. W02009/039127 which is incorporated by reference 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 stered 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/kg to about 15 mg/kg or from about 1 mg/kg to about 10 mg/kg. As non-limiting examples, therapeutic 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 therapeutic agent 4 or a salt thereof to a subject. Therapeutic agent 4 is Compound 4 or a salt thereof.

ZI J Compound 4 Compound 4 is also known as dimethyl (2S,2’S)-1,1’-((2S,2’S)-2,2’-(4,4’-((2S,5$)(4-tert- butylphenyl)pyrrolidine-2,5,diyl)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 described in, for example, US. Publication No. 2010/0317568, 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 n. In some embodiments, the total daily dosage amount for therapeutic agent 4 is about 25 mg.

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

Other erons include, but are not limited to, interferon-alpha-2a (e.g., Roferon-A by Roche), interferon-alpha-2b (e. g., lntron-A by Schering-Plough), and interferon alfacon-l (consensus interferon) (e.g., lnfergen by Valeant). Less than 50% of patients with chronic HCV ion 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 temporary disability in some cases. A substantial proportion of patients will experience a panoply of side effects ranging from a “flu-like” me (the most common, experienced for a few days after the weekly injection of eron) to severe adverse events including anemia, cardiovascular events and atric problems such as suicide or al ideation. The latter are bated by the general physiological stress experienced by the ts. Ribavirin also has a number of side effects, including, anemia, high pill burden (e.g. 5-6 pills a day split BID) and genicity restricting use in women of childbearing age.

The present methods provide effective treatment of HCV infection without the use of interferon or ribavirin and for a shorter period of time, such as a treatment duration of no more than twelve weeks, alternatively no more than eleven weeks, alternatively no more than ten weeks, alternatively no more than nine weeks, alternatively 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 logy provides methods for ng HCV infection in a subject comprising administering at least two DAAs in the absence of interferon and ribavirin for a duration of no more than twelve weeks, alternatively no more than eight weeks. Put another way, the present methods e interferon and ribavirin, or the subject does not receive interferon or rin for the duration of the ent. The at least two DAAs can be co-administered or can be administered independently (with the same or different dosing frequencies) and can be administered once a day, alternatively twice a day, alternatively three times a day.

In some embodiments, the s 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 administered 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 are administered in effective amounts to provide a desired measure of effectiveness in the subject.

Preferably, the treatment has reduced side effects as compared with interferon-containing treatments.

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. 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 serum of the t after 12 weeks of ent. 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 therapy (EOT).

Another measure is SVR, which, as used , means that the virus is undetectable at the end of y and for at least 8 weeks after the end of therapy (SVR8); 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 ctable at the end of therapy and for at least 24 weeks after the end of therapy (SVR24). SVR24 is often considered as a functional deﬁnition 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. Likewise, a high rate of SVR at less than 12 week post-treatment (e.g., SVR4 or SVR8) can be predictive of a high rate of SVR12. A high rate of EOT (e.g., at week 8 or week 12) can also be tive of a signiﬁcant rate of SVR12 or SVR24.

In some embodiments, the amounts of the two or more DAAs, and/or the duration of the treatment regimen of the two or more DAAs, are effective to provide an RVR in a subject, or an EVR in a subject, or a cEVR in a t, 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. treatment na'ive subjects), and the methods comprise stering at least two DAAs to the subjects for a duration of no more than 12 weeks, or for another duration disclosed herein, n the at least two DAAs 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 population, alternatively at least about 90% of the population, alternatively at least about 95% of the population, alternatively about 100% of the population.

In some ments, the present methods comprise treating a population of IFN experienced subjects (e.g., interferon non-responders) having HCV infection, and the s comprise administering at least two DAAs to the subjects for a duration of no more than 12 weeks, or for another duration disclosed herein, wherein the at least two DAAs 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 50% of the population, atively 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 ments, the amount of DAAs and the duration 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, atively at least about 90% of the tion, alternatively at least about 95% of the population, alternatively about 100% of the population. For example, the present s comprise administering at least two DAAs in amounts and for ons effective to provide an SVR (e. g., SVR after 8 weeks post- treatment, or SVR after 24 weeks reatment) in a t. In some embodiments, the present technology provides for an SVR (e.g., SVR 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, 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 d by such methods herein described, more preferably in at least 80% of the population, 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 addition 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 NS5B inhibitor, an HCV entry inhibitor, a cyclophilin inhibitor, a CD81 inhibitor, or an al ribosome entry site inhibitor. The HCV polymerase inhibitor may be a nucleoside or nucleotide polymerase inhibitor or a non-nucleoside polymerase inhibitor. The HCV polymerase inhibitor may be a nucleotide polymerase inhibitor or a cleotide polymerase tor.

In yet another example of this aspect of the technology, the combination oftwo 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 0052 and BMS-650032. In yet another example, the combination of two or more DAAs comprises GS—5885, GS-9190, and 1. 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 e, the ation of two or more DAAs comprises 5 and GS—945 1. 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 77 and EMS-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 PSI-7977, BMS-650032 (asunaprevir) and BMS-790052 (daclatasvir). In another example, the combination of two or more DAAs es INX-189 and BMS- 790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INX-189 and EMS-650032 (asunaprevir). In still another example, the combination of two or more DAAs includes INX-189, 0032 (asunaprevir) and EMS-790052 (daclatasvir). In yet another example, the ation of two or more DAAs ses TMC—435 and daclatasvir.

It was unexpected that an eron-free and ribavirin-free treatment using a combination of two or more DAAs, and for a duration of no more than 12 weeks, can achieve signiﬁcant SVR. In some cases, such a treatment can achieve an SVR in at least about 75% of patients, and in some cases, such a treatment can achieve an SVR in at least about 85% of patients, and in certain cases, such a treatment can achieve an SVR in at least about 90% of ts. It was also unexpected that an interferon-free and rin-free treatment using a combination of two or more DAAs, and for a duration of no more than 12 weeks, may achieve signiﬁcant SVR in interferon non-responders (e.g., null responders), for example, such a treatment may 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 population.

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. The treatment lasts 8 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequencies. The patient being treated can be a treatment naive patient, a treatment enced patient, including, but not limited to, a relapser, an interferon partial responder, or an interferon non-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 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 tors, HCV polymerase inhibitors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a ation 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 ation 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 tor and at least one non-nucleoside polymerase inhibitor). For another ce, 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 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 tors (e.g., a combination of at least two nucleoside or nucleotide rase inhibitors, or a ation of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least two non-nucleoside polymerase inhibitors). For r 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 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 polymerase inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide rase 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 e, the combination of two or more DAAs is a ation of nd 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 f) and Compound 3 (or a salt thereof).

Compound 1 (or a salt thereof) can be co-formulated with ritonaVir. In still another e, the combination of two 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 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 r 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 can be co-formulated with ritonaVir. In yet another example of this aspect of the technology, the combination of two or more DAAs comprises PSI-7977 and PSI-938. In yet r example, the ation 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 EMS-790052 and BMS-650032. In yet another e, the combination of two or more DAAs ses 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 ses 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 example, the combination of two or more DAAs includes PSI-7977 and EMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI-7977, EMS-650032 (asunapreVir) and BMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes 9 and EMS-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 INK-189, EMS-650032 (asunapreVir) and EMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes 9 and EMS-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 es mericitabine and danopreVir. In still another example, the ation 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- 2012/061085 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 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. 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 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 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 e, the method comprises stering 100 or 150 mg nd 1 together with 100 mg ritonavir once daily, 25 mg Compound 4 once daily, and 400 mg Compound 3 twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology. 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 increasing the amount of the binder (e.g., done) in a solid formulation of Compound 2 (or a pharmaceutically 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 al formulation.

In another aspect, the present technology features a method of treating HCV, sing administering to a t in need thereof an effective amount of a combination of two or more DAAs.

The treatment lasts 7 weeks and does not include administration of any interferon or any ribavirin. The DAAs can be administered at the same or different dosing frequency. The patient being treated can be a treatment na'ive patient, a treatment experienced t, 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 t 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 ive 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 se inhibitor and at least one HCV rase 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 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 polymerase 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 ce, 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 rase 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-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 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 ation 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 cleoside 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 tor, 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 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 or inistered with ritonaVir. In still another example, the combination of two or more DAAs is a ation 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 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 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 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 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 asVir. In yet another example, the ation of two or more DAAs comprises EMS-790052 and BMS-650032. In yet another example, the combination of two or more DAAs comprises GS—5 885, 0, and GS-9451. In yet another example, the ation of two or more DAAs comprises 335 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 another e, the combination of two or more DAAs includes PSI-7977 and BMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs es PSI-7977 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 another example, the combination of two or more DAAs includes INK-189, EMS-650032 (asunapreVir) and EMS-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 INK-189, BMS-650032 (asunapreVir) and BMS-790052 (daclatasVir). In still another example, the ation of two or more DAAs includes tabine and danopreVir. In still another example, the combination of two or more DAAs includes 9, daclatasVir and BMS- . In still another example, the combination of two or more DAAs includes PSI-7977 and GS- 5885. In still another e, 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. 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 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 Vir 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. 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.

The treatment lasts 6 weeks and does not e administration of any interferon or any ribavirin. The patient being treated can be a treatment naive patient, a treatment enced 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 pe 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 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 itions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, 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 rase inhibitor (e.g., a ation 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 tide polymerase inhibitor, or a combination of at least one HCV protease inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one leoside polymerase 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 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 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 rase inhibitors (e. g., a combination of at least two nucleoside or tide 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 cleoside 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 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 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 another example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and nd 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 nd 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 ation 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 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 f) can be co-formulated with Vir. 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 example, the combination of two or more DAAs ses EMS-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 ses 335 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 EMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- 650032 (asunapreVir) and EMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and 0052 (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 INK-189, BMS-650032 (asunapreVir) and EMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-650032 (asunapreVir). In still another e, the combination of two or more DAAs includes INK-189, EMS-650032 (asunapreVir) and EMS-790052 (daclatasVir). In still another e, 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 1325. In still another example, the ation 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 r example, the method comprises administering to a patient in need thereof an ive amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs. In still another example, the method comprises administering 100 or 200 mg Compound 1 er 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 vir 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 r 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 r 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 Compound 3 twice daily. Other DAA(s) can also be included in a treatment n according to this aspect of the technology.

The treatment lasts 5 weeks and does not include administration of any interferon or any ribavirin. The DAAs can be administered at the same or different dosing frequency. The patient being treated can be a treatment naive patient, a treatment experienced patient, including, but not d to, a relapser, an interferon partial responder, or 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 genotypes. The DAAs can be administered around the same time or at different times, and can be mulated in a single formulation or formulated in ent compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase tors, or HCV NSSA inhibitors. For instance, the combination of two or more DAAs can be a ation 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 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 rase inhibitor). 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 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 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 tors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one cleoside 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 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 tor, or a combination of at least one HCV NSSA inhibitor and at least one side or nucleotide polymerase tor, 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 example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) and Compound 3 (or a salt f).

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 nd 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 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 Compound 1 (or a salt thereof), Compound 3 (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 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 EMS-790052 and EMS-650032. In yet r e, the combination of two or more DAAs comprises 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 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 es PSI-7977 and EMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes 77, EMS-650032 (asunaprevir) and EMS-790052 tasvir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-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 previr) and BMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes 9 and EMS-650032 (asunaprevir). In still another e, the combination of two or more DAAs includes INK-189, EMS-650032 (asunaprevir) and 0052 (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 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, nd 1 (with ritonavir), and Compound 4. In still r 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. 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 er 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 vir 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 together with 100 mg ritonavir once daily, 25 mg Compound 4 once daily, and 400 mg Compound 3 twice daily. Other DAA(s) can also be included in a treatment regimen ing to this aspect of the technology.

In yet another , 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.

The treatment lasts 4 weeks and does not e administration of any interferon or ribavirin. The DAAs can be administered at the same or ent dosing frequency. 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, or 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 ive 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 formulated in ent 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 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 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 rase inhibitor and at least one non-nucleoside polymerase 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 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 or nucleotide polymerase tors, 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 cleoside 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 nucleoside or nucleotide polymerase tor and at least one non-nucleoside polymerase 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 nd 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 nd 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), nd 2 (or a salt thereof) and nd 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 is a ation 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-formulated with ritonaVir. 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 ses 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 EMS-790052 and EMS-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 combination of two or more DAAs comprises 335 and BI-207l27. In yet another example, the combination of two or more DAAs comprises eVir 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 ation of two or more DAAs includes PSI-7977 and EMS-790052. In yet r example, the combination of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still r example, the combination of two or more DAAs includes PSI-7977, EMS-650032 (asunapreVir) and EMS-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 another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunapreVir) and EMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs es 9 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs es INK-189, EMS-650032 (asunapreVir) and EMS-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 EMS-791325. In still r example, the combination of two or more DAAs includes 77 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 r 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. 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 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 e, 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 vir once daily, 25 mg Compound 4 once daily, and 400 mg Compound 3 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 logy 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.

