WO2005062949A2

WO2005062949A2 - Method for treating hepatitis virus infection

Info

Publication number: WO2005062949A2
Application number: PCT/US2004/043414
Authority: WO
Inventors: Lawrence M. Blatt
Original assignee: Intermune, Inc.
Priority date: 2003-12-23
Filing date: 2004-12-22
Publication date: 2005-07-14
Also published as: WO2005062949A3

Abstract

The present invention provides methods of treating a hepatitis virus infection, particularly a hepatitis C virus infection, the method generally involving administering to an individual having a hepatitis virus infection an effective amount of a Type I interferon receptor agonist that is not modified with a poly(ethylene glycol) (PEG) moiety, for a period of time sufficient to reduce serum viral load to undetectable levels; followed by administering an effective amount of a Type I interferon receptor agonist that is modified with a PEG moiety, for a period of time sufficient to achieve a sustained viral response.

Description

METHOD FOR TREATING HEPATITIS VIRUS INFECTION

FIELD OF THE INVENTION

[0001] This invention is in the field of treatments for viral infections, in particular hepatitis virus infection.

BACKGROUND OF THE INVENTION

[0002] Hepatitis C virus (HCN) infection is the most common chronic blood borne infection in the United States. Although the numbers of new infections have declined, the burden of chronic infection is substantial, with Centers for Disease Control estimates of 3.9 million (1.8%) infected persons in the United States. Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is HCN-related, resulting in an estimated 8,000-10,000 deaths each year. HCN-associated end- stage liver disease is the most frequent indication for liver transplantation among adults.

[0003] Antiviral therapy of chronic hepatitis C has evolved rapidly over the last decade, with significant improvements seen in the efficacy of treatment. Nevertheless, even with combination therapy using PEGylated IFN-α plus ribavirin, 40% to 50% of patients fail therapy, i.e., are nonresponders or relapsers. These patients currently have no effective therapeutic alternative. In particular, patients who have advanced fibrosis or cirrhosis on liver biopsy are at significant risk of developing complications of advanced liver disease, including ascites, jaundice, variceal bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma.

[0004] The high prevalence of chronic HCN infection has important public health implications for the future burden of chronic liver disease in the United States. Data derived from the National Health and Nutrition Examination Survey (NHANES III) indicate that a large increase in the rate of new HCV infections occurred from the late 1960s to the early 1980s, particularly among persons between 20 to 40 years of age. It is estimated that the number of persons with long-standing HCV infection of 20 years or longer could more than quadruple from 1990 to 2015, from 750,000 to over 3 million. The proportional increase in persons infected for 30 or 40 years would be even greater. Since the risk of HCN-related chronic liver disease is related to the duration of infection, with the risk of cirrhosis progressively increasing for persons infected for longer than 20 years, this will result in a substantial increase in cirrhosis-related morbidity and mortality among patients infected between the years of 1965- 1985.

[0005] Chronic hepatitis C virus infection is characterized by intermittent or persistent elevations in serum alanine aminotransferase (ALT) levels and constant levels of HCN RΝA in the circulation. Currently, approved therapies use alpha interferons derived from natural leukocytes or by recombinant methods using cDΝA sequences of specific subtypes or consensus interferon-α (IFΝ-α). The accepted dosage regimen is a subcutaneous administration of IFΝ-α in the dose ranges of 6-50 μg three times in week for a period of 24 - 48 weeks.

[0006] Cyclical administration of IFΝ-α has also been conducted, in the hope that viral clearance can be achieved. The repeat dosing has been deemed necessary in view of the rapid clearance and in vivo degradation of IFΝ-α. In another attempt to achieve better efficacy, combination therapies such as IFΝ-α and ribavirin have been carried out. Recent interim results from a Phase IN clinical trial comparing the use of Infergen plus ribavirin to the use of interferon alfa-2b plus ribavirin (Rebetron™) indicate that some of the interferons may be more potent in achieving a sustained viral response (SVR) than others. For example, patients treated with Infergen in combination with ribavirin achieved and SNR of 56% compared with an SVR of 31% in patients treated with Rebetron.

[0007] In attempts to improve further the therapeutic methods, various investigators have attempted a chemical modification of IFΝ-α by adding a polymer chain(s) to increase the molecular weight and size of the protein and to prolong the systemic circulation times. While these manipulations of IFΝ-α increased the circulation times and improved the efficacies further, a significant fraction of the protein loses its biological activity. Thus higher amounts of the protein have to be delivered to the patient with adverse effects such as neutropenia accompanying such administrations.

[0008] An example of such modification of IFΝ-α is addition of polyethylene glycol (PEG) chains to the IFΝ-α molecule, in a process known as "PEGylation." The PEGylation of alpha interferons can lead to a significant reduction in the antiviral activity of the polypeptide, and thus PEGylation must be carefully controlled to avoid modification of residues that may result in an undesirable reduction of activity. For example, chemical modifications in the receptor binding domains in the interferon molecule, such as the AB loop (residues 29-35), helix D (123-140) and subtype differentiating domain (residues 78-95), lead to significant losses in the antiviral activity of the protein. Mutagenesis, deletion, chemical modification and nuclear magnetic resonance studies have shown that the lysines or histidines in these domains such as His 34 are critical determinants for activity. [0009] Viral kinetics during treatment regimens that include IFN-α have been examined. In general, an initial rapid decline in viral titers (early viral response; EVR) is seen in some individuals. The EVR results in an approximately 0.5- to 3-log decrease in serum HCV RNA levels in a period of 24-48 hours after initiation of treatment. An early robust response is favorable toward achieving a durable response. In some individuals, the EVR is followed by a further, less rapid decline of the virus in blood (second phase decline). The second phase decline is a slower decrease in the level of the virus over several weeks or months.

[0010] Despite the availability of approved treatment regimens discussed above, only a small fraction of the individuals treated attain a sustained viral response. Thus, there is a need in the art for improved methods for treating HCV infection. The present invention addresses this need. Literature

[0011] U.S. Patent Nos. 6,172,046; 6,245,740; 5,824,784; 5,372,808; 5,980,884; published international patent applications WO 96/21468; WO 96/11953; Torre et al. (2001) J. Med. Virol. 64:455-459; Bekkering et al. (2001) J Hepatol. 34:435-440; Zeuzem et al. (2001) Gastroenterol. 120:1438-1447; Zeuzem (1999) J. Hepatol. 31:61-64; Keeffe and Hollinger (1997) Hepatol. 26:101S-107S; Wills (1990) Clin. Pharmacokinet. 19:390-399; Heathcote et al. (2000) New Engl. J. Med. 343:1673-1680; Husa and Husova (2001) Bratisl. Let Listy 102:248-252; Glue et al. (2000) Clin. Pharmacol. 68:556-567; Bailon et al. (2001) Bioconj. Chem. 12:195-202; and Neumann et al. (2001) Science 282:103; Zalipsky (1995) Adv. Drug Delivery Reviews S. 16, 157-182; Mann et al. (2001) Lancet 358:958-965; Zeuzem et al. (2000) New Engl. J. Med. 343:1666-1672; U.S. Patent Nos. 5,985,265; 5,908,121; 6,177,074; 5,985,263; 5,711,944; 5,382,657; and 5,908,121; WO 03/028754; WO 03/049760; WO 03/028755; WO 03/030923.

SUMMARY OF THE INVENTION

[0012] The present invention provides methods of treating a hepatitis virus infection, particularly a hepatitis C virus infection, the method generally involving administering to an individual having a hepatitis virus infection an effective amount of a Type I interferon receptor agonist that is not modified with a poly(ethylene glycol) (PEG) moiety, for a period of time sufficient to achieve undetectable serum levels of HCN; followed by administering an effective amount of a Type I interferon receptor agonist that is modified with a PEG moiety, for a period of time sufficient to achieve a sustained viral response. In many embodiments, such methods involve administering the unPEGylated Type I interferon in bolus form to the individual. FEATURES OF THE INVENTION

[0013] The present invention features a method for treating a hepatitis virus infection, the method generally involving administering to an individual having a hepatitis virus infection an effective amount of a first Type I interferon receptor agonist that is not modified with a poly(ethylene glycol) (PEG) moiety for a first period of time that is sufficient to achieve undetectable levels of hepatitis virus in the serum of the individual, e.g., where the virus is a hepatitis C virus (HCN), the level of HCN RΝA in the serum is undetectable; followed by administering an effective amount of a second Type I interferon agonist that is PEGylated, for a second period of time that is sufficient to avoid relapse, e.g., a period of time sufficient to achieve a sustained viral response.

[0014] In many embodiments, the first Type I interferon receptor agonist is administered in bolus form. In some embodiments, the first Type I interferon receptor agonist is administered subcutaneously in bolus form. In some embodiments, the first Type I interferon receptor agonist is administered in bolus form by subcutaneous injection.

[0015] In many embodiments, the first Type I interferon receptor agonist is IFΝ-α. In some embodiments, the IFΝ-α is INFERGEN® consensus IFN-α. In other embodiments, the first Type I interferon receptor agonist is interferon alfa 2a, 2b or 2c.

[0016] In some embodiments, the second Type I interferon receptor agonist is a PEGylated IFN-α. In some embodiments, the PEGylated IFN-α is monoPEG(30 kD, linear)-ylated consensus IFN-α. In some embodiments, the PEGylated IFN-α is PEG-INTRON® peginterferon alfa-2b. In some embodiments, the PEGylated IFN-α is PEGASYS® peginterferon alfa-2a.

[0017] In some embodiments, a subject treatment regimen further involves administering an effective amount of one or more of an immunomodulatory agent, and an inhibitor of an HCN enzyme. In many embodiments, the immunomodulatory agent is selected from i) a Type II interferon receptor agonist; ii) a TΝF antagonist; iii) pirfenidone or a pirfenidone analog; and iv) thymosin-α. In some embodiments, the HCN enzyme inhibitor is an ΝS3 protease inhibitor. In other embodiments, the HCN enzyme inhibitor is an ΝS5B RNA-dependent RNA polymerase inhibitor.

[0018] In some embodiments, a subject treatment regimen further involves administering an effective amount of a nucleoside analog. In many embodiments, the nucleoside analog is selected from ribavirin, levovirin, viramidine, isatoribine, or an L-nucleoside. DEFINITIONS

[0019] As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease (as in liver fibrosis that can result in the context of chronic HCN infection); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.

[0020] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.

[0021] "Treatment failure patients" as used herein generally refers to HCN-infected patients who failed to respond to previous therapy for HCN (referred to as "non-responders") or who initially responded to previous therapy, but in whom the therapeutic response was not maintained (referred to as "relapsers"). The previous therapy generally can include treatment with IFΝ-α monotherapy or IFΝ-α combination therapy, where the combination therapy may include administration of IFΝ-α and an antiviral agent such as ribavirin.

[0022] As used herein, the term "a Type I interferon receptor agonist" refers to any naturally occurring or non-naturally occurring ligand of human Type I interferon receptor, which binds to and causes signal transduction via the receptor. Type I interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[0023] The "unPEGylated," "unpegylated," "non-PEGylated," or "non-pegylated," form(s) of a Type I interferon receptor agonist, or any language of similar meaning, refers to the subject interferon receptor agonist molecule(s) free of any derivatization with poly (ethylene glycol) (PEG) or other non-proteinaceous polymer moiety, where such derivatization reduces the serum clearance of the derivatized interferon receptor agonist by at least two-fold compared to the serum clearance of the underivatized interferon receptor agonist. For example, an "unPEGylated IFN-α" means an IFN-α molecule free of any derivatization with poly (ethylene glycol) (PEG) or other non-proteinaceous polymer moiety, where such derivatization reduces the serum clearance of the derivatized IFN-α by at least two-fold compared to the serum clearance of the underivatized IFN-α.

[0024] As used herein, the term "immunomodulatory agent" refers to any agent, other than (i) a Type I or Type III interferon receptor agonist and (ii) a nucleoside, that stimulates immune cell mediated destruction of virus-infected cells. The term "immunomodulatory agent" includes, but is not limited to, Type II interferon receptor agonists (including IFN-γ); TNF antagonists; pirfenidone and pirfenidone analogs; and thymosin-α (Zadaxin®; SciClone Pharmaceuticals); and the like.

[0025] As used herein, the term "nucleoside" refers to a compound composed of any pentose or modified pentose moiety attached to a specific position of a heterocycle or to the natural position of a purine (9-position) or pyrimidine (1-position) or to the equivalent position in an analog.

[0026] As used herein, the term "nucleotide" refers to a phosphate ester substituted on the 5'- position of a nucleoside.

[0027] As used herein, the term "heterocycle" refers to a monovalent saturated or unsaturated carbocyclic radical having at least one hetero atom, such as N, O, S, Se or P, within the ring, each available position of which can be optionally substituted, independently, with, e.g., hydroxyl, oxo, amino, imino, lower alkyl, bromo, chloro and/or cyano. Included within the term "heterocycle" are purines and pyrimidines.

[0028] As used herein, the term "purine" refers to nitrogenous bicyclic heterocycles.

[0029] As used herein, the term "pyrimidine" refers to nitrogenous monocyclic heterocycles.

[0030] As used herein, the term "L-nucleoside" refers to a nucleoside compound that has an L- ribose sugar moiety.

[0031] As used herein, the term "pirfenidone" refers to 5 -methyl- l-phenyl-2-(lH)-pyridone. As used herein, the term "pirfenidone analog" refers to any compound of Formula I, IIA or IIB below. A "specific pirfenidone analog," and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.

[0032] As used herein, the term "a Type II interferon receptor agonist" refers to any naturally- occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[0033] As used herein, the term "HCV enzyme inhibitor" refers to any agent that inhibits an enzymatic activity of an enzyme encoded by HCV. The term "HCV enzyme inhibitor" includes, but is not limited to, agents that inhibit HCV NS3/NS4A protease activity; agents that inhibit HCV NS3 helicase activity; and agents that inhibit HCV NS5B RNA-dependent RNA polymerase activity.

[0034] As used herein, the terms "HCV NS3 protease inhibitor" and "NS3 protease inhibitor" refer to any agent that inhibits the protease activity of HCV NS3/NS4A complex.

