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Conquering Hepatitis C, Step by Step

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  • claudine intexas
    The New England Journal of Medicine -- December 7, 2000 -- Vol. 343, No. 23 Conquering Hepatitis C, Step by Step ... -- Hepatitis C virus (HCV) infection is
    Message 1 of 1 , Dec 7, 2000
      The New England Journal of Medicine -- December 7,
      2000 -- Vol. 343, No. 23

      Conquering Hepatitis C, Step by Step


      Hepatitis C virus (HCV) infection is the most common
      chronic blood-borne
      infection in the United States. (1) In most of the
      estimated 2.7 million
      people who have the infection it has not been
      diagnosed, and most of those
      with a diagnosed infection have not been treated.
      Because the best current
      medical therapy is expensive, complex, relatively
      ineffective, and fraught
      with side effects, many physicians are understandably
      reluctant to offer it
      to their patients. Without a highly effective therapy,
      the condition of
      patients with hepatitis C continues to deteriorate
      until complications of
      cirrhosis develop. The infection progresses to
      end-stage liver disease in
      only a small percentage of patients; nevertheless, a
      small percentage of a
      large number is still a large number. HCV-related
      disease is now the leading
      indication for liver transplantation. Unfortunately,
      transplantation does not
      cure the infection. Recurrence is universal.
      Interferon alfa has been the basis of all effective
      regimens against HCV
      since the discovery of the virus. In fact, interferon
      alfa was found to be
      active against chronic hepatitis C in a trial
      conducted before the virus was
      identified. (2) This trial was performed in patients
      with post-transfusion
      hepatitis, a common disease in the late 1980s that
      turned out -- after the
      virus was discovered -- to be largely caused by HCV.
      During the past 10
      years, investigators have focused on optimizing the
      doses used and the length
      of therapy and on testing combinations of interferon
      alfa with other drugs.
      Ribavirin, a drug that has little or no activity
      against HCV when used alone,
      doubles the effectiveness of interferon alfa when
      added to it. Combination
      therapy with interferon alfa and ribavirin is now
      considered the treatment of
      choice for chronic hepatitis C. (3) Even this therapy
      is none too good,
      however: more than half the patients who receive
      treatment will continue to
      have viremia once treatment is stopped.

      The complex and shifting balance between host and
      virus has driven
      hepatologists to adopt the language of oncologists.
      Instead of "cure," we
      have "response" (loss of measurable levels of virus in
      the blood during
      therapy) and "sustained response" (loss of measurable
      levels of virus 24
      weeks after the completion of therapy). Clinical
      trials focus on a variety of
      end points, including biochemical, virologic, and
      histologic responses. This
      cautious terminology is necessary for a disease with a
      variable natural
      history and a rate of progression that is measured in

      Two reports on the treatment of chronic hepatitis C
      appear in this issue of
      the Journal. In one, Zeuzem et al. (4) report that a
      new formulation of
      interferon alfa, called peginterferon alfa-2a, offers
      significantly better
      results than the standard formulation. Peginterferon
      alfa-2a is produced by
      the addition of a polyethylene glycol molecule to
      standard interferon alfa-2a
      and results in substantial changes in the metabolism
      of the drug, with
      prolongation of its half-life such that only one dose
      per week is required to
      maintain effective levels in the blood. This sustained
      action reduces the
      viral replication that occurs on days without
      treatment during the standard
      thrice-weekly regimen of unmodified interferon alfa.
      (5) In the study by
      Zeuzem et al., the incidence of adverse effects
      (including headache, fatigue,
      myalgia, depression, neutropenia, and
      thrombocytopenia) in patients receiving
      peginterferon alfa-2a was similar to that in patients
      receiving standard
      interferon alfa-2a; such adverse effects prompted
      discontinuation of therapy
      in 10 percent or fewer of the patients in each
      treatment group. The rate of
      sustained virologic response in the patients receiving
      peginterferon alfa-2a
      was 39 percent, a figure similar to that reported in
      patients treated with a
      combination of standard interferon alfa and ribavirin.

      In the second report in this issue, Heathcote et al.
      (6) describe a subgroup
      of patients whose condition is difficult to treat:
      those with compensated
      cirrhosis or extensive fibrosis. Patients whose
      neutrophil count was below
      1500 per cubic millimeter or whose platelet count was
      below 75,000 per cubic
      millimeter were excluded from the trial. Patients with
      cirrhosis often have
      many problems that are made worse by interferon
      therapy, including fatigue,
      depression, thrombocytopenia, and neutropenia. Still,
      therapy with
      peginterferon alfa-2a was remarkably well tolerated.
      No patient in either of
      the two groups treated with peginterferon alfa-2a (90
      �g or 180 �g once
      weekly) or in the group treated with interferon
      alfa-2a discontinued therapy
      because of neutropenia, and about 3 percent
      discontinued it because of
      thrombocytopenia; overall, about 10 percent of the
      patients discontinued
      therapy because of adverse effects. Thirty percent of
      the patients treated
      with 180 �g of peginterferon alfa-2a per week had a
      sustained virologic
      response, and 54 percent had a histologic response.

      These reports suggest that the treatment of hepatitis
      C may be extended in
      two ways. Zeuzem et al. document the increased
      likelihood of a response in a
      group of patients already targeted for therapy.
      Heathcote et al. broaden the
      definition of patients who should or could receive
      therapy. Treatment with
      peginterferon alfa-2a in combination with ribavirin is
      the next obvious step
      in the treatment of chronic HCV infection. Studies of
      safety have been
      published, (7) and phase 3 trials are under way.

      One encouraging point and two cautionary points can be
      made. On an
      encouraging note, patients who do not have a
      biochemical or virologic
      response may still have a histologic response,
      indicated by a lessening of
      the inflammation in the liver. This effect may be
      related to the observation
      that hepatocellular cancer may be less likely to
      develop in patients who have
      been treated with interferon, even if they continue to
      carry the virus. (8)
      On the cautionary side, physicians may not be able to
      achieve the overall
      results obtained in the two current trials.
      Seventy-five percent of infected
      persons in the United States carry a variant of HCV
      (genotype 1) that is more
      resistant than other viral genotypes to interferon
      alfa therapy. Sixty-two
      percent (4) and 56 percent (6) of the patients in
      these two trials had
      genotype 1 virus; the 180-�g dose of peginterferon
      alfa-2a produced a
      sustained virologic response in 28 percent and 12
      percent, respectively, of
      these patients. In addition, black patients were
      underrepresented in these
      trials, relative to the proportion of patients with
      this infection in the
      United States who are black. Black patients may have a
      lower rate of response
      to current therapies than patients from other racial
      and ethnic groups.

      In summary, progress against HCV infection has been
      important and is
      continuing. The Albert Lasker awards for clinical
      medical research were given
      this year to two pioneers in the field: Michael
      Houghton, for his discovery
      of the virus, and Harvey Alter, for his role in
      eliminating post-transfusion
      hepatitis. (11) Approval of peginterferon is pending
      in the United States.
      Trials of other drugs are currently under way. As with
      other diseases,
      prevention is the best strategy. The prevention of
      chronic HCV infection must
      take several forms. Medically related transmission has
      been dramatically
      reduced by the screening of blood and blood products.
      Parenteral transmission
      among drug users is currently the most common mode of
      transmission of HCV in
      the United States and must be approached through
      behavioral change. An
      effective vaccine is not an immediate prospect for
      this genetically mutable
      RNA virus. Finally, HCV infection has further
      increased the demand for organs
      used in liver transplantation, especially since
      patients with recurrent
      disease may need a second transplantation.

      The AIDS epidemic has taught us that there are ways of
      expediting the
      translation of scientific progress into improved
      clinical practice. We must
      foster a similar sense of urgency and concern with
      respect to hepatitis C.

      Daniel F. Schafer, M.D.
      Michael F. Sorrell, M.D.
      University of Nebraska Medical Center
      Omaha, NE 68198


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