Combination Therapy for Hepatitis C Infection


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About 4 million people in the United States and probably more than 100 million people worldwide are infected with the hepatitis C virus (HCV). (1) The majority have no symptoms, although they can transmit this blood-borne virus to others. People who have been infected for decades may first come to medical attention because of complications related to advanced liver disease. Ironically, the public health implications of HCV infection have only recently been widely appreciated, as a result of epidemiologic studies that pointed out the magnitude of infection and an alarming increase in morbidity and mortality due to HCV-related disease. In the United States, the rate of death from hepatitis C is increasing and may approach or even surpass the number of deaths from AIDS in the next few years. (1,2) This change reflects the advent of improved treatments for the human immunodeficiency virus (HIV) and an anticipated increase in the number of people with end-stage liver disease as a result of chronic hepatitis C. Recent studies of the natural history of HCV infection indicate that the majority of people with chronic infection have relatively mild disease with slow progression, and many of them will probably die with the infection rather than of it. (3) Nonetheless, the proportion of people with more serious liver disease -- that is, those who require medical treatment -- is expected to increase.

Currently, treatment is recommended for patients with persistently elevated aminotransferase concentrations, HCV viremia, and findings of fibrosis and moderate inflammation on liver biopsy. (4) For other groups of patients, the indications for treatment are less clear and decisions should be made on an individual basis.

Even before the virus was identified, treatment for what was then known as non-A, non-B hepatitis relied on the antiviral effects of interferon. Treatment with the standard dose of interferon alfa (3 million U three times a week for 12 months) normalizes aminotransferase concentrations and leads to the disappearance of HCV RNA from serum in approximately 40 percent of patients with chronic hepatitis C. (5) However, this response is transient in the majority of patients; only 10 to 15 percent have a sustained response after treatment is stopped. Although longer duration (18 to 24 months) of treatment, higher doses of interferon alfa (up to 30 million U per week), and treatment with other types of interferon may improve the response, many patients still relapse. Moreover, these alternatives are costly or poorly tolerated. (6,7,8)

Two studies in this issue of the Journal address the role of interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis C. McHutchison et al. (9) studied the effect of this combination as an initial treatment, and Davis et al. (10) as a treatment after relapse. The findings of both studies indicate that this combination therapy represents an important advance. These large multicenter, randomized, controlled trials expanded on the findings of earlier, small studies that the combination of interferon and ribavirin was more efficacious than interferon alone. (11,12) Both studies reported impressive rates of sustained virologic response, defined as the absence of serum HCV RNA 24 weeks after treatment was completed, with combination therapy. The rate was 31 to 38 percent when combination therapy was used as the initial treatment and 49 percent when it was used for the treatment of relapse. These rates are 5 to 10 times as high as those achieved with monotherapy. The rates of histologic response were similar to the rates of virologic and biochemical response. The factors associated with a response to combination therapy were similar to those that predict a response to treatment with interferon alone: a low viral titer before treatment, an HCV genotype other than 1 (there are at least six genotypes), and the absence of cirrhosis before treatment. (5)

An interesting paradox emerges from these studies. In patients treated with interferon alone, early clearance of the virus (after 4 or 12 weeks of treatment) has been associated with a sustained virologic response. (13,14) Davis et al. also found this to be true with the use of interferon and ribavirin for the treatment of relapse. In contrast, McHutchison et al. reported that in at least 50 percent of patients with a sustained response after initial treatment with interferon and ribavirin for either 24 or 48 weeks, HCV RNA was not cleared from serum until after week 12 or 24 of therapy. Surprisingly, there was also no significant association between early viral clearance and a sustained virologic response among patients treated with interferon alone; up to 52 percent of such patients had late viral clearance and a sustained response. Therefore, the recommendation that an early virologic response should be used as a guide to the duration of therapy (4) should be reevaluated.

Why is the combination of interferon and ribavirin much more effective than interferon alone for the treatment of chronic hepatitis C, and what is the mechanism of action? Unfortunately, there are no readily available answers. Ribavirin is a synthetic guanosine analogue with activity against a broad spectrum of DNA and RNA viruses, but its molecular mechanism of action remains unclear. (15) Like other nucleoside analogues, ribavirin may have a direct antiviral effect, but it may also have an immunomodulatory effect. (16) Treatment with ribavirin alone has no effect on serum HCV RNA levels, although it does lead to a transient decrease in aminotransferase concentrations. (17) Therefore, ribavirin may enhance the effect of interferon, leading to a more vigorous immune response against HCV.

The chief and most frequent side effect of ribavirin is hemolytic anemia, which in rare instances can be severe enough to require the discontinuation of treatment. (17) This side effect, in conjunction with the bone marrow suppression that is commonly observed with interferon treatment, excludes as candidates for combination therapy many patients at risk for heart disease. How ribavirin causes hemolytic anemia is not known; therefore, this side effect cannot be predicted or prevented. In addition, ribavirin is teratogenic and must be used with caution in women of childbearing age.

The study by McHutchison et al., as well as other reports, (18) makes a compelling argument for the use of the combination of interferon and ribavirin as the initial treatment for hepatitis C. However, some questions require further study before a clear recommendation can be made. For example, should all patients be treated for 48 weeks, or should the duration of therapy be based on established prognostic factors? McHutchison et al. found that the difference in the overall rates of sustained response between the group treated with 24 weeks of combination therapy and the group treated with 48 weeks was barely significant. The patients who would benefit the most from 48 weeks of therapy are probably those with factors that are associated with a poor response, including HCV genotype 1 and high viral titers and cirrhosis before treatment. In addition, both medications, especially when given in combination for more than 24 weeks, have clinically significant side effects. In the study by McHutchison et al., 21 percent of the patients assigned to combination therapy for 48 weeks discontinued treatment because of severe side effects. Since the studies by McHutchison et al. and Davis et al. were carefully monitored clinical trials in tertiary academic centers and the patients were presumably highly motivated, the use of this combination in routine practice may be associated with a lower rate of efficacy, more severe side effects, and greater noncompliance. Moreover, the promising results of these studies should not alter the current recommendations regarding the initiation of treatment. (4) The role of treatment earlier in the course of HCV infection remains to be established.

It is often the case that for the treatment of viral infections, two antiviral drugs are better than one; HCV infection is no exception. Many other antiviral compounds in addition to interferon and ribavirin may soon be available for the treatment of hepatitis C. Many of these new drugs are likely to be the result of molecular engineering, based on incremental increases in our understanding of the molecular virology and pathogenesis of HCV infection and targeted to specific virally encoded functions. As has been true in the search for the best therapy for HIV infection, it will be a daunting challenge to develop the most effective and least costly combination therapies for HCV infection.

T. Jake Liang, M.D.; National Institutes of Health; Bethesda, MD 20892

SOURCE: The New England Journal of Medicine -- November 19, 1998 -- Volume 339, Number 21

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