[0035] The term "sustained viral response" (SVR; also referred to as a "sustained response" or a "durable response"), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of serum HCV titer. Generally, a "sustained viral response" refers to no detectable HCV RNA (e.g., less than about 500, less than about 200, or less than about 100 genome copies per milliliter serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of treatment.

[0036] The term "hepatitis virus infection" refers to infection with one or more of hepatitis A, B, C, D, or E virus, with blood-borne hepatitis viral infection being of particular interest.

[0037] As used herein, the term "hepatic fibrosis," used interchangeably herein with "liver fibrosis," refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.

[0038] As used herein, the term "liver function" refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ- glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[0039] Drug delivery devices that are suitable for use in the subject methods include, but are not limited to, injection devices; an implantable device, e.g., pumps, such as an osmotic pump, that may or may not be connected to a catheter; biodegradable implants; liposomes; depots; and microspheres.

[0040] The terms "controlled drug delivery device" and "controlled delivery device" are used interchangeably herein to refer to any device wherein (i) the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, and (ii) the release of (i) occurs at a rate that is reproducible within the environment of use.

[0041] The term "dosing event" as used herein refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device. Thus, the term "dosing event," as used herein, includes, but is not limited to, installation of a depot comprising an antiviral agent; installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.

[0042] The term "depot" refers to any of a number of implantable, biodegradable or non- biodegradable, controlled release systems that are generally non-containerized and that act as a reservoir for a drug, and from which drug is released. Depots include polymeric non- polymeric biodegradable materials, and may be solid, semi-solid, or liquid in form.

[0043] The term "microsphere" (also referred to as "microparticles," "nanospheres," or "nanoparticles") refers to small particles, generally prepared from a polymeric material and usually having a size in the range of from about 0.01 μm to about 0.1 μm, or from about 0.1 μm to about 10 μm in diameter.

[0044] The term "therapeutically effective amount" is meant an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent, effective to facilitate a desired therapeutic effect. The precise desired therapeutic effect will vary according to the condition to be treated, the formulation to be administered, and a variety of other factors that are appreciated by those of ordinary skill in the art.

[0045] The terms "International Units" and "Units" are used interchangeably herein to refer to units of measurement for quantitation of the ability of the interferon to inhibit the cytopathic effect of a suitable virus (e.g. encephalomyocarditis virus (EMC), vesicular stomatitis virus, Semliki forest virus) after infection of an appropriate cell line (e.g., the human lung carcinoma cell lines, A549; HEP2/C; and the like). The antiviral activity is normalized to "Units" of antiviral activity exhibited by a reference standard such as human interferon alpha supplied by WHO. Such methods are detailed in numerous references. A particular method for measuring International Units is described in Familletti, P.C., Rubinstein, S and Pestka, S.(1981) "A convenient and rapid cytopathic effect inhibition assay for interferon", Methods in Enzymol, Vol 78 (S.Pestka, ed), Academic Press, New York pages 387-394. For the most part, the reference standard is human interferon alpha supplied by the World Health Organization, and the method for measuring International Units is that described in Familletti, supra.

[0046] The amounts of interferon administered will depend on the specific activities of the compounds and their biological performance in vivo. For example, IFN-α 2b is administered at 11.54 μg protein three times a week corresponding to 3 x 10⁶ IU per injection (specific activity, 2.68 x 10⁶ IU/mg). On the other hand, CIFN alfa-con 1 is administered at 9 μg doses per injection corresponding to 9 x 10⁶IU per administration (specific activity, 1 x 10⁹ IU/mg). However, in view of the fact that PEGylation reactions often result in a reduction in activity, larger mass doses of PEGylated material are administered to achieve efficacy (e.g. reduction in viral load; sustained viral response, etc.).

[0047] As used herein, any compound or agent described as "effective for the avoidance or amelioration of side effects induced by a Type I interferon receptor agonist," or as "effective for reducing or eliminating the severity or occurrence of side effects induced by a Type I interferon receptor agonist," or any compound or agent described by language with a meaning similar or equivalent to that of either of the foregoing quoted passages, is/are defined as a compound(s) or agent(s) that when co-administered to a patient in an effective amount along with a given dosing regimen of a subject Type I interferon receptor agonist therapy, abates or eliminates the severity or occurrence of side effects experienced by a patient in response to the given dosing regimen of the Type I interferon receptor agonist therapy, as compared to the severity or occurrence of side effects that would have been experienced by the patient in response to the same dosing regimen of the a Type I interferon receptor agonist therapy without co-administration of the agent.

[0048] In many embodiments, the effective amounts of a Type I interferon receptor agonist and a second therapeutic agent are synergistic amounts. As used herein, a "synergistic combination" or a "synergistic amount" of a Type I interferon receptor agonist and a second therapeutic agent is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a disease than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the Type I interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the second therapeutic agent when administered at the same dosage as a monotherapy. [0049] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0050] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0052] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an interferon-alpha polypeptide" includes a plurality of such polypeptides and reference to "the dosing regimen" includes reference to one or more dosing regimens and equivalents thereof known to those skilled in the art, and so forth.

[0053] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION [0054] The present invention provides methods of treating a hepatitis virus infection in an individual. The methods generally involve administering to an individual having a hepatitis virus infection an effective amount of a Type I interferon receptor agonist that is not modified with a poly(ethylene glycol) (PEG) moiety, for a period of time sufficient to reduce viral load to an undetectable level; followed by administering an effective amount of a Type I interferon receptor agonist that is modified with a PEG moiety, for a period of time sufficient to achieve a sustained viral response.

[0055] The methods described herein are generally useful in treatment of any hepatitis viral infection (HBV, HCV, delta, etc.). In many embodiments, treatment of hepatitis C virus (HCV) infection is of particular interest. Reference to HCV herein is for illustration only and is not meant to be limiting. METHODS OF TREATING A HEPATITIS VIRUS INFECTION

[0056] The instant invention provides method of treating a hepatitis virus infection. The methods generally involve administering a first Type I interferon receptor agonist that is not PEGylated; followed by administering a second Type I interferon receptor agonist that is PEGylated. The first Type I interferon receptor agonist is administered in an induction regimen for a period of time sufficient to achieve undetectable levels of hepatitis virus in the serum of the individual, e.g., to reduce viral load to an undetectable level. The second, PEGylated Type I interferon receptor agonist is administered in a maintenance regimen for a period of time sufficient to avoid relapse, e.g., to achieve a sustained viral response (SVR). In many embodiments, the first Type I interferon receptor agonist is administered in bolus form. In some embodiments, the first Type I interferon receptor agonist is administered subcutaneously in bolus form. In some embodiments, the first Type I interferon receptor agonist is administered in bolus form by subcutaneous injection.

[0057] The present invention provides a method for treating a hepatitis C virus infection in an individual, the method generally involving: a) administering to an individual having an HCV infection a non-PEGylated interferon-alpha (IFN-α) in an effective amount and for a first period of time to reduce serum viral load to an undetectable level; and b) administering to the individual who has been treated as in step (a) a PEGylated IFN-α in an effective amount and for a second period of time to achieve a sustained viral response. In many embodiments, the second period of time is at least as long as the first period of time. In many embodiments, the non-PEGylated IFN-α is administered in bolus form. In some embodiments, the non- PEGylated IFN-α is administered subcutaneously in bolus form. In some embodiments, the non-PEGylated IFN-α is administered in bolus form by subcutaneous injection. [0058] The induction phase regimen, i.e., treatment with a first, non-PEGylated Type I interferon receptor agonist, is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3-log, a 3.5- log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual.

[0059] The induction phase regimen is effective to achieve a 1.5-log, a 2-log, a 2.5-log, a 3- log, a 3.5-log, a 4-log, a 4.5-log, or a 5-log reduction in viral titer in the serum of the individual within a period of from about 12 hours to about 48 hours, or from about 16 hours to about 24 hours after the beginning of the dosing regimen.

[0060] The first, non-PEGylated Type I interferon receptor agonist is administered over a period of from about 24 hours to about 48 hours, from about 2 days to about 4 days, from about 4 days to about 7 days, from about 1 week to about 2 weeks, from about 2 weeks to about 4 weeks, from about 4 weeks to about 6 weeks, from about 6 weeks to about 8 weeks, from about 8 weeks to about 12 weeks, from about 12 weeks to about 16 weeks, from about 16 weeks to about 24 weeks, or from about 24 weeks to about 48 weeks. In particular embodiments, the first, non-PEGylated Type I interferon receptor agonist is administered for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks.

[0061] In the induction phase, the concentration of the non-PEGylated Type I interferon receptor agonist in the serum is effective to reduce viral titers to undetectable levels, e.g., to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL serum. In some embodiments, an effective amount of non-PEGylated Type I interferon receptor agonist is an amount that is effective to reduce viral load to lower than 100 genome copies/mL serum.

[0062] The dosing regimen of PEGylated Type I interferon receptor agonist in the maintenance phase is effective to achieve a sustained viral response, e.g., no detectable HCV RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter serum) is found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.

[0063] In some embodiments, the subject method provides for (a) administering the subject non-PEGylated Type I interferon receptor agonist for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level, and (b) administering the subject PEGylated Type I interferon receptor agonist for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first period of time and the second period of time is at least about 24 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, or 48 weeks, such that a sustained viral response is achieved.

[0064] Whether a subject method is effective in treating an HCV infection can be determined by measuring viral load, or by measuring a parameter associated with HCV infection, including, but not limited to, liver fibrosis, elevations in serum transaminase levels, and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

[0065] Viral load can be measured by measuring the titer or level of virus in serum. These methods include, but are not limited to, a quantitative polymerase chain reaction (PCR) and a branched DNA (bDNA) test. Quantitative assays for measuring the viral load (titer) of HCV RNA have been developed. Many such assays are available commercially, including a quantitative reverse transcription PCR (RT-PCR) (Amplicor HCV Monitor™, Roche Molecular Systems, New Jersey); and a branched DNA (deoxyribonucleic acid) signal amplification assay (Quantiplex™ HCV RNA Assay (bDNA), Chiron Corp., Emeryville, California). See, e.g., Gretch et al. (1995) Ann. Intern. Med. 123:321-329. Also of interest is a nucleic acid test (NAT), developed by Gen-Probe Inc. (San Diego) and Chiron Corporation, and sold by Chiron Corporation under the trade name Procleix®, which NAT simultaneously tests for the presence of HIV-1 and HCV. See, e.g., Vargo et al. (2002) Transfusion 42:876- 885.

[0066] As noted above, whether a subject method is effective in treating an HCV infection can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods of determining the extent of liver fibrosis are discussed in detail below. In some embodiments, the level of a serum marker of liver fibrosis indicates the degree of liver fibrosis.

[0067] As one non-limiting example, levels of serum alanine aminotransferase (ALT) are measured, using standard assays. In general, an ALT level of less than about 45 international units is considered normal. In some embodiments, an effective amount of a therapeutic agent that is administered as part of a subject combination therapy is an amount effective to reduce ALT levels to less than about 45 U/ml serum.

[0068] Therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist and a PEGylated Type I interferon receptor agonist are amounts that, when administered as part of a subject therapeutic regimen, are effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%o, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or to a placebo-treated individual. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker. Liver fibrosis

[0069] Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.

[0070] Whether treatment with a non-PEGylated Type I interferon receptor agonist, followed by treatment with a PEGylated Type I interferon receptor agonist, as part of a subject therapeutic regimen, is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade" as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage" as being reflective of long- term disease progression. See, e.g., Brunt (2000) Hepatol. 31 :241-246; and METAVIR (1994) Hepatology 20: 15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems.

[0071] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[0072] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation ; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.

[0073] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J Hepatol. 13:372.

[0074] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite .

[0075] The benefit of anti-fibrotic therapy can also be measured and assessed by using the Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon the presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C.

[0076] In some embodiments, therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, effect a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system. [0077] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with a subject combination therapy. Morphometric computerized semi- automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[0078] In another embodiment, effective amounts of a non-PEGylated Type I interferon receptor agonist, and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, are effective to increase an index of liver function by at least about 10%, at least about 20%), at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%), at least about 55%, at least about 60%, at least about 65%, at least about 70%), at least about 75%), or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[0079] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include α- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[0080] In another embodiment, therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist, and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, are effective to reduce a serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%), at least about 30%, at least about 35%), at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the level of the marker in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e.g., enzyme-linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[0081] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with a subject treatment regimen. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[0082] As used herein, a "complication associated with cirrhosis of the liver" refers to a disorder that is a sequelae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[0083] In another embodiment, therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist, and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, are effective in reducing the incidence of (e.g., the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%>, at least about 25%, at least about 30%, at least about 35%), at least about 40%, at least about 45%), at least about 50%, at least about 55%, at least about 60%, at least about 65%>, at least about 70%, at least about 75%, or at least about 80%>, or more, compared to an untreated individual, or in a placebo-treated individual.

[0084] Whether therapy with a first Type I interferon receptor agonist, followed by a second, PEGylated Type I interferon receptor agonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[0085] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering a therapeutically effective amount of a first, non-PEGylated Type I interferon receptor agonist for a first period of time; followed by administering a therapeutically effective amount of a PEGylated Type I interferon receptor agonist for a second period of time. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'- nucleosidase, γ-glutamuiyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[0086] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[0087] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control.

[0088] In another embodiment, therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist, and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, are effective to increase liver function by at least about 10%>, at least about 20%, at least about 30%>, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist, and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, are effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%), at least about 30%, at least about 40%, at least about 50%, at least abont 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. Therapeutically effective amounts of a non-PEGylated Type I interferon receptor agonist, and a PEGylated Type I interferon receptor agonist are any dosages that, when administered as part of a subject therapeutic regimen, are effective to increase a reduced level of a serum marker of liver function by at least about 10%>, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range. Type I Interferon Receptor Agonists

[0089] Type I interferon receptor agonists suitable for use in a subject method include an IFN- α; an IFN-β; an IFN-tau; an IFN-ω; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists. Interferon-Alpha

[0090] Any known IFN-α can be used in the instant invention. The term "interferon-alpha" as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term "IFN-α" includes naturally occurring IFN-α; synthetic IFN-α; derivatized IFN-α (e.g., PEGylated IFN-α, glycosylated IFN-α, and the like); and analogs of naturally occurring or synthetic IFN-α; essentially any IFN-α that has antiviral properties, as described for naturally occurring IFN-α.