The treatment lasts 3 weeks (or even less, depending on the patient’s ion) and does not include administration of any interferon or rin. The DAAs can be administered at the same or different dosing frequency. The t being treated can be a treatment naive patient, a treatment experienced patient, including, but not d to, a relapser, an interferon partial responder, or an interferon non- responder (e.g., a null responder), or a t 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 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 different 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 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 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 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 polymerase 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 polymerase inhibitors (e. g., a ation 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- nucleoside rase 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 inhibitor (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 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 cleoside polymerase inhibitor). In one example, the combination of two or more DAAs is a combination of nd 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 f). 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). 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 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 f), nd 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 ses 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 5 and asVir. In yet another example, the combination of two or more DAAs comprises EMS-790052 and BMS-650032. In yet another e, the combination of two or more DAAs comprises GS—S 885, GS—9190, and 1. 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 0052 (daclatasVir). In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI-7977, EMS-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 another example, the combination of two or more DAAs es INK-189 and EMS-650032 (asunapreVir). In still r example, the combination of two or more DAAs includes INK-189, EMS-650032 (asunapreVir) and EMS-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 INK-189, BMS-650032 (asunapreVir) and BMS-790052 (daclatasVir). In still another e, the combination of two or more DAAs includes mericitabine and danopreVir. In still another example, the combination of two or more DAAs es INK-189, daclatasvir and EMS- 791325. In still another e, the ation 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 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. 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 ses 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 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. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In yet another aspect, the present logy 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.

The treatment lasts 24 weeks and does not include administration of any interferon or ribavirin. The DAAs can be administered at the same or different dosing frequency. The patient being treated can be a treatment naive patient, a treatment experienced t, including, but not limited to, a relapser, an interferon partial responder, an interferon 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 pe 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 ent compositions. Each DAA can be selected from HCV protease tors, 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 rase inhibitor (e.g., a combination of at least one HCV protease tor and at least one non-nucleoside rase inhibitor, or a ation 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 inhibitor). For another instance, the ation 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 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 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 ce, 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- side 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 nucleotide polymerase inhibitor and at least one non-nucleoside polymerase 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 f) 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 mulated with ritonaVir. In a further example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f), 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 example, the combination of two or more DAAs comprises PSI-7977 and 8. In yet another example, the combination of two or more DAAs comprises PSI-7977 and TMC-435. In yet another example, the ation of two or more DAAs ses TMC-435 and daclatasVir. In yet another example, the combination of two or more DAAs comprises EMS-790052 and EMS-650032. In 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 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 evir (with ritonavir) and R7128. In yet another example, the combination of two or more DAAs includes 77 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 EMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes INK-189 and 0032 (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 INK-189, daclatasvir and EMS-791325. In still r example, the combination 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.

In still another example, the method comprises stering 100 or 200 mg Compound 1 together with 100 mg vir 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 ritonavir once daily, and 400 mg Compound 3 once daily. In r example, the method comprises administering 150 mg Compound 1 together with 100 mg ritonavir once daily, and 400 mg nd 3 twice daily. In r e, 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 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. 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. The treatment lasts from 13 to 23 weeks (e.g., the duration of the treatment is selected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 weeks) and does not include administration of any interferon or ribavirin. The DAAs 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 eron non-responder (e.g., a null responder), or a t unable to take interferon. The patient can be ed with, for example and without limitation, HCV 2012/061085 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 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 instance, the combination of two or more DAAs can be a combination of at least one HCV se tor 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 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 another ce, 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 ation of at least one HCV se 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 tors (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 ation of two or more DAAs can be a ation 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 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 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 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 r 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 e, the combination of two or more DAAs is a combination of Compound 1 (or a salt f), 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 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 EMS-790052 and EMS-650032. In yet another example, the ation of two or more DAAs comprises GS—5885, GS-9190, 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 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 Vir) and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-790052. In yet another example, the combination of two or more DAAs includes 77 and EMS-650032 preVir). In still another e, the combination of two or more DAAs includes PSI-7977, EMS-650032 (asunapreVir) and EMS-790052 (daclatasVir). In yet another e, the combination of two or more DAAs includes INK-189 and EMS-790052 (daclatasVir). In yet another example, the ation of two or more DAAs includes INK-189 and EMS-650032 preVir). In still another example, the combination of two or more DAAs es INK-189, BMS-650032 (asunapreVir) and EMS-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 EMS-791325. In still r 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.

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 r example, the method comprises administering 150 mg Compound 1 er 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 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. Other DAA(s) can also be included in a ent regimen according to this aspect of the logy.

In yet another aspect, the present technology features a method of treating HCV, comprising administering to a patient in need thereof an ive amount of a combination of two or more DAAs.

The treatment lasts 12 weeks and does not include stration of any interferon or ribaVirin. The DAAs 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, or 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 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 compositions. Each DAA can be ed from HCV protease inhibitors, HCV polymerase inhibitors, or HCV NSSA tors. 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 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 polymerase inhibitor). For r 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 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 tor. For r 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 cleoside polymerase inhibitor, or a combination of at least two cleoside 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 inhibitor, or a combination of at least one HCV NSSA inhibitor and at least one nucleoside or nucleotide rase 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 nd 1 (or a salt f) 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 ation of Compound 1 (or a salt thereof) and Compound 4 (or a salt thereof). Compound 1 (or a salt f) can be mulated with Vir. In a further example, the ation of two or more DAAs is a combination 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 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 example, the combination of two or more DAAs ses 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 EMS-790052 and EMS-650032. In yet another e, the combination of two or more DAAs comprises 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 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 Vir and R7128. In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-790052 (daclatasvir). In yet another e, the combination of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes PSI-7977, BMS- 650032 preVir) and EMS-790052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-790052 (daclatasVir). In yet another e, the combination of two or more DAAs es INK-189 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunapreVir) and EMS-790052 tasVir). In yet another 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 EMS-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 EMS-791325. In still another example, the combination of two or more DAAs includes PSI-7977 and GS-5885. In still another WO 59638 example, the combination of two or more DAAs includes PSI-7977, Compound 1 (with ritonavir), and nd 4. 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. 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 r example, the method comprises administering 150 mg nd 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 Compound 3 twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

The ent lasts 11 weeks and does not include administration of any eron or any ribavirin. The DAAs can be administered at the same or different dosing frequency. The patient being d can be a treatment naive patient, a treatment experienced patient, including, but not limited to, a relapser, an interferon partial responder, or 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 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 ation or formulated in different compositions. Each DAA can be selected from HCV protease inhibitors, HCV polymerase inhibitors, 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 inhibitor, or a combination of at least one HCV se inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase 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 2012/061085 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 or nucleotide polymerase inhibitors, or a combination of at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase tor, or a combination of at least two non-nucleoside rase inhibitors). For another ce, 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 ation 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 inhibitor). In one example, the combination of two or more DAAs is a combination of Compound 1 (or a salt f) 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 Vir. 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 mulated 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 nd 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 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 EMS-790052 and EMS-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 combination of two or more DAAs comprises BI-201335 and BI-207127. 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 comprises 5 and GS-9451. In yet another example, the combination of two or more DAAs includes danopreVir with ritonaVir and R7128. In yet another 2012/061085 e, the combination of two or more DAAs includes PSI-7977 and EMS-790052. In yet another example, the combination of two or more DAAs includes PSI-7977 and EMS-650032 previr). In still another example, the combination of two or more DAAs includes PSI-7977, 0032 (asunaprevir) and EMS-790052 (daclatasvir). In yet another example, the combination of two or more DAAs includes 9 and EMS-790052 (daclatasvir). In yet another example, the combination 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 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 INK-189, EMS-650032 (asunaprevir) and EMS-790052 tasvir). 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 1325. 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 comprises administering to a t in need thereof an ive amount of PSI-7977 as the sole DAA in lieu of a combination of two or more DAAs. 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 er 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 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 together with 100 mg ritonavir once daily, 25 mg Compound 4 once daily, and 400 mg nd 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. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

The ent lasts 10 weeks and does not include administration of any interferon or rin. The DAAs can be administered at the same or different dosing frequency. 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, or an interferon non-responder (e.g., a null responder), or a patient unable to take interferon. The patient can be ed 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 genotypes. The DAAs can be administered around the same time or at different times, and can be mulated 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 instance, the combination of two or more DAAs can be a ation 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 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 inhibitor, at least one nucleoside or nucleotide polymerase inhibitor and at least one cleoside polymerase inhibitor). For another 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 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 rase inhibitors (e.g., a combination of at least two nucleoside or nucleotide 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 ation of at least two HCV NSSA inhibitors. For another instance, the combination of two or more DAAs can be a ation 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 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 nucleoside or nucleotide rase 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 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 nd 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 Compound 1 (or a salt thereof), 2012/061085 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 f), 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 ation of two or more DAAs comprises TMC-435 and daclatasVir. In yet another example, the combination of two or more DAAs comprises EMS-790052 and EMS-650032. In yet another e, the combination of two or more DAAs comprises 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 e, 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 EMS-790052. In yet another example, the ation of two or more DAAs includes PSI-7977 and EMS-650032 (asunapreVir). In still r example, the combination of two or more DAAs includes PSI-7977, EMS-650032 (asunapreVir) and 0052 (daclatasVir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-790052 tasVir). In yet another example, the combination of two or more DAAs includes INK-189 and EMS-650032 (asunapreVir). In still another e, the combination of two or more DAAs includes INK-189, BMS-650032 (asunapreVir) and EMS-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 INK-189, EMS-650032 (asunapreVir) and 0052 (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 EMS-791325. In still another e, the ation 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 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. In still r example, the method ses 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 er with 100 mg ritonaVir once daily, and 400 mg Compound 2 twice daily. In another example, the method ses administering 150 mg Compound 1 together with 100 mg ritonaVir once daily, and 400 mg Compound 3 once daily. In another example, the WO 59638 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 Compound 3 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 treating HCV, comprising administering to a patient in need f an ive amount of a combination of two or more DAAs.

The treatment lasts 9 weeks and does not include administration of any interferon or rin. The DAAs can be administered at the same or different dosing frequency. The patient being treated can be a treatment naive patient, a treatment experienced patient, including, but not limited to, a er, or an interferon l responder, or 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 logy 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 tors. 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 protease inhibitor and at least one nucleoside or nucleotide polymerase inhibitor, or a combination of at least one HCV se inhibitor, at least one nucleoside or nucleotide polymerase tor and at least one non-nucleoside polymerase inhibitor). 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 combination of at least one HCV se 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-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 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 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 e, 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 example, the combination of two or more DAAs is a combination of Compound 1 (or a salt thereof) and Compound 3 (or a salt f).

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 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 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 ses 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 EMS-790052 and EMS-650032. In yet another example, the combination of two or more DAAs comprises GS—5885, 0, 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 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 EMS-790052. In yet another e, the combination of two or more DAAs includes PSI-7977 and 0032 (asunapreVir). In still r example, the ation of two or more DAAs includes PSI-7977, EMS-650032 (asunapreVir) and EMS-790052 (daclatasVir). In yet r e, the combination of two or more DAAs includes INK-189 and EMS-790052 (daclatasVir). In yet another example, the ation of two or more DAAs includes INK-189 and EMS-650032 (asunapreVir). In still another example, the combination of two or more DAAs includes INK-189, BMS-650032 (asunapreVir) and EMS-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 INK-189, EMS-650032 (asunaprevir) and EMS-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 EMS-791325. In still another example, the ation of two or more DAAs includes PSI-7977 and 5. In still another example, the ation of two or more DAAs includes PSI-7977, Compound 1 (with ritonavir), and Compound 4. In still another e, 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. 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 nd 3 once daily. In r 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 stering 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 nd 3 twice daily. Other DAA(s) can also be included in a treatment regimen according to this aspect of the technology.

