Loading ...
Sorry, an error occurred while loading the content.

Article-Marty

Expand Messages
  • 2byteme@bellsouth.net
    Hepatology Focus Update on Hepatitis C Treatment Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles,
    Message 1 of 106 , Feb 25, 2001
    • 0 Attachment
      Hepatology Focus
      Update on Hepatitis C Treatment

      Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
      School of
      Medicine, Los Angeles, California

      Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
      Angeles, California, and
      Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
      Medical Center,
      Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
      California

      [Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]

      Background

      Although screening of blood products and other interventions such as
      clean-needle exchange
      programs have significantly reduced the incidence of acute hepatitis C
      in the United States and
      elsewhere, there remains a large reservoir of chronically infected
      individuals, many of whom are
      unaware of their infection. Current estimates suggest a seroprevalence
      of 1.8% among Americans,
      most of whom are viremic.[1] The clinical burden of chronic hepatitis C
      virus (HCV) infection is
      expected to increase over the next 2-3 decades as a large cohort of
      patients infected between the
      1960s and 1980s, primarily as a result of recreational drug use,
      develops progressive liver disease.
      Between 8000 and 10,000 deaths each year in the United States are
      believed to be caused by
      infection with HCV -- which is now the most frequent indication for
      liver transplantation.[2]

      Even before identification of HCV, interferon-alfa (IFN-alfa) had been
      evaluated as a potential
      therapy for what had been called chronic non-A, non-B hepatitis.[3]

      Further studies using normalization of serum alanine aminotransferase
      (ALT) levels and
      improvement in liver histology as endpoints demonstrated the efficacy of
      IFN-alfa as therapy for
      the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
      Subsequent advances in
      molecular diagnosis have now increasingly allowed establishment of
      virologic criteria to evaluate
      efficacy of treatment in patients with chronic hepatitis C (see Table).

      Definition of Virologic Response in Patients Receiving Therapy for
      Chronic Hepatitis C

      End-of-treatment response (ETR) refers to absence of viremia (ie, serum
      HCV RNA below level
      of detection) at completion of therapy. Sustained response (SR)
      indicates persistent absence of
      serum HCV RNA 6 months or more after cessation of therapy. A study by
      Marcellin and
      coworkers[6] on the long-term clinical outcome in 80 patients with
      chronic HCV followed for a
      mean of 4 years following therapy highlighted the clinical implications
      of a virologic SR. Persistent
      absence of HCV RNA from serum was observed in 96% of patients with a
      lack of histologic
      progression on serial liver biopsy. In addition, ALT levels were
      persistently normal in over 90%.
      The most recent follow-up biopsy showed normal or near normal histologic
      findings in 62% of
      these patients. Thus, virologic SR was shown to be associated with both
      an absence of detectable
      serum HCV RNA and marked histologic improvement.

      Relapsers are defined as patients who have undetectable serum HCV RNA at
      completion of
      therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
      patients who fail to
      clear HCV RNA from serum during therapy.

      A recent paper by Everson and associates[7] underscores the importance
      of HCV RNA testing in
      defining treatment response. In patients with marked fibrosis and
      cirrhosis, they found a major
      discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
      to therapy. Two of
      7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
      cirrhosis cleared HCV RNA
      without normalizing ALT. In contrast, only 3 patients (10%) without
      significant fibrosis had an
      HCV RNA response without normalization of ALT. Thus, clinical trials for
      chronic HCV are now
      typically reported using virologic response rates.

      What then are the current goals of antiviral therapy in patients with
      chronic hepatitis C? Immediate
      goals are eradication of viral replication and improvement in hepatic
      inflammation and fibrosis.
      Long-term potential goals include prevention of cirrhosis,
      hepatocellular carcinoma, and liver
      failure.

      Interferon Monotherapy

      IFN-alfa 2 was the first agent approved for the treatment of chronic
      HCV. Since the initial trials
      establishing its efficacy, data regarding treatment duration and dose
      have evolved. Currently, 2
      forms of IFN-alfa that differ by a single amino acid residue are
      approved for treatment of chronic
      HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
      IFN-alfa 2a
      (Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
      million units 3 times each
      week for up to 12 months.