[0091] Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-α (including, but not limited to, naturally occurring IFN-α2a, IFN-α2b); recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, NJ.; recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N. J.; recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.; interferon alpha- nl, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain; and interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.

[0092] The term "IFN-α" also encompasses consensus IFN-α. Consensus IFN-α (also referred to as "CIFN" and "IFN-con" and "consensus interferon") encompasses but is not limited to the amino acid sequences designated IFN-con! , IFN-con and IFN-con₃ which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (e.g., Infergen®, InterMune, Inc., Brisbane, Calif). IFN-con! is the consensus interferon agent in the Infergen® alfacon-1 product. The Infergen® consensus interferon product is referred to herein by its brand name (Infergen®) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.

[0093] Also suitable for use in the present invention are fusion polypeptides comprising an IFN-α and a heterologous polypeptide. Suitable IFN-α fusion polypeptides include, but are not limited to, Albuferon-alpha™ (a fusion product of human albumin and IFN-α; Human Genome Sciences; see, e.g., Osborn et al. (2002) J. Pharmacol. Exp. Therap. 303 :540-548). Also suitable for use in the present invention are gene-shuffled forms of IFN-α. See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113. PEGylated Interferon- Alpha

[0094] The term "IFN-α" also encompasses derivatives of IFN-α that are derivatized (e.g., are chemically modified) to alter certain properties such as serum half-life. As such, the term "IFN-a" includes glycosylated IFN-α; IFN-α derivatized with polyethylene glycol ("PEGylated IFN-α"); and the like. PEGylated IFN-α, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; and 5,951,974. PEGylated IFN-α encompasses conjugates of PEG and any of the above-described IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N. J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N. J.), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif).

[0095] Any of the above-mentioned IFN-α polypeptides can be modified with one or more polyethylene glycol moieties, i.e., PEGylated. The PEG molecule of a PEGylated IFN-α polypeptide is conjugated to one or more amino acid side chains of the IFN-α polypeptide. In some embodiments, the PEGylated IFN-α contains a PEG moiety on only one amino acid. In other embodiments, the PEGylated IFN-α contains a PEG moiety on two or more amino acids, e.g., the IFN-α contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.

[0096] IFN-α may be coupled directly to PEG (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.

[0097] In some embodiments, the PEGylated IFN-α is PEGylated at or near the amino terminus (N-terminus) of the IFN-α polypeptide, e.g., the PEG moiety is conjugated to the IFN-α polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10. [0098] In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues from about 10 to about 28.

[0099] In other embodiments, the PEGylated IFN-α is PEGylated at or near the carboxyl terminus (C-terminus) of the IFN-α polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.

[00100] In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.

[00101] The polyethylene glycol derivatization of amino acid residues at or near the receptor- binding and/or active site domains of the IFN-α protein can disrupt the functioning of these domains. In certain embodiments of the invention, amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.

[00102] In some embodiments, PEG is attached to IFN-α via a linking group. The linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SBA), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.

[00103] Methods for making succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.

[00104] Methods for attaching a PEG to an IFN-α polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1 :373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); U.S. Patent No. 5,985,265; U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106. [00105] Pegylated IFN-α, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; 5,985,265; and 5,951,974. Pegylated IFN-α encompasses conjugates of PEG and any of the above-described IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, NJ.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N J.), where PEGylated Intron is known as PEG-Intron (Schering- Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of^" naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif), where PEGylated Infergen is referred to as PEG-Infergen.

[00106] In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-α polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.

[00107] In one non-limiting example, PEG is linked to IFN-α via an SPA linking grc p. SPA esters of PEG, and methods for making same, are described in U.S. Patent No. 5,672,662. SPA linkages provide for linkage to free amine groups on the IFN-α polypeptide.

[00108] For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-α polypeptide. Such a bond can be formed, e.g., by condensation of an α-methoxy, omega propanoic acid activated ester of PEG (mPEGspa).

[00109] As one non-limiting example, one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, 101 tOO 11/1 1 ζ 1 ^ lys , lys , lys , lys , and lys , and the amide bond is formed by condensation of an α- methoxy, omega propanoic acid activated ester of PEG. Polyethylene glycol [00110] Polyethylene glycol suitable for conjugation to an IFN-α polypeptide is soluble in water at room temperature, and has the general formula R(O-CH -CH₂)_nO-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons. [00111] In many embodiments, PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N- terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.

[00112] In other embodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-α polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN-α polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-α include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH₂).

[00113] In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Because of the reactive nature of the thio acid, selectivity of certain amino groups over others is achieved. For example, -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the ε-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.

[00114] In other embodiments, the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain. Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH conditions such as neutral 6.5-7.5. For example, the N-terminal amino groups may be selectively modified under neutral pH conditions. However, if the reactivity of the reagent were extreme, accessible-NH₂ groups of lysine may also react.

[00115] The PEG can be conjugated directly to the IFN-α polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-α polypeptide, forming a linker-modified IFN- α polypeptide. Such linkers provide various functionalities, e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-oc polypeptide.

[00116] In some embodiments, the PEG conjugated to the IFN-α polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-α polypeptide is branched. Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, "star-PEG's" and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998." Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.

[00117] PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa, is generally used, where the term "about," in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight. For example, PEG suitable for conjugation to IFN-α has a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa. Preparing PEG-IFN-α conjugates

[00118] As discussed above, the PEG moiety can be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C-terminus of the IFN-α polypeptide. Conjugation can be carried out in solution or in the solid phase. N-terminal linkage

[00119] Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-α polypeptide are known in the art. See, e.g., U.S. Patent No. 5,985,265.

[00120] In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-α are used. For example, a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein can be used. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved. The reaction is performed at pH which allows one to take advantage of the pK_a differences between the ε- arnino groups of the lysine residues and that of the α-amino group of the N-terminal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-α is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-α and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs. C-terminal linkage

[00121] N-terminal-specific coupling procedures such as described in U.S. Patent No. 5,985,265 provide predominantly monoPEGylated products. However, the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, such processes lead to significant increases in manufacturing costs. For example, examination of the structure of the well-characterized Infergen® Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C- terminal sequence. Thus, in some embodiments, N-terminally PEGylated IFN-α is not used; instead, the IFN-α polypeptide is C-terminally PEGylated.

[00122] An effective synthetic as well as therapeutic approach to.obtain mono PEGylated Infergen product is therefore envisioned as follows:

[00123] A PEG reagent that is selective for the C-terminal can be prepared with or without spacers. For example, polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.

[00124] Preparing or obtaining a water-soluble carbodiimide as the condensing agent can be carried out. Coupling IFN-α (e.g., Infergen® Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous medium with a suitable buffer system at an optimal pH to effect the amide linkage. A high molecular weight PEG can be added to the protein covalently to increase the molecular weight.

[00125] The reagents selected will depend on process optimization studies. A non-limiting example of a suitable reagent is ED AC or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide. The water solubility of ED AC allows for direct addition to a reaction without the need for prior organic solvent dissolution. Excess reagent and the isourea formed as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration. A concentrated solution of ED AC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent. Most of the synthetic protocols in literature suggest the optimal reaction medium to be in pH range between 4.7 and 6.0. However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent. In view of the contemplated use of Infergen, preferably the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6.0. However, 0.1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer. The ratios of PEG amine to the IFN-α molecule is optimized such that the C- terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).

[00126] Even though the use of PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH-NH₂ which will also condense with the carboxyl group of the IFN-α protein, can also be used. In addition to aqueous phase, the reactions can also be conducted on solid phase. Polyethylene glycol can be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological performance of the purified derivative in vitro and in vivo i.e., circulation times, anti viral activities etc.

[00127] Additionally, suitable spacers can be added to the C-terminal of the protein. The spacers may have reactive groups such as SH, NH or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN-α derivatives. A combined solid/solution phase methodology can be devised for the preparation of C-terminal pegylated interferons. For example, the C-terminus of IFN-α is extended on a solid phase using a Gly-Gly-Cys-NH₂ spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisioned processes and products will be beneficial with respect to cost (a third of the protein is not wasted as in N-terminal PEGylation methods) and contribute to the economy of the therapy to treat chronic hepatitis C infections, liver fibrosis etc.

[00128] There may be a more reactive carboxyl group of amino acid residues elsewhere in the molecule to react with the PEG reagent and lead to monoPEGylation at that site or lead to multiple PEGylations in addition to the -COOH group at the C-terminus of the IFN-α. It is envisioned that these reactions will be minimal at best owing to the steric freedom at the C- terminal end of the molecule and the steric hindrance imposed by the carbodiimides and the PEG reagents such as in branched chain molecules. It is therefore the preferred mode of PEG modification for Infergen and similar such proteins, native or expressed in a host system, which may have blocked N-termini to varying degrees to improve efficiencies and maintain higher in vivo biological activity.

[00129] Another method of achieving C-terminal PEGylation is as follows. Selectivity of C- terminal PEGylation is achieved with a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN-α. For example, one such reagent could be a branched chain PEG ~40kd in molecular weight and this agent could be synthesized as follows:

[00130] OH₃C-(CH₂CH₂O)n-CH₂CH₂NH₂ + Glutamic Acid i.e., HOCO-CH₂CH₂CH(NH2)- COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble ED AC to provide the branched chain PEG agent OH₃C-(CH₂CH₂O)_n- CH₂CH₂NHCOCH(NH₂)CH₂OCH₃-(CH₂CH₂O)„-CH₂CH₂NHCOCH₂. O II H₃C-0-(CH₂CH₂0)_n-CH₂CH₂NH₂+ HO C-CH₂CH₂CH-COOH

CHNH₂ F.DAC

H₃C-0-(CH₂CH₂0)_n-CH₂CH₂NH-CO

CH TI₂ (CH₂)₂

H₃C-0-(CH₂CH₂0)_u-CH₂CH₂NH-CO

[00131] This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-α to form the peptide bond.

[00132] If desired, PEGylated IFN-α is separated from unPEGylated IFN-α using any known method, including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the PEG-IFN-α conjugate is a monoPEGylated IFN-α, the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi- PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography. MonoPEG (30 kD, linear)-ylated IFN-α

[00133] PEGylated IFN-α that is suitable for use in the present invention includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN polypeptide. In some embodiments, the monoPEG (30 kD, linear)~ylated IFN-α is monoPEG (30 kD, linear)-ylated INFERGEN® interferon alfacon-1.

[00134] In some embodiments, the PEG moiety is linked to either the alpha-amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon- amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.

[00135] In some embodiments, the PEG moiety is linked to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.

[00136] In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the lysine residue in the CIFN polypeptide.

[00137] In some embodiments, the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.

[00138] In some embodiments, the PEG moiety is linlced to a lysine chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.

[00139] In some embodiments, the PEG moiety is linked to a lysine chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In other embodiments, the PEG moiety is linlced to the epsilon-amino group of a lysine chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the chosen lysine residue in the CIFN polypeptide.

[00140] In connection with the above-described monopegylated CIFN molecules, the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-con_! , interferon alpha-con₂, and interferon alpha-con₃, the amino acid sequences of which CIFN polypeptides are disclosed in U.S. Pat. No. 4,695,623. Populations of IFN-α

[00141] In addition, any of the methods of the invention can employ a PEGylated IFN-α composition that comprises a population of monopegylated IFNα molecules, where the population consists of one or more species of monopegylated IFNα molecules as described above. A subject method will in some embodiments employ a composition comprising a population of modified IFN-α polypeptides, each with a single PEG molecule linlced to a single amino acid residue of the polypeptide. [00142] In some of these embodiments, the population comprises a mixture of a first IFN-α polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-α polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-α polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-α polypeptide is not the same as the location of the second amino acid residue in the second IFN-α polypeptide. As one non- limiting example, a composition suitable for use in subject method comprises a population of PEG-modified IFN-α polypeptides, the population comprising an IFN-α polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-α polypeptide linked to a linear PEG molecule at a lysine residue.

[00143] Generally, a given modified IFN-α species represents from about 0.5%) to about 99.5%) of the total population of monopegylated IFNα polypeptide molecules in a population, e.g, a given modified IFN-α species represents about 0.5%>, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%o, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%), about 85%), about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-α polypeptide molecules in a population. In some embodiments, a composition suitable for use in subject method comprises a population of monopegylated IFN- α polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%), at least about 95%, or at least about 99%), IFN-α polypeptides linlced to PEG at the same site, e.g., at the N-terminal amino acid.

[00144] In particular embodiments of interest, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue of the CIFN polypeptide.

[00145] The amino acid residue to which the PEG is attached is in many embodiments the N- terminal amino acid residue. In other embodiments, the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. [00146] As an example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in subject method can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00147] As another example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface- exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in subject method can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 lcD.

[00148] As another example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in subject method can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced to a second lysine residue selected from one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in subject method may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00149] As another example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in subject method can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in subject method may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00150] As another non-limiting example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in subject method may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD. [00151] As another non-limiting example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced at a first lysine residue chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys , lys , lys , lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD. [00152] As another non-limiting example, a composition suitable for use in subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced at a first lysine residue chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced at a second lysine residue chosen from lys¹²¹, lys¹³ , lys ⁵, and lys ⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linlced to one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00153] As another non-limiting example, a composition suitable for use in subject method comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface- exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in subject method may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00154] In connection with each of the above-described populations of monopegylated CIFN molecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-con_! , interferon alpha- con₂, and interferon alpha-con₃.

[00155] The invention further features treatment methods, as described above, that involve use of a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega-propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1:1 to about 1:5 CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1 :3 CIFN:mPEGsρa and the reaction is conducted at a pH of about 8. In another embodiment where the product is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1 :2 CIFN:mPEGspa and the reaction is conducted at a pH of about 8.0.

