Drugs for the therapy of HCV Dr Ramesh R Rai Jaipur

2. Interferons

6. Effects of interferon-alpha

9. Viral kinetics: early viral response to IFN therapy Slide 22. Early Viral Response to IFN Therapy Studies of early HCV kinetics in responders to IFN therapy have demonstrated a biphasic viral decline, usually after a brief lag phase. The first-phase slope is determined by the free virion clearance, with the second-phase slope determined by the infected-cell death rate. Both slopes are affected by efficacy of therapy as well.    Neumann AU et al. Science. 1998;282:103-107. Slide 22. Early Viral Response to IFN Therapy Studies of early HCV kinetics in responders to IFN therapy have demonstrated a biphasic viral decline, usually after a brief lag phase. The first-phase slope is determined by the free virion clearance, with the second-phase slope determined by the infected-cell death rate. Both slopes are affected by efficacy of therapy as well.    Neumann AU et al. Science. 1998;282:103-107.

10. Nomenclature of initial virological response Slide 23. Nomenclature of Initial Virological Response Zeuzem et al conducted a study designed to compare the viral kinetics of conventional IFN with those of PEGASYS® (peginterferon alfa-2a [40KD]). The initial virological response to treatment with IFN in patients with CHC was characterized by two response phases, as shown in Slide 22 “Early Viral Response to IFN Therapy.” During the first phase (day 1) of treatment, the decline in HCV RNA levels was rapid and dose dependent, reflecting the inhibition of HCV replication and the clearance of free virus (c). The first-phase response was generally similar in all responders. After the first phase of the initial response, the rate of viral degradation slowed down, ushering in the second phase (day ?2) of the initial response. During this phase, the rate of infected-cell death (?) was variable among the various responder types (ie, partial responders, rapid responders). A lack of response to treatment during the initial phase was predictive of IFN resistance. The viral kinetics model suggested by Zeuzem et al imparts predictive value to the second-phase response (P = 0.003). Those patients whose rate of response was rapid during the second phase (ie, rapid responders) were more likely than “flat” responders to achieve a sustained virological response (SVR) at 24 weeks after treatment discontinuation. In this study, all patients who rapidly responded to PEGASYS® (n = 3) achieved SVR status. Conversely, those patients whose rate of viral decline was flat (n = 8) did not attain an SVR. Zeuzem S et al. Gastroenterology. 2001;120:1438-1447. Slide 23. Nomenclature of Initial Virological Response Zeuzem et al conducted a study designed to compare the viral kinetics of conventional IFN with those of PEGASYS® (peginterferon alfa-2a [40KD]). The initial virological response to treatment with IFN in patients with CHC was characterized by two response phases, as shown in Slide 22 “Early Viral Response to IFN Therapy.” During the first phase (day 1) of treatment, the decline in HCV RNA levels was rapid and dose dependent, reflecting the inhibition of HCV replication and the clearance of free virus (c). The first-phase response was generally similar in all responders. After the first phase of the initial response, the rate of viral degradation slowed down, ushering in the second phase (day ?2) of the initial response. During this phase, the rate of infected-cell death (?) was variable among the various responder types (ie, partial responders, rapid responders). A lack of response to treatment during the initial phase was predictive of IFN resistance. The viral kinetics model suggested by Zeuzem et al imparts predictive value to the second-phase response (P = 0.003). Those patients whose rate of response was rapid during the second phase (ie, rapid responders) were more likely than “flat” responders to achieve a sustained virological response (SVR) at 24 weeks after treatment discontinuation. In this study, all patients who rapidly responded to PEGASYS® (n = 3) achieved SVR status. Conversely, those patients whose rate of viral decline was flat (n = 8) did not attain an SVR. Zeuzem S et al. Gastroenterology. 2001;120:1438-1447.

11. Time course of virological response to IFN therapy in patients with CHC Slide 24. Time Course of Virological Response to IFN Therapy in Patients With CHC The time course of virological response to IFN in patients with CHC can be characterized as a biphasic decline in HCV RNA levels. During the first phase—the induction phase—IFN therapy induces early viral clearance from circulating blood by inhibiting HCV cellular replication. Additionally, degradation of free virus occurs in the initial stages of the induction phase in IFN responders.1 The response to IFN therapy in this phase is dose dependent.2 During the second, or maintenance, phase, which begins approximately 14 to 28 days after the initial dose of IFN and continues throughout the treatment period, the immune system begins to eliminate HCV-infected cells.1 The goal of IFN maintenance therapy is clearance of HCV-infected cells, which is dependent on the length of the treatment period.    1. Zeuzem S et al. Gastroenterology. 2001;120:1438-1447. 2. Neumann AU et al. Science. 1998;282:103-107.Slide 24. Time Course of Virological Response to IFN Therapy in Patients With CHC The time course of virological response to IFN in patients with CHC can be characterized as a biphasic decline in HCV RNA levels. During the first phase—the induction phase—IFN therapy induces early viral clearance from circulating blood by inhibiting HCV cellular replication. Additionally, degradation of free virus occurs in the initial stages of the induction phase in IFN responders.1 The response to IFN therapy in this phase is dose dependent.2 During the second, or maintenance, phase, which begins approximately 14 to 28 days after the initial dose of IFN and continues throughout the treatment period, the immune system begins to eliminate HCV-infected cells.1 The goal of IFN maintenance therapy is clearance of HCV-infected cells, which is dependent on the length of the treatment period.    1. Zeuzem S et al. Gastroenterology. 2001;120:1438-1447. 2. Neumann AU et al. Science. 1998;282:103-107.

12. Treatment: goals of therapy Primary objective = cure No virus1 No progression(histology/fibrosis) No symptoms Slide 26. Goals of Therapy The primary objective in managing HCV-infected patients is to effect a “cure.” The best indicator of a beneficial, curative treatment effect is an SVR, defined as undetectable HCV RNA levels in the blood 6 months after completing antiviral treatment.1 Other indicators of successful treatment include lack of progression of fibrosis (a histologic response) and no clinical symptomatology of HCV infection. Not all HCV-infected patients are cured after receiving antiviral therapy. Nevertheless, secondary treatment goals such as slowing the progression of fibrosis and cirrhosis as well as preventing liver decompensation and HCC are important to avert premature mortality.1,2   1. Worman HJ. Hepatitis C: current treatment. 2. Peters MG et al. Medscape HIV/AIDS eJournal. 2002;8(1). 3. Nishiguchi S et al. Lancet. 1995;346:1051-1055. Slide 26. Goals of Therapy The primary objective in managing HCV-infected patients is to effect a “cure.” The best indicator of a beneficial, curative treatment effect is an SVR, defined as undetectable HCV RNA levels in the blood 6 months after completing antiviral treatment.1 Other indicators of successful treatment include lack of progression of fibrosis (a histologic response) and no clinical symptomatology of HCV infection. Not all HCV-infected patients are cured after receiving antiviral therapy. Nevertheless, secondary treatment goals such as slowing the progression of fibrosis and cirrhosis as well as preventing liver decompensation and HCC are important to avert premature mortality.1,2   1. Worman HJ. Hepatitis C: current treatment. 2. Peters MG et al. Medscape HIV/AIDS eJournal. 2002;8(1). 3. Nishiguchi S et al. Lancet. 1995;346:1051-1055.