      When used alone in monotherapy, the alfa interferons have similar
      efficacies, with SRs of only 10%
      to 20%, with the modestly higher response rates associated with more
      prolonged therapy.
      Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
      between 8% and 20% in
      treatment-naive patients. High-dose IFN-alfa has also been studied in
      NRs and relapsers, but with
      mixed results. With prior NR, SRs achieved with higher doses are only
      between 0% and 4%. In
      relapsers, SRs range from 20% to 40%. However, side effects are more
      troublesome with higher
      doses.[8]

      Because of the low overall response rate to standard IFN-alfa, more
      recent studies have focused
      on newer regimens, including synthetic IFN (IFN alfacon-1),
      "combination" therapy (IFN-alfa 2b
      + ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
      pretherapy predictors
      of NR have been identified, notably HCV genotype 1, the presence of
      cirrhosis, and higher viral
      load.[9] In addition, patient's race appears to affect response to IFN,
      with African Americans
      having an overall low SR to therapy.[10]

      Combination Therapy

      A significant improvement in SR resulted from the addition of ribavirin
      to standard IFN-alfa.
      Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
      for chronic HCV because
      of its antiviral activity against other RNA viruses.[11-13] Although as
      monotherapy it reduces ALT
      levels, it does not appear to have a direct antiviral effect and fails
      to lower serum HCV RNA
      levels. Moreover, results of most studies with ribavirin have found no
      improvement in hepatic
      histology, although a longer 2-year treatment regimen was shown to
      reduce necroinflammatory
      activity.[13]

      However, in combination with IFN-alfa 2b, ribavirin leads to a
      significant increase in SR in
      treatment-naive patients.[14] SRs of 31% with 24 weeks and 38% with 48
      weeks of combination
      therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
      monotherapy.[14] In
      relapsers, enhanced SR rates also occur on retreatment using combination
      therapy, from 30% to
      49%; in prior NRs, SR of 14% has been reported with 6 months of
      combination therapy.[15,16]

      Histologic improvement was more common among treatment-naive patients
      treated with
      combination therapy.[14] Similar improvement was found in a randomized
      controlled trial of
      treatment-relapse patients.[15]

      However, the improved SR rates observed with combination therapy are
      also associated with
      more expense and an increased frequency of adverse effects compared with
      IFN-alfa
      monotherapy.[14] Dose-related hemolytic anemia is a particular concern
      with ribavirin[11,13] as is
      teratogenicity, based on animal studies.[16] The mean drop in hemoglobin
      in patients treated with
      combination therapy is between 2 and 3 g/dL, although a fall of more
      than 4 g/dL has been
      observed in about 10% of patients. The anemia may be poorly tolerated in
      patients with ischemic
      heart disease in particular as treatment is extended to older
      patients.[17] Accumulation of ribavirin
      metabolites that are not cleared by dialysis occurs in end-stage renal
      disease.(18)

      Consensus Interferon

      Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
      a genetically
      engineered compound synthesized by combining the most common amino acid
      sequences from
      naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
      and 30% with
      IFN-beta. Although it has greater cytokine induction, antiviral,
      antiproliferative, natural killer cell,
      and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
      an equal mass basis, initial
      studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
      with chronic hepatitis C
      resulted in viral response rates similar to those achieved with standard
      IFN-alfa monotherapy.[19,20]

      More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
      reported to result in
      virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48
      weeks.[21]

      Pegylated Interferon

      Pharmacokinetic studies have provided a rationale for enhanced IFN
      dosing. The initial decline in
      serum HCV RNA levels seen after a single dose of IFN therapy is believed
      to reflect a direct
      antiviral effect, whereas the subsequent and more delayed decline in HCV
      RNA levels is due to
      destruction of infected hepatocytes.[22] An important limitation of the
      antiviral effect of standard
      IFN dosing is the rapid decline in circulating drug level with
      thrice-weekly administration. The short
      half-life of the drug and the rapid production of HCV virions diminish
      the efficacy of standard IFN
      therapy. In an effort to achieve more stable and efficacious IFN
      activity, pegylated formulations
      have been developed.

      The production of a pegylated IFN involves the addition of a nontoxic
      long-acting formulation of
      interferon using the drug delivery system of pegylation. Polyethylene
      glycol molecules are added to
      IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
      Schering-Plough).
      Pegylation is already used in the delivery of other drugs. Its
      attachment to IFN-alfa permits
      once-weekly dosing.

      In a recent report, Zeuzem and colleagues[23] indicate that at week 72,
      the SR was 39% after 48
      weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
      compared with a 19% SR in
      control patients. Drug discontinuation in these treatment-naive patients
      and frequency of dose
      reduction were similar in the 2 treatment arms. Heathcote and
      colleagues[24] have also reported on
      the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
      patients. SR was 30% following 48
      weeks of therapy with 180 mcg, compared with 8% for patients treated
      with standard alfa IFN,
      again without a significant increase in side effects with the pegylated
      product.

      Trepo and colleagues[25] have also reported, in abstract form, initial
      studies with pegylated IFN-alfa
      2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
      weekly for 48 weeks) was
      12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
      with 0.5 mcg/kg,
      1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
      treatment-naive patients.