[00156] In connection with the above-described product-by-process, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-con_l5 interferon alpha- con₂, and interferon alpha-con₃. IFN-β

[00157] The term interferon-beta ("IFN-β") includes IFN-β polypeptides that are naturally occurring; non-naturally-occurring IFN-β polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-β that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-β. Any known IFN-β can be administered in a subject treatment method.

[00158] Any of a variety of beta interferons can be used in a subject treatment method. Suitable beta interferons include, but are not limited to, naturally-occurring IFN-β; IFN-β la, e.g., Avonex® (Biogen, Inc.), and Rebif® (Serono, SA); IFN-βlb (Betaseron®; Berlex); and the like.

[00159] The IFN-β formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-β.

[00160] IFN-β polypeptides can be produced by any known method. DNA sequences encoding IFN-β may be synthesized using standard methods. In many embodiments, IFN-β polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-β is "recombinant IFN- β." Where the host cell is a bacterial host cell, the IFN-β is modified to comprise an N- terminal methionine.

[00161] It is to be understood that IFN-β as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. IFN-tau

[00162] The term interferon-tau includes IFN-tau polypeptides that are naturally occurring; non- naturally-occurring IFN-tau polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau. Any known interferon-tau can be administered in a subject treatment method.

[00163] Suitable tau interferons include, but are not limited to, naturally-occurring IFN-tau; Tauferon® (Pepgen Corp.); and the like.

[00164] IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank Accession Nos. P15696; P56828; P56832; P56829; P56831; Q29429; Q28595; Q28594; S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171. The sequence of any known IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00165] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.

[00166] The IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.

[00167] IFN-tau polypeptides can be produced by any known method. DNA sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is "recombinant IFN-tau." Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine. [00168] It is to be understood that IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. IFN-ω

[00169] The term interferon-omega ("IFN-ω") includes IFN-ω polypeptides that are naturally occurring; non-naturally-occurring IFN-ω polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-ω that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-ω.

[00170] Any known omega interferon can be administered in a subject treatment method. Suitable IFN-ω include, but are not limited to, naturally-occurring IFN-ω; recombinant IFN-ω, e.g., Biomed 510 (BioMedicines); and the like.

[00171] IFN-ω may comprise an amino acid sequence as set forth in GenBank Accession No. NP_002168; or AAA70091. The sequence of any Icnown IFN-ω polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00172] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.

[00173] The IFN-ω formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-ω.

[00174] IFN-ω polypeptides can be produced by any known method. DNA sequences encoding IFN-ω may be synthesized using standard methods. In many embodiments, IFN-ω polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-ω is "recombinant IFN- ω." Where the host cell is a bacterial host cell, the IFN-ω is modified to comprise an N- terminal methionine.

[00175] It is to be understood that IFN-ω as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. Immunomodulatory agents

[00176] Immunomodulatory agents that are suitable for use in a subject combination therapy include, but are not limited to, Type II interferon receptor agonists (including IFN-γ); TNF antagonists; pirfenidone and pirfenidone analogs; and thymosin-α. Type II interferon receptor agonists

[00177] Type II interferon receptor agonists include any naturally occurring or non-naturally- occurring ligand of a human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[00178] A specific example of a Type II interferon receptor agonist is IFN-gamma and variants thereof. While the present invention exemplifies use of an IFN-gamma polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method. Interferon-Gamma

[00179] The nucleic acid sequences encoding IFN-gamma polypeptides may be accessed from public databases, e.g., Genbank, journal publications, and the like. While various mammalian IFN-gamma polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-gamma coding sequence may be found in Genbank, accession numbers X13274; N00543; and ΝM_000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and N00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderknecht et al. (1984) J.B.C. 259:6790.

[00180] IFΝ-γlb (Actimmune®; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinantly in E.coli and is unglycosylated (Rinderknecht et al. 1984, J. Biol. Chem. 259:6790-6797). Recombinant IFΝ-gamma as discussed in U.S. Patent No. 6,497,871 is also suitable for use herein. [00181] The IFN-gamma to be used in the methods of the present invention may be any of natural IFN-gamma, recombinant IFN-gamma and the derivatives thereof so far as they have an IFN-γ activity, particularly human IFN-gamma activity. Human IFN-gamma exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art. Although IFN-gamma is based on the sequences as provided above, the production of the protein and proteolytic processing can result in processing variants thereof. The unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa). Although the recombinant IFN-gamma produced in E. coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-gamma is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria. During purification, the mature protein can additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g. if required for bacterial expression. The N-terminal methionine is an artifact encoded by the mRNA translational "start" signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.

[00182] For use in the subject methods, any of the native IFN-gamma peptides, modifications and variants thereof, or a combination of one or more peptides may be used. IFN-gamma peptides of interest include fragments, and can be variously truncated at the carboxyl tenninus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences can be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5.690,925. Native IFN- gamma moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152; 24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN-γ activity, may be used in the present methods.

[00183] The sequence of the IFN-γ polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00184] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. IFN-gamma may be modified with one or more polyethylene glycol moieties (PEGylated). In one embodiment, the invention contemplates the use of IFN-gamma variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN-gamma polypeptide variants described in International Patent Publication No. WO 01/36001. Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine.

[00185] Included in the subject invention are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see, for example, Friedler et al. 2000, J. Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability.

[00186] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like. [00187] The polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. For the most part, the compositions which are used will comprise at least 20%> by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification. Usually, the percentages will be based upon total protein. TNF Antagonists

[00188] Suitable TNF-α antagonists for use herein include agents that decrease the level of TNF-α synthesis, agents that block or inhibit the binding of TNF-α to a TNF-α receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction. Unless otherwise expressly stated, every reference to a "TNF-α antagonist" or "TNF antagonist" herein will be understood to mean a TNF-α antagonist other than pirfenidone or a pirfenidone analog.

[00189] As used herein, the terms "TNF receptor polypeptide" and "TNFR polypeptide" refer to polypeptides derived from TNFR (from any species) which are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or p55 TNFR or TNFRI). The mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD). The mature full- length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD. Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide; fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.

[00190] TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR. U.S. Pat. No. 5,605,690 provides examples of TNFR polypeptides, including soluble TNFR polypeptides, appropriate for use in the present invention. In many embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR. In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgGi molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e.g., human IgGi. [00191] Monovalent and multivalent forms of TNFR polypeptides may be used in the present invention. Multivalent forms of TNFR polypeptides possess more than one TNF binding site. In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et al, 1993, J. Immunol., 151:1548-1561, a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both of the immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present invention. Generally, when such a chimeric TNFR:antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.

[00192] In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBREL® etanercept. ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (ρ75) TNFR linked to the Fc portion of human IgGi. The Fc component of ENBREL® contains the CH2 domain, the CH3 domain and hinge region, but not the CHI domain of IgGi . ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023; Mohler et al. (1993) J. Immunol. 151:1548-1561; U.S. Pat. No. 5,395,760; and U.S. Pat. No. 5,605,690.

[00193] Also suitable for use are monoclonal antibodies that bind TNF-α. Monoclonal antibodies include "humanized" mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%>, or 100% human in amino acid sequence; and the like. See, e.g., WO 90/10077; WO 90/04036; and WO 92/02190. Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab')₂ and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.

[00194] Examples of suitable monoclonal antibodies include infliximab (REMICADE®, Centocor); and adalimumab (HUMIRA™, Abbott) REMICADE® is a chimeric monoclonal anti-TNF-α antibody that includes about 25% mouse amino acid sequence and about 75%> human amino acid sequence. REMICADE®comprises a variable region of a mouse monoclonal anti-TNF-α antibody fused to the constant region of a human IgGi . Elliott et al. (1993) Arthritis Rheum. 36:1681-1690; Elliott et al. (1994) Lancet 344:1105-1110; Baert et al. (1999) Gastroenterology 116:22-28. HUMIRA™ is a human, full-length IgGi monoclonal antibody that was identified using phage display technology. Piascik (2003) J Am. Pharm. Assoc. 43:327-328.

[00195] Also included in the term "TNF antagonist," and therefore suitable for use in a subject method, are stress-activated protein kinase (SAPK) inhibitors. SAPK inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Patent No. 6,548,520; 1,4, 5 -substituted imidazole compounds disclosed in U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S. Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S. Patent No. 6,288,089; and heteroaryl aminobenzophenones disclosed in U.S. Patent No. 6,432,962. Also of interest are compounds disclosed in U.S. Patent Application Publication No. 2003/0149041; and U.S. Patent No. 6,214,854. A stress-activated protein kinase is a member of a family of mitogen- activated protein kinases which are activated in response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).

[00196] Methods to assess TNF antagonist activity are known in the art and exemplified herein. For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an assay, radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence of the TNF antagonist.

[00197] As another example, TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells. In such an assay, target cells, cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis. TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence of the TNF antagonist. Pirfenidone and Analogs Thereof

[00198] Pirfenidone (5-methyl-l-phenyl-2-(lH)-pyridone) and specific pirfenidone analogs can be used to enhance the methods of treatment for HCN infection disclosed herein. Pirfenidone

Pirfenidone analogs

I.

II.A II.B

Descriptions for Substituents Ri, R₂, X

[00199] Ri: carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

[00200] Ri can further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichlorocyclohexyl, guanidinyl- cyclohexenyl and the like.

[00201] R₂: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

[00202] X: may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents can be the same or different. Substituents can include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like. [00203] The substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.

[00204] Specific Examples include those shown in Table 1 :

Table 1 IA IIB

[00205] U.S. Pat. Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562; 5,518,729; 5,716,632; and 6,090,822 describe methods for the synthesis and formulation of pirfenidone and specific pirfenidone analogs in pharmaceutical compositions suitable for use in the methods of the present invention. Thymosin-α

[00206] Thymosin-α (Zadaxin™; available from SciClone Pharmaceuticals, Inc., San Mateo, CA) is a synthetic form of thymosin alpha 1, a hormone found naturally in the circulation and produced by the thymus gland. Thymosin-α increases activity of T cells and NK cells. Zadaxin™ formulated for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymosin alpha 1. Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac - Ser - Asp - Ala - Ada - Val - Asp - Thr - Ser - Ser - Glu - lie - Thr - Thr - Lys - Asp - Leu - Lys - Glu - Lys - Lys - Glu - Nal - Nal - Glu - Glu - Ala - Glu - Asn - OH, and having a molecular weight of 3,108 daltons. The lyophilized preparation contains 1.6 mg synthetic thymosin-α, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8. Ribavirin

[00207] Ribavirin, 1 -β-D-ribofuranosyl- 1 H- 1 ,2,4-triazole-3 -carboxamide, available from ICΝ Pharmaceuticals, Inc., Costa Mesa, Calif, is described in the Merck Index, compound No . 8199, Eleventh Edition. Its manufacture and formulation is described in U.S. Pat. No. 4,211,771. The invention also contemplates use of derivatives of ribavirin (see, e.g. , U.S . Pat. No. 6,277,830). The ribavirin may be administered orally in capsule or tablet form, or in the same or different administration form and in the same or different route as the IFN-α (either PEGylated or non-PEGylated form). Of course, other types of administration of both medicaments, as they become available are contemplated, such as by nasal spray, transdermally, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the proper dosages are delivered without destroying the active ingredient.

[00208] Ribavirin is generally administered in an amount ranging from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day. In some embodiments, ribavirin is administered throughout the entire course of PEGylated IFN-α or non-PEGylated IFN-α therapy. In other embodiments, ribavirin is administered only during the first period of time. In still other embodiments, ribavirin is administered only during the second period of time. Levovirin [00209] Levovirin is the L-enantiomer of ribavirin, and exhibits the property of enhancing a Thl immune response over a Th2 immune response. Levovirin is manufactured by ICN Pharmaceuticals. [00210] Levovirin has the following structure:

Viramidine [00211] Viramidine is a 3-carboxamidine derivative of ribavirin, and acts as aprodrug of ribavirin. It is efficiently converted to ribavirin by adenosine deaminases. [00212] Viramidine has the following structure:

Nudeoside analogs

[00213] Nucleoside analogs that are suitable for use in a subject therapy include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, an L-ribofuranosyl nucleoside as disclosed in U.S. Patent No. 5,559,101 and encompassed by Formula I of U.S. Patent No. 5,559,101 (e.g., 1-β-L-ribofuranosyluracil, l-β-L-ribofuranosyl-5-fluorouracil, 1-β-L- ribofuranosylcytosine, 9-β-L-ribofuranosyladenine, 9-β-L-ribofuranosylhypoxanthine, 9-β-L- ribofuranosylguanine, 9-β-L-ribofuranosyl-6-thioguanine, 2-amino-α-L- ribofuranl[l',2' :4,5]oxazoline, O²,O²-annydro-l-α-L-ribofuranosyluracil, 1-α-L- ribofuranosyluracil, 1 -(2,3 ,5 -tri-O-benzoyl-α — ribofuranosyl)-4-thiouracil, 1 -α-L- ribofuranosylcytosine, l-α-L-ribofuranosyl-4-thiouracil, l-α-L-ribofuranosyl-5-fluorouracil, 2- amino-β-L-arabinofurano[l ',2' :4,5]oxazoline, O²,O²-anhydro-β-L-arabinofuranosyluracil, 2'- deoxy-β-L-uridine, 3'5'-Di-O-benzoyl-2'deoxy-4-thio β-L-uridine, 2'-deoxy-β-L-cytidine, 2'- deoxy-β-L-4-thiouridine, 2'-deoxy-β-L-thymidine, 2'-deoxy-β-L-5-fluorouridine, 2',3'- dideoxy-β-L-uridine, 2'-deoxy-β-L-5-fluorouridine, and 2'-deoxy-β-L-inosine); a compound as disclosed in U.S. Patent No. 6,423,695 and encompassed by Formula I of U.S. Patent No. 6,423,695; a compound as disclosed in U.S. Patent Publication No. 2002/0058635, and encompassed by Formula 1 of U.S. Patent Publication No. 2002/0058635; a nucleoside analog as disclosed in WO 01/90121 A2 (Idenix); a nucleoside analog as disclosed in WO 02/069903 A2 (Biocryst Pharmaceuticals Inc.); a nucleoside analog as disclosed in WO 02/057287 A2 or WO 02/057425 A2 (both Merck/Isis); and the like. HCV NS3 inhibitors