13. Virological response: definitions End-of-treatment response Undetectable HCV RNA levels (<50 IU/ml) at the end of treatment (24 weeks for HCV genotype non-1, 48 weeks for HCV genotype 1) Sustained virological response Undetectable HCV RNA levels (<50 IU/ml) at end of follow-up (24 weeks post treatment) Nonresponse Detectable HCV RNA levels (=50 IU/ml) at the end of treatment Breakthrough Undetectable HCV RNA levels during treatment, but return to detectable HCV RNA levels prior to completion of therapy Relapse Patient who is HCV RNA negative at the end of treatment but subsequently becomes positive during the follow-up period Slide 27. Virological Response: Definitions Response to antiviral therapy varies in degree and duration. Patients who manifest an end-of-treatment response are those with undetectable HCV RNA levels (<50 IU/mL) at the end of the treatment period, generally 48 or 24 weeks depending on HCV genotype. When this response is maintained over an additional 24 weeks following treatment discontinuation, the patient is considered to exhibit an SVR, or sustained virological response. A nonresponse occurs when HCV RNA levels are detectable (³50 IU/mL) at the end of treatment. Some nonresponders exhibit breakthrough: They temporarily respond to treatment by becoming HCV RNA negative during the treatment period, but subsequently become HCV RNA positive while still on treatment. Patients are considered relapsers if they exhibit end-of-treatment response and subsequently become HCV RNA positive during the follow-up period. The term late relapse has been applied to the very uncommon occurrence of a relapse after achieving an SVR. Slide 27. Virological Response: Definitions Response to antiviral therapy varies in degree and duration. Patients who manifest an end-of-treatment response are those with undetectable HCV RNA levels (<50 IU/mL) at the end of the treatment period, generally 48 or 24 weeks depending on HCV genotype. When this response is maintained over an additional 24 weeks following treatment discontinuation, the patient is considered to exhibit an SVR, or sustained virological response. A nonresponse occurs when HCV RNA levels are detectable (³50 IU/mL) at the end of treatment. Some nonresponders exhibit breakthrough: They temporarily respond to treatment by becoming HCV RNA negative during the treatment period, but subsequently become HCV RNA positive while still on treatment. Patients are considered relapsers if they exhibit end-of-treatment response and subsequently become HCV RNA positive during the follow-up period. The term late relapse has been applied to the very uncommon occurrence of a relapse after achieving an SVR.

14. Patterns of virological response Slide 29. Patterns of Virological Response Virological response is determined first by the presence or absence of serum HCV RNA and then by the viral load in patients with HCV RNA positivity. Patients who manifest no change from baseline in HCV RNA levels during the treatment period and throughout the follow-up period are termed virological nonresponders. Patients who exhibit an initial decline in HCV RNA levels during therapy and subsequently return to near-baseline HCV RNA levels during the treatment period are deemed partial responders. Patients who exhibit breakthrough are those who test HCV RNA negative and then test positive again prior to the end of treatment. Patients who demonstrate end-of-treatment response (HCV RNA <50 IU/mL) and subsequently test positive for HCV RNA are considered relapsers. Only those patients in whom HCV RNA levels are undetectable (<50 IU/mL) at the end of treatment and who maintain this response status throughout the follow-up period can be regarded as sustained responders. Slide 29. Patterns of Virological Response Virological response is determined first by the presence or absence of serum HCV RNA and then by the viral load in patients with HCV RNA positivity. Patients who manifest no change from baseline in HCV RNA levels during the treatment period and throughout the follow-up period are termed virological nonresponders. Patients who exhibit an initial decline in HCV RNA levels during therapy and subsequently return to near-baseline HCV RNA levels during the treatment period are deemed partial responders. Patients who exhibit breakthrough are those who test HCV RNA negative and then test positive again prior to the end of treatment. Patients who demonstrate end-of-treatment response (HCV RNA <50 IU/mL) and subsequently test positive for HCV RNA are considered relapsers. Only those patients in whom HCV RNA levels are undetectable (<50 IU/mL) at the end of treatment and who maintain this response status throughout the follow-up period can be regarded as sustained responders.