In another embodiment, the t logy provides interferon- and ribavirin-free treatment comprising administering daily two DAAs, where the two DAAs include a HCV polymerase inhibitor, for example PSI-7977 and a NSSA inhibitor, for e EMS-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 and ribavirin for a duration of no more than twelve weeks, preferably no more than eight weeks. In some ments, ritonavir (or an equivalent thereof) is co-administered with one or more protease inhibitors to improve the cokinetics of the protease inhibitor(s). The treatment excludes administering ribavirin to the patient. In some embodiments, the HCV polymerase inhibitor is at least one nucleoside or nucleotide polymerase inhibitor or at least one non-nucleoside polymerase inhibitor. In some embodiments, both a side or tide polymerase inhibitor and a non-nucleoside 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 enced patient. Treatment enced patients include interferon non-responders (e.g., null responders), partial responders (patients whose HCV RNA levels declined but never became ctable), and relapsers (patients who achieved ctable levels of HCV RNA during therapy but rebound). Methods of the present logy may also be used to treat patients who are not candidates for interferon treatment. Patients who are not candidates for eron 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 rome P-450 inhibitor, e.g. ritonavir, is administered either in the same or separate ceutical composition with the protease inhibitor (e.g. Compound 1 (or a pharmaceutically acceptable salt thereof)) to improve the pharmacokinetics. A cytochrome P450 tor reduces the metabolism of some protease inhibitors, such as Compound 1, thereby improving the pharmacokinetics and bioavailability of the protease inhibitor, for example nd 1. More preferably, Compound 1 (or a pharmaceutically acceptable 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 cytochrome P450, such as vir, may be co-administered with the DAAs, either tially 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 strains of HCV when inistered with a DAA, thus ing the effectiveness in a shorter treatment. In some embodiments, ritonavir is co-administered with therapeutic 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 protease inhibitor and at least one HCV polymerase inhibitor in a course of treatment of no more than, or less than, eight weeks in the absence of interferon and ribavirin.

In some embodiments, the HCV polymerase inhibitor is Compound 1 (or a pharmaceutically acceptable salt thereof).

In some embodiments, the t technology provides a method of treating HCV infection without using eron and ribavirin, the method comprising administering at least two DAAs to a patient in need of such treatment, wherein the at least two DAAs include at least one se inhibitor and at least one HCV polymerase inhibitor. In some embodiments, the at least two DAAs includes therapeutic agent 1 with at least one HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor is at least one cleoside polymerase inhibitor. In some embodiments, the non- nucleoside polymerase inhibitor is therapeutic agent 2 or therapeutic agent 3 or a combination thereof.

In some embodiments, the present technology provides a method of ng HCV infection without using interferon and rin, the method comprising 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 tor is therapeutic agent 4.

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

Preferred HCV protease tors include, but are not d to, therapeutic agent 1, telaprevir (Vertex), boceprevir (Merck), BI-201335 (Boehringer Ingelheim), 1 d), and EMS-650032 (BMS). Other suitable protease tors include, but are not limited to, ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BMS— 650032 (BMS), danoprevir (RG7227/ITMN—191, Roche), GS-9132 (Gilead), GS-9256 (Gilead), IDX-136 (Idenix), IDX-3l6 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir (Schering-Plough Corp), PHX-l766 mix), TMC—435 (Tibotec), vaniprevir (MK-7009, Merck), VBY708 (Virobay), VX-SOO (Vertex), VX-813 (Vertex), VX-985 (Vertex), or a combination thereof.

Preferred non-nucleoside HCV polymerase tors for use in the present technology include, but are not limited to, therapeutic agent 2, therapeutic agent 3, GS-9190 (Gilead), BI-207127 (Boehringer Ingelheim), and VX-222 (VCH-222) (Vertex & 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 e ANA-598 (Anadys), BI-207127 inger Ingelheim), BILB-l94l (Boehringer Ingelheim), EMS-791325 (BMS), fllibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), 1 (Merck), tegobuvir, 7055 ec), VCH-759 (Vertex & em), VCH-916 (ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102 (Idenix), IDX-l84 (Idenix), INK-189 (Inhibitex), MK-O608 (Merck), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), ALS-2200 (Alios BioPharma/Vertex), ALS-2158 (Alios BioPharma/Vertex), or a combination thereof. A polymerase inhibitor may be a nucleoside or nucleotide polymerase inhibitor, such as 0 (Gilead), 2 (Idenix), IDX-l84 x), INX-l89 (Inhibitex), MK-O608 (Merck), 77 (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 68554 (Pﬁzer), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-l94l (Boehringer eim), BMS- 791325 (BMS), ﬁlibuVir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuVir (Gilead),, TMC—647055 (Tibotec), VCH-759 (Vertex & ViraChem), 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, EMS-790052 (EMS) and GS-5885 (Gilead). Non-limiting es of suitable NSSA inhibitors include GSK62336805 (GlaxoSmithKline), ACH-2928 (Achillion), AZD2836 (Astra-Zeneca), 5 (Astra-Zeneca), BMS- 790052 (BMS), EMS-824393 (BMS), GS-5885 (Gilead), PPI-1301 (Presidio), PPI-461 (Presidio) A-831 (Arrow Therapeutics), A-689 (Arrow Therapeutics) or a combination thereof Non-limiting examples of le cyclophilin inhibitors include alisporovir (Novartis & Debiopharm), NM-8ll (Novartis), SCY-635 (Scynexis), or a combination thereof.

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

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) (NSSA inhibitor), INXO8189 (Inhibitex) (polymerase inhibitor), ITMN—l9l (Intermune/Roche) (NS3/4A se inhibitor), VBY-376 (Protease Inhibitor) (Virobay), ACH-l625 (Achillion, Protease tor), IDX136 (Idenix, Protease Inhibitor), IDX316 (Idenix, Protease inhibitor), VX-8l3 x), SCH 900518 (Schering-Plough), TMC-435 (Tibotec), ITMN—l9l mune, Roche), MK-7009 (Merck), IDX-PI (Novartis), R7128 (Roche), PF-868554 (Pﬁzer) (non-nucleoside polymerase tor), PF-4878691 (Pﬁzer), IDX-l84 x), IDX-375 (Idenix, NSSB polymerase inhibitor), PPI-46l (Presidio), BILB- 1941 (Boehringer Ingelheim), GS-919O (Gilead), EMS-790052 (BMS), 27 (Conatus), GS-9620 (Gilead), 869l (Pﬁzer), R05303253 (Roche), ALS-2200 (Alios BioPharma/Vertex), 58 (Alios BioPharma/Vertex), GSK62336805 (GlaxoSmithKline), or any combinations thereof In some ments, the present technology features methods for treating patients with genotype 1, such as la or lb, HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e. g., the on 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 or ribaVirin. Patients with genotype 1, such as la or lb, infection can be treated with a combination of at least 2 DAAs without interferon and without ribavirin where the at least two DAAs e therapeutic agent 1 and therapeutic agent 2. Therapeutic agent 1 and therapeutic agent 2 can be administered in eutically 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 on being 12 weeks), ably no more than 8 weeks (e.g., the duration being 8 weeks). The ts may be treatment naive ts 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 4 weeks, or no more than 3 weeks, e. g., the on 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 eutic agent 1 in any of the dosages of therapeutic agent 1 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, about 1000 mg, about 1500 mg, or 1800 mg. In some embodiments, ritonavir can be either co-administered or stered separately with therapeutic agent 1. le 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, if the treatment regimen of the present technology does not provide the desired SVR after treatments ofno more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In some embodiments, the present technology features methods for treating patients with genotype 2 or 3 HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin. Patients with genotype 2 or 3 HCV ion can be treated with a combination of at least 2 DAAs without eron and without ribavirin where the at least two DAAs include therapeutic agent 1 and therapeutic agent 2. Therapeutic 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 (e. g., the duration being 12 weeks), preferably no more than 8 weeks (e.g., the duration being 8 weeks). The patients may be treatment na'1've HCV patients or treatment experienced HCV ts. 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 on 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 therapeutic agent 1 in any of the dosages of therapeutic agent 1 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, about 1000 mg, about 1500 mg, or 1800 mg. In some embodiments, ritonavir can be either co-administered or stered 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, if the treatment regimen of the t technology does not provide the desired SVR after treatments of no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In some embodiments, the present technology features methods for treating patients with HCV infection. The s comprise administering to such a patient a ation of at least 2 DAAs 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 eron or ribavirin.

The combination comprises therapeutic agent 1 and therapeutic agent 2. Suitably, the patient may be a treatment naive patient, a ent experienced patient or an interferon nonresponder. In some embodiments, 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 t 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 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 2 can be administered in therapeutically effective amounts to e 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 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 stered with therapeutic agent 1 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, about 1000 mg. In some embodiments, ritonavir can be either co-administered or administered 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, if the treatment regimen of the present technology does not provide the desired SVR after a treatment duration of no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In some ments, the present technology es methods for treating ts with HCV infection who are not candidates for interferon treatment. The methods comprise administering to such a patient a ation of at least 2 DAAs 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 or ribavirin. 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 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. A non-candidate for interferon ent can be ed with HCV genotype 1 or 2, for example, genotype 1a or 1b. A non-candidate for interferon ent can be infected with HCV genotype 2, for example, genotype 2a or 2b. The treatment ing to this aspect of the technology can also be effective against other HCV genotypes. In some embodiments, non-candidate for eron treatment patients can be treated with a combination of at least 2 DAAs without interferon and t 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 on 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 rase inhibitor. Suitably, the at least one HCV protease inhibitor can be therapeutic agent 1 and the at least one HCV polymerase inhibitor can be therapeutic agent 2. Therapeutic agent 1 and therapeutic agent 2 can be administered in therapeutically ive amounts to provide 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 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 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. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments of no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In another aspect, the present technology features methods for treating patients with HCV infection. The methods se administering to such a patient a combination of at least 2 DAAs 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 or ribavirin.

The combination comprises therapeutic agent 1, therapeutic agent 2 and therapeutic agent 4. In some ments, the patient is infected with HCV genotype 1, such as genotype 1a. The treatment according to this aspect of the technology can also be effective against other HCV genotypes. The treatment on 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, eutic agent 2, and therapeutic agent 3 can be provided in effective s to e a SVR (for example, a SVR8, SVR12, SVR16, or SVR24) after a treatment on 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. eutic 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 about 1000 mg. Therapeutic agent 4 can be provided in combination with therapeutic agent 1 and eutic agent 2 in which therapeutic 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 combination 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 ably 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 dosages of ritonavir include, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. ly, in some embodiments, the patient may be a treatment naive patient, a treatment experienced patient, or an interferon nonresponder. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after ents of 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In some embodiments, the t technology features methods for treating ts with genotype 1, such as genotype 1a or 1b, HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 3. . The treatment duration may 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). 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 d to, for example, 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. 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. In some embodiments, ritonavir can be either co-administered or administered 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, if the treatment regimen of the present technology does not provide the desired SVR after treatments of no more than 12 weeks, the patient may be treated with a rin-containing regimen.

In some embodiments, the present technology features methods for ng patients with pe 2 or 3, such as pe 2a, 2b or 3a, HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 3. . 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 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 duration being 8 weeks). Therapeutic agent 1 and therapeutic agent 3 can be administered in therapeutically ive amounts to e 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 d 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. 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. 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, ably about 100 mg per day. In some embodiments, if the treatment regimen of the present technology does not provide the d SVR after treatments ofno more than 12 weeks, the patient may be treated with a ribavirin-containing regime.

In some embodiments, the present logy features methods for ng patients with HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs for no more than 12 weeks (e.g., the duration being 12 weeks), ably no more than 8 weeks (e.g., the duration being 8 weeks), wherein the treatment does not include administration of interferon or ribavirin.

The combination comprises therapeutic agent 1 and therapeutic agent 3. Suitably, the patient may be a treatment na'1've patient, a treatment experienced patient or an interferon nonresponder. 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 embodiments, the patient is infected with HCV pe 3a. The treatment according to this aspect of the technology can also be effective against other HCV pes. 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 connection 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 d 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. In some embodiments, ritonavir can be either co-administered or administered separately with therapeutic agent 1. Suitable s of ritonavir e, from about 50 mg to about 400 mg per day, preferably about 100 mg per day. In some ments, if the treatment regimen of the present technology does not provide the desired SVR after treatments of no more than 12 weeks, the t may be treated with a ribavirin- ning regimen.

In some embodiments, the present technology features methods for ng patients with HCV infection who are not candidates for eron treatment. The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 3. 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 treatment, patients with medical conditions which preclude them from taking interferon, and patients who have an increased risk of side effects or ion by taking interferon. In some WO 59638 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 embodiments, the patient is infected with HCV genotype 3a. The treatment according to this aspect of the technology can also be ive against other HCV genotypes. 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 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 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. In some ments, ritonavir can be either co- administered or administered separately with therapeutic agent 1. Suitable dosages of vir include, from about 50 mg to about 400 mg per day, ably about 100 mg per day.