[00214] Suitable HCV non-structural protein-3 (NS3) inhibitors include, but are not limited to, a tri-peptide as disclosed in U.S. Patent Nos. 6,642,204, 6,534,523, 6,420,380, 6,410,531, 6,329,417, 6,329,379, and 6,323,180 (Boehringer-Ingelheim); a compound as disclosed in U.S. Patent No. 6,143,715 (Boehringer-Ingelheim); a macrocyclic compound as disclosed in U.S. Patent no. 6,608,027 (Boehringer-Ingelheim); an NS3 inhibitor as disclosed in U.S. Patent Nos. 6,617,309, 6,608,067, and 6,265,380 (Vertex Pharmaceuticals); an azapeptide compound as disclosed in U.S. Patent No. 6,624,290 (Schering); a compound as disclosed in U.S. Patent No. 5,990,276 (Schering); a compound as disclosed in Pause et al. (2003) J. Biol. Chem. 278:20374-20380; NS3 inhibitor BILN 2061 (Boehringer-Ingelheim; Lamarre et al. (2002) Hepatology 36:301A; and Lamarre et al. (Oct. 26, 2003) Nature doi:10.1038/nature02099); NS3 inhibitor VX-950 (Vertex Pharmaceuticals; Kwong et al. (Oct. 24-28, 2003) 54^th Ann. Meeting AASLD); NS3 inhibitor SCH6 (Abib et al. (October 24-28, 2003) Abstract 137. Program and Abstracts of the 54^l1 Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). October 24-28, 2003. Boston, MA.); any of the NS3 protease inhibitors disclosed in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929 or WO 02/060926 (e.g., compounds 2, 3, 5, 6, 8, 10, 11, 18, 19, 29, 30, 31, 32, 33, 37, 38, 55, 59, 71, 91, 103, 104, 105, 112, 113, 114, 115, 116, 120, 122, 123, 124, 125, 126 and 127 disclosed in the table of pages 224-226 in WO 02/060926); an NS3 protease inhibitor as disclosed in any one of U.S. Patent Publication Nos. 2003019067, 20030187018, and 20030186895; and the like.

[00215] Of particular interest in many embodiments are NS3 inliibitors that are specific NS3 inhibitors, e.g., NS3 inhibitors that inhibit NS3 serine protease activity and that do not show significant inhibitory activity against other serine proteases such as human leukocyte elastase, porcine pancreatic elastase, or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B. NS5B inhibitors

[00216] Suitable HCV non-structural protein-5 (NS5; RNA-dependent RNA polymerase) inhibitors include, but are not limited to, a compound as disclosed in U.S. Patent No. 6,479,508 (Boehringer-Ingelheim); a compound as disclosed in any of Intemational Patent Application Nos. PCT/CA02/01127, PCT/CA02/01128, and PCT/CA02/01129, all filed on July 18, 2002 by Boehringer Ingelheim; a compound as disclosed in U.S. Patent No. 6,440,985 (ViroPharma); a compound as disclosed in WO 01/47883, e.g., JTK-003 (Japan Tobacco); a dinucleotide analog as disclosed in Zhong et al. (2003) Antimicrob. Agents Chemother. 47:2674-2681; a benzothiadiazine compound as disclosed in Dhanak et al. (2002) J. Biol Chem. 277(41):38322-7; anNS5B inhibitor as disclosed in WO 02/100846 Al or WO 02/100851 A2 (both Shire); anNS5B inhibitor as disclosed in WO 01/85172 Al or WO 02/098424 Al (both Glaxo SmithKline); anNS5B inhibitor as disclosed in WO 00/06529 or WO 02/06246 Al (both Merck); an NS5B inhibitor as disclosed in WO 03/000254 (Japan Tobacco); an NS5B inhibitor as disclosed in EP 1 256,628 A2 (Agouron); JTK-002 (Japan Tobacco); JTK-109 (Japan Tobacco); and the like.

[00217] Of particular interest in many embodiments are NS5 inhibitors that are specific NS5 inhibitors, e.g., NS5 inhibitors that inhibit NS5 RNA-dependent RNA polymerase and that lack significant inhibitory effects toward other RNA dependent RNA polymerases and toward DNA dependent RNA polymerases. Additional antiviral therapeutic agents

[00218] Additional antiviral therapeutic agents that can be administered in a subject combination therapy include, but are not limited to, inhibitors of inosine monophosphate dehydrogenase (IMPDH); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors; and the like. IMPDH inhibitors

[00219] IMPDH inhibitors that are suitable for use in a subject combination therapy include, but are not limited to, NX-497 ((S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl- carbamicacid tetrahydrofuran-3-yl-ester); Vertex Pharmaceuticals; see, e.g., Markland et al. (2000) Antimicrob. Agents Chemother. 44:859-866); ribavirin; levovirin (Ribapharm; see, e.g., Watson (2002) Curr Opin Investig Drugs 3(5):680-3); viramidine (Ribapharm); and the like. Ribozyme and antisense

[00220] Ribozyme and antisense antiviral agents that are suitable for use in a subject combination therapy include, but are not limited to, ISIS 14803 (ISIS Pharmaceuticals/Elan Corporation; see, e.g., Witherell (2001) Curr Opin Investig Drugs. 2(11): 1523-9); Heptazyme™; and the like. Side effect management agents

[00221] In some embodiments, a subject therapy comprises administering a palliative agent (e.g., an agent that reduces patient discomfort caused by a therapeutic agent), or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent. Such agents are also referred to as "side effect management agents."

[00222] Suitable side effect management agents include agents that are effective in pain management; agents that ameliorate gastrointestinal discomfort; analgesics, anti- inflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any compound for palliative care of patients suffering from pain or any other side effect in the course of treatment with a subject therapy. Exemplary palliative agents include acetaminophen, ibuprofen, and other NSAIDs, H2 Mockers, and antacids.

[00223] Analgesics that can be used to alleviate pain in the methods of the invention include non-narcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen, salicylate, acetyl-salicylic acid (aspirin, diflunisal), ibuprofen, Motrin, Naprosyn, Nalfon, and Trilisate, indomethacin, glucametacine, acemetacin, sulindac, naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac tromethamine, ketorolac, nabumetone, and the like, and mixtures of two or more of the foregoing.

[00224] Other suitable analgesics include fentanyl, buprenorphine, codeine sulfate, morphine hydrochloride, codeine, hydromorphone (Dilaudid), levoφhanol (Levo-Dromoran), methadone (Dolophine), morphine, oxycodone (in Percodan), and oxymorphone (Numorphan). Also suitable for use are benzodiazepines including, but not limited to, flurazepam (Dalmane), diazepam (Valium), and Versed, and the like. Anti-inflammatory agents

[00225] Suitable anti-inflammatory agents include, but are not limited to, steroidal anti- inflammatory agents, and non-steroidal anti-inflammatory agents.

[00226] Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, conisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chloφrednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures of two or more of the foregoing.

[00227] Suitable non-steroidal anti-inflammatory agents, include, but are not limited to, 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, and sudoxicam; 2) the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, piφrofen, catprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents.

[00228] Suitable anti-inflammatory agents include, but are not limited to, Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Caφrofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; -Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; -Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lornoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Momiflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Oφanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Piφrofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.

[00229] Antipsychotic and antineurotic drugs that can be used to alleviate psychiatric side effects in the methods of the invention include any and all selective serotonin receptor inhibitors (SSRIs) and other anti-depressants, anxiolytics (e.g. alprazolam), etc. Anti- depressants include, but are not limited to, serotonin reuptake inhibitors such as Celexa®, Desyrel®, Effexor®, Luvox®, Paxil®, Prozac®, Zolofit®, and Serzone®; tricyclics such as Adapin®, Anafrinil®, Elavil®, Janimmine®, Ludiomil®, Pamelor®, Tofranil®, Vivactil®, Sinequan®, and Surmontil®; monoamine oxidase inhibitors such as Eldepryl®, Maφlan®, Nardil®, and Parnate®. Anti-anxiety agents include, but are not limited to, azaspirones such as BuSpar®, benzodiazepines such as Ativan®, Librium®, Tranxene®, Centrax®, Klonopin®, Paxipam®, Serax®, Valium®, and Xanax®; and beta-blockers such as Inderal® and Tenormin®.

[00230] Agents that reduce gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like are suitable palliative agents for use in a subject combination therapy. Suitable agents include, but are not limited to, antiemetics, anti-diarrheal agents, H2 blockers, antacids, and the like. [00231] Suitable H2 blockers (histamine type 2 receptor antagonists) that are suitable for use as a palliative agent in a subject therapy include, but are not limited to, Cimetidine (e.g., Tagamet, Peptol, Nu-cimet, apo-cimetidine, non-cimetidine); Ranitidine (e.g., Zantac, Nu-ranit, Novo- randine, and apo-ranitidine); and Famotidine (Pepcid, Apo-Famotidine, and Novo-Famotidine).

[00232] Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide (Maalox®, Mylanta®); aluminum carbonate gel (Basajel®); aluminum hydroxide (Amphojel®, AlternaGEL®); calcium carbonate (Turns®, Titralac®); magnesium hydroxide; and sodium bicarbonate.

[00233] Antiemetics include, but are not limited to, 5-hydroxytryptophan-3 (5HT3) inhibitors; corticosteroids such as dexamethasone and methylprednisolone; Marinol® (dronabinol); prochloφerazine; benzodiazepines; promethazine; and metoclopramide cisapride; Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide; Chloφromazine; Chloφromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride; Pancopride; Prochloφerazine; Prochloφerazine Edisylate; Prochloφerazine Maleate; Promethazine Hydrochloride; Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride..

[00234] Anti-diarrheal agents include, but are not limited to, Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine), and the like.

[00235] Suitable hematopoietic agents that can be used to prevent or restore depressed blood cell populations in the methods of the invention include erythropoietins, such as EPOGEN™ epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGEN™ filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), thrombopoietins, etc. DOSAGES, FORMULATIONS, AND ROUTES OF ADMINISTRATION

[00236] A therapeutic agent used in a subject therapeutic regimen, e.g., i) a non-PEGylated Type I interferon receptor agonist; ii) a PEGylated Type I interferon receptor agonist, etc., is administered to individuals in a formulation with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described

for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20^th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7^th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3^rd ed. Amer. Pharmaceutical Assoc.

[00237] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[00238] In the subject methods, the active agents may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agents can be incoφorated into a variety of formulations for therapeutic administration. More particularly, the agents of the present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[00239] As such, administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In some embodiments, two different routes of administration are used. For example, in some embodiments, an IFN-α is administered subcutaneously, while ribavirin is administered orally.

[00240] Subcutaneous administration of a therapeutic agent, e.g., a PEGylated IFN-α, a non- PEGylated IFN-α, etc., can be accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328. A combination of a subcutaneous injection port and a device for administration of a therapeutic agent to a patient through the port is referred to herein as "a subcutaneous injection port delivery system." In some embodiments, subcutaneous administration is achieved by a combination of devices, e.g., bolus delivery by needle and syringe, followed by delivery using a continuous delivery system.

[00241] In some embodiments, a therapeutic agent, e.g., a non-PEGylated Type I interferon receptor agonist is delivered by a continuous delivery system. The terms "continuous delivery system," "controlled delivery system," and "controlled drug delivery device," are used interchangeably to refer to controlled drug delivery devices, and encompass pumps in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.

[00242] Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. Typically, the agent is in a liquid formulation in a drug-impermeable reservoir, and is delivered in a continuous fashion to the individual.

[00243] In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal of the drug delivery device.

[00244] Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incoφorated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drag release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.

[00245] Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general, the present methods of drug delivery can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97/27840 and U.S. Pat. Nos. 5,985,305 and 5,728,396)). Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.

[00246] In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.

[00247] In some embodiments, a therapeutic agent is delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of a therapeutic agent. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos. 4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present invention is the Synchromed infusion pump (Medtronic).

[00248] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[00249] For oral preparations, the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as com starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[00250] The agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[00251] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the present invention can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[00252] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may comprise the inhibitor(s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[00253] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the novel unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[00254] In connection with each of the methods described herein, the invention provides embodiments in which the unPEGylated Type I interferon receptor agonist, e.g. an unPEGylated IFN-α, is administered to the patient by a controlled drug delivery device so as to achieve an oscillating serum concentration profile of the unPEGylated Type I interferon receptor agonist that mimics the "peaks and troughs" serum concentration profile that would be achieved by bolus delivery of an effective amount of the unPEGylated Type I interferon receptor agonist at a selected dosing interval (e.g., qd, qod, tiw, or biw), for the desired treatment duration in the subject method, e.g., for a period of time sufficient to reduce the serum viral load in the patient to an undetectable level. Optionally, an implantable infusion pump is used to deliver the unPEGylated Type I interferon receptor agonist to the patient by subcutaneous infusion so as to achieve the oscillating serum concentration profile of the unPEGylated Type I interferon receptor agonist for the desired treatment duration in the subject method, e.g., for a period of time sufficient to reduce the serum viral load in the patient to an undetectable level. Non-PEGylated Type I interferon receptor agonist

[0O255] In some embodiments, the non-PEGylated Type I receptor agonist is a non-PEGylated IFN-α. Effective dosages of a non-PEGylated IFN-α can range from about 1 μg to about 30 μg, from about 3 μg to about 27 μg, from about 1 MU to about 20 MU, or from about 3 MU to about 10 MU.

[00256] Effective dosages of Infergen® consensus IFN-α include about 3 μg, about 9 μg, about 15 μg, about 18 μg, or about 27 μg of drag per dose. Effective dosages of IFN-α 2a, 2b or 2c can range from 3 million Units (MU) to 10 MU per dose.

[00257] A non-PEGylated Type I interferon receptor agonist is administered for a first period of time. The dosing regimen of non-PEGylated Type I interferon receptor agonist (also referred to as "the induction regimen ") generally involves administration the non-PEGylated Type I interferon receptor agonist for a first period of time that is sufficient to reduce viral load to an undetectable level (i.e., such that the level of the virus in the serum of the individual is undetectable). The dosing regimen of non-PEGylated Type I interferon receptor agonist can encompass a single dosing event, or at least two or more dosing events. The dosing regimen of the non-PEGylatedType I interferon receptor agonist can be administered daily, every other day, three times a week, or twice weekly.

[00258] The dosing regimen of the non-PEGylatedType I interferon receptor agonist involved administration of non-PEGylated Type I interferon receptor agonist for a first period of time, which time period can be at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or up to about 24 weeks. For example, in particular embodiments, the first, non-PEGylated Type I interferon receptor agonist is administered for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks. PEGylated Type I interferon receptor agonist

[00259] Effective dosages of a PEGylated Type I interferon receptor agonist range from about 10 μg to about 200 μg. For example, effective dosages of PEGylated IFN-α2a can contain an amount of about 90 μg to 180 μg, or about 135 μg, of drug per dose. Effective dosages of PEGylated IFN-α2b can contain an amount of about 0.5 μg to 1.5 μg of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 18 μg to about 90 μg, or from about 27 μg to about 60 μg, or about 45 μg, of CIFN amino acid weight per dose of PEG-CIFN. PEGylated IFN-α can be administered once a week, twice a week, three times a week, every other week, three times per month, or once monthly.

[00260] In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered at a dosing interval of every 8 days to every 14 days, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective dosages of monoPEG (30 kD, linear)-ylated consensus IFN-α generally range from about 45 μg to about 270 μg per dose, e.g., 60 μg per dose, 100 μg per dose, 150 μg per dose, 200 μg per dose, etc.

[00261] The dosing regimen of the PEGylated Type I interferon receptor agonist (also referred to as "the maintenance dose") generally involves administration of PEGylated Type I interferon receptor agonist for a second period of time that is sufficient to achieve an SVR. The sum of the first and second periods of time (i.e., the total duration of IFN-α therapy in the subject method) can be from about 24 weeks to about 48 weeks or more, e.g., about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, or about 48 weeks, or longer.

[00262] The second dosing regimen can encompass a single dosing event, or at least two or more dosing events. The dosing regimen of the PEGylated Type I interferon receptor agonist can be administered once per week, twice per week, three times a week, every other week, three times per month, or once monthly. Type II interferon receptor agonist

[00263] In some embodiments, a subject therapeutic regimen further involves administering a Type II interferon receptor agonist. In some embodiments, the Type II interferon receptor agonist is an IFN-γ.

[00264] Effective dosages of IFN-γ can range from about 0.5 μg/m to about 500 μg/m , usually from about 1.5 μg/m² to 200 μg/m², depending on the size of the patient. This activity is based on 10⁶ international units (U) per 50 μg of protein. IFN-γ can be administered daily, every other day, three times a week, or substantially continuously or continuously. [00265] In specific embodiments of interest, IFN-γ is administered to an individual in a unit dosage form of from about 25 μg to about 500 μg, from about 50 μg to about 400 μg, or from about 10O μg to about 300 μg. In particular embodiments of interest, the dose is about 200 μg IFN-γ. In many embodiments of interest, IFN-γ lb is administered.

[00266] Where the dosage is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 μg IFN-γ per kg body weight to about 1.48 μg IFN-γ per kg body weight.

[00267] The body surface area of subject individuals generally ranges from about 1.33 m² to about 2.50 m². Thus, in many embodiments, an IFN-γ dosage ranges from about 150 μg/m² to about 20 μg/m². For example, an IFN-γ dosage ranges from about 20 μg/m² to about 30 μg/m², from about 30 μg/m² to about 40 μg/m², from about 40 μg/m² to about 50 μg/m², from about 50 9 9 9 9 9 μg/m to about 60 μg/m , from about 60 μg/m to about 70 μg/m , from about 70 μg/m to about 80 μg/m², from about 80 μg/m² to about 90 μg/m², from about 90 μg/m² to about 100 μg/m², from about 100 μg/m² to about 110 μg/m², from about 110 μg/m² to about 120 μg/m², from about 120 μg/m² to about 130 μg/m², from about 130 μg/m² to about 140 μg/m², or from 9 9 about 140 μg/m to about 150 μg/m . In some embodiments, the dosage groups range from 9 9 about 25 μg/m to about 100 μg/m . In other embodiments, the dosage groups range from about 25 μg/m² to about 50 μg/m².

[00268] In many embodiments, multiple doses of an IFN-γ are administered. For example, an IFN-γ is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. TNF antagonist

[00269] In some embodiments, a subject therapeutic regimen further involves administering a TNF antagonist. Effective dosages of a TNF-α antagonist range from 0.1 μg to 40 mg per dose, e.g., from about 0.1 μg to about 0.5 μg per dose, from about 0.5 μg to about 1.0 μg per dose, from about 1.0 μg per dose to about 5.0 μg per dose, from about 5.0 μg to about 10 μg per dose, from about 10 μg to about 20 μg per dose, from about 20 μg per dose to about 30 μg per dose, from about 30 μg per dose to about 40 μg per dose, from about 40 μg per dose to about 50 μg per dose, from about 50 μg per dose to about 60 μg per dose, from about 60 μg per dose to about 70 μg per dose, from about 70 μg to about 80 μg per dose, from about 80 μg per dose to about 100 μg per dose, from about 100 μg to about 150 μg per dose, from about 150 μg to about 200 μg per dose, from about 200 μg per dose to about 250 μg per dose, from about 250 μg to about 300 μg per dose, from about 300 μg to about 400 μg per dose, from about 400 μg to about 500 μg per dose, from about 500 μg to about 600 μg per dose, from about 600 μg to about 700 μg per dose, from about 700 μg to about 800 μg per dose, from about 800 μg to about 900 μg per dose, from about 900 μg to about 1000 μg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[00270] In some embodiments, the TNF-α antagonist is ENBREL® etanercept. Effective dosages of etanercept range from about 0.1 μg to about 40 mg per dose, from about 0.1 μg to about 1 μg per dose, from about 1 μg to about 10 μg per dose, from about 10 μg to about 100 μg per dose, from about 100 μg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[00271] In some embodiments, effective dosages of a TNF-α antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-α antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[00272] In some embodiments, the TNF-α antagonist is REMICADE® infliximab. Effective dosages of REMICADE® range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[00273] In some embodiments the TNF-α antagonist is HUMIRA™ adalimumab. Effective dosages of HUMIRA™ range from about 0.1 μg to about 35 mg, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[00274] In many embodiments, a TNF-α antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-α antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, tliree times per month, once monthly, substantially continuously, or continuously.

[00275] In many embodiments, multiple doses of a TNF-α antagonist are administered. For example, a TNF-α antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or tliree times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00276] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound. Pirfenidone or a pirfenidone analog

[00277] In some embodiments, a subject therapeutic regimen further involves administering pirfenidone or a pirfenidone analog. Pirfenidone or a pirfenidone analog can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00278] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822. Thymosin-a

[00279] In some embodiments, a subject therapeutic regimen further involves administering Thymosin-α. Thymosin-α (Zadaxin™) is generally administered by subcutaneous injection. Thymosin-α can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously. In many embodiments, thymosin-α is administered twice per week.

[00280] Effective dosages of thymosin-α range from about 0.5 mg to about 5 mg, e.g., from about 0.5 mg to about 1.0 mg, from about 1.0 mg to about 1.5 mg, from about 1.5 mg to about 2.0 mg, from about 2.0 mg to about 2.5 mg, from about 2.5 mg to about 3.0 mg, from about 3.0 mg to about 3.5 mg, from about 3.5 mg to about 4.0 mg, from about 4.0 mg to about 4.5 mg, or from about 4.5 mg to about 5.0 mg. In particular embodiments, thymosin-α is administered in dosages containing an amount of 1.0 mg or 1.6 mg.

[00281] Thymosin-α can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. Ribavirin, levovirin, viramidine

[00282] In some embodiments, a subject therapeutic regimen further involves administering one or more of ribavirin, levovirin, and viramidine. Ribavirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, ribavirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day.

[00283] Levovirin is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, levovirin is administered orally in dosages of about 400, about 800, about 1000, or about 1200 mg per day.

[00284] Viramidine is generally administered in an amount ranging from about 30 mg to about 60 mg, from about 60 mg to about 125 mg, from about 125 mg to about 200 mg, from about 200 mg to about 300 gm, from about 300 mg to about 400 mg, from about 400 mg to about 1200 mg, from about 600 mg to about 1000 mg, or from about 700 to about 900 mg per day, or about 10 mg/kg body weight per day. In some embodiments, viramidine is administered orally in dosages of about 800, or about 1600 mg per day. L-nucleosides

[00285] In some embodiments, a subject therapeutic regimen further involves administering an L-nucleoside. Effective dosages of an L-nucleoside range from about 10 mg to about 200 mg per dose, e.g., from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, from about 35 mg to about 40 mg per dose, from about 40 mg per dose to about 45 mg per dose, from about 45 mg per dose to about 50 mg per dose, from about 50 mg per dose to about 60 mg per dose, from about 60 mg per dose to about 70 mg per dose, from about 70 mg per dose to about 80 mg per dose, from about 80 mg per dose to about 90 mg per dose, from about 90 mg per dose to about 100 mg per dose, from about 100 mg per dose to about 125 mg per dose, from about 125 mg per dose to about 150 mg per dose, from about 150 mg per dose to about 175 mg per dose, or from about 175 mg per dose to about 200 mg per dose. [00286] In some embodiments, effective dosages of an L-nucleoside are expressed as mg/kg body weight. In tliese embodiments, effective dosages an L-nucleoside are from about 5 mg/kg body weight to about 400 mg/kg body weight, e.g., from about 5 mg/kg body weight to about 50 mg/kg body weight, from about 50 mg/kg body weight to about 100 mg/kg body weight, from about 100 mg/kg body weight to about 200 mg/kg body weight, from about 200 mg/kg body weight to about 300 mg/kg body weight, or from about 300 mg/kg body weight to about 400 mg/kg body weight.

[00287] In many embodiments, an L-nucleoside is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The L-nucleoside can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[00288] In many embodiments, multiple doses of an L-nucleoside are administered. For example, an L-nucleoside is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or tliree times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00289] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound. NS3 inhibitors, NS5B inhibitors

[00290] In some embodiments, e.g., where the hepatitis virus infection is an HCN infection, a subject therapeutic regimen further involves administering an HCN enzyme inhibitor. Effective dosages of an HCN enzyme inhibitor can range from about 10 mg to about 200 mg per dose, e.g., from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, from about 35 mg to about 40 mg per dose, from about 40 mg per dose to about 45 mg per dose, from about 45 mg per dose to about 50 mg per dose, from about 50 mg per dose to about 60 mg per dose, from about 60 mg per dose to about 70 mg per dose, from about 70 mg per dose to about 80 mg per dose, from about 80 mg per dose to about 90 mg per dose, from about 90 mg per dose to about 100 mg per dose, from about 100 mg per dose to about 125 mg per dose, from about 125 mg per dose to about 150 mg per dose, from about 150 mg per dose to about 175 mg per dose, or from about 175 mg per dose to about 200 mg per dose.

[00291] In some embodiments, effective dosages of an HCN enzyme inhibitor are expressed as mg/kg body weight. In these embodiments, effective dosages an HCN enzyme inhibitor are from about 0.01 mg/kg body weight to about 100 mg/kg body weight, from about 0.1 mg/kg body weight to about 1 mg/kg body weight, from about 1 mg/kg body weight to about 10 mg/kg body weight, from about 10 mg/kg body weight to about 100 mg/kg body weight, from about 5 mg/kg body weight to about 400 mg/kg body weight, from about 5 mg/kg body weight to about 50 mg/kg body weight, from about 50 mg/kg body weight to about 100 mg/kg body weight, from about 100 mg/kg body weight to about 200 mg/kg body weight, from about 200 mg/kg body weight to about 300 mg/kg body weight, or from about 300 mg/kg body weight to about 400 mg/kg body weight.

[00292] In many embodiments, an HCN enzyme inhibitor is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The HCN enzyme inhibitor can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[00293] In many embodiments, multiple doses of an HCN enzyme inhibitor are administered. For example, an HCN enzyme inhibitor is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or tliree times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00294] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound. Side effect management agent

[00295] Any subject therapeutic regimen can be modified to include administration of a side effect management agent. An effective amount of a side effect management agent reduces one or more side effects by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the side effect management agent is not administered.

[00296] Side effects of Type I interferon receptor agonist treatment include, but are not limited to, fever, malaise, tachycardia, chills, headache, arthralgia, myalgia, myelosuppression, suicide ideation, platelet suppression, neutropenia, lymphocytopenia, erythrocytopenia (anemia), and anorexia. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a Type I interferon receptor agonist by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the Type I interferon receptor agonist is administered without the palliative agent. For example, if a fever is experienced with the Type I interferon receptor agonist therapy, then the body temperature of an individual treated with the Type I interferon receptor agonist therapy and palliative agent according to the instant invention is reduced by at least 0.5 degree Fahrenheit, and in some embodiments is within the normal range, e.g., at or near 98.6 °F.