15. Limitations of conventional IFN alfa therapy Rapid absorption after subcutaneous injection Wide fluctuation in serum concentration Inadequate antiviral coverage Vast systemic distribution High renal clearance Short serum half-life (2 to 5 hours) Slide 31. Limitations of Conventional IFN Alfa Therapy Conventional IFN alfa administered as a subcutaneous (sc) injection is rapidly absorbed, with wide fluctuations in serum concentrations. The peak serum concentration of a single sc injection of 36 MIU of IFN alfa-2a (ROFERON®-A, Hoffmann-La Roche) ranges from 1250 to 2320 pg/mL (mean, 1730 pg/mL) within a mean time of 7.3 hours.1 The mean serum concentration following a single injection of 5 MIU/m2 of IFN alfa-2b (INTRON® A, Schering) ranges from 18 to 116 IU/mL within 3 to 12 hours after sc administration.2 As a result of such wide fluctuations in serum concentrations, conventional IFN alfa fails to provide constant antiviral coverage and can allow viral replication when its concentrations are not measurable. The widely fluctuating concentrations may also account for more peak-related side effects. Vast systemic distribution of conventional IFN alfa has been reported. For example, the volume of distribution at steady state (Vdss) for IFN alfa-2a ranges from 0.223 to 0.748 L/kg after a single intravenous dose (IFN alfa-2a 36 MIU), with a mean Vdss of 0.400 L/kg.1 Conventional IFN alfa undergoes rapid clearance (11.8 L/h for IFN alfa-2a),3 being metabolized predominantly by the kidneys and minimally by the liver.1 For this reason, conventional IFN alfa is contraindicated or should be used with caution in patients with impaired renal function (consult prescribing information).1,2 Because conventional IFN alfa preparations have short elimination half-lives (3.7 to 8.5 hours [mean, ˜5 hours] for IFN alfa-2a and 2 to 3 hours for IFN alfa-2b), frequent dosing is required.1,2   1. ROFERON®-A. PDR ®. 56th ed. 2002. 2. INTRON® A. PDR ®. 56th ed. 2002. 3. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.Slide 31. Limitations of Conventional IFN Alfa Therapy Conventional IFN alfa administered as a subcutaneous (sc) injection is rapidly absorbed, with wide fluctuations in serum concentrations. The peak serum concentration of a single sc injection of 36 MIU of IFN alfa-2a (ROFERON®-A, Hoffmann-La Roche) ranges from 1250 to 2320 pg/mL (mean, 1730 pg/mL) within a mean time of 7.3 hours.1 The mean serum concentration following a single injection of 5 MIU/m2 of IFN alfa-2b (INTRON® A, Schering) ranges from 18 to 116 IU/mL within 3 to 12 hours after sc administration.2 As a result of such wide fluctuations in serum concentrations, conventional IFN alfa fails to provide constant antiviral coverage and can allow viral replication when its concentrations are not measurable. The widely fluctuating concentrations may also account for more peak-related side effects. Vast systemic distribution of conventional IFN alfa has been reported. For example, the volume of distribution at steady state (Vdss) for IFN alfa-2a ranges from 0.223 to 0.748 L/kg after a single intravenous dose (IFN alfa-2a 36 MIU), with a mean Vdss of 0.400 L/kg.1 Conventional IFN alfa undergoes rapid clearance (11.8 L/h for IFN alfa-2a),3 being metabolized predominantly by the kidneys and minimally by the liver.1 For this reason, conventional IFN alfa is contraindicated or should be used with caution in patients with impaired renal function (consult prescribing information).1,2 Because conventional IFN alfa preparations have short elimination half-lives (3.7 to 8.5 hours [mean, ˜5 hours] for IFN alfa-2a and 2 to 3 hours for IFN alfa-2b), frequent dosing is required.1,2   1. ROFERON®-A. PDR ®. 56th ed. 2002. 2. INTRON® A. PDR ®. 56th ed. 2002. 3. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

16. Pegylated interferons: protein pegylation Addition of polyethylene glycol (PEG) moiety to protein may result in1: Prolonged plasma half-life (increased conc. 7 folds) Reduced clearance (10 folds) Less immunogenicity Characteristics of new protein depend on:1,2 Structure of PEG moiety (eg, size, branching, linkage bond strength) Site(s) of attachment to parent compound Slide 32. Protein Pegylation Pegylation prolongs the plasma half-life of protein drugs (from 3- to 486-fold) and renders them less immunogenic. Since pegylated proteins are surrounded by an attached polyethylene glycol (PEG) moiety, they are less rapidly metabolized by the body's enzymes than are unmodified proteins and remain in the host longer to perform their therapeutic activity. The size of the PEG moiety is of particular importance, since larger pegylated molecules can provide more sustained drug exposure, thus eliminating critical peak-to-trough fluctuations and optimizing suppression of HCV infection.1 Additional enhancements conferred by pegylation include improved solubility, decreased proteolysis, reduced kidney clearance, and beneficial alterations in distribution and absorption.2,3 Pegylation of therapeutic proteins or peptides is generally accomplished by means of establishing a covalent bond between an amino or sulfhydryl group on the parent compound and a chemically reactive group (ie, carbonate, ester, aldehyde, tresylate) on the PEG moiety. The characteristics of the resulting molecule depend on the structure of the PEG moiety (eg, size, linear or branched, linkage bond strength) and the site of attachment to the parent compound.1 In HCV-infection therapy, pegylation of conventional IFN has enhanced its pharmacokinetic profile and therapeutic efficacy. For example, pegylation of the IFN alfa-2a molecule augments its terminal half-life from 5.1 hours (IFN alfa-2a) to 77 hours (PEGASYS® [peginterferon alfa-2a (40KD)], Hoffmann-La Roche) in healthy adults,4,5 thus permitting less frequent dosing. Additionally, compared with conventional IFN alfa-2a, PEGASYS® exhibits reduced renal clearance, and its pharmacokinetics are not affected in patients with renal impairment.5,6 Currently, two pegylated formulations of IFN have been developed for the treatment of CHC— PEGASYS® and PEG-Intron™ (peginterferon alfa-2b [12KD], Schering).   1. Hoffmann-La Roche. Roche Facets. PEGASYS?. 2. Delgado C et al. Clin Rev Ther Drug Carrier Syst. 1992;9:249-304. 3. Kozlowski A et al. BioDrugs. 2001;15:419-429. 4. ROFERON®-A. PDR ®. 56th ed. 2002. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 6. Martin P et al. Hepatology. 2000;32(suppl):370A. Slide 32. Protein Pegylation Pegylation prolongs the plasma half-life of protein drugs (from 3- to 486-fold) and renders them less immunogenic. Since pegylated proteins are surrounded by an attached polyethylene glycol (PEG) moiety, they are less rapidly metabolized by the body's enzymes than are unmodified proteins and remain in the host longer to perform their therapeutic activity. The size of the PEG moiety is of particular importance, since larger pegylated molecules can provide more sustained drug exposure, thus eliminating critical peak-to-trough fluctuations and optimizing suppression of HCV infection.1 Additional enhancements conferred by pegylation include improved solubility, decreased proteolysis, reduced kidney clearance, and beneficial alterations in distribution and absorption.2,3 Pegylation of therapeutic proteins or peptides is generally accomplished by means of establishing a covalent bond between an amino or sulfhydryl group on the parent compound and a chemically reactive group (ie, carbonate, ester, aldehyde, tresylate) on the PEG moiety. The characteristics of the resulting molecule depend on the structure of the PEG moiety (eg, size, linear or branched, linkage bond strength) and the site of attachment to the parent compound.1 In HCV-infection therapy, pegylation of conventional IFN has enhanced its pharmacokinetic profile and therapeutic efficacy. For example, pegylation of the IFN alfa-2a molecule augments its terminal half-life from 5.1 hours (IFN alfa-2a) to 77 hours (PEGASYS® [peginterferon alfa-2a (40KD)], Hoffmann-La Roche) in healthy adults,4,5 thus permitting less frequent dosing. Additionally, compared with conventional IFN alfa-2a, PEGASYS® exhibits reduced renal clearance, and its pharmacokinetics are not affected in patients with renal impairment.5,6 Currently, two pegylated formulations of IFN have been developed for the treatment of CHC— PEGASYS® and PEG-Intron™ (peginterferon alfa-2b [12KD], Schering).   1. Hoffmann-La Roche. Roche Facets. PEGASYS?. 2. Delgado C et al. Clin Rev Ther Drug Carrier Syst. 1992;9:249-304. 3. Kozlowski A et al. BioDrugs. 2001;15:419-429. 4. ROFERON®-A. PDR ®. 56th ed. 2002. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 6. Martin P et al. Hepatology. 2000;32(suppl):370A.