In some embodiments, the present technology features methods for treating patients with HCV genotype 1, such as la or lb, infection. The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin. The combination comprises therapeutic agent 1 and eutic agent 4. Patients with genotype 1a or 1b infection can be treated with a combination of at least 2 DAAs without interferon and without ribavirin in which the at least two DAAs include therapeutic agent 1 and therapeutic agent 4. Therapeutic agent 1 and eutic agent 4 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 patients may be treatment na'ive patients or ent experienced patients. 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). 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 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 d to, for example, about 20 mg, about 25 mg, about 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 stered tely with therapeutic agent 1.

Suitable dosages of ritonavir e, 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.

In some embodiments, the present technology features methods for treating patients with HCV infection. The methods comprise stering to such a patient a combination of at least 2 DAAs 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 or ribavirin.

The combination comprises therapeutic agent 1 and therapeutic agent 4. The patients may be treatment naive patients or treatment experienced patients. The treatment can be administered for a on 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 patient can have HCV genotype 1, such as HCV genotype 1a or 1b.

In other embodiments, the patient may have HCV genotype 1b. In some embodiments, it is contemplated to treat other HCV genotypes. The total daily dosage of eutic 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. eutic agent 4 can be administered in connection with therapeutic agent 1 in any of the dosages bed above. Therapeutic agent 4 can be provided alone or 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 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.

In some embodiments, the present logy features methods for ng patients with HCV infection. The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin.

The combination ses therapeutic agent 1 and therapeutic agent 4. The patients may be treatment naive patients or ent experienced patients. The treatment can be administered for a duration of 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). 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 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 4 can be administered in connection with therapeutic agent 1 in which 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- stered or administered tely 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 ments, if the ent regimen of the present technology does not provide the desired SVR after treatments of no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In some embodiments, the present logy features methods for treating patients with HCV infection who are not candidates for interferon treatment. The methods se administering to such a patient a combination of at least 2 DAAs 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 stration of interferon or ribavirin. The combination comprises therapeutic agent 1 and therapeutic agent 4. 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 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 patient is infected with HCV genotype 1, such as genotype 1a. In some embodiments, the t is infected with HCV genotype 1b. In some other ments, the patient is infected 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 ive t other HCV genotypes. 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 of no more than 12 weeks, preferably no more than 8 weeks. The interferon non-responder patients include partial interferon responders and interferon rebound patients. See GUIDANCE FOR INDUSTRY — CHRONIC TIS C VIRUS INFECTION: DEVELOPING DIRECT-ACTING ANTIVIRAL AGENTS FOR TREATMENT (FDA, September 2010, draft guidance) for the deﬁnitions of naive, partial responder, responder relapser (i.e., rebound), and null responder patients. The interferon non-responder patients also include null der 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 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 WO 59638 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 where therapeutic agent 1 is administered in any of the s 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 ments, ritonavir can be either co-administered or administered tely 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, if the treatment regimen of the present technology does not provide the d SVR after treatments of no more than 12 weeks, the patient may be treated with a ribavirin-containing regimen.

In some embodiments, the present technology features methods for treating patients with HCV infection who are interferon non-responders (e. g., null responders). The methods comprise administering to such a patient a combination of at least 2 DAAs 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 or ribavirin. eron nonresponder patients can be treated with a combination of at least 2 DAAs without interferon and t ribavirin wherein the two DAAs include therapeutic agent 1 and therapeutic agent 4. Therapeutic agent 1 and therapeutic agent 4 can be administered in therapeutically ive 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 sponder patients include partial interferon responders and interferon rebound patients. The interferon nonresponder t may have HCV genotype 1, such as 1a. The interferon nonresponder t may have HCV genotype 1b. The interferon nonresponder patient can have HCV genotype 2 or 3, such as HCV genotype 2a. In some embodiments, the t 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 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 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 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 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 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 le embodiments, eutic agent 1 and therapeutic agent 4 are administered once a day. Therapeutic agent 1 and therapeutic agent 4 can be administered in any combination of suitable s as bed above. In some embodiments, if the treatment regimen of the present technology does not provide the desired SVR after treatments of no more than about 12 weeks, the patient may be treated with ribavirin-containing regimen.

Accordingly, in some embodiments, the present logy 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 without ribavirin. The treatment lasts no more than 12 weeks (e.g., the duration being 12 weeks), atively no more than 11 weeks, alternatively no more than 10 weeks, alternatively no more than 9 weeks, preferably no more than 8 weeks (e.g., the duration being 8 , alternatively no more than 7 weeks, alternatively no more than 6 weeks, alternatively no more than 5 weeks, alternatively no more than 4 weeks, alternatively no more than 3 weeks and does not include administration of any interferon or ribavirin. The DAAs can be stered at the same or different dosing frequencies. The patient being treated can be an HCV-treatment na'1've t or HCV-treatment experienced patient, including, interferon non-responders (e. g., null 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 d) or a patient unable to take eron. The patient can be infected with, for example and without limitation, HCV genotypes 1 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 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 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 protease tor, at least one nucleoside or nucleotide polymerase inhibitor and at least one non-nucleoside polymerase 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 combination of two or more DAAs comprises GS-5885 (an NSSA inhibitor), and GS-9451 (a protease inhibitor or an NS3 protease tor). 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 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-5 885 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 150 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 1; atively about 60 mg GS-5885 and about 200 mg GS-9451; alternatively about 90 mg 5 and about 200 mg GS-9451.

In another instance, the present technology provides the at least two DAAs comprise at least two HCV rase inhibitors. In some embodiments, the at least two HCV polymerase inhibitors comprise at least one nucleoside or nucleotide analog polymerase inhibitor. In some embodiments, the at least two HCV polymerase inhibitors comprise at least two nucleoside or nucleotide analog polymerase inhibitors. Suitable nucleotide analog polymerase inhibitors include PSI-7977 (Pharmasset) and PSI-938 asset). Suitable daily dosages 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 limited to, for e, 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 e, a suitable ation includes 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. In yet another instance, the combination of two or more DAAs comprises at least one HCV protease tor and at least one HCV polymerase tor. In some embodiments, the at least one protease inhibitor is TMC-435 and the at least one polymerase inhibitor is a nucleotide/nucleoside analog rase 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 5 and about 400 mg PSI-7977, alternatively about 150 mg 5 and about 400 mg PSI-7977, alternatively about 100 mg TMC-435 and about 400 mg 77, alternatively about 75 mg 5 and about 200 mg PSI-7977, alternatively about 150 mg TMC—435 and about 200 mg PSI-7977, alternatively 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 TMC—435 and about 100 mg PSI-7977, atively about 150 mg 5 and about 100 mg PSI-7977, and can include other suitable combinations. Suitably, in some embodiments, ritonavir or a suitable equivalent can be added to the at least two DAAs comprising at least one protease inhibitor, ly in an amount from about 100 mg to about 400 mg per day, preferably about 100 mg per day. In alternative embodiments, the at least one protease is BI-201335 (NS3/4A protease inhibitor) and the at least one HCV polymerase inhibitor is a non-nucleoside polymerase inhibitor, e.g. BI-207127. In some examples, the BI-201335 is provided in a total daily dose from about 100 mg to about 400 mg, alternatively 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 BI-207127 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 Bl-201335 and about 1200 mg Bl-207127, alternatively about 120 mg Bl-201335 and about 1500 mg Bl-207127, alternatively about 120 mg Bl-201335 and about 1800 mg Bl-207127, alternatively about 120 mg Bl- 201335 and about 2100 mg Bl-207127, alternatively about 240 mg Bl-201335 and about 1200 mg Bl- 207127, alternatively about 240 mg Bl-201335 and about 1500 mg Bl-207127, alternatively about 240 mg Bl-201335 and about 1800 mg Bl-207127, alternatively about 240 mg Bl-201335 and about 2100 mg Bl-207127. Suitably, in some ments, 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.

Suitably, 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, ably about 100 mg per day. In yet another e, the combination of two or more DAAs comprises telaprevir (VX-950, protease inhibitor) and VX-222 (non-nucleoside polymerase inhibitor). In some examples, the telaprevir 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, 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 combination with the dosage s of evir 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 d 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, atively 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 evir can be a total daily dose of about 2250 mg and VX-222 can be a total daily dose of about 400 mg, alternatively 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, atively 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 stered 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 WO 59638 one protease inhibitor, suitably in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day.

In yet another example, the combination of two or more DAAs includes danoprevir (protease inhibitor) and R7128 (nucleoside polymerase inhibitor). In some ments, danoprevir can be administered in a total daily dosage from about 100 mg to about 2000 mg, atively from about 200 mg to about 1800 mg, atively from about 400 mg to about 1800 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, 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, including, but not limited to, for example, about 150 mg, about 200 mg, about 400 mg, about 500 mg, 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 evir is about 200 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 200 mg, alternatively, the total daily dose of the danoprevir is about 1000 mg and the total daily dose of R7128 is 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, alternatively 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, alternatively 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 danoprevir is about 1000 mg and the total daily dose of R7128 is about 2000 mg, alternatively 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.

In le 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.

In some other instances of the present logy, the combinations of two or more DAAs may be at least one protease inhibitor and at least one NS5A inhibitor. In some examples, the at least one protease tor is an NS3 protease inhibitor. In some embodiments, the at least one protease inhibitor and at least one NS5A tor comprises BMS-650032 (BMS) and BMS-790052 (BMS) respectively.

In suitable embodiments, EMS-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 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 EMS-790052 (BMS) can have a total daily dose from about 10 mg to about 200 mg, atively 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 about 1200 mg and EMS-790052 (BMS) total daily dose is about 60 mg, alternatively EMS-650032 (BMS) total daily dose is about 300 mg and BMS-790052 (BMS) total daily dose is about 60 mg.

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 NSSA inhibitor. In some examples, the at least one protease inhibitor is an NS3 se inhibitor. In some ments, the at least one nucleoside or tide polymerase inhibitor is INX- 189, the at least one protease inhibitor is EMS-650032 (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 e, 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 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 EMS-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 es, EMS-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 0052 (BMS) total daily dose is about 60 mg.

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. In an example, the combination of two or more DAAs comprises GS—5885 (an NSSA inhibitor), GS-9190 (tegobuvir, a non-nucleoside polymerase inhibitor), 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, atively from about 3 mg to about 100 mg, alternatively from about 30 mg to about 90 mg, ing, but not limited to, for e, 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 0 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 amounts of about mg GS—5885, about 60 mg GS—9190 and about 200 mg GS—9451; alternatively about 60 mg 5, 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 0, GS-9451, and GS-5885 is administered with ritonavir or a suitable equivalent, ly in an amount of about 100 mg to about 400 mg per day, preferably about 100 mg per day. 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.

In another embodiment, the present technology provides interferon-free treatment comprising administering daily two DAAs without ribavirin, where the two DAAs include a HCV polymerase inhibitor, for example PSI-7977 and a NSSA inhibitor, for example EMS-790052 for a on of no more than eleven weeks, preferably no more than eight weeks. PSI-7977 and BMS-790052 are administered in an effective amount to provide an SVR 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 naïve patients or treatment experienced 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, 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, about 500 mg. BMS-790052 can be stered in combination with 77 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 0052 is administered in a total daily dose of 60 mg.

The chemical structures of some of these HCV inhibitors as reported by numerous sources are provided below: evir 6273780_1 (GHMatters) P99394.NZ LAURAW BI-201335 TMC-435 (TMC-435350) Vaniprevir, MK-7009 0_1 (GHMatters) P99394.NZ LAURAW BMS-650032 (Asunaprevir) danoprevir 6273780_1 (GHMatters) P99394.NZ LAURAW ANA-598 (Setrobuvir) GS-333126 (GS-9190 or tegobuvir) 6582066_1 (GHMatters) P99394.NZ Mericitabine (R-4048 or RG7128) filibuvir (PF-00868554) 6273780_1 (GHMatters) P99394.NZ LAURAW PSI-7977 0052 (daclatasvir) BIT-225 6582066_1 (GHMatters) P99394.NZ PSI-352938 INX-189 GS-9256 6582066_1 ters) P99394.NZ GS-5885 Alisporivir (Debio 025) TMC-647055 0_1 (GHMatters) P99394.NZ LAURAW O O S N N N 1325 preferably is . As used herein, BMS- 791325 may also be . See also publications at http://www1.easl.eu/easl2011/program/Posters/Abstract680.htm; and http://clinicaltrials.gov/show/NCT00664625. For GS-5885, see publications at http://www.natap.org/2011/EASL/EASL_68.htm; /www1.easl.eu/easl2011/program/Posters/Abstract1097.htm; and http://clinicaltrials.gov/ct2/show/NCT01353248.

