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Hepatology Focus - Update on Hepatitis C Treatment

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      --------------------------------------------------------------------------------

      Hepatology Focus
      Update on Hepatitis C Treatment

      Series Editor: Paul Martin, MD, Cedars-Sinai Medical
      Center, and 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.
      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


      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.

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