17. Peginterferon alfa-2a [40KD] Slide 33. PEGASYS® (Peginterferon Alfa-2a [40KD]) PEGASYS® (peginterferon alfa-2a [40KD]) is a pegylated form of recombinant Escherichia coli–expressed IFN alfa-2a (ROFERON®-A) that is formed by the covalent attachment of a 40-kDa PEG branched moiety to the IFN alfa-2a molecule by means of a stable amide bond. The PEG moiety 40kDa,1 and 19 kDa2 IFN alfa-2a molecule together yield a total molecular mass of approximately 59 kDa for the pegylated molecule. PEGASYS® is indicated for the treatment of histologically proven CHC in adults who have elevated transaminases and who are positive for serum HCV RNA, including patients with compensated cirrhosis. PEGASYS® can be used alone or in combination with ribavirin (RBV) in IFN-naïve patients or in those who have previously responded to IFN therapy and have relapsed posttreatment.3 Pegylation of the IFN alfa-2a molecule clearly enhances the absorption, distribution, and clearance of IFN. The pharmacokinetics of PEGASYS® in healthy individuals are characterized by an absorption half-life of 50 hours,4 a terminal half-life of 77 hours (compared with 5.1 hours for IFN alfa-2a),2,5 and a 10-fold decrease in systemic clearance compared with the conventional IFN alfa-2a molecule,4 resulting in antiviral serum concentrations that are constant and sustained throughout the entire 1-week (168 hours) dosing period.5 1. Biopharma. Interferon alpha-2a, rDNA, PEG. 2. ROFERON® -A. PDR ®. 56th ed. 2002. 3. EMEA. PEGASYS®. 4. Reddy KR. Ann Pharmacother. 2000;34:915-923. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. Slide 33. PEGASYS® (Peginterferon Alfa-2a [40KD]) PEGASYS® (peginterferon alfa-2a [40KD]) is a pegylated form of recombinant Escherichia coli–expressed IFN alfa-2a (ROFERON®-A) that is formed by the covalent attachment of a 40-kDa PEG branched moiety to the IFN alfa-2a molecule by means of a stable amide bond. The PEG moiety 40kDa,1 and 19 kDa2 IFN alfa-2a molecule together yield a total molecular mass of approximately 59 kDa for the pegylated molecule. PEGASYS® is indicated for the treatment of histologically proven CHC in adults who have elevated transaminases and who are positive for serum HCV RNA, including patients with compensated cirrhosis. PEGASYS® can be used alone or in combination with ribavirin (RBV) in IFN-naïve patients or in those who have previously responded to IFN therapy and have relapsed posttreatment.3 Pegylation of the IFN alfa-2a molecule clearly enhances the absorption, distribution, and clearance of IFN. The pharmacokinetics of PEGASYS® in healthy individuals are characterized by an absorption half-life of 50 hours,4 a terminal half-life of 77 hours (compared with 5.1 hours for IFN alfa-2a),2,5 and a 10-fold decrease in systemic clearance compared with the conventional IFN alfa-2a molecule,4 resulting in antiviral serum concentrations that are constant and sustained throughout the entire 1-week (168 hours) dosing period.5 1. Biopharma. Interferon alpha-2a, rDNA, PEG. 2. ROFERON® -A. PDR ®. 56th ed. 2002. 3. EMEA. PEGASYS®. 4. Reddy KR. Ann Pharmacother. 2000;34:915-923. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

18. Peginterferon alfa-2b [12KD] Slide 34. PEG-Intron™ (Peginterferon Alfa-2b [12KD]) PEG-Intron™ (peginterferon alfa-2b [12KD]) is a lyophilized (freeze-dried) powder formulation of a pegylated form of recombinant Escherichia coli–expressed IFN alfa-2b (Intron® A).1 PEG-Intron™ is indicated for use alone or in combination with RBV for the treatment of CHC in adults with compensated liver disease who have not been previously treated with IFN alfa.1,2 In combination with RBV, PEG-Intron™ is indicated for naïve patients as well as those who have responded to IFN alfa therapy and subsequently relapsed.3 PEG-Intron™—a prodrug of IFN alfa-2b—is formed by covalent conjugation of recombinant IFN alfa-2b with monomethoxy PEG, forming the pegylated IFN.4 The amino acids involved in the PEG attachment to IFN in PEG-Intron™ are lysine and histidine.5 The tertiary structure of the protein slows the hydrolysis of the PEG-imidazole bond. Unlike PEGASYS® (peginterferon alfa-2a [40KD]), the PEG in PEG-Intron™ detaches from the IFN in solution (after administration). Once depegylation occurs, the IFN molecule is free to begin its antiviral activity, but is rapidly metabolized like conventional, unmodified IFN.4 The PEG portion of the molecule is linear and weighs 12 kDa.1   1. Biopharma. Interferon alfa-2b, rDNA, PEG. 2. PEG-Intron™. PDR ®. 56th ed. 2002. 3. EMEA. PegIntron™. 4. Wang Y-S et al. Biochemistry. 2000;39:10634-10640. 5. Bartnof HS. Highlights from DDW 2000. Slide 34. PEG-Intron™ (Peginterferon Alfa-2b [12KD]) PEG-Intron™ (peginterferon alfa-2b [12KD]) is a lyophilized (freeze-dried) powder formulation of a pegylated form of recombinant Escherichia coli–expressed IFN alfa-2b (Intron® A).1 PEG-Intron™ is indicated for use alone or in combination with RBV for the treatment of CHC in adults with compensated liver disease who have not been previously treated with IFN alfa.1,2 In combination with RBV, PEG-Intron™ is indicated for naïve patients as well as those who have responded to IFN alfa therapy and subsequently relapsed.3 PEG-Intron™—a prodrug of IFN alfa-2b—is formed by covalent conjugation of recombinant IFN alfa-2b with monomethoxy PEG, forming the pegylated IFN.4 The amino acids involved in the PEG attachment to IFN in PEG-Intron™ are lysine and histidine.5 The tertiary structure of the protein slows the hydrolysis of the PEG-imidazole bond. Unlike PEGASYS® (peginterferon alfa-2a [40KD]), the PEG in PEG-Intron™ detaches from the IFN in solution (after administration). Once depegylation occurs, the IFN molecule is free to begin its antiviral activity, but is rapidly metabolized like conventional, unmodified IFN.4 The PEG portion of the molecule is linear and weighs 12 kDa.1   1. Biopharma. Interferon alfa-2b, rDNA, PEG. 2. PEG-Intron™. PDR ®. 56th ed. 2002. 3. EMEA. PegIntron™. 4. Wang Y-S et al. Biochemistry. 2000;39:10634-10640. 5. Bartnof HS. Highlights from DDW 2000.

