Correspondence
Combination Therapy for Hepatitis C Infection
N Engl J Med 1999; 340:1207-1209April 15, 1999
- Article
To the Editor:
Two studies in the November 19 issue, one by McHutchison et al.1 and one by Davis et al.,2 were supported by Schering-Plough and show that combining interferon alfa-2b with ribavirin leads to better virologic and biochemical rates of response in patients with hepatitis C. The cost to the patient of a 48-week course of this drug combination (Rebetron, Schering-Plough, Kenilworth, N.J.) is about $18,000. The side effects of an initial course of treatment are considerable: in the study by McHutchison et al., about two thirds of patients had influenza-like symptoms, and about one third each had nausea, depression, insomnia, and alopecia.1 The only death reported in the two studies was the result of suicide.2
In deciding whether the substantial cost and year-long decrement in the quality of life associated with this treatment are justified by future health benefits, patients, physicians, and payers need to know the extent to which treatment will ultimately affect clinically relevant outcomes, such as survival, liver failure, and liver cancer. A major limitation of the studies that neither the authors nor the editorialist3 mentions is that only short-term and intermediate outcomes were assessed. It is not clear to what extent, if at all, the higher rate of virologic response will translate into lower rates of cirrhosis, liver failure, liver transplantation, or death. Such a determination must be made on an intention-to-treat basis, with mortality rates compared in entire groups of patients who are randomly assigned to various treatments or to no treatment. Any other type of comparison could be biased by a selection effect, in which patients destined to do poorly cannot tolerate or have no response to antiviral drugs, whereas patients whose prognosis is better to begin with are more likely to have a response.
In the absence of evidence that allows us to make unbiased estimates of the efficacy of treatment in terms of global measures of health or mortality, a recommendation for the widespread use of antiviral drugs to treat hepatitis C seems imprudent4 and extravagant.
4 ReferencesThomas B. Newman, M.D., M.P.H.
University of California, San Francisco, San Francisco, CA 94143-05601
McHutchison JG ,Gordon SC ,Schiff ER , et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-1492
Full Text | Web of Science | Medline2
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. N Engl J Med 1998;339:1493-1499
Full Text | Web of Science | Medline3
Liang TJ . Combination therapy for hepatitis C infection. N Engl J Med 1998;339:1549-1550
Full Text | Web of Science | Medline4
Froom J ,Froom P . “Prudence“ in disease prevention. J Clin Epidemiol 1991;44:1127-1130
CrossRef | Web of Science | Medline
To the Editor:
The issue that I fail to see directly addressed by McHutchison et al. and Davis et al. is the effect of this very expensive intervention on any “hard” end point, specifically overall survival or a decrease in the need for transplantation. I am aware that an improvement in biochemical markers reflects an improvement in histologic findings, but have yet to see data supporting the idea that such an approach improves the overall outcome.
The logic that such a relation should exist is reasonable, but as oncologists have learned from studying chronic lymphocytic leukemia, myeloma, and even breast cancer treated with high-dose regimens, what seems to be a logical approach — aggressive and early treatment — does not always translate into any long-term benefit. Until a real benefit of this expensive and toxic therapy is demonstrated, I wonder whether patients should not continue to be treated only in clinical studies and not as a matter of standard practice.
Christina M. Clay, M.D.
741 Millbrook Ln., Haverford, PA 19041Author/Editor Response
The authors reply:
To the Editor: Our studies demonstrate that the combination of interferon alfa-2b and ribavirin is far more likely than interferon alfa-2b alone to lead to a long-term response with no detectable virus when used as initial treatment or after relapse in patients with chronic hepatitis C. A sustained virologic response is the goal of antiviral treatment, since it is not associated with late relapse and is a reliable indicator of the normalization of serum aminotransferase levels and of the reduction of hepatic inflammation, or even its disappearance, on liver biopsy.1 The likelihood of progression to fibrosis and cirrhosis depends on the severity of periportal inflammation. Indeed, a response to combination therapy results in a significant reduction in the rate of hepatic fibrosis and in regression of septal fibrosis in more than half of patients.2
Although we agree with Dr. Clay that it is logical to assume that these short-term benefits would translate into a reduction in morbidity and mortality, clinical trials have not demonstrated that survival is increased or that the rate of hepatic failure and the need for transplantation are reduced, nor would we expect them to do so. In view of the usually slow rate of progression of chronic hepatitis C, a controlled clinical study designed to show such a benefit would require hundreds or perhaps thousands of patients who were followed for many years. Such a study would be impractical, considering the probable development of better therapeutic regimens during the study period. Including a placebo group would probably be unethical, since currently available therapy is capable of eradicating infection in more than a third of patients. Although the duration of the study and enrollment requirements could be reduced by including only patients who were at high risk for progression to liver failure (e.g., those with advanced fibrosis or cirrhosis), it would still be difficult to justify withholding treatment in the control group.
The National Institutes of Health is currently designing studies to test the effect on morbidity and mortality of long-term treatment with interferon to suppress the virus in patients with fibrosis or cirrhosis in whom the virus was not eradicated during the initial course of treatment. The effect of treatment on morbidity and mortality might also be better addressed in other ways, such as through modeling and cost–benefit analyses.3,4 Finally, we agree with Drs. Newman and Clay that the use of other end points can also provide meaningful information. Indeed, a response to treatment with interferon alone or in combination with ribavirin is associated with an improvement in the health-related quality of life.5,6
6 ReferencesGary L. Davis, M.D.
University of Florida, Gainesville, FL 32610-0214John G. McHutchison, M.D.
Scripps Clinic and Research Foundation, La Jolla, CA 920371
Marcellin P ,Boyer N ,Degott C , et al. Long-term histologic and viral changes in patients with chronic hepatitis C who responded to alpha interferon. Liver 1994;14:302-307
CrossRef | Medline2
Poynard T ,McHutchison J ,Davis GL , et al. Impact of interferon alfa-2b and ribavirin on the liver fibrosis progression in patients with chronic hepatitis C. Hepatology 1998;28:497A-497A abstract.
CrossRef | Web of Science3
Davis GL ,Albright JE ,Cook SF ,Rosenberg DM . Projecting the future healthcare burden from hepatitis C in the United States. Hepatology 1998;28:390A-390A abstract.
CrossRef | Web of Science4
Wong JB ,Davis GL ,Pauker SG . Cost-effectiveness of ribavirin and interferon alfa-2b after interferon relapse in chronic hepatitis C. Hepatology 1998;28:591A-591A abstract.
CrossRef | Web of Science5
Bonkovsky HL, Woