Conquering Hepatitis C, Step by Step
    
Daniel F. Schafer, M.D., Michael F. Sorrell, M.D.(University of Nebraska Medical Center, Omaha, NE 68198) for The New England Journal of Medicine -- December 7, 2000 -- Vol. 343, No. 23

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States.  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.  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. 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 decades.

Two reports on the treatment of chronic hepatitis C appear in this issue of the Journal. In one, Zeuzem et al. 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.  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. 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,  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. 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  and 56 percent  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. 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.