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

The following table lists non-limiting examples of the treatment regimens 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 interferon-free and ribavirin-free. Each treatment regimen may also optionally comprise administering one or more other onal DAAs to the patient. The duration of each treatment regimen may last, for e 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, atively 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 described 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 used in a regimen can be co-formulated in amorphous forms or molecularly dispersed in a matrix comprising a water-soluble polymer and optionally a tant; for another instance, therapeutic agent 1 and ritonavir (RTV) are formulated in an amorphous form or molecularly sed in a matrix comprising a water-soluble polymer and optionally a surfactant, and therapeutic agent 3 can be combined with amorphous Compound 1 and RTV in a single solid dosage 6273780_1 (GHMatters) P99394.NZ LAURAW form. For yet another instance, Compound 1 and RTV are ated in a different dosage form than that of therapeutic agent 3.

Table 1 Non-Limiting Examples of Interferon-free Treatment Regimens with two or more DAAs (without ribavirin and with or without ritonavir) n 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) 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) Therapeutic Agent 1* + 150-250 mg (pref. 150 mg or 250 mg) Therapeutic Agent 3 + 50 mg-1000 mg (pref. 400 mg) eutic 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) PSI-938 100 mg to 500 mg (pref. 300 mg) 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 3 mg to 200 mg (pref. 30 to 90 mg) GS 9451 100 mg to 500 mg (pref. 200 mg) p—x BI-201335 + 100 mg to 400 mg (pref 120 mg or 240 mg) BI-207127 300 mg to 3600 mg (pref. 1200 mg to 2100 11 PSI-7977+ 100 mg to 500 mg (pref. 400 mg) WO 59638 Regimen Drugs Used in Suitable total daily dosages Treatment TMC-435 25 mg to 200 mg (pref. 75 mg to 150 mg) 12 telaprevir + 1000 mg to 2500 mg (pref. 2250 mg) VX-222 200 mg to 800 mg 13 Danoprevir* + 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) 77 - 100 mg to 2000 mg (pref. 1800 mg or 2000 asunaprevir (BMS- 300-1500 mg (pref 1200 mg) 650032) PSI-7977 + 100 mg to 500 mg (pref. 400 mg) daclatasvir (BMS— 10-200 mg (pref 60 mg) 790052) asunaprevir (BMS- 00 mg (pref 1200 mg) 650032) * vir 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 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 Additional non-limiting es of interferon-free treatment regimens with two or more DAAs, without 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 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 2012/061085 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) Therapeutic 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); (f) GS—5885 at a total daily dose of3 mg to 200 mg (pref. 30 mg, 60 mg, or 90 mg), and GS-9451 at a total daily dose of 100 mg to 500 mg (pref 200 mg); (g) 335 at a total daily dose of 100 mg to 400 mg (pref 120 mg, 240 mg), and B1—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) INK-189 at a total daily dose of 5 mg to 400 mg (pref 50 mg, 100 mg or 200 mg), and daclatasvir (EMS-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 of 300 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), daclatasvir (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 ents as bed and may be added to any of these treatments 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.

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

In general and depending on patients’ ions, the total daily dose of the DAAs of the present technology may be administered r 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 compound or salt per kg body weight), and e 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, 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 2012/061085 mg to about 500 mg, from about 25 mg to about 250 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1000 mg, from 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 patient will depend upon a variety of factors including the activity of the speciﬁc compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the e 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 rome 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 stered 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 embodiments, the rome 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 ments, the cytochrome P-450 inhibitor is stered in a total daily dose amount of about 125 mg.

The one or more DAAs can be administered, for example and t limitation, concurrently 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 another DAA. A short delay or time gap may exist between the administration of one DAA and that of r DAA. The frequency of administration may also be different. For example, a ﬁrst DAA may be administered once a day and a second DAA may be administered twice or three times a day. For example, a ﬁrst DAA with or without ritonavir may be administered 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 nd 1 as a solid dosage form is described in U.S. 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 ably, the dosage form is a solid dosage form in which at least one of the DAAs is in an amorphous form, or highly preferably molecularly dispersed, in a matrix which comprises a pharmaceutically acceptable water-soluble polymer and a pharmaceutically acceptable surfactant. The other DAAs can also be in an amorphous form or larly dispersed in the matrix, or formulated in different form(s) (e. g., in a crystalline form).

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

In one embodiment, a method for treating a naive subject comprises administering Therapeutic agent 1 at a dose of 150 mg, and ritonavir at a dose of 100 mg, once a day; and Therapeutic agent 2 at a dose of 400 mg or 800 mg twice a day. The treatment lasts for 12 weeks, and at the end of treatment, the subject has no detectable virus.

In one embodiment, a method for treating a naive subject comprises administering Therapeutic agent 1 at a dose of 50 mg, and ritonavir at a dose of 100 mg, once a day; eutic agent 2 at a dose of 400 mg or 800 mg twice a day. The treatment lasts for 12 weeks, and the end of treatment, the t has no detectable virus.

In one ment, a method for treating a naive subject comprises administering Therapeutic agent 1 at a dose of 250 mg, and ritonavir at a dose of 100 mg, once a day; and eutic agent 2 at a dose of 400 mg BID. The treatment lasts for 12 weeks, and 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, and ritonavir at a dose of 100 mg, once a day; and Therapeutic agent 2 at a dose of 400 mg BID. The treatment lasts for 12 weeks, and the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method for treating a erferon + ribavirin (P/RBV) non- responder comprises administering Therapeutic agent 1 at a dose of 150 mg, and ritonavir at a dose of 100 mg, once a day; and Therapeutic agent 2 at a dose of 400 mg BID. The treatment lasts for 12 weeks, and the end of treatment, the t 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, and ritonavir at a dose of 100 mg 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 comprises administering Therapeutic agent 1 at a total daily dose of 150 mg, Therapeutic agent 3 at a total daily dose of 400 mg, and ritonavir at a dose of 100 mg once a day for 12 weeks. At the end of treatment, the subject has no detectable virus.

In another embodiment, a method for treating a naïve subject ses administering Therapeutic 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, ritonavir at a dose of 100 mg QD for 12 weeks. At the end of treatment, the subject has no detectable virus.

In yet another embodiment, a method for treating a naïve subject comprises stering eutic agent 1 at a total daily dose of 100 mg or 150 mg QD, Therapeutic agent 2 at a dose of 400 mg BID, Therapeutic agent 4 at a total daily dose of 25 mg, ritonavir at a dose of 100 mg QD for 12 weeks. At the end of treatment, the subject has no detectable virus. [0171A] There is further provided use of PSI-7977 and/or GS-5885 in the cture of a medicament for the treatment of HCV in a patient infected with HCV genotype 1, wherein said treatment does not include administration of either eron or ribavirin, and wherein said ent lasts for 8, 9, 10 or 11 weeks, wherein the medicament ses: (a) 77 and GS-5885 co-formulated in a single composition; or (b) PSI-7977, wherein the medicament is for administration in combination with 5; or (c) GS-5885, wherein the ment is for administration in ation with PSI-7977.

] There is further provided the use as described herein, wherein the treatment lasts for 8 weeks. [0171C] There is further provided the use as described herein, wherein said patient is an HCV treatment-naive patient. [0171D] There is further provided the use as described herein, wherein said patient is infected with HCV genotype 1a. [0171E] There is further provided the use as described herein, wherein the two DAAs are administered once daily. [0171F] There is further provided the use as described herein, wherein the two DAAs are coformulated in a single composition and administered concurrently. 6837291_1 (GHMatters) P99394.NZ [0171G] 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 [0171H] 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 [0171I] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic se (SVR) in at least 75% of patients infected with HCV genotype [0171J] 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, wherein said treatment does not include administration of either interferon or ribavirin, and wherein said treatment lasts for 12 weeks, wherein the medicament comprises: (a) PSI-7977 and GS-5885 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. [0171K] There is further ed the use as described herein, wherein said t is an HCV treatment-naive patient.

] There is further provided the use as described herein, wherein said patient is infected with HCV genotype 1a. [0171M] There is further provided the use as bed herein, wherein the two DAAs are administered once daily. [0171N] There is r provided the use as bed herein, wherein the two DAAs are coformulated in a single composition and administered concurrently. [0171O] There is further provided the use as described , wherein said treatment comprises administering 90 mg QD of GS-5885 and 400 mg QD of PSI-7977 to a genotype 1 naive patient. [0171P] There is further provided the use as described herein, wherein the treatment of HCV achieves ned gic response (SVR) in at least 70% of patients ed with HCV genotype 101a 6837291_1 (GHMatters) P99394.NZ [0171Q] There is further provided the use as described herein, wherein the treatment of HCV es sustained virologic response (SVR) in at least 90% of patients infected with HCV genotype [0171R] There is further provided use of PSI-7977 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 does not include administration of either interferon or ribavirin, 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 administration in combination with HCV NS5A inhibitor; or (c) HCV NS5A inhibitor, n the medicament is for administration in combination with PSI-7977.

] There is further provided the use as described , wherein the treatment lasts for 8 weeks. [0171T] There is further provided the use as described herein, wherein the treatment lasts for 12 weeks. [0171U] There is further ed the use as described herein, wherein said patient is an HCV treatment-naive patient. [0171V] There is r provided the use as described herein, wherein said t is infected with HCV genotype 1a. [0171W] There is further provided the use as bed herein, wherein 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. [0171Y] There is further provided the use as described herein, wherein said treatment comprises administering 400 mg QD of PSI-7977 to a genotype 1 naive patient. [0171Z] There is r provided the use as described , wherein the ent of HCV achieves sustained virologic response (SVR) in at least 70% of patients ed with HCV genotype [0171AA] There is further provided the use as described herein, wherein the treatment of HCV achieves sustained virologic se (SVR) in at least 75% of patients infected with HCV genotype 101b 6837291_1 (GHMatters) P99394.NZ [0171BBB] Therre is further provided thee use as desccribed hereinn, wherein thhe treatmentt of HCV ess sustained vvirologic respponse (SVR)) in at least 990% of patieents infected with HCV ggenotype 1, whereein said treatment lasts foor 12 weeks. [0171CCC] Therre is furtherr provided use of PSI-7u 7977 and/or an HCV NSS5A inhibitoor in the manufaccture of a ament foor the treatmment of HCVV in a patientt infected wiith HCV gennotype 1, wherein said eent lasts for 6 or 7 weekks and does nnot include aadministration of either innterferon or ribaviirin to said ppatient, wherein the medicamment comprisses: (a) 777 and an HCCV NS5A inhhibitor co-forrmulated in aa single commposition; or (b) PSI-79777, wherein thhe meent is for admministration in combination with HCCV NS5A inhibitorr; or (c) HCV NSS5A inhibitoor, wherein tthe medicamment is for addministrationn in combinattion with PSI-79777; and wheerein the meddicament furrther comprises r DDAA or is aadministered in combinattion with another DAA. [0171DDD] Therre is further provided thhe use as desscribed hereiin, wherein said anotherr DAA is Compouund 1( ), annd said HCVV NS5A inhhibitor is und 4 ( ) 101c 6837291_1 (GHMatters) P99394.NZ [0171EE] There is further provided the use as described herein, wherein said PSI-7977 is administered at a dose of 400 mg once daily. [0171FF] There is further provided the use as described herein, wherein said another DAA is an HCV protease inhibitor. [0171GG] There is further provided the use as described herein, wherein said another DAA is an HCV polymerase tor. [0171HH] There is further provided the use as described herein, wherein said patient is a treatment naive patient. [0171II] There is further provided the use as bed herein, n said patient is an interferon non-responder. [0171JJ] There is further provided the use as bed herein, wherein the treatment of HCV achieves sustained gic response (SVR) in at least 70% of patients infected with HCV genotype [0171KK] There is further ed the use as described herein, wherein the treatment of HCV achieves sustained virologic response (SVR) in at least 75% of patients ed with HCV genotype It should be understood that the above-described embodiments and the following examples are given by way of illustration, not limitation. Various changes and cations within the scope of the present invention will become apparent to those skilled in the art from the present description.

Example 1. Synergistic concentrations of nd 1 and Compound 2 in genotype 1b HCV replicon assay Examples 1-3 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 tors (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 NS5A inhibitor (such as nd 4)) may contribute to the effectiveness of the short-duration, interferon- and ribavirin-free therapies of the present technology. als: A replicon cell line was derived from the human hepatoma cell line Huh7.

It was derived from HCV genotype 1b (Con1), and is a bicistronic subgenomic replicon, essentially r 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. on cells were maintained in Dulbecco’s Modified Eagle Media (DMEM) containing 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), 200 mg/ml G418, an aminoglycoside antibiotic (Invitrogen) and 10% fetal bovine serum (FBS) at 37º C and 5% CO2. 101d 6837291_1 ters) P99394.NZ 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% FBS. The following day, Compounds 1 and 2 were diluted in dimethyl ide (DMSO) to generate a 200X stock in a series of 6 two-fold dilutions. The dilution series was then further diluted 100-fold in the medium containing 5% FBS.

Combination s: Combination studies were performed to evaluate the interaction s of therapeutic agent 1 and therapeutic agent 2 in the replicon assay bed above. The purpose of these studies was to determine whether there are doses or concentrations of each compound where synergy or antagonism is demonstrated with the other compound. Three experiments with three plates in each ment were performed on three separate days. Six concentrations of Compound 1 alone and six concentrations of Compound 2 alone were d 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 luciferase signal.

The dilutions of each compound were combined with the dilutions of the other compound in a checkerboard 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 ning 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 ga) following the manufacturer’s instructions. Passive Lysis buffer (30 pl, Promega) was added to each well, and the plates were incubated for 15 minutes with rocking to lyse the cells. Luciferin on (100 pl, Promega) was added to each well and the luciferase activity was measured using a Victor ll luminometer (Perkin-Elmer). To ine the EC50, the luciferase inhibition data were ed 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 according to the Pritchard and Shipman model (Antiviral Research 14:181-206 (1990)).

Combination Analysis: Prichard and Shipman proposed a direct approach to solve this drug- drug interaction problem. The method was able to calculate theoretical additive effects ly from the individual dose-response curves determined in the assay. The calculated theoretical additivity was then compared to the experimental dose-response surface, and subsequently subtracted to reveal any areas of aberrant interaction. The following on was used to calculate the theoretical ve 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 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 equation above. For each concentration ation, the replicates (across all plates and experiments) were used to ate a mean ence between observed and predicted fraction of inhibition, its standard error and its two-sided 95% confidence interval. y or nism for a concentration combination was determined based on the ing 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% Cl is larger than zero, then the drug combination would be considered having a synergistic effect; if the upper bound of 95% Cl 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.

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 differences of statistical signiﬁcance caused by very small variance could be excluded. ation of Therapeutic Agent 1 and Therapeutic Agent 2.‘ The inhibitory effects on replicons produced by each drug alone or in combination with the other at concentrations up to ten-fold above the EC50 were ed in the pe lb (Conl) replicon using a checkerboard ion 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 on range. For Compound 1, concentrations ranged from 0.031 nM to 1.0 nM. For Compound 2, trations ranged from 0.125 nM to 4.0 nM. Synergy, additivity, and antagonism were evaluated using the Pritchard and Shipman model.

Results: The results of the assay analysis are illustrated in Figures 1 and 2 and Table 2. In the 3-D surface plot of Figure 1, deviations from expected interactions between Compound 1 and Compound 2 are purely additive at concentrations associated with a horizontal plane at 0%. Synergistic interactions between Compound 1 and Compound 2 appear as a peak above the horizontal plane with a height corresponding 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 interactions appear white, and antagonistic interactions appear as ed.

As illustrated in the 3-D e plot of Figure l and the contour plot of Figure 2, an additive or synergistic effect exists at most of the concentrations for Compound 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 trations of Compound 2.

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

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

The results presented in Figures 1 and 2 and Table 2 demonstrate that the combination of therapeutic agent 1 and therapeutic 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 agent 2 should produce a signiﬁcant antiviral effect in patients when administered in combination with therapeutic agent 1 in patients infected with HCV.

Table 2 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 nce limit .125 .12500 0.06176 52 0.007912 0.11561 .125 .25000 0.05321 0.022199 0.002024 0.10440 .125 .50000 6 0.002680 0.005583 0.01794 .250 .25000c 0.06626 0.020630 0.018692 0.11384 .250 .50000 0.01061 0.002677 38 0.01679 .500 .06250 0.04373 0.014897 0.009375 0.07808 .500 .12500 6 0.026757 54 0.16586 .500 .25000 0.09327 0.019859 0.047471 0.13906 .500 .50000 0.01422 0.003333 0.006535 0.02191 1.00 .06250 0.06696 0.020488 0.019715 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 4 0.007690 04 0.07747 Mean difference in fraction of inhibition: Standard error Lower 95% nd Compound Observed - of mean conﬁdence Upper 95% 2, nM 1, nM Predicted difference limit conﬁdence limit 2.00 .12500 0.10032 0.011820 0.073066 0.12758 2.00 .25000 0.07117 0.009428 0.049428 1 4.00 .03125 0.03235 0.003950 0.023236 0.04145 4.00 .06250 0.05141 0.004313 0.041470 0.06136 4.00 .12500 0.06572 0.004692 0.054901 0.07654 4.00 .25000 0.03452 0.004775 0.023509 0.04553 Example 2. Synergistic concentrations of nd 1 and Compound 4 in genotype 1b HCV replicon assay Materials: The on cell line was derived from the human hepatoma cell line Huh7. It was derived from HCV genotype 1b (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) containing 100 lU/ml penicillin, 100 mg/ml streptomycin (lnvitrogen), 200 mg/ml G418 (lnvitrogen) and 10% fetal bovine serum (FBS) at 370 C and 5% C02.

Replicon Cell Culture: Replicon cells were seeded at a y of 5000 cells per well of a 96- well plate in 100 pl DMEM containing 5% FBS. The following day, compounds were diluted in dimethyl sulfoxide (DMSO) to generate a 200K stock in a series of 6 two-fold dilutions. The dilution series was then further d 100-fold in the medium ning 5% FBS.

Combination Studies: Combination s were med to evaluate the interaction s 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 separate days. Six concentrations of nd 1 alone and six trations of Compound 2 alone were assayed in each plate. In addition, 36 combinations of concentrations of the two compounds were d for each plate. The variable analyzed was the fraction of inhibition of the luciferase signal.

The dilutions of each nd were combined with the dilutions of the other compound in a checkerboard 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% FBS. The cells were ted in a tissue culture incubator at 370 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 ctions. 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 luciferase activity was measured using a Victor 11 luminometer n-Elmer). To determine the EC50, the luciferase inhibition data were analyzed using GraphPad Prism 4 software. Three experiments were med with three replicates per experiment.

The percent inhibition results were analyzed for synergy, additivity and antagonism according to the Pritchard and Shipman model (Antiviral Research 14: 1 81-206 ).

Combination Analysis: The Prichard and n approach to calculating theoretical additive s (described in e 1) was used for the present example.

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 ve 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 difference between observed and predicted fraction of inhibition, its standard error and its two-sided 95% conﬁdence interval.

Synergy or antagonism for a concentration ation was determined based on the same rules set forth in Example 1. ation of Therapeutic Agent I and Therapeutic Agent 4.‘ The inhibitory effects in replicon 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 1b (Conl) replicon using a checkerboard titration pattern (two-fold serial dilutions) 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 dilution 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 ted using the Pritchard and Shipman model.

Results: The results of the assay analysis are illustrated in Figures 3 and 4 and Table 3. 1n the 3-D surface plot of Figure 3, ions from expected interactions n Compound 1 and Compound 4 are purely additive at concentrations associated with a horizontal plane at 0%. Synergistic interactions n Compound 1 and Compound 4 appear as a peak above the horizontal plane with a height corresponding to the percent above calculated vity. Antagonistic interactions between nd 1 and Compound 4 appear as a pit or trough below the horizontal plane with a negative value signifying the percent below the ated vity. 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 3 below lists combinations of concentrations of Compound 1 and Compound 4 with statistically signiﬁcant synergistic or antagonistic effects based on the Prichard and Shipman Model analysis. For each combination of concentrations, Table 3 es the mean difference in the observed and predicted on of inhibition, the standard ion or error of the mean difference, and the upper and lower limits of the 95% conﬁdence interval.

According to Table 3, most of the combinations of Compound 1 and Compound 4 listed in the table have statistically signiﬁcant synergistic effects. A small amount of antagonism was observed at the lowest concentrations of Compound 1.

The results presented in Figures 3 and 4 and Table 3 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 tration 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 produce a signiﬁcant antiviral effect in patients when administered in combination with therapeutic agent 1 in patients infected with HCV.

Table 3 Mean difference in Standard error Lower 95% Upper 95% Compound Compound fraction of inhibition: of mean conﬁdence conﬁdence 4, nM 1, nM Observed - Predicted difference limit limit 97 0.375000 5 0.033975 0.02060 0.17729 0.000394 0.187500 0.16900 0.038934 2 0.25878 0.000394 0.375000 0.11401 0.027710 0.05011 1 0.000788 0.187500 9 0.038860 0.06388 0.24310 0.000788 0.375000 0.09992 66 0.03704 0.16279 0.001575 0.023438 -0.08326 0.027126 -0. 14582 71 0.001575 0.046875 -0.11894 0.026099 -0. 17913 76 0.001575 0.187500 0.07958 0.020080 8 0.12588 Mean difference in Standard error Lower 95% Upper 95% Compound Compound fraction of inhibition: of mean conﬁdence conﬁdence 4, nM 1, nM Observed - Predicted difference limit limit 0.003150 0.023438 -0.10156 0.018406 -0.14401 -0.05912 0.003150 0.046875 -0.08091 15 -0.11462 21 r results were also trated for the combination of therapeutic agent 2 and therapeutic agent 4, where additivity was observed at most of the concentration ations of the two agents and synergy was observed at low concentrations of therapeutic agent 2 and therapeutic agent 4.

Example 3. 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 s combinations of these agents, the stable subgenomic replicon cell line d from HCV genotype 1a (H77; Genbank accession number AF011751) was utilized. The replicon construct was bicistronic and the cell line was generated by introducing the constructs into cell lines derived from the human hepatoma cell line Huh-7. The replicon also has a ﬁreﬂy rase reporter and a neomycin phosphotransferase (Neo) selectable marker. The two coding regions, separated by the FMDV 2a protease, comprise the ﬁrst cistron of the bicistronic replicon construct, with the second cistron containing the HCV NS3-NSSB coding region with addition of ve mutations E1202G, K1691R, K2040R and S2204l. This HCV replicon cell line was maintained in Dulbecco’s d Eagles medium (DMEM; lnvitrogen) containing 10% (v/v) fetal bovine serum, 100 IU/ml penicillin, 100 ug/ml streptomycin, and 200 ug/ml G418 (all from ogen). 1a-H77 replicon cells (105-106) were plated in 150 mm cell culture plates and grown in the ce of G418 (400 ug/ml) and Compound 1, Compound 2, and/or Compound 4 at concentrations that were either 10-fold (10X) or 100- fold (100X) above the EC50 value for the HCV genotype 1a replicon cell line. The EC50 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% crystal violet in 10% Protocol SafeFix ll reagent (Fisher Scientiﬁc), and counted. As shown in Figure 5A, the combination of Compound 4 plus either Compound 1 or Compound 2 at either 10-fold or 100-fold above their respective EC50 value resulted in cantly fewer colonies than either Compound 1, Compound 2, or Compound 4 alone at -fold or 100-fold above their respective EC50 value.

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

Figures 5C and 5D show the effect of a combination of Compounds 1 and 4 in long-term HCV RNA ion assays in genotype 1 replicon cell lines. In long-term replicon RNA reduction assays, 106 on cells were plated in the absence of G418. The inhibitors at concentrations of either 10-fold (10X) or 100-fold (100X) 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 ﬂask with fresh media and inhibitors. RNA was extracted from 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 d 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 predominant resistance variants in 1a-H77 replicons include R155K, D168A and D168V with fold resistance of 26, 48 and 128, respectively; and the predominant resistance variants in 1b-Con1 ons include R155K, A156T and D168V with fold resistance of 48, 9 and 190, respectively. For Compound 2, the predominant resistance ts in 1a-H77 replicons include C316Y, M414T, Y448C and S556G with fold resistance of 1600, 36, 980 and 15, respectively; and the predominant resistance variants in 1b-Con1 replicons include C316Y, M414T and D559G with fold resistance of 1400, 26 and 100, respectively. 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 ts in 1b-Con1 replicons include 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 Compound 1, and that in genotype 1b, one variant (C316Y) selected by Compound 2 conferred a higher level of ance than those selected by either Compound 1 or Compound 4.