20. Optimizing IFN alfa pharmacokinetics Slide 35. Optimizing IFN Alfa Pharmacokinetics Conventional IFN is rapidly metabolized and has a very short half-life; therefore, it is injected three times weekly. This is a burdensome administration schedule and still provides for only modest efficacy. Increasing the dose of IFN does not dramatically alter the pharmacokinetic (PK) profile; thus, it must still be given three times weekly. The goal of pegylation of IFN alfa is to optimize the PK of the native molecule by reducing its clearance, slowing its metabolism, and retaining or improving its in vivo biologic activity. PEGASYS® (peginterferon alfa-2a [40KD]) was specifically designed to overcome the deficiencies of conventional IFN therapy. Shown here is the ideal PK curve around which PEGASYS® was designed. This optimized PK curve indicates a rapid rise to therapeutic levels and a long time to maximum concentration. It remains flat throughout the entire week and has a low peak-to-trough ratio, eliminating peak-related side effects and providing for true 7-day viral suppression.    1. Kozlowski A et al. BioDrugs. 2001;15:419-429. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 3. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. Slide 35. Optimizing IFN Alfa Pharmacokinetics Conventional IFN is rapidly metabolized and has a very short half-life; therefore, it is injected three times weekly. This is a burdensome administration schedule and still provides for only modest efficacy. Increasing the dose of IFN does not dramatically alter the pharmacokinetic (PK) profile; thus, it must still be given three times weekly. The goal of pegylation of IFN alfa is to optimize the PK of the native molecule by reducing its clearance, slowing its metabolism, and retaining or improving its in vivo biologic activity. PEGASYS® (peginterferon alfa-2a [40KD]) was specifically designed to overcome the deficiencies of conventional IFN therapy. Shown here is the ideal PK curve around which PEGASYS® was designed. This optimized PK curve indicates a rapid rise to therapeutic levels and a long time to maximum concentration. It remains flat throughout the entire week and has a low peak-to-trough ratio, eliminating peak-related side effects and providing for true 7-day viral suppression.    1. Kozlowski A et al. BioDrugs. 2001;15:419-429. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 3. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567.

21. Mean concentration-time profiles of multiple-dose injections Slide 37. Mean Concentration-Time Profiles of Multiple-Dose Injections  The graph on the left depicts the mean concentration-time curves after multiple doses of PEG-Intron™ (peginterferon alfa-2b [12KD]) 0.5, 1.0, and 1.5 ?g/kg administered weekly. As illustrated in the graph, wide fluctuations in serum concentration occurred during the course of the weekly dosing interval for all doses shown. The peak-to-trough ratio was 1:100. The mean terminal half-life for the three doses was 34.2, 37.1, and 33.9 hours, respectively. Maximum concentration occurred at 22, 16, and 19 hours, respectively; serum concentrations of PEG-Intron™ were no longer measurable at 84, 148, and 160 hours postdose, respectively, indicating insufficient bioavailability and diminished antiviral coverage prior to administration of the next dose.1 Illustrated on the right is the mean time-concentration curves after multiple doses of PEGASYS® (peginterferon alfa-2a [40KD]) 180 ?g given weekly.2 At the time of injection (0 hours), the concentration of the agent maintained from previous doses is sufficient to provide sustained systemic exposure during the full 7-day dosing interval.2,3 1. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 2. Modi MW. AASLD Annual Meeting. 2000. 3. Modi MW et al. Hepatology. 2000;32(suppl):394A. Slide 37. Mean Concentration-Time Profiles of Multiple-Dose Injections  The graph on the left depicts the mean concentration-time curves after multiple doses of PEG-Intron™ (peginterferon alfa-2b [12KD]) 0.5, 1.0, and 1.5 ?g/kg administered weekly. As illustrated in the graph, wide fluctuations in serum concentration occurred during the course of the weekly dosing interval for all doses shown. The peak-to-trough ratio was 1:100. The mean terminal half-life for the three doses was 34.2, 37.1, and 33.9 hours, respectively. Maximum concentration occurred at 22, 16, and 19 hours, respectively; serum concentrations of PEG-Intron™ were no longer measurable at 84, 148, and 160 hours postdose, respectively, indicating insufficient bioavailability and diminished antiviral coverage prior to administration of the next dose.1 Illustrated on the right is the mean time-concentration curves after multiple doses of PEGASYS® (peginterferon alfa-2a [40KD]) 180 ?g given weekly.2 At the time of injection (0 hours), the concentration of the agent maintained from previous doses is sufficient to provide sustained systemic exposure during the full 7-day dosing interval.2,3 1. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 2. Modi MW. AASLD Annual Meeting. 2000. 3. Modi MW et al. Hepatology. 2000;32(suppl):394A.