[00297] Side effects of pirfenidone or a pirfenidone analog include gastrointestinal disturbances and discomfort. Gastrointestinal disturbances include nausea, diarrhea, gastrointestinal cramping, and the like. In some embodiments, an effective amount of a palliative agent reduces a side effect induced by treatment with a pirfenidone or a pirfenidone analog by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or more, compared to the rate of occurrence or the degree or extent of the side effect when the pirfenidone or pirfenidone analog is administered without the palliative agent. Therapeutic regimens

[00298] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCN infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of from about 1 μg to about 30 μg of drag per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00299] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCN infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 9 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-CIFN containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00300] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCN infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 15 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-CIFN containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00301] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 18 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-CIFN containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00302] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 27 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-CIFN containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG -CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 3 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00303] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of from about 1 μg to about 30 μg of drag per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00304] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 9 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drag per dose of PEGASYS® subcutaneously q , qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00305] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 15 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drag per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00306] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 18 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00307] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 27 μg of drag per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drag per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00308] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® contaimng an amount of from about 1 μg to about 30 μg of drag per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved. [00309] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 9 μg of drag per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drag per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00310] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 15 μg of drag per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, tliree times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00311] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 18 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00312] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 27 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00313] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® contaimng an amount of from about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00314] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 9 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)- ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00315] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 15 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)- ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00316] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 18 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)- ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00317] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of INFERGEN® containing an amount of about 27 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drag per dose of mono PEG(30 lcD, linear)- ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00318] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of from about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00319] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-CIFN containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00320] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-CIFN containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00321] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of from about 3 MU to about 10 MU of drag per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved. [00322] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00323] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 10 MU of drag per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00324] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of from about 3 MU to about 10 MU of drag per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG- INTRON® subcutaneously biw, qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00325] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 3 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00326] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) admimstering to the patient a dosage of PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, tliree times per month, or monthly for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00327] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of from about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drag per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00328] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 3 MU of drag per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved.

[00329] In some embodiments, the invention provides a therapy method using effective amounts of i) a non-PEGylated Type I interferon receptor agonist, and ii) a PEGylated Type I interferon receptor agonist in the treatment of an HCV infection in a patient, comprising a) administering to the patient a dosage of IFN-α 2a, 2b or 2c containing an amount of about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, or biw, for a first period of time of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks, or until the serum viral load in the individual is reduced to an undetectable level; followed by b) administering to the patient a dosage of mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drag per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for a second period of time where (i) the second period of time is at least as long as the first period of time and (ii) the sum of the first and second periods of time is at least about 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, 52 weeks, 56 weeks, or 60 weeks, such that a sustained viral response is achieved. Combination regimens for treating a hepatitis C virus infection

[00330] Any of the above-described treatment regimens can further include administration of an effective amount of one or more additional therapeutic agents. For example, any of the above- described treatment regimens can further include administration of an effective amount of one or more of an immunomodulatory agent; an HCV enzyme inhibitor; and a side effect management agent. Immunomodulatory agents can be selected from i) a Type II interferon receptor agonist; ii) a TNF antagonist; iii) pirfenidone or a pirfenidone analog; and iv) thymosin-α. Where the immunomodulatory agent is a Type II interferon receptor agonist, in many embodiments the Type II interferon receptor agonist is IFN-γ. HCV enzyme inhibitors can be selected from one or more of an NS3 protease inhibitor; an NS3 helicase inhibitor; and an NS5B RNA-dependent RNA polymerase inhibitor. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

[00331] In some embodiments, at least one additional therapeutic agent is administered during the entire course of treatment with the non-PEGylated Type I interferon receptor agonist. In other embodiments, the at least one additional therapeutic agent is administered for a period of time that is overlapping with the course of treatment with the non-PEGylated Type I interferon receptor agonist, e.g., the at least one additional therapeutic agent treatment can begin before the treatment with the non-PEGylated Type I interferon receptor agonist begins and end before treatment with the non-PEGylated Type I interferon receptor agonist ends; the at least one additional therapeutic agent treatment can begin after the treatment with the non-PEGylated Type I interferon receptor agonist begins and end after the treatment with the non-PEGylated Type I interferon receptor agonist ends; the at least one additional therapeutic agent treatment can begin after the treatment with the non-PEGylated Type I interferon receptor agonist begins and end before the treatment with the non-PEGylated Type I interferon receptor agonist ends; or the at least one additional therapeutic agent treatment can begin before the treatment with the non-PEGylated Type I interferon receptor agonist begins and end after the treatment with the non-PEGylated Type I interferon receptor agonist ends.

[00332] Likewise, in some embodiments, at least one additional therapeutic agent is administered during the entire course of treatment with the PEGylated Type I interferon receptor agonist. In other embodiments, the at least one additional therapeutic agent is administered for a period of time that is overlapping with the course of treatment with the PEGylated Type I interferon receptor agonist, e.g., the at least one additional therapeutic agent treatment can begin before the treatment with the PEGylated Type I interferon receptor agonist begins and end before treatment with the PEGylated Type I interferon receptor agonist ends; the at least one additional therapeutic agent treatment can begin after the treatment with the PEGylated Type I interferon receptor agonist begins and end after the treatment with the PEGylated Type I interferon receptor agonist ends; the at least one additional therapeutic agent treatment can begin after the treatment with the PEGylated Type I interferon receptor agonist begins and end before the treatment with the PEGylated Type I interferon receptor agonist ends; or the at least one additional therapeutic agent treatment can begin before the treatment with the PEGylated Type I interferon receptor agonist begins and end after the treatment with the PEGylated Type I interferon receptor agonist ends.

[00333] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of an HCV NS3 protease inhibitor containing an amount of from about 0.01 mg to about 100 mg of drug per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration.

[00334] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of an HCV NS5B RNA-dependent RNA polymerase inhibitor containing an amount of from about 0.01 mg to about 100 mg of drag per kilogram of body weight per dose, orally tid, bid, qd, qod, tiw, biw, qw, qow, three times per month, or once monthly, for the desired treatment duration.

[00335] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of IFN-γ containing an amount of from about 10 μg to about 300 μg of drug per dose of IFN-γ, subcutaneously qd, qod, tiw, or biw, or per day substantially continuously or continuously.

[00336] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of Zadaxin™ containing an amount of 1.0 mg or 1.6 mg, administered subcutaneously twice per week for the desired treatment duration.

[00337] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of ribavirin or a derivative thereof, in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration.

[00338] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of levovirin in an amount of about 400 mg, 800 mg, 1000 mg, or 1200 mg orally daily for the desired treatment duration.

[00339] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of viramidine in an amount of from about 800 mg to about 1600 mg orally daily for the desired treatment duration.

[00340] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration. [00341] The subject invention provides any of the above-described treatment methods, modified to include administering a dosage of a TNF-α antagonist selected from (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drag subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration. IFN-α and ribavirin combination therapy

[00342] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and ribavirin for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and ribavirin for a second period of time effective to achieve a sustained viral response in the individual.

[00343] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and ribavirin for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[00344] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and ribavirin for a second period of time effective to achieve a sustained viral response in the individual.

[00345] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00346] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00347] Therapeutically effective ribavirin dosages, dosing intervals and treatment durations are described above.

[00348] Any of the above-described methods featuring IFN-α and ribavirin combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amount of one or more of: an NS3 inhibitor, an NS5B inhibitor, a Type II interferon receptor agonist (e.g., IFN-γ), a TNF antagonist (e.g., etanercept, infliximab, adalimumab, etc.), pirfenidone or a pirfenidone analog, or thymosin-α. IFN-α and IFN-γ combination therapy

[00349] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and IFN-γ for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and IFN-γ for a second period of time effective to achieve a sustained viral response in the individual.

[00350] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and IFN-γ for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[00351] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and IFN-γ for a second period of time effective to achieve a sustained viral response in the individual.

[00352] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00353] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00354] Therapeutically effective IFN-γ dosages, dosing intervals and treatment durations are described above.

[00355] Any of the above-described methods featuring IFN-α and IFN-γ combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amount of one or more of: a nucleoside analog (e.g., ribavirin, levovirin, viramidine, an L-nucleoside, etc.), an NS3 inhibitor, an NS5B inhibitor, a TNF antagonist (e.g., etanercept, infliximab, adalimumab, etc.), pirfenidone or a pirfenidone analog, or thymosin-α. IFN-α and TNF antagonist combination therapy

[00356] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and a TNF antagonist for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and the TNF antagonist for a second period of time effective to achieve a sustained viral response in the individual.

[00357] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) admimstering to the individual a combined amount of a non-PEGylated IFN-α and a TNF antagonist for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[00358] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and a TNF antagonist for a second period of time effective to achieve a sustained viral response in the individual.

[00359] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00360] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00361] Therapeutically effective TNF antagonist dosages, dosing intervals and treatment durations are described above.

[00362] In any of the above-described IFN-α and TNF antagonist combination regimens, the TNF antagonist can be selected from etanercept, infliximab and adalimumab.

[00363] Any of the above-described methods featuring IFN-α and TNF antagonist combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amount of one or more of: a nucleoside analog (e.g., ribavirin, levovirin, viramidine, an L-nucleoside, etc.), an NS3 inhibitor, an NS5B inhibitor, a Type II interferon receptor agonist (e.g., IFN-γ), pirfenidone or a pirfenidone analog, or thymosin-α. IFN-α and pirfenidone combination therapy

[00364] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and pirfenidone or a pirfenidone analog for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and pirfenidone or pirfenidone analog for a second period of time effective to achieve a sustained viral response in the individual.

[00365] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and pirfenidone or a pirfenidone analog for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[00366] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and pirfenidone or a pirfenidone analog for a second period of time effective to achieve a sustained viral response in the individual.

[00367] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00368] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00369] Therapeutically effective pirfenidone and pirfenidone analog dosages, dosing intervals and treatment durations are described above.

[00370] Any of the above-described methods featuring IFN-α and pirfenidone or a pirfenidone analog combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amount of one or more of: a nucleoside analog (e.g., ribavirin, levovirin, viramidine, an L-nucleoside, etc.), an NS3 inhibitor, an NS5B inhibitor, a Type II interferon receptor agonist (e.g., IFN-γ), a TNF antagonist (e.g., etanercept, infliximab, adalimumab, etc.), or thymosin-α. IFN-α and thymosin-α combination therapy

[O0371] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and thymosin-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and thymosin-α for a second period of time effective to achieve a sustained viral response in the individual.

[O0372] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and thymosin-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[O0373] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and thymosin-α for a second period of time effective to achieve a sustained viral response in the individual.

[00374] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00375] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00376] Therapeutically effective thymosin-α dosages, dosing intervals and treatment durations are described above.

[00377] Any of the above-described methods featuring IFN-α and thymosin-α combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amount of one or more of: a nucleoside analog (e.g., ribavirin, levovirin, viramidine, an L-nucleoside, etc.), an NS3 inhibitor, an NS5B inhibitor, a Type II interferon receptor agonist (e.g., IFN-γ), a TNF antagonist (e.g., etanercept, infliximab, adalimumab, etc.), or pirfenidone or a pirfenidone analog. IFN-α and NS3 inhibitor combination therapy

[00378] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and an NS3 inhibitor for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and the NS3 inhibitor for a second period of time effective to achieve a sustained viral response in the individual.

[00379] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and an NS3 inhibitor for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[00380] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amoxmt of a PEGylated IFN-α and an NS3 inhibitor for a second period of time effective to achieve a sustained viral response in the individual.

[00381] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00382] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00383] Therapeutically effective NS3 inhibitor dosages, dosing intervals and treatment durations are described above.

[00384] Any of the above-described methods featuring IFN-α and NS3 inhibitor combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amount of one or more of: a nucleoside analog (e.g., ribavirin, levovirin, viramidine, an L-nucleoside, etc.), an NS5B inhibitor, a Type II interferon receptor agonist (e.g., IFN-γ), a TNF antagonist (e.g., etanercept, infliximab, adalimumab, etc.), pirfenidone or a pirfenidone analog, or thymosin-α. IFN-α and NS5B inhibitor combination therapy

[00385] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and an NS5B inhibitor for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and the NS5B inhibitor for a second period of time effective to achieve a sustained viral response in the individual.

[00386] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual a combined amount of a non-PEGylated IFN-α and an NS5B inhibitor for a first period of time effective to reduce the serum concentration of HCV RNA in the individual to an undetectable level; and (ii) then administering to the individual an amount of a PEGylated IFN-α for a second period of time effective to achieve a sustained viral response in the individual.

[00387] In some embodiments, the invention provides a method for the treatment of HCV infection in an individual comprising (i) administering to the individual an amount of a non- PEGylated IFN-α for a first period of time effective to reduce the serum concentration of HCV RNA. in the individual to an undetectable level; and (ii) then administering to the individual a combined amount of a PEGylated IFN-α and an NS5B inhibitor for a second period of time effective to achieve a sustained viral response in the individual.

[00388] Therapeutically effective non-PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00389] Therapeutically effective PEGylated IFN-α dosages, dosing intervals and treatment durations are described above.

[00390] Therapeutically effective NS5B inhibitor dosages, dosing intervals and treatment durations are described above.

[00391] Any of the above-described methods featuring IFN-α and NS5B inhibitor combination therapy for the treatment of HCV infection can be modified to further comprise administering to the individual during the first and/or second time period(s) an effective amoxmt of one or more of: a nucleoside analog (e.g., ribavirin, levovirin, viramidine, an L-nucleoside, etc.), an NS3 inhibitor, a Type II interferon receptor agonist (e.g., IFN-γ), a TNF antagonist (e.g., etanercept, infliximab, adalimumab, etc.), pirfenidone or a pirfenidone analog, or thymosin-α. Exemplary Dosing Schedules

[00392] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α regimen can be modified to replace the subject PEGylated IFN-α regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days for the desired treatment duration.

[00393] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α regimen can be modified to replace the subject PEGylated IFN-α regimen with a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days for the desired treatment duration.

[00394] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α regimen can be modified to replace the subject PEGylated IFN-α regimen with a regimen of monoPEG (30 IcD, linear)-ylated consensus IFN-α comprising administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days for the desired treatment duration.

[00395] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α regimen can be modified to replace the subject non-PEGylated IFN-α regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily or three times per week, for the desired treatment duration.

[00396] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α regimen can be modified to replace the subject non-PEGylated IFN-α regimen with a regimen of INFERGEN® interferon alfacon-1 comprising administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily or three times per week, for the desired treatment duration.

[00397] As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 25 μg of drag per dose, subcutaneously three times per week for the desired treatment duration. [00398] As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amoxmt of 50 μg of drag per dose, subcutaneously three times per week for the desired treatment duration.

[00399] As non-limiting examples, any of the above-described methods featuring an IFN-γ regimen can be modified to replace the subject IFN-γ regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week for the desired treatment duration.