      As with standard IFN-alfa monotherapy, ribavirin may augment response
      rates when combined
      with the pegylated IFNs.[26,27] Recent trials will help evaluate further
      the role of ribavirin in
      augmenting the efficacy of pegylated IFN (see Figure).



      Figure. Initial antiviral therapy against hepatitis C virus.*
      * Abbreviations: IFN = interferon; CSN = consensus interferon;
      IFN/RIB =
      interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
      pegylated interferon +
      ribavirin.

      Future Trends

      There has been continued interest in developing non-IFN-based therapies
      for HCV despite the
      promise of the pegylated IFNs. A recent study examined the role of human
      interleukin-10 in
      treating prior NRs with chronic HCV.[28] Although, HCV RNA remained
      detectable in all patients
      at the end of treatment,[25] 5 (23%) of the 22 treated patients had
      persistent ALT normalization at
      the end of follow-up. Future studies should determine whether combining
      interleukin-10 with other
      antiviral agents will increase efficacy in this setting. Interleukin-12
      has also been evaluated as
      monotherapy, again without clear antiviral benefit.[29]

      There is also increasing enthusiasm for targeting HCV molecular
      products. For example, ribozyme
      gene therapy has the potential to accurately degrade HCV RNA.[30] Human
      studies are anticipated.

      Conclusion

      Treatment options for HCV infection continue to expand. Whereas SRs of
      10% were achieved
      with IFN monotherapy only several years ago, it may soon be possible to
      achieve SR rates greater
      than 50% with combination pegylated IFN and ribavirin. Molecular-based,
      specific therapeutic
      strategies are also likely to become a reality in the future, although
      therapy will remain
      interferon-based the next several years.

      Table. Response (HCV RNA/ALT*) to Antiviral Therapy

      Type of Response†
      During
      Treatment
      End of
      Treatment
      6 Months After
      Treatment
      Completed
      End-of-Treatment
      Negative
      Negative

      Sustained
      Negative
      Negative
      Negative
      Relapse
      Negative
      Negative
      Positive
      Nonresponder
      Positive
      Positive
      Positive


      * HCV RNA measured by polymerase chain reaction; ALT = alanine
      aminotransferase; HCV = hepatitis C virus.
      † Positive denotes HCV RNA present in the serum by polymerase chain
      reaction and
      abnormal alanine aminotransferase values. Negative denotes no serum
      HCV RNA by
      polymerase chain reaction and normal alanine aminotransferase
      values.

      References

      1.Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of
      hepatitis C virus
      infection in the United States, 1988 through 1994. N Engl J Med.
      1999;341:556-562.
      2.Centers for Disease Control and Prevention Web site. Available at
      www.cdc.gov.
      Accessed February 1, 2000.
      3.Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic
      non-A, non-B hepatitis
      with recombinant human alpha interferon. A preliminary report. N
      Engl J Med.
      1986;315:1575-1578.
      4.Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant
      interferon alfa therapy for
      chronic hepatitis C. A randomized, double-blind, placebo-controlled
      trial. N Engl J Med.
      1989;321:1506-1510.
      5.Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic
      hepatitis C with recombinant
      interferon alfa. A multicenter randomized, controlled trial.
      Hepatitis Interventional Therapy
      Group. N Engl J Med. 1989;321:1501-1506.
      6.Marcellin P, Boyer N, Gervais A, et al. Long-term histologic
      improvement and loss of
      detectable intrahepatic HCV RNA in patients with chronic hepatitis
      C and sustained
      response to interferon-alpha therapy. Ann Intern Med.
      1997;127:875-881.
      7.Everson GT, Jensen DM, Craig JR, et al. Efficacy of interferon
      treatment for patients with
      chronic hepatitis C: comparison of response in cirrhotics,
      fibrotics, or nonfibrotics.
      Hepatology. 1999;30:271-276.
      8.Iino S. High dose interferon treatment in chronic hepatitis C. Gut.
      1993;34:114S-118S.
      9.Davis GL, Lau JY. Factors predictive of a beneficial response to
      therapy of hepatitis C.
      Hepatology. 1997;26:122S-127S.
      10.Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in
      responses to therapy with
      interferon in chronic hepatitis C. Consensus Interferon Study
      Group. Hepatology.
      1999;30:787-793.
      11.Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for
      patients with chronic hepatitis
      C: results of a placebo-controlled study. J Hepatol.
      1996;25:591-598.
      12.Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and
      efficacy of oral ribavirin
      treatment of chronic hepatitis C: a multicenter trial. Hepatology.
      1997;26:473-477.
      13.Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as
      therapy for chronic
      hepatitis C. A randomized, double-blind, placebo-controlled trial.
      Ann Intern Med.
      1995;123:897-903.
      14.McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b
      alone or in combination
      with ribavirin as initial treatment for chronic hepatitis C.
      Hepatitis Interventional Therapy
      Group. N Engl J Med. 1998;339:1485-1492.
      15.Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone
      or in combination with
      ribavirin for the treatment of relapse of chronic hepatitis C.
      International Hepatitis
      Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.
      16.Barbaro G, Di Lorenzo G, Belloni G, et al. Interferon alpha-2B and
      ribavirin in combination
      for patients with chronic hepatitis C who failed to respond to, or
      relapsed after, interferon
      alpha therapy: a randomized trial. Am J Med. 1999;107:112-118.
      17.Lyons M, Coddou A, Varon C, et al. Side effect profile of
      combination with interferon
      alpha-2b and ribavirin in a community-based clinical trial.
      Gastroenterology. 1999;116:A77.
      18.Glue P, Tan Y, Sacks M, et al. Use of ribavirin in patients with
      renal and hepatic dysfunction
      -- pharmacokinetic data and recommendations. Hepatology.
      1999;30:309A.
      19.Ozes ON, Reiter Z, Klein S, et al. A comparison of interferon-Con1
      with natural
      recombinant interferons-alpha: antiviral, antiproliferative, and
      natural killer-inducing activities.
      J Interferon Res. 1992;12:55-59.
      20.Klein SB, Blatt LM, Taylor MW. Consensus interferon induces peak
      mRNA accumulation
      at lower concentrations than interferon-alpha 2a. J Interferon Res.
      1993;13:341-347.
      21.Heathcote EJ, Keeffe EB, Lee SS, et al. Re-treatment of chronic
      hepatitis C with consensus
      interferon. Hepatology. 1998;27:1136-1143.
      22.Zeuzem S. Clinical implications of hepatitis C viral kinetics. J
      Hepatol. 1999;31:61S-64S.
      23.Zeuzem S, Feinman SV, Raseneck J, et al. Peginterferon alfa-2a in
      patients with chronic
      hepatitis C. N Engl J Med. 2000;343:1666-1672.
      24.Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon
      alfa-2a in patients with
      chronic hepatitis C and cirrhosis. N Engl J Med.
      2000;343:1673-1680.
      25.Trepo C, Lindsay K, Niederau C, et al. Pegylated interferon alfa-2B
      (PEG-Intron)
      monotherapy is superior to interferon alfa-2B (Intron A) for the
      treatment of chronic
      hepatitis C. J Hepatol. 2000;32:29.
      26.Sulkowski MS, Reindollar R, Yu J. Pegylated interferon alfa-2A
      (PEGASYS) and ribavirin
      combination therapy for chronic hepatitis C: a phase II open-label
      study. Gastroenterology.
      2000;118:A950.
      27.Manns MP, McHutchinson JG, Gordan S, et al. Peginterferon alfa-2b
      plus ribavirin
      compared to interferon alfa-2b plus ribavirin for the treatment of
      chronic hepatitis C: 24
      week treatment analysis of a multicenter, multinational phase III
      randomized controlled trial.
      Hepatology. 2000;32:297A.
      28.Nelson DR, Lauwers GY, Lau JY, et al. Interleukin 10 treatment
      reduces fibrosis in patients
      with chronic hepatitis C: a pilot trial of interferon
      nonresponders. Gastroenterology.
      2000;118:655-660.
      29.Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of
      recombinant human
      interleukin-12 in patients with chronic hepatitis C. Hepatology.
      1999;29:1280-1287.
      30.Welch PJ, Yei S, Barber JR. Ribozyme gene therapy for hepatitis C
      virus infection. Clin
      Diagn Virol. 1998;10:163-171.
    • 2byteme@bellsouth.net
      Hepatology Focus Update on Hepatitis C Treatment Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles,
      Message 106 of 106 , Feb 25, 2001
      • 0 Attachment
        Hepatology Focus
        Update on Hepatitis C Treatment

        Series Editor: Paul Martin, MD, Cedars-Sinai Medical Center, and UCLA
        School of
        Medicine, Los Angeles, California

        Sammy Saab, MD, Clinical Instructor, UCLA School of Medicine, Los
        Angeles, California, and
        Paul Martin, MD, Medical Director, Liver Transplantation, Cedars-Sinai
        Medical Center,
        Associate Professor of Medicine, UCLA School of Medicine, Los Angeles,
        California

        [Medscape Gastroenterology 3(1), 2001. © 2001 Medscape, Inc.]

        Background

        Although screening of blood products and other interventions such as
        clean-needle exchange
        programs have significantly reduced the incidence of acute hepatitis C
        in the United States and
        elsewhere, there remains a large reservoir of chronically infected
        individuals, many of whom are
        unaware of their infection. Current estimates suggest a seroprevalence
        of 1.8% among Americans,
        most of whom are viremic.[1] The clinical burden of chronic hepatitis C
        virus (HCV) infection is
        expected to increase over the next 2-3 decades as a large cohort of
        patients infected between the
        1960s and 1980s, primarily as a result of recreational drug use,
        develops progressive liver disease.
        Between 8000 and 10,000 deaths each year in the United States are
        believed to be caused by
        infection with HCV -- which is now the most frequent indication for
        liver transplantation.[2]

        Even before identification of HCV, interferon-alfa (IFN-alfa) had been
        evaluated as a potential
        therapy for what had been called chronic non-A, non-B hepatitis.[3]

        Further studies using normalization of serum alanine aminotransferase
        (ALT) levels and
        improvement in liver histology as endpoints demonstrated the efficacy of
        IFN-alfa as therapy for
        the causative agent of chronic non-A, non-B hepatitis (HCV).[4,5]
        Subsequent advances in
        molecular diagnosis have now increasingly allowed establishment of
        virologic criteria to evaluate
        efficacy of treatment in patients with chronic hepatitis C (see Table).

        Definition of Virologic Response in Patients Receiving Therapy for
        Chronic Hepatitis C

        End-of-treatment response (ETR) refers to absence of viremia (ie, serum
        HCV RNA below level
        of detection) at completion of therapy. Sustained response (SR)
        indicates persistent absence of
        serum HCV RNA 6 months or more after cessation of therapy. A study by
        Marcellin and
        coworkers[6] on the long-term clinical outcome in 80 patients with
        chronic HCV followed for a
        mean of 4 years following therapy highlighted the clinical implications
        of a virologic SR. Persistent
        absence of HCV RNA from serum was observed in 96% of patients with a
        lack of histologic
        progression on serial liver biopsy. In addition, ALT levels were
        persistently normal in over 90%.
        The most recent follow-up biopsy showed normal or near normal histologic
        findings in 62% of
        these patients. Thus, virologic SR was shown to be associated with both
        an absence of detectable
        serum HCV RNA and marked histologic improvement.

        Relapsers are defined as patients who have undetectable serum HCV RNA at
        completion of
        therapy but who subsequently redevelop viremia. Nonresponders (NRs) are
        patients who fail to
        clear HCV RNA from serum during therapy.

        A recent paper by Everson and associates[7] underscores the importance
        of HCV RNA testing in
        defining treatment response. In patients with marked fibrosis and
        cirrhosis, they found a major
        discrepancy between biochemical (ALT) and virologic (HCV RNA) responses
        to therapy. Two of
        7 (29%) patients with marked fibrosis and 2 of 6 (33%) patients with
        cirrhosis cleared HCV RNA
        without normalizing ALT. In contrast, only 3 patients (10%) without
        significant fibrosis had an
        HCV RNA response without normalization of ALT. Thus, clinical trials for
        chronic HCV are now
        typically reported using virologic response rates.

        What then are the current goals of antiviral therapy in patients with
        chronic hepatitis C? Immediate
        goals are eradication of viral replication and improvement in hepatic
        inflammation and fibrosis.
        Long-term potential goals include prevention of cirrhosis,
        hepatocellular carcinoma, and liver
        failure.

        Interferon Monotherapy

        IFN-alfa 2 was the first agent approved for the treatment of chronic
        HCV. Since the initial trials
        establishing its efficacy, data regarding treatment duration and dose
        have evolved. Currently, 2
        forms of IFN-alfa that differ by a single amino acid residue are
        approved for treatment of chronic
        HCV infection: IFN-alfa 2b (Schering-Plough, Kenilworth, New Jersey) and
        IFN-alfa 2a
        (Hoffmann-La Roche, Basel, Switzerland). The recommended dose is 3
        million units 3 times each
        week for up to 12 months.

        When used alone in monotherapy, the alfa interferons have similar
        efficacies, with SRs of only 10%
        to 20%, with the modestly higher response rates associated with more
        prolonged therapy.
        Higher-dose IFN-alfa (ie, > 9 million units per week) results in SRs
        between 8% and 20% in
        treatment-naive patients. High-dose IFN-alfa has also been studied in
        NRs and relapsers, but with
        mixed results. With prior NR, SRs achieved with higher doses are only
        between 0% and 4%. In
        relapsers, SRs range from 20% to 40%. However, side effects are more
        troublesome with higher
        doses.[8]

        Because of the low overall response rate to standard IFN-alfa, more
        recent studies have focused
        on newer regimens, including synthetic IFN (IFN alfacon-1),
        "combination" therapy (IFN-alfa 2b
        + ribavirin), and longer-acting IFNs (pegylated IFNs). A number of major
        pretherapy predictors
        of NR have been identified, notably HCV genotype 1, the presence of
        cirrhosis, and higher viral
        load.[9] In addition, patient's race appears to affect response to IFN,
        with African Americans
        having an overall low SR to therapy.[10]

        Combination Therapy

        A significant improvement in SR resulted from the addition of ribavirin
        to standard IFN-alfa.
        Ribavirin, a guanosine analogue, was initially evaluated as monotherapy
        for chronic HCV because
        of its antiviral activity against other RNA viruses.[11-13] Although as
        monotherapy it reduces ALT
        levels, it does not appear to have a direct antiviral effect and fails
        to lower serum HCV RNA
        levels. Moreover, results of most studies with ribavirin have found no
        improvement in hepatic
        histology, although a longer 2-year treatment regimen was shown to
        reduce necroinflammatory
        activity.[13]

        However, in combination with IFN-alfa 2b, ribavirin leads to a
        significant increase in SR in
        treatment-naive patients.[14] SRs of 31% with 24 weeks and 38% with 48
        weeks of combination
        therapy were achieved vs 6% with 24 weeks and 13% with 48 weeks of IFN
        monotherapy.[14] In
        relapsers, enhanced SR rates also occur on retreatment using combination
        therapy, from 30% to
        49%; in prior NRs, SR of 14% has been reported with 6 months of
        combination therapy.[15,16]

        Histologic improvement was more common among treatment-naive patients
        treated with
        combination therapy.[14] Similar improvement was found in a randomized
        controlled trial of
        treatment-relapse patients.[15]

        However, the improved SR rates observed with combination therapy are
        also associated with
        more expense and an increased frequency of adverse effects compared with
        IFN-alfa
        monotherapy.[14] Dose-related hemolytic anemia is a particular concern
        with ribavirin[11,13] as is
        teratogenicity, based on animal studies.[16] The mean drop in hemoglobin
        in patients treated with
        combination therapy is between 2 and 3 g/dL, although a fall of more
        than 4 g/dL has been
        observed in about 10% of patients. The anemia may be poorly tolerated in
        patients with ischemic
        heart disease in particular as treatment is extended to older
        patients.[17] Accumulation of ribavirin
        metabolites that are not cleared by dialysis occurs in end-stage renal
        disease.(18)

        Consensus Interferon

        Consensus IFN (CIFN; IFN alfacon-1, Amgen, Thousand Oaks, California) is
        a genetically
        engineered compound synthesized by combining the most common amino acid
        sequences from
        naturally occurring IFNs.[19,20] CIFN shares 88% homology with IFN-alfa
        and 30% with
        IFN-beta. Although it has greater cytokine induction, antiviral,
        antiproliferative, natural killer cell,
        and gene-induction activities than both IFN-alfa 2a and IFN-alfa 2b on
        an equal mass basis, initial
        studies with the recommended CIFN dose of 9 mcg in IFN-naive patients
        with chronic hepatitis C
        resulted in viral response rates similar to those achieved with standard
        IFN-alfa monotherapy.[19,20]

        More recently, higher-dosage CIFN regimens of 15 mcg thrice weekly were
        reported to result in
        virologic SRs of 13% in prior NRs and 58% in relapsers treated for 48
        weeks.[21]

        Pegylated Interferon

        Pharmacokinetic studies have provided a rationale for enhanced IFN
        dosing. The initial decline in
        serum HCV RNA levels seen after a single dose of IFN therapy is believed
        to reflect a direct
        antiviral effect, whereas the subsequent and more delayed decline in HCV
        RNA levels is due to
        destruction of infected hepatocytes.[22] An important limitation of the
        antiviral effect of standard
        IFN dosing is the rapid decline in circulating drug level with
        thrice-weekly administration. The short
        half-life of the drug and the rapid production of HCV virions diminish
        the efficacy of standard IFN
        therapy. In an effort to achieve more stable and efficacious IFN
        activity, pegylated formulations
        have been developed.

        The production of a pegylated IFN involves the addition of a nontoxic
        long-acting formulation of
        interferon using the drug delivery system of pegylation. Polyethylene
        glycol molecules are added to
        IFN-alfa 2a (Pegasys, Hoffmann-La Roche) and IFN-alfa 2b (PEG-Intron,
        Schering-Plough).
        Pegylation is already used in the delivery of other drugs. Its
        attachment to IFN-alfa permits
        once-weekly dosing.

        In a recent report, Zeuzem and colleagues[23] indicate that at week 72,
        the SR was 39% after 48
        weeks of therapy at a dose of 180 mcg with pegylated IFN alfa-2a
        compared with a 19% SR in
        control patients. Drug discontinuation in these treatment-naive patients
        and frequency of dose
        reduction were similar in the 2 treatment arms. Heathcote and
        colleagues[24] have also reported on
        the use of pegylated IFN alfa-2a in a controlled trial in cirrhotic
        patients. SR was 30% following 48
        weeks of therapy with 180 mcg, compared with 8% for patients treated
        with standard alfa IFN,
        again without a significant increase in side effects with the pegylated
        product.

        Trepo and colleagues[25] have also reported, in abstract form, initial
        studies with pegylated IFN-alfa
        2b. Virologic SR for the unmodified IFN-alfa 2b (3 million units, thrice
        weekly for 48 weeks) was
        12%, whereas the SR for the pegylated IFN-alfa 2b was 18%, 25%, and 23%
        with 0.5 mcg/kg,
        1.0 mcg/kg, and 1.5 mcg/kg, respectively, administered weekly in
        treatment-naive patients.

        As with standard IFN-alfa monotherapy, ribavirin may augment response
        rates when combined
        with the pegylated IFNs.[26,27] Recent trials will help evaluate further
        the role of ribavirin in
        augmenting the efficacy of pegylated IFN (see Figure).



        Figure. Initial antiviral therapy against hepatitis C virus.*
        * Abbreviations: IFN = interferon; CSN = consensus interferon;
        IFN/RIB =
        interferon + ribavirin; PEG = pegylated interferon; PEG/RIB =
        pegylated interferon +
        ribavirin.

        Future Trends

        There has been continued interest in developing non-IFN-based therapies
        for HCV despite the
        promise of the pegylated IFNs. A recent study examined the role of human
        interleukin-10 in
        treating prior NRs with chronic HCV.[28] Although, HCV RNA remained
        detectable in all patients
        at the end of treatment,[25] 5 (23%) of the 22 treated patients had
        persistent ALT normalization at
        the end of follow-up. Future studies should determine whether combining
        interleukin-10 with other
        antiviral agents will increase efficacy in this setting. Interleukin-12
        has also been evaluated as
        monotherapy, again without clear antiviral benefit.[29]

        There is also increasing enthusiasm for targeting HCV molecular
        products. For example, ribozyme
        gene therapy has the potential to accurately degrade HCV RNA.[30] Human
        studies are anticipated.

        Conclusion

        Treatment options for HCV infection continue to expand. Whereas SRs of
        10% were achieved
        with IFN monotherapy only several years ago, it may soon be possible to
        achieve SR rates greater
        than 50% with combination pegylated IFN and ribavirin. Molecular-based,
        specific therapeutic
        strategies are also likely to become a reality in the future, although
        therapy will remain
        interferon-based the next several years.

        Table. Response (HCV RNA/ALT*) to Antiviral Therapy

        Type of Response†
        During
        Treatment
        End of
        Treatment
        6 Months After
        Treatment
        Completed
        End-of-Treatment
        Negative
        Negative

        Sustained
        Negative
        Negative
        Negative
        Relapse
        Negative
        Negative
        Positive
        Nonresponder
        Positive
        Positive
        Positive


        * HCV RNA measured by polymerase chain reaction; ALT = alanine
        aminotransferase; HCV = hepatitis C virus.
        † Positive denotes HCV RNA present in the serum by polymerase chain
        reaction and
        abnormal alanine aminotransferase values. Negative denotes no serum
        HCV RNA by
        polymerase chain reaction and normal alanine aminotransferase
        values.