22. Pharmacokinetics of peginterferon alfa-2a [40KD] Slide 38. Pharmacokinetics of PEGASYS® (Peginterferon Alfa-2a [40KD]) PEGASYS® (peginterferon alfa-2a [40KD]) is associated with antiviral coverage that is sustained throughout the weekly dosing interval. After one sc injection of PEGASYS® 180 ?g, the serum drug level reaches a maximum concentration of 14.2 ng/mL (bottom curve).1 Unlike the drug concentration-time curve for nonpegylated IFNs2 (see Slide 35), serum concentrations of PEGASYS® are constant and sustained throughout the week. Until steady state is reached (5 to 9 weeks), serum concentrations more than double and are constant and sustained throughout the week.3 After steady state is reached, further drug accumulation does not occur (the amount of PEGASYS® eliminated from the body equals the amount entering via administration). The concentration-time curve for the week 9 injection (not shown) would be similar to that for the week 48 injection (top curve).3 Once the entire treatment course with PEGASYS® 180 ?g once weekly has been completed, the serum concentration levels slowly descend4; complete elimination of the drug occurs within 50 to 60 days posttreatment (not shown, see Slide 40 [Metabolic Fate of PEGASYS® (Peginterferon Alfa-2a [40KD]): Metabolism and Excretion via Urine and Bile]).3 1. Algranati NE et al. AASLD Annual Meeting. 1999. 2. Koslowski A et al. BioDrugs. 2001;15:419-429. 3. Modi MW. AASLD Annual Meeting. 2000. 4. Modi MW et al. Hepatology. 2000;32(suppl):394A.Slide 38. Pharmacokinetics of PEGASYS® (Peginterferon Alfa-2a [40KD]) PEGASYS® (peginterferon alfa-2a [40KD]) is associated with antiviral coverage that is sustained throughout the weekly dosing interval. After one sc injection of PEGASYS® 180 ?g, the serum drug level reaches a maximum concentration of 14.2 ng/mL (bottom curve).1 Unlike the drug concentration-time curve for nonpegylated IFNs2 (see Slide 35), serum concentrations of PEGASYS® are constant and sustained throughout the week. Until steady state is reached (5 to 9 weeks), serum concentrations more than double and are constant and sustained throughout the week.3 After steady state is reached, further drug accumulation does not occur (the amount of PEGASYS® eliminated from the body equals the amount entering via administration). The concentration-time curve for the week 9 injection (not shown) would be similar to that for the week 48 injection (top curve).3 Once the entire treatment course with PEGASYS® 180 ?g once weekly has been completed, the serum concentration levels slowly descend4; complete elimination of the drug occurs within 50 to 60 days posttreatment (not shown, see Slide 40 [Metabolic Fate of PEGASYS® (Peginterferon Alfa-2a [40KD]): Metabolism and Excretion via Urine and Bile]).3 1. Algranati NE et al. AASLD Annual Meeting. 1999. 2. Koslowski A et al. BioDrugs. 2001;15:419-429. 3. Modi MW. AASLD Annual Meeting. 2000. 4. Modi MW et al. Hepatology. 2000;32(suppl):394A.

23. Pegylated interferons: pharmacokinetic properties Slide 39. Pegylated Interferons: Pharmacokinetic Properties The pharmacokinetics of conventional IFNs differ significantly from those of pegylated IFNs (PEG-IFNs). In addition, PEG-IFN pharmacokinetics differ based on the type of pegylation employed, principally the size and nature of the PEG molecule attached. In the case of PEGASYS® (peginterferon alfa-2a [40KD]), the use of a 40-KD PEG molecule results in a molecular entity with a low volume of distribution, reduced clearance, and an increased half-life.1-6 1. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 2. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 3. PEG-Intron™. PDR ®. 56th ed. 2002. 4. INTRON® A. PDR ®. 56th ed. 2002. 5. Reddy KR. Ann Pharmacother. 2000;34:915-923. 6. Hoffmann-La Roche. PEGASYS®. Monograph.Slide 39. Pegylated Interferons: Pharmacokinetic Properties The pharmacokinetics of conventional IFNs differ significantly from those of pegylated IFNs (PEG-IFNs). In addition, PEG-IFN pharmacokinetics differ based on the type of pegylation employed, principally the size and nature of the PEG molecule attached. In the case of PEGASYS® (peginterferon alfa-2a [40KD]), the use of a 40-KD PEG molecule results in a molecular entity with a low volume of distribution, reduced clearance, and an increased half-life.1-6 1. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. 2. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 3. PEG-Intron™. PDR ®. 56th ed. 2002. 4. INTRON® A. PDR ®. 56th ed. 2002. 5. Reddy KR. Ann Pharmacother. 2000;34:915-923. 6. Hoffmann-La Roche. PEGASYS®. Monograph.

24. Metabolic fate of peginterferon alfa-2a [40KD]: metabolism and excretion via urine and bile Slide 40. Metabolic Fate of PEGASYS® (Peginterferon Alfa-2a [40KD]): Metabolism and Excretion via Urine and Bile PEGASYS® (peginterferon alfa-2a [40KD]) is metabolized in the liver and other organs and is excreted by the kidneys. Because of the large size (40 kDa) and branched nature of its PEG attachment, PEGASYS® undergoes sustained absorption and reduced renal clearance compared with its native molecule (IFN alfa-2a). This results in 7-day, uninterrupted antiviral activity with PEGASYS®.1,2 The pegylated compound undergoes metabolism via the liver and kidneys by means of nonspecific proteolytic enzymes, with the inert PEG moiety attached to IFN fragments being eliminated from the body within 50 to 60 days.3 Less than 10% of an administered dose is eliminated by the kidneys as intact PEGASYS®.4 Chronic renal impairment (creatinine clearance ?20 mL/min) has limited or minimal influence on the pharmacokinetics of PEGASYS®.5   1. Modi MW et al. Hepatology. 2000;32(suppl):394A. 2. Algranati NE et al. AASLD Annual Meeting. 1999. 3. Modi MW. AASLD Annual Meeting. 2000. 4. Lamb MW et al. Hepatology. 2001;34(pt 2 of 2):326A. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.Slide 40. Metabolic Fate of PEGASYS® (Peginterferon Alfa-2a [40KD]): Metabolism and Excretion via Urine and Bile PEGASYS® (peginterferon alfa-2a [40KD]) is metabolized in the liver and other organs and is excreted by the kidneys. Because of the large size (40 kDa) and branched nature of its PEG attachment, PEGASYS® undergoes sustained absorption and reduced renal clearance compared with its native molecule (IFN alfa-2a). This results in 7-day, uninterrupted antiviral activity with PEGASYS®.1,2 The pegylated compound undergoes metabolism via the liver and kidneys by means of nonspecific proteolytic enzymes, with the inert PEG moiety attached to IFN fragments being eliminated from the body within 50 to 60 days.3 Less than 10% of an administered dose is eliminated by the kidneys as intact PEGASYS®.4 Chronic renal impairment (creatinine clearance ?20 mL/min) has limited or minimal influence on the pharmacokinetics of PEGASYS®.5   1. Modi MW et al. Hepatology. 2000;32(suppl):394A. 2. Algranati NE et al. AASLD Annual Meeting. 1999. 3. Modi MW. AASLD Annual Meeting. 2000. 4. Lamb MW et al. Hepatology. 2001;34(pt 2 of 2):326A. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

25. Pegylated IFNs:dosing and administration Slide 41. Pegylated IFNs: Dosing and Administration PEG-Intron™ (peginterferon alfa-2b [12KD]) is provided as a white lyophilized powder supplied in 2-mL vials for sc use. Vials contain from 74 to 222 ?g of PEG-Intron™, which, when reconstituted, contain doses from 50 to 150 ?g per 0.5 mL, respectively.1 PEG-Intron™ exhibits a mean apparent volume of distribution of 0.99 L/kg.2 Because of the statistically significant positive effect of body weight on apparent clearance and activity, weight-based dosing is recommended.3 The recommended dose for monotherapy with PEG-Intron™ is 1.0 ?g/kg/week, with adjustments according to patient weight, as shown in the table below. For use in combination with RBV, the recommended dose is 1.5 ?g/kg/week (see table). The recommended dose of RBV is 800 mg/day in two divided doses.1 *When reconstituted as directed. PEGASYS® (peginterferon alfa-2a [40KD]) is dispensed as a stable solution in vials and in single-use prefilled syringes. The recommended regimen for PEGASYS® is the same fixed dose for all patients, regardless of weight, age (elderly) or liver status (cirrhotics): once-weekly sc administration of 180 ?g, which has been established as the optimal dose based on virological response and toxicity data.4 Because of its restricted biodistribution (8 to 12 L),4 PEGASYS® is given as a fixed dose without regard to the patient’s weight. 1. PEG-Intron™. PDR ?. 56th ed. 2002. 2. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 3. Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935. 4. Reddy KR. Ann Pharmacother. 2000;34:915-923. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.Slide 41. Pegylated IFNs: Dosing and Administration PEG-Intron™ (peginterferon alfa-2b [12KD]) is provided as a white lyophilized powder supplied in 2-mL vials for sc use. Vials contain from 74 to 222 ?g of PEG-Intron™, which, when reconstituted, contain doses from 50 to 150 ?g per 0.5 mL, respectively.1 PEG-Intron™ exhibits a mean apparent volume of distribution of 0.99 L/kg.2 Because of the statistically significant positive effect of body weight on apparent clearance and activity, weight-based dosing is recommended.3 The recommended dose for monotherapy with PEG-Intron™ is 1.0 ?g/kg/week, with adjustments according to patient weight, as shown in the table below. For use in combination with RBV, the recommended dose is 1.5 ?g/kg/week (see table). The recommended dose of RBV is 800 mg/day in two divided doses.1 *When reconstituted as directed. PEGASYS® (peginterferon alfa-2a [40KD]) is dispensed as a stable solution in vials and in single-use prefilled syringes. The recommended regimen for PEGASYS® is the same fixed dose for all patients, regardless of weight, age (elderly) or liver status (cirrhotics): once-weekly sc administration of 180 ?g, which has been established as the optimal dose based on virological response and toxicity data.4 Because of its restricted biodistribution (8 to 12 L),4 PEGASYS® is given as a fixed dose without regard to the patient’s weight. 1. PEG-Intron™. PDR ?. 56th ed. 2002. 2. Glue P et al. Clin Pharmacol Ther. 2000;68:556-567. 3. Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935. 4. Reddy KR. Ann Pharmacother. 2000;34:915-923. 5. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

26. PEG attachment versus detachment Slide 42. PEG Attachment Versus Detachment The PEG molecule, which is highly water soluble, can enhance the bioavailability of water-insoluble and poorly soluble drugs. The choice of coupling chemistry is critical to the properties of the pegylated protein and affects the strength of the covalent attachment of the PEG to the therapeutic protein.1,2 PEG moieties vary considerably in molecular weight and conformation. The early moieties (monofunctional PEGs) are linear with molecular weights of 12 kDa or less. Later moieties have increased molecular weights.1 For the two pegylated forms of IFN, the coupling characteristics of the chemical bonds between the PEG moiety and the IFN protein molecule are markedly different and affect their pharmacokinetic profiles and clinical efficacy. The nature of the pegylation employed for PEG-IFNs also affects the absorption, distribution, and metabolism of the molecular entity. It is believed that in the case of PEG-Intron™ (peginterferon alfa-2b [12KD]), the PEG dissociates from the IFN molecule, which is then rapidly degraded by the usual peptidase mechanisms.2 With PEGASYS® (peginterferon alfa-2a [40KD]), the PEG molecule appears not to dissociate from the IFN molecule at any time. Tissue distribution is largely to the liver and spleen and degradation is slower; however, there is no evidence of hepatic accumulation.3 1. Kozlowski A et al. BioDrugs. 2001;15:419-429. 2. Wang Y-S et al. Biochemistry. 2000;39:10634-10640. 3. Modi MW. AASLD Annual Meeting. 2000. Slide 42. PEG Attachment Versus Detachment The PEG molecule, which is highly water soluble, can enhance the bioavailability of water-insoluble and poorly soluble drugs. The choice of coupling chemistry is critical to the properties of the pegylated protein and affects the strength of the covalent attachment of the PEG to the therapeutic protein.1,2 PEG moieties vary considerably in molecular weight and conformation. The early moieties (monofunctional PEGs) are linear with molecular weights of 12 kDa or less. Later moieties have increased molecular weights.1 For the two pegylated forms of IFN, the coupling characteristics of the chemical bonds between the PEG moiety and the IFN protein molecule are markedly different and affect their pharmacokinetic profiles and clinical efficacy. The nature of the pegylation employed for PEG-IFNs also affects the absorption, distribution, and metabolism of the molecular entity. It is believed that in the case of PEG-Intron™ (peginterferon alfa-2b [12KD]), the PEG dissociates from the IFN molecule, which is then rapidly degraded by the usual peptidase mechanisms.2 With PEGASYS® (peginterferon alfa-2a [40KD]), the PEG molecule appears not to dissociate from the IFN molecule at any time. Tissue distribution is largely to the liver and spleen and degradation is slower; however, there is no evidence of hepatic accumulation.3

27. Peginterferon alfa-2a [40KD] need not be dosed by weight Slide 43. PEGASYS® (Peginterferon Alfa-2a [40KD]) Need Not Be Dosed By Weight PEGASYS® (peginterferon alfa-2a [40KD]) has a restricted distribution and is predominantly found in the bloodstream and interstitial fluid rather than in the tissues.1 Its volume of distribution is small (8 to 12 L).2 Because its maximum tolerated and minimum effective doses are widely separated, PEGASYS® has a broad therapeutic index.1 In an analysis of patient variability in volume of distribution and clearance of PEGASYS® examined in relation to body surface, body weight, and body mass index, body weight accounted for less than 1% of the observed between-patient variability in these pharmacokinetic parameters.1 Moreover, the efficacy and safety of PEGASYS® are not altered by variations in patient body weight.1   1. Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288. Slide 43. PEGASYS® (Peginterferon Alfa-2a [40KD]) Need Not Be Dosed By Weight PEGASYS® (peginterferon alfa-2a [40KD]) has a restricted distribution and is predominantly found in the bloodstream and interstitial fluid rather than in the tissues.1 Its volume of distribution is small (8 to 12 L).2 Because its maximum tolerated and minimum effective doses are widely separated, PEGASYS® has a broad therapeutic index.1 In an analysis of patient variability in volume of distribution and clearance of PEGASYS® examined in relation to body surface, body weight, and body mass index, body weight accounted for less than 1% of the observed between-patient variability in these pharmacokinetic parameters.1 Moreover, the efficacy and safety of PEGASYS® are not altered by variations in patient body weight.1   1. Lamb MW, Martin NE. Ann Pharmacother. 2002;36:933-935. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

29. Ribavarin Ribavarin is a nucleoside analogue, structurally similar to guanosine Broad spectrum anti-viral activity Inhibits replication of RNA viruses Less inhibition of DNA viruses Mode of action is not completely understood

33. Efficacy: results of HCV therapy: SVR Slide 46. Results of HCV Therapy: SVR There have been significant advances in the effectiveness of antiviral therapy with IFN for the treatment of CHC infection. In a study published in 1998, treatment with IFN alfa-2b alone for 24 or 48 weeks resulted in SVRs at 24 weeks after discontinuation of therapy (end of follow-up) in 6% and 13% of patients, respectively.1 In the same 1998 study, 48 weeks of treatment with the combination of IFN alfa-2b 3 MIU sc thrice weekly (tiw) with RBV 1000 or 1200 mg/day orally (po) resulted in SVRs in 38% (87/228) of patients.1 In a second trial conducted in 1998 by the same group (Hepatitis Interventional Therapy Group), treatment with this combination for 48 weeks produced SVRs in 43% (119/277) of patients.2 Combining the results of these two trials yields an overall SVR of 41% (206/505). Studies with PEG-IFNs as monotherapy conducted in 2000 yielded better results than the earlier trials with IFN alone. Monotherapy with PEGASYS® (peginterferon alfa-2a [40KD]) 180 mg sc once weekly (qw) for 48 weeks has been shown to result in SVRs in 39% of patients.3 Results from another trial indicated an SVR of 25% for 48 weeks of treatment with PEG-Intron™ (peginterferon alfa-2b [12KD]) 1.0 mg/kg sc qw.4 The combination of PEG-IFN plus RBV has been demonstrated to result in even higher SVRs. The results of one recent trial (2002) indicated that 48 weeks of treatment with the combination of PEG-Intron™ 1.5 mg/kg sc qw plus RBV 800 mg/day produced SVRs in 54% of patients.5 Most recently, it has been reported that 48 weeks of treatment with the combination of PEGASYS® (peginterferon alfa-2a [40KD]) 180 mg sc qw plus RBV 1000 or 1200 mg/day produced SVRs in 61% of patients.6   1. McHutchison JG et al. N Engl J Med. 1998;339:1485-1492. 2. Poynard T et al. Lancet. 1998;352:1426-1432. 3. Zeuzem S et al. N Engl J Med. 2000;343:1666-1672. 4. Lindsay KL et al. Hepatology. 2001;34:395-403. 5. Manns MP et al. Lancet. 2001;358:958-965. 6. Hadziyannis SJ et al. EASL Annual Meeting. 2002. Slide 46. Results of HCV Therapy: SVR There have been significant advances in the effectiveness of antiviral therapy with IFN for the treatment of CHC infection. In a study published in 1998, treatment with IFN alfa-2b alone for 24 or 48 weeks resulted in SVRs at 24 weeks after discontinuation of therapy (end of follow-up) in 6% and 13% of patients, respectively.1 In the same 1998 study, 48 weeks of treatment with the combination of IFN alfa-2b 3 MIU sc thrice weekly (tiw) with RBV 1000 or 1200 mg/day orally (po) resulted in SVRs in 38% (87/228) of patients.1 In a second trial conducted in 1998 by the same group (Hepatitis Interventional Therapy Group), treatment with this combination for 48 weeks produced SVRs in 43% (119/277) of patients.2 Combining the results of these two trials yields an overall SVR of 41% (206/505). Studies with PEG-IFNs as monotherapy conducted in 2000 yielded better results than the earlier trials with IFN alone. Monotherapy with PEGASYS® (peginterferon alfa-2a [40KD]) 180 mg sc once weekly (qw) for 48 weeks has been shown to result in SVRs in 39% of patients.3 Results from another trial indicated an SVR of 25% for 48 weeks of treatment with PEG-Intron™ (peginterferon alfa-2b [12KD]) 1.0 mg/kg sc qw.4 The combination of PEG-IFN plus RBV has been demonstrated to result in even higher SVRs. The results of one recent trial (2002) indicated that 48 weeks of treatment with the combination of PEG-Intron™ 1.5 mg/kg sc qw plus RBV 800 mg/day produced SVRs in 54% of patients.5 Most recently, it has been reported that 48 weeks of treatment with the combination of PEGASYS® (peginterferon alfa-2a [40KD]) 180 mg sc qw plus RBV 1000 or 1200 mg/day produced SVRs in 61% of patients.6   1. McHutchison JG et al. N Engl J Med. 1998;339:1485-1492. 2. Poynard T et al. Lancet. 1998;352:1426-1432. 3. Zeuzem S et al. N Engl J Med. 2000;343:1666-1672. 4. Lindsay KL et al. Hepatology. 2001;34:395-403. 5. Manns MP et al. Lancet. 2001;358:958-965. 6. Hadziyannis SJ et al. EASL Annual Meeting. 2002.

36. Contra-indications to use of IFN – ribavarin therapy Cytopenia Major psychiatric illness Cardiac diseases * Poorly controlled diabetes Seizure disorders Auto immune / potentially autoimmune diseases