The above examples show that the combination 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 se inhibitor and a HCV NSSA inhibitor, or a ation of a HCV polymerase tor 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 combination of a HCV protease inhibitor, a HCV rase tor, and a HCV NSSA inhibitor) can lead to even more significant barrier to resistance. Improvement in the barrier to resistance achieved through co-administration of multiple DAAs of different classes or with different ism of action is expected to correlate with enhanced efficacy in patients.

Example 4. Use of 2-DAA Combination without Interferon and Ribavirin to Treat ent- Na'ive Subjects Infected with Genotype 1, 2 or 3 Genotype I Ten usly untreated subjects infected with HCV genotype 1 were treated with a 2-DAA combination for 12 weeks. The treatment was interferon- and ribavirin-free and was designed to last for 12 weeks. The 2-DAA combination included Compound 1/r (200/100 mg QD) and nd 4 (25 mg QD). At week 3 the treatment, seven of the ten subjects showed no detectable HCV RNA; and the remaining three subjects had HCV RNA levels of less than 25 IU/mL. At week 4, eight subjects showed no detectable HCV RNA, and the remaining two showed (or were ed to have) an HCV RNA level of less than 25 IU/mL. At week 5, nine subjects had no detectable HCV RNA and the remaining one had an HCV RNA level of less than 25 IU/mL. At weeks 6 and 7 of the treatment, all ten ts were tested and found no detectable HCV RNA. At weeks 9, 10, 11 and 12 of the treatment, one subject showed viral rebound (breakthrough), and the remaining nine ts showed no detectable HCV RNA.

At post-treatment week 2, at least seven subjects found no detectable HCV RNA. At post- treatment week 4, seven subjects found no detectable HCV RNA. At post-treatment week 8, seven subjects found no detectable HCV RNA. At post-treatment week 12, six subjects found no detectable HCV RNA. At post-treatment week 24, at least two subjects found no detectable HCV RNA.

Genotype 2 Ten previously untreated subjects infected with HCV genotype 2 were treated with the same regimen of this Example. At week 3 of the treatment, eight of the ten subjects showed no detectable HCV RNA, one had viral d, and one had HCV RNA levels of less than 25 IU/mL. At week 5 of the treatment, nine of the ten subjects showed no detectable HCV RNA, and one had hrough. At weeks , 11 and 12 of the treatment, at least seven of the ten subjects were tested and found no detectable HCV RNA.

At post-treatment week 2, six subjects found no detectable HCV RNA; and two more ts had breakthrough. At post-treatment week 4, ﬁve subjects found no detectable HCV RNA. At post- treatment week 8, six subjects found no detectable HCV RNA. At post-treatment week 4, at least ﬁve subjects found no detectable HCV RNA.

Genotype 3 rly, ten previously untreated subjects infected with HCV genotype 3 were d with the same regimen of this Example. At weeks 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of the treatment, two ts showed no detectable HCV RNA. At post-treatment weeks 2 and 4, the same two subjects were confirmed with no detectable HCV RNA. A number of subjects ed to have breakthrough during the treatment.

At post-treatment week 24, at least three subjects showed no detectable HCV RNA.

Example 5. Use of 3-DAA Combination without Interferon and Ribavirin to Treat ent- Na'l've ts Infected with Genotype 1 Twelve previously untreated subjects with HCV genotype 1 infection were treated with a 3- DAA ation for 12 weeks. The ent was interferon- and rin-free. The 3-DAA 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 3 of the treatment, seven of the twelve subjects had no detectable HCV RNA, and the ﬁve remaining subjects had HCV RNA levels of less than 25 IU/mL. At week 4 of the treatment, nine of the twelve subjects had no detectable HCV RNA, and the three remaining subjects had HCV RNA levels of less than 25 IU/mL. At weeks 6 and 8, all twelve subjects had no detectable HCV RNA. At weeks 10 and 12, eleven of the twelve ts showed no detectable HCV RNA, and one subject had detectable HCV RNA.

At post-treatment weeks 2 and 4, at least ten of the twelve subjects were tested and found no detectable HCV RNA. At post-treatment week 8, at least seven of the twelve subjects were tested and found no detectable HCV RNA. Two subjects appeared to have breakthrough during or after the treatment. Further g showed that at post-treatment weeks 12, at least nine of the initial twelve subjects found no detectable HCV RNA.

A larger clinical study using the same drug combination showed about 91% (or about 97% if non-virologic failures were removed) SVR4 rate, and about 82% (or about 90% if non-virologic failures were removed) SVR12 rate, after 12-week treatment regimen in treatment-naive patients. Among these patients, the SVR4 and SVR12 rates (non-virologic failures removed) in genotype 1a patients were about 96% and 86%, respectively. All of these SVR4 and SVR12 rates were based on observed data. 2012/061085 Example 6. Clinical Modeling for Interferon-free DAA Combination Therapies This example describes a novel clinical model for evaluating optimal doses and durations of eron-free HCV therapies using combinations of different DAAs. This model reasonably ted the effectiveness of numerous DAA combinations in interferon-free, short-duration ies.

A mechanistic model was used to model the relationship between DAA exposures and antiviral efﬁcacy in HCV-infected subjects. This model was used to t clinical trial simulations of clinical outcomes following administration of various DAA combination ns (e.g., speciflc DAA combinations and different doses of DAAs) and ons of therapy.

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 Example included single and double mutants. Speciﬁcally, the model included 2 single mutants and one double mutant for 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 combination of a protease inhibitor, a polymerase inhibitor and a NSSA tor, such as a combination of a protease inhibitor, a non-nucleoside polymerase inhibitor (NNPI) and a NSSA inhibitor) included 3 single and 2 double s.

The model has 3 components: hepatocytes (uninfected or target cell), infected cell and viral dynamics. The differential equations describing the dynamics of the 3 ents 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 cs (a) Infected with Wild type Virus (1 IWT/dt = (1—n)*[3 *T* VLWT — 8 *IWT (b) Infected with Polymerase Mutant Virus (1 lPoly/dt = (1-n)*[3 *T*VLPoly - 8*1Poly (c) Infected with Protease Mutant Virus (1 lProt/dt = (1-n)*[3 *T*VLProt - 8 *lProt (d) Infected with NS5A Mutant Virus d INSSA/dt = (1-n)*B *T*VLNSSA - 8 *INSSA (e) ed with Protease-NS5A Double Mutant Virus (1 INSSAProt/dt = B *T*VLNSSAPr0t - 8 Prot 09 Infected with Protease- rase Double Mutant Virus (1 IPolyProt/dt = (l-n)*B*T*VLP01yPr0t - 8 *IPolyProt (3) Viral dynamics (a) Wild Type Virus (1 t = (1-3*u)*p*(1-Eff1)*IWT + u *(p*(1-Eff2)*Fit1*IPoly + p*(1-Eff3)*Fit2*IPr0t + p*(1- Eff4)*Fit3*INSSA)- c*VLWT (b) Polymerase Mutant Virus (1 VLPOly/dt = (1- * p*(1-Eff1)*IWT + I1. -(I))* p*(1-Eff2)*Fit1*IP01y + IJ. (I) * p*(1-Eff5)*Fit4* IPoly- Prot - c*VLP01y (c) Protease Mutant Virus (1 VLProt/dt = (1- * p*(1-Eff3)*IWT + I1. - 2*(I))* p*(1-Eff3)*Fit2*IPr0t + IJ. (I) *(p*(1- Eff5)*Fit4*IP01yPr0t + p*(1-Eff6)*Fit5*INSSAPr0t) - c*VLPr0t (d) NS5A Mutant Virus (1 VLNSSA/dt = (1— u — (I))*p*(1-Eff4)*Fit3*INSSA + u *p*(1-Eff1)*IWT + (I) *p*(1- Eff6)*Fit5*INSSAProt — c*VLNSSA (e) NS5A and Protease Double Mutant Virus (1 VLNSSAProt/dt = (1-2* (I))*p*(1-Eff6)*Fit5*INSSAPr0t + (I) *(p*(1-Eff4)*Fit3*INSSA + p*(1- Eff3)*Fit2*IPr0t) - c*VLNSSAPr0t 09 Poly and Protease Mutant Double Mutant Virus d VLPolyProt/dt = (1-2* (|))*p*(l-Eff5)*Fit4*lPolyProt + (I) *(p*(l-Eff2)*Fitl*lPoly + p*(l- Eff3)*Fit2*lProt) - lyProt The parameters used in the above equations are described in Table 5.

Table 5. Viral Dynamic Parameters Parameter Description s zero-order production of hepatocytes T number of Target or uninfected hepatocytes de first-order rate nt for the death of hepatocytes 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 ion of cytes 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 nce rate of the virus Effl, Eff2, Eff3, inhibition of production of Wild Type, polymerase, protease, Eff4 and NSSA mutant, respectively Eff5, Eff6 inhibition of production of polymerase-protease and NSSA- protease double mutant, respectively Fitl, Fit2, Fit3 fitness of polymerase, protease and NSSA mutant ve to wild type virus, respectively Parameter Description Fit4, Fit5 ﬁtness of polymerase-protease and NSSA-protease double mutant relative to wild type virus, respectively IWT, lPoly, lprot, number of cells infected with wild type, polymerase, protease INSSA and NSSA mutants, respectively lPoly-Prot, INSSA- number of cells infected with polymerase-protease and NSSA- Prot protease double mutant, respectively VLWT, VLPoly, viral load for wild type virus, polymerase, protease and NSSA VLProt, VLNSSA mutant virus, respectively VLPoly-Prot, viral load for polymerase-protease and rotease double VLNSSA-Prot mutant, respectively As shown in the ential equations for viral dynamics, the effect of DAA is included as an inhibition of viral load tion. For e, the effect of DAA(s) on tion 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 Eff1=0 and in the presence of drug Effl takes a value n 0 and l. Effl is described using an Emax model: Effl = Emax*Conc/(EC50 + Conc) where Emax ents maximum inhibition, Conc is the plasma DAA concentration and EC50 is the concentration that inhibits viral load production by 50%. As the fold-change in EC50 for the mutants compared to wild type virus was based on values obtained from in vitro replicon studies, EC50 was estimated only for wild type virus.

For DAA combinations, the effect was assumed to be multiplicative and incorporated as follows: (1 'Effl) = (l'EffDAAl)*(1"EffDAA2)*(1'EffDAA3) The effect of ribavirin (RBV) can also be added on infection rate B as an Emax model. In presence 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 d to simulate a 2-DAA n containing 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 IU, this constitutes about 0.5 million viruses in the body at LOD. Hence, subjects have to be treated for cant period of time after their viral load falls below the LOD to achieve cure. This duration depends on the y of the compounds and the individual response to therapy.

In order to t the duration required for cure, a “threshold” t was used. For simulations, an HCV-infected subject was assumed to e 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 5000 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 patients treated with N and ribavirin, subjects were estimated to achieve SVR when the predicted 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 combination of DAAs, with or without interferon, and with or without ribavirin.

As non-limiting examples, various interferon-free treatment ns using ent combinations 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 Compound 2, the model ed one mutant resistant to Compound 1, one mutant ant to Compound 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 exposure.

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 ant proﬁle of Compound 1. Hence, the Compound 2/Compound 4 double mutant is not expected to affect clinical outcomes for treatments ning Compound 1.

Single mutants included in the model were based on mutants observed for the individual DAAs in the Phase lb and 2a studies (e.g., clinical studies M10-351, M12-116, 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 combination of the 2 single mutants. Thus, for Compound 1 and Compound 2, the single mutants were D168V and M414T, tively, 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 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 compared to wild type virus was based on values obtained from in vitro replicon studies. Since monotherapy data for Compound 4 indicated a y of mutants with ent EC50s, a value of 1000x fold change in EC50 was used for nd 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. cokinetic data and viral load data from 140 treatment-naive HCV-infected subjects were used to construct the model. For ng, number of target cells at baseline, number of infected cells at baseline, death rate of target cells and mutation rates were based on literature values.

See, e.g., Snoeck et al. supra; Rong er 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 et al. SCIENCE 282(5386):103-7 (1998); Shudo et al. 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 ters in the model. All other parameters were estimated. Exposure-antiviral response modeling was performed using NONMEM 7.2.