[00400] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject PEGylated IFN- α and IFN-γ combination regimen with a PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drag per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00401] As non-limiting examples, any of the above-described methods featuring a TNF antagonist regimen can be modified to replace the subject TNF antagonist regimen with a TNF antagonist regimen comprising administering a dosage of a TNF antagonist selected from the group of: (a) etanercept in an amount of 25 mg of drag per dose subcutaneously twice per week, (b) infliximab in an amount of 3 mg of drag per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (c) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; for the desired treatment duration.

[00402] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject PEGylated IFN- α and IFN-γ combination regimen with a PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drag per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00403] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject PEGylated IFN- α and IFN-γ combination regimen with a PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00404] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject PEGylated IFN- α and IFN-γ combination regimen with a PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00405] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and IFrST-γ combination regimen can be modified to replace the subject PEGylated IFN- α and IFN-γ combination regimen with a PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00406] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject PEGylated IFN- α and IFN-γ combination regimen with a PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00407] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00408] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00409] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00410] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00411] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00412] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amoxmt of 100 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00413] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00414] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration.

[00415] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amoxmt of 15 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00416] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 25 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00417] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration. [00418] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and IFN-γ combination regimen can be modified to replace the subject non- PEGylated IFN-α and IFN-γ combination regimen with a non-PEGylated IFN-α and IFN-γ combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00419] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amoxmt of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00420] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amoxmt of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00421] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amoxmt of 3 mg of drug per kilogram of body weight intravenously at weeks O, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00422] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amoxmt of 3 mg of drug per kilogram of body weight intravenously at weeks O, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00423] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration. [00424] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α contaimng an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously tliree times per week; and (c) admimstering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00425] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimtimab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00426] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously tliree times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00427] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amoxmt of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00428] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00429] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00430] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amoxmt of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amoxmt of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00431] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00432] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amoxmt of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00433] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00434] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amoxmt of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 25 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00435] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00436] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen with a non- PEGylated IFN-α, IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00437] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α and TNF antagonist combination regimen with a PEGylated IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00438] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α and TNF antagonist combination regimen with a PEGylated IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00439] As non-limiting examples, any of the above-described methods featuring a PEGylated IFN-α and TNF antagonist combination regimen can be modified to replace the subject PEGylated IFN-α and TNF antagonist combination regimen with a PEGylated IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 IcD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00440] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α and TNF antagonist combination regimen with a non-PEGylated IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amoxmt of 9 μg of drug per dose, subcutaneously once daily, or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00441] As non-limiting examples, any of the above-described methods featuring a non- PEGylated IFN-α and TNF antagonist combination regimen can be modified to replace the subject non-PEGylated IFN-α and TNF antagonist combination regimen with a non-PEGylated IFN-α and TNF antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily, or three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amoxmt of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00442] As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amoxmt of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00443] As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (b) administering a dosage of a TNF antagonist selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amoxmt of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00444] As non-limiting examples, any of the above-described methods featuring an IFN-γ and TNF antagonist combination regimen can be modified to replace the subject IFN-γ and TNF antagonist combination regimen with an IFN-γ and TNF antagonist combination regimen comprising: (a) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously tliree times per week; and (b) administering a dosage of a TNF antagomst selected from (i) etanercept in an amount of 25 mg subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter or (iii) adalimumab in an amount of 40 mg subcutaneously once weekly or once every other week; for the desired treatment duration.

[00445] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 IcD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 IcD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 180 μg of drug per dose, subcutaneously once weekly for the desired treatment duration. [00446] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 1.0 μg of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[00447] As non-limiting examples, any of the above-described methods can be modified to include administering a dosage of ribavirin containing an amount of 400 mg, 800 mg, 1000 mg or 1200 mg of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[00448] As non-limiting examples, any of the above-described methods can be modified to include administering a dosage of ribavirin containing (i) an amount of 1000 mg of drug orally per day for patients having a body weight of less than 75 kg or (ii) an amount of 1200 mg of drug orally per day for patients having a body weight of greater than or equal to 75 kg, optionally in two or more divided doses per day, for the desired treatment duration.

[00449] As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 0.01 mg to 0.1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00450] As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00451] As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00452] As non-limiting examples, any of the above-described methods featuring an HCV NS3 inhibitor regimen can be modified to replace the subject HCV NS3 inhibitor regimen with an HCV NS3 inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00453] As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising admimstering a dosage of 0.01 mg to 0.1 mg of drag per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00454] As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 0.1 mg to 1 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00455] As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 1 mg to 10 mg of drag per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00456] As non-limiting examples, any of the above-described methods featuring an HCV NS5B inhibitor regimen can be modified to replace the subject HCV NS5B inhibitor regimen with an HCV NS5B inhibitor regimen comprising administering a dosage of 10 mg to 100 mg of drug per kilogram of body weight orally daily, optionally in two or more divided doses per day, for the desired treatment duration.

[00457] As non-limiting examples, any of the above-described methods providing for the administration of a non-PEGylated IFN-α to the patient can be practiced by using a controlled drug delivery device to administer the subject non-PEGylated IFN-α to the patient, so as to achieve an oscillating serum concentration profile of the non-PEGylated IFN-α that mimics the "peaks and troughs" serum concentration profile of the non-PEGylated IFN-α that would be achieved by bolus delivery of the non-PEGylated IFN-α according to the subject method, for the desired treatment duration (the induction period). In some embodiments, the controlled drug delivery device is an implantable infusion pump.

[00458] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. Patient identification

[00459] In certain embodiments, the specific regimen of drug therapy used in treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, genotype of the HCV infection in the patient, liver histology and or stage of liver fibrosis in the patient.

[00460] Thus, in some embodiments, the present invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a treatment failure patient for a duration of 48 weeks.

[00461] In other embodiments, the invention provides any of the above-described methods for HCV in which the subject method is modified to treat a non-responder patient, where the patient receives a 48 week course of therapy.

[00462] In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a relapser patient, where the patient receives a 48 week course of therapy.

[00463] In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naive patient infected with HCV genotype 1, where the patient receives a 48 week course of therapy.

[00464] In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naϊ^'ve patient infected with HCV genotype 4, where the patient receives a 48 week course of therapy.

[00465] In other embodiments, the invention provides any of the above-described methods for the treatment of HCV infection in which the subject method is modified to treat a naϊve patient infected with HCV genotype 1, where the patient has a high viral load (HVL), where "HNL" refers to an HCV viral load of greater than 2 x 10⁶ HCV genome copies per mL serum, and where the patient receives a 48 week course of therapy.

[00466] In one embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks. [00467] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.

[00468] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[00469] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drag therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.

[00470] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[00471] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of greater than 2 million viral genome copies per ml of patient serum and no or early stage liver fibrosis as measured by a Knodell score of 0, 1, or 2 and then (2) administering to the patient the drug therapy of the subject method for a time period of about 40 weeks to about 50 weeks, or about 48 weeks.

[00472] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drag therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.

[00473] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drag therapy of the subject method for a time period of about 20 weeks to about 24 weeks.

[00474] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load of less than or equal to 2 million viral genome copies per ml of patient serum and then (2) administering to the patient the drag therapy of the subject method for a time period of about 24 weeks to about 48 weeks.

[00475] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drag therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[00476] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 50 weeks, or about 24 weeks to about 48 weeks, or about 30 weeks to about 40 weeks, or up to about 20 weeks, or up to about 24 weeks, or up to about 30 weeks, or up to about 36 weeks, or up to about 48 weeks.

[00477] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 20 weeks to about 24 weeks.

[00478] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks.

[00479] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and then (2) administering to the patient the drug therapy of the subject method for a time period of about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks.

[00480] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drag therapy of the subject method for a time period of about 20 weeks to about 50 weeks.

[00481] In another embodiment, the invention provides any of the above-described methods for the treatment of an HCV infection, where the subject method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of HCV genotypes 5, 6, 7, 8 and 9 and then (2) administering to the patient the drug therapy of the subject method for a time period of at least about 24 weeks and up to about 48 weeks.

I l l SUBJECTS SUITABLE FOR TREATMENT

[00482] Individuals who are to be treated according to the methods of the invention include individuals who have been clinically diagnosed as infected with HCV. Individuals who are infected with HCV are identified as having HCV RNA in their blood, and/or having anti-HCV antibody in their serum.

[00483] Individuals who are clinically diagnosed as infected with HCV include naϊve individuals (e.g., individuals not previously treated for HCV, particularly those who have not previously received IFN-α-based and/or ribavirin-based therapy) and individuals who have failed prior treatment for HCV ("treatment failure" patients). Treatment failure patients include non-responders (i.e., individuals in whom the HCV titer was not significantly or sufficiently reduced by a previous treatment for HCV, e.g., a previous IFN-α monotherapy, a previous IFN-α and ribavirin combination therapy, or a previous pegylated IFN-α and ribavirin combination therapy); and relapsers (i.e., individuals who were previously treated for HCV, e.g., who received a previous IFN-α monotherapy, a previous IFN-α and ribavirin combination therapy, or a previous pegylated IFN-α and ribavirin combination therapy, whose HCV titer decreased, and subsequently increased).

[00484] In particular embodiments of interest, individuals have an HCV titer of at least about 10^s, at least about 5 x 10⁵, or at least about 10 , or at least about 2 x 10⁶, genome copies of HCV per milliliter of serxxm. The patient may be infected with any HCV genotype (genotype 1, including la and lb, 2, 3, 4, 6, etc. and subtypes (e.g., 2a, 2b, 3a, etc.)), particularly a difficult to treat genotype such as HCV genotype 1 and particular HCV subtypes and quasispecies.

[00485] Also of interest are HCV-positive individuals (as described above) who exhibit severe fibrosis or early cirrhosis (non-decompensated, Child' s-Pugh class A or less), or more advanced cirrhosis (decompensated, Child' s-Pugh class B or C) due to chronic HCV infection and who are viremic despite prior anti-viral freatment with IFN-α-based therapies or who cannot tolerate IFN-α-based therapies, or who have a contraindication to such therapies. In particular embodiments of interest, HCV-positive individuals with stage 3 or 4 liver fibrosis according to the METAVIR scoring system are suitable for treatment with the methods of the present invention. In other embodiments, individuals suitable for treatment with the methods of the instant invention are patients with decompensated cirrhosis with clinical manifestations, including patients with far-advanced liver cirrhosis, including those awaiting liver transplantation. In still other embodiments, individuals suitable for treatment with the methods of the instant invention include patients with milder degrees of fibrosis including those with early fibrosis (stages 1 and 2 in the METAVIR, Ludwig, and Scheuer scoring systems; or stages 1, 2, or 3 in the Ishak scoring system.). While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the sco e of the claims appended hereto.

Claims

CLAIMSWhat is claimed is:

1. A method for treating a hepatitis C virus infection in an individual, the method comprising: a) administering to the individual a non-PEGylated interferon-alpha (IFN-α) in an effective amount and for a first period of time to reduce serum viral load to an undetectable level; and b) administering to the individual who has been treated as in step (a) a PEGylated IFN-α in an effective amount and for a second period of time to achieve a sustained viral response.

2. The method of claim 1 , wherein the non-PEGylated IFN-α is INFERGEN® administered in an amount of from about 1 μg to about 30 μg of INFERGEN®⁾ subcutaneously daily.

3. The method of claim 1 , wherein the non-PEGylated IFN-α is IFN-2a, 2b or 2c administered in an amount of from about 3 MU to about 10 MU of IFN-2a, 2b or 2c subcutaneously daily.

4. The method of claim 1, wherein the non-PEGylated IFN-α is administered for a first period of time of from about 2 weeks to about 24 weeks.

5. The method of claim 4, wherein the second period of time is at least as long as the first period of time, and wherein the sum of the first and second periods of time is at least about 24 weeks.

6. The method of claim 5, wherein the sum of the first and second periods of time is at least about 48 weeks.

7. The method of claim 1 , wherein the PEGylated IFN-α is monoPEG (30 IcD, linear)-ylated INFERGEN® interferon alfacon-1 consensus interferon.

8. The method of claim 1 , wherein the PEGylated IFN-α is PEGASYS® administered in an amount of from about 90 μg to about 360 μg of drug per dose of PEGASYS® subcutaneously once weekly.

9. The method of claim 1 , wherein the PEGylated IFN-α is PEG-INTRON® administered an amount of about 0.75 μg to about 3.0 μg of drag per kilogram of body weight per dose of PEG-INTRON® subcutaneously once or twice weekly.

10. The method of claim 1 , wherein the PEGylated IFN-α is mono PEG(30 kD, linear)-ylated consensus IFN-α administered in an amount of from about 100 μg to about 200 μg of drug per dose subcutaneously once weekly or once every 8 days.

11. The method of claim 1 , further comprising administering an HCV enzyme inhibitor.

12. The method of claim 11, wherein the HCV enzyme inhibitor is an HCV NS3 protease inhibitor or an HCV NS5B RNA-dependent RNA polymerase inhibitor.

13. The method of claim 1, further comprising administering an immunomodulatory agent, wherein the immunomodulatory agent is an agent that stimulates immune cell-mediated destruction of virus-infected cells.

14. The method of claim 13, wherein the immunomodulatory agent is IFN-γ administered in an amount of from about 25 μg to about 100 μg subcutaneously three times per week.

15. The method of claim 13, wherein the immxmomodulatory agent is pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg.

16. The method of claim 1, further comprising administering ribavirin in an amount of from about 1000 mg to about 1200 mg orally daily.

17. The method of claim 1, further comprising administering levovirin in an amount of from about 1000 mg to about 1200 mg orally daily.

18. The method of claim 1 , further comprising administering viramidine in an amount of from about 800 mg to about 1600 mg orally daily.

19. The method of claim 13, wherein the immunomodulatory agent is thymosin-α administered subcutaneously in an amount of from about 1.0 mg to about 1.6 mg twice weekly.

20. The method of any of claims 1-19, wherein the unPEGylated IFN-α is delivered to the individual in the form of a bolus.

21. The method of claim 20, wherein the individual receives the bolus form subcutaneously.

22. The method of claim 20, wherein the individual receives the bolus form by subcutaneous injection.

23. The method of any of claims 1 -22, wherein the individual is a human.