        References

        1.Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of
        hepatitis C virus
        infection in the United States, 1988 through 1994. N Engl J Med.
        1999;341:556-562.
        2.Centers for Disease Control and Prevention Web site. Available at
        www.cdc.gov.
        Accessed February 1, 2000.
        3.Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic
        non-A, non-B hepatitis
        with recombinant human alpha interferon. A preliminary report. N
        Engl J Med.
        1986;315:1575-1578.
        4.Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant
        interferon alfa therapy for
        chronic hepatitis C. A randomized, double-blind, placebo-controlled
        trial. N Engl J Med.
        1989;321:1506-1510.
        5.Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic
        hepatitis C with recombinant
        interferon alfa. A multicenter randomized, controlled trial.
        Hepatitis Interventional Therapy
        Group. N Engl J Med. 1989;321:1501-1506.
        6.Marcellin P, Boyer N, Gervais A, et al. Long-term histologic
        improvement and loss of
        detectable intrahepatic HCV RNA in patients with chronic hepatitis
        C and sustained
        response to interferon-alpha therapy. Ann Intern Med.
        1997;127:875-881.
        7.Everson GT, Jensen DM, Craig JR, et al. Efficacy of interferon
        treatment for patients with
        chronic hepatitis C: comparison of response in cirrhotics,
        fibrotics, or nonfibrotics.
        Hepatology. 1999;30:271-276.
        8.Iino S. High dose interferon treatment in chronic hepatitis C. Gut.
        1993;34:114S-118S.
        9.Davis GL, Lau JY. Factors predictive of a beneficial response to
        therapy of hepatitis C.
        Hepatology. 1997;26:122S-127S.
        10.Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in
        responses to therapy with
        interferon in chronic hepatitis C. Consensus Interferon Study
        Group. Hepatology.
        1999;30:787-793.
        11.Dusheiko G, Main J, Thomas H, et al. Ribavirin treatment for
        patients with chronic hepatitis
        C: results of a placebo-controlled study. J Hepatol.
        1996;25:591-598.
        12.Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and
        efficacy of oral ribavirin
        treatment of chronic hepatitis C: a multicenter trial. Hepatology.
        1997;26:473-477.
        13.Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as
        therapy for chronic
        hepatitis C. A randomized, double-blind, placebo-controlled trial.
        Ann Intern Med.
        1995;123:897-903.
        14.McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b
        alone or in combination
        with ribavirin as initial treatment for chronic hepatitis C.
        Hepatitis Interventional Therapy
        Group. N Engl J Med. 1998;339:1485-1492.
        15.Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone
        or in combination with
        ribavirin for the treatment of relapse of chronic hepatitis C.
        International Hepatitis
        Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.
        16.Barbaro G, Di Lorenzo G, Belloni G, et al. Interferon alpha-2B and
        ribavirin in combination
        for patients with chronic hepatitis C who failed to respond to, or
        relapsed after, interferon
        alpha therapy: a randomized trial. Am J Med. 1999;107:112-118.
        17.Lyons M, Coddou A, Varon C, et al. Side effect profile of
        combination with interferon
        alpha-2b and ribavirin in a community-based clinical trial.
        Gastroenterology. 1999;116:A77.
        18.Glue P, Tan Y, Sacks M, et al. Use of ribavirin in patients with
        renal and hepatic dysfunction
        -- pharmacokinetic data and recommendations. Hepatology.
        1999;30:309A.
        19.Ozes ON, Reiter Z, Klein S, et al. A comparison of interferon-Con1
        with natural
        recombinant interferons-alpha: antiviral, antiproliferative, and
        natural killer-inducing activities.
        J Interferon Res. 1992;12:55-59.
        20.Klein SB, Blatt LM, Taylor MW. Consensus interferon induces peak
        mRNA accumulation
        at lower concentrations than interferon-alpha 2a. J Interferon Res.
        1993;13:341-347.
        21.Heathcote EJ, Keeffe EB, Lee SS, et al. Re-treatment of chronic
        hepatitis C with consensus
        interferon. Hepatology. 1998;27:1136-1143.
        22.Zeuzem S. Clinical implications of hepatitis C viral kinetics. J
        Hepatol. 1999;31:61S-64S.
        23.Zeuzem S, Feinman SV, Raseneck J, et al. Peginterferon alfa-2a in
        patients with chronic
        hepatitis C. N Engl J Med. 2000;343:1666-1672.
        24.Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon
        alfa-2a in patients with
        chronic hepatitis C and cirrhosis. N Engl J Med.
        2000;343:1673-1680.
        25.Trepo C, Lindsay K, Niederau C, et al. Pegylated interferon alfa-2B
        (PEG-Intron)
        monotherapy is superior to interferon alfa-2B (Intron A) for the
        treatment of chronic
        hepatitis C. J Hepatol. 2000;32:29.
        26.Sulkowski MS, Reindollar R, Yu J. Pegylated interferon alfa-2A
        (PEGASYS) and ribavirin
        combination therapy for chronic hepatitis C: a phase II open-label
        study. Gastroenterology.
        2000;118:A950.
        27.Manns MP, McHutchinson JG, Gordan S, et al. Peginterferon alfa-2b
        plus ribavirin
        compared to interferon alfa-2b plus ribavirin for the treatment of
        chronic hepatitis C: 24
        week treatment analysis of a multicenter, multinational phase III
        randomized controlled trial.
        Hepatology. 2000;32:297A.
        28.Nelson DR, Lauwers GY, Lau JY, et al. Interleukin 10 treatment
        reduces fibrosis in patients
        with chronic hepatitis C: a pilot trial of interferon
        nonresponders. Gastroenterology.
        2000;118:655-660.
        29.Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of
        recombinant human
        interleukin-12 in patients with chronic hepatitis C. Hepatology.
        1999;29:1280-1287.
        30.Welch PJ, Yei S, Barber JR. Ribozyme gene therapy for hepatitis C
        virus infection. Clin
        Diagn Virol. 1998;10:163-171.
      Your message has been successfully submitted and would be delivered to recipients shortly.