Clinical trial tions were performed using Trial Simulator version 2.2.1. Fifty subjects and 50 replicates were simulated for each treatment. A subject drop out rate from the study due to any reason was assumed to be 8% over 24 weeks based on available ture on trials in subjects with HCV. All simulations were conducted assuming 100% compliance. Covariates included in the simulations were genotype 1a/1b . Clinical outcomes simulated included: ( 1) percentage of ts below limit of detection (LOD) of 10 lU/mL and (2) percentage of subjects 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., Compound 1/ritonavir at 0, 150/100 or 100/100 mg QD, Compound 4 at 5, 25 or 100 mg QD, and nd 2 at 400 or 800 mg BID) and across a range oftreatment durations (e.g., 2. 4, 6, 8, 10, 12, 16, and 24 .

Optimal dose and duration were predicted based on percentage of subjects with viral load of less than -510g IU/mL threshold 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 doses of Compound 1. Figure 6A shows the predicted median SVR percentage (“% SVR”) and 90% conﬁdence interval (the vertical bar at the top of each SVR tage column) for different treatment durations using a combination of nd 1 and Compound 2; Figure 6B shows the predicted median and 90% conﬁdence interval for different treatment ons using a ation of Compound 1 and Compound 4; and Figure 6C shows the predicted median and 90% conﬁdence al for different ent durations using a combination of Compound 1, Compound 2 and Compound 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 ted 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 signiﬁcant number of subjects. A 2-DAA regimen was predicted to cure over 40% of the subjects and a 3-DAA regimen was predicted to cure about 60% of the subjects with only 6 weeks of . Dosing for durations of over 12 weeks was not ed to increase the percentage of subjects with SVR significantly. Addition of the 3ml DAA was predicted to shorten treatment duration by 2 to 4 weeks as optimal ons 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 ations when used with ribavirin. In addition, the effect of interferon (e.g., ted 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 determining the effect of s parameters is very difﬁcult if not impossible, they can be examined using the model.

Thus SVR in patient population that have ent mutants can be ted with the model.

The model was used to simulate a treatment regimen which included 150/100 mg Compound 1/ritonavir QD + 400 mg nd 3 QD + weight-based amounts of RBV BID for 12 weeks. Subjects under the treatment included 11 treatment na'1've subjects between the ages of 18 and 65.

All subjects completed 12 weeks of therapy with Compound 1 and ritonavir (Compound 1/r) dosed in combination with Compound 3 and rin (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 in treatment na'1've subjects infected with pe (GT) 1 HCV. The percentage of subjects with HCV RNA less than LOD at 2, 4, 8, 10, and 12 weeks was summarized in Figure 7. The mean predicted versus observed percentage of ts 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 respective predicted LOD percentage column) were also indicated. As shown in Figure 7, the model reasonably predicted the al outcome of %LOD.

The model was also used to simulate another treatment regimen. The regimen included three groups of patients. In Group 1, 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 19 treatment e subjects between the ages of 18 and 65 . One subject discontinued 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 na'1've subjects infected with GT1 HCV.

In 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 na'1've subjects n 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 ts completed 12 weeks of therapy with Compound 1/r dosed in combination with Compound 2 and RBV. Compound 1 (150 mg QD) was dosed with 100 mg QD ritonavir, 400 mg BID Compound 2, and RBV in ent na'1've subjects infected with GT1 HCV.

In Group 3, peginterferon + ribavirin (P/RBV) non-responders were treated with a protease inhibitor (in combination with ritonavir), a polymerase tor, and rin. The treatment was without interferon. Subjects included 17 P/RBV non-responders between the ages of 18 and 65.

Subjects were treated with Compound 1/r dosed in combination with Compound 2 and RBV for 12 weeks. Compound 1 (150 mg QD) was dosed with 100 mg QD vir, 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 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 indicated. As shown in Figure 8, the predicted SVR percentages aligned well with the observed SVR percentages. Simulations also t that the same ent regimen but without ribavirin has similar or comparable LOD percentages for ent treatment ons.

The exposure response viral dynamic model of this Example ed a quantitative method to reasonably predict SVR for various combination of antiviral compounds. Based on the exposure-antiviral se modeling and clinical 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 optimal 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 t of the subjects.

Example 7. Clinical Modeling for Interferon-free DAA Combination ies Containing EMS-790052 and EMS-650032 The model described above was also used to predict the SVR percentage of interferonfree treatment regimens containing BMS-790052 and BMS-650032 without rin, based on existing published clinical data including two Phase 1 and one Phase 2 study of BMS-790052 and one Phase 1 and one Phase 2a study of BMS-650032. Figure 9 shows the predicted median SVR percentage and 90% SVR conﬁdence interval for different treatment durations of a 2-DAA regimen containing 0052 (60 mg QD) and BMS-650032 (600 BID) in genotype 1 na'1've 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 durations of 12 weeks or greater with predicted SVR rates of about 70% for 10 weeks of dosing. Similar regimens but containing ribavirin, or regimens with similar s of BMS-790052 and BMS-650032 with or without ribavirin, are expected to achieve r SVR rates.

Example 8. Clinical Modeling for Interferon-free ies Containing PSI-7977 Likewise, a 3-DAA regimen without interferon and ribavirin was modeled for genotype 1 patients based on ng clinical data. The 3-DAA regimen contains 200/100 mg QD Compound 1/r, 50 mg QD nd 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 combination was predicted to have over 60% SVR in 6 weeks and over 80% SVR at on of 8-week, 10-week, 12-week or longer treatment. Similar regimens but containing ribavirin, or regimens with similar dosings of Compound l/r, Compound 4 and PSI-7977 with or without ribavirin, 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 pe 1 treatment-na'ive patients were obtained. Figure 11 depicts the predicted median and 90% nce interval of SVR percentage for different treatment durations of such a regimen containing 77 (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 respective predicted SVR percentage column) is also indicated in Figure 11. The prediction was based on the y published clinical data for PSI-7977. SVR rate for PSI-7977 + ribavirin was ted to be around 75-90% following 12 weeks of dosing, and about 55-75% following 8 weeks dosing, in genotype 1 subjects.

Similar SVR percentages for genotype 1 treatment-na'ive patients are expected for similar regimens containing similar PSI-7977 QD dosing (e.g., 0 mg QD) but without ribavirin.

Data from two Phase 1 and one Phase 2 study of Daclatasvir (EMS-790052) and one Phase 1 and one Phase 2 study of PSI-7977 were used for estimating the pharmacokinetic and viral c model parameters. Predictions for a 2-DAA combination with Daclatasvir (EMS-790052) and PSI-7977 in genotype 1 na'ive 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 genotype 1 na'1've patients can achieve SVR. rly, 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 na'ive patients are shown in Figure 13. The model predicts that following 10-12 weeks of dosing with the combination of TMC-435 and PSI-7977 without rin, at least 90% of HCV patients can e SVR.

Example 9. Clinical Modeling for Interferon-free DAA Combination ies Containing Danoprevir and Mercitabine In addition, data from one Phase 1 and one Phase 2 study of Danoprevir and Mercitabine were used for estimating the pharmacokinetic and viral dynamic model parameters. vir was co- administered with evir to improve the pharmacokinetics of danoprevir. Predictions for a 2-DAA combination with Danoprevir and Mercitabine in genotype 1 na'ive patients are shown in Figure 14. The model predicts that following 16 weeks of dosing with the ation of Danoprevir and Mercitabine without ribavirin, at least 90% ofHCV patients can achieve SVR.

Example 10. Clinical 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 parameters. Predictions for the combination with GS—9190 (tegobuvir), GS—945 1 and GS-S885 and without ribavirin in genotype 1 naive patients are shown in Figure 15. The model predicts that following 12 weeks of dosing with the combination of GS-9190 (tegobuvir) + GS-9451 + GS-5885 + RBV and without ribavirin, about 70% of genotype 1 naive patients can achieve SVR and following 24 weeks of treatment > 80% of genotype 1 na'ive patients can achieve SVR.

Example 11. Clinical Modeling for Interferon-free DAA ation 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 ters. Predictions for the combination with 1 and 7 (PSI-7977) and without ribavirin in genotype 1 naive patients are shown in Figure 16.

Data from Phase 1 and Phase 2 s of GS-5885 and GS—7977 (PSI-7977) were used for estimating the pharmacokinetic and viral dynamic model parameters. Predictions for the ation with GS-5885 and GS-7977 977) and without ribavirin 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-5885 and GS-7977 (PSI-7977) and without ribavirin in genotype 1 naive patients are shown in Figure 16.

The model predicts that following 12 weeks of dosing with the combination of 1 and GS-7977 (PSI-7977), or the ation of GS-5885 and 7 (PSI-7977), or the combination of GS-9451, GS—5885 and GS-7977 (PSI-7977), and in the absence of ribavirin, at least 90% of genotype 1 na'ive patients can e SVR.

Example 12. Clinical Modeling for Interferon-free DAA ation Therapies Containing TMC-43 and Daclatasvir (BMS-790052) Data from one Phase la study of TMC—435 and from two Phase 1 and one Phase 2 study of daclatasvir (EMS-790052) were used for estimating the pharmacokinetic and viral dynamic model parameters. Predictions for the combination with TMC—435 and asvir in genotype 1 naive patients are shown in Figure 17.

The model predicts that following 12 weeks of dosing with the combination of TMC—435 and daclatasvir (EMS-790052), about 80% of genotype 1 na'1've patients can achieve SVR.

The foregoing description of the present invention provides illustration and ption, but is not intended to be exhaustive or to limit the ion 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 ion is deﬁned by the claims and their equivalents.

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Claims

1. Use of PSI-7977 ( ) and an HCV NS5A inhibitor in the manufacture of a medicament for the treatment of hepatitis C virus (HCV) in a patient infected with HCV genotype 1, wherein said treatment does not include administration of either interferon or rin, and wherein said treatment lasts for 8, 9, 10, 11 or 12 weeks, wherein the medicament comprises PSI-7977 and an HCV NS5A inhibitor co-formulated in a single composition.

2. The use of claim 1, wherein the ent lasts for 12 weeks.

3. The use of claim 1, wherein the HCV NS5A tor is GS-5885 ( ), and wherein said treatment lasts for 8, 9, 10 or 11 weeks.

4. The use of claim 1, wherein the HCV NS5A inhibitor is GS-5885, and wherein said treatment lasts for 12 weeks.

5. The use according to claim 1 or claim 3, wherein the treatment lasts for 8 weeks.

6. The use according to any one of claims 1 to 5, n said patient is an HCV ent-naive patient. [Annotation] amandam None set by amandam [Annotation] amandam MigrationNone set by amandam [Annotation] m Unmarked set by amandam

7. The use according to any one of claims 1 to 6, wherein said patient is infected with HCV genotype 1a.

8. The use ing to any one of claims 1 to 7, wherein the medicament is formulated for administration once daily.

9. The use ing to any one of claims 1 to 8, wherein said treatment comprises administering 400 mg QD of PSI-7977 to a genotype 1 naive patient.

10. The use according to any one of claims 3 to 9, wherein said medicament is formulated for the administration of 90 mg QD of GS-5885 and 400 mg QD of PSI-7977 to a genotype 1 naive patient.

11. The use according to any one of claims 1 to 10, wherein the treatment of HCV es sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype 1.

12. The use according to any one of claims 1 to 10, n the treatment of HCV achieves sustained gic response (SVR) in at least 75% of patients infected with HCV genotype 1.

13. The use according to any one of claims 1, 2, 4 or 6 to 10, wherein the treatment of HCV es sustained virologic response (SVR) in at least 90% of patients infected with HCV genotype 1, wherein said treatment lasts for 12 weeks.

14. 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 either interferon or ribavirin to said patient, wherein the medicament comprises PSI-7977 and an HCV NS5A inhibitor co-formulated in a single composition; and wherein the ment further comprises another direct acting antiviral (DAA) or is stered in ation with another DAA.

15. The use according to claim 14, wherein said another DAA is Compound 1 ( ), and said HCV NS5A inhibitor is Compound 4 ( ).

16. The use according to claim 14 or claim 15, wherein said ment is formulated for administration of PSI-7977 at a dose of 400 mg once daily.

17. The use according to claim 14, wherein said another DAA is an HCV protease inhibitor.

18. The use according to claim 14, wherein said another DAA is an HCV polymerase inhibitor.

19. The use according to any one of claims 14 to 18, wherein said patient is a treatment naive patient.

20. The use according to any one of claims 14 to 19, 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

21. The use according to any one of claims 14 to 20, n the treatment of HCV achieves sustained virologic response (SVR) in at least 70% of patients infected with HCV genotype 1.

22. The use according to any one of claims 14 to 20, wherein the treatment of HCV achieves sustained virologic se (SVR) in at least 75% of patients infected with HCV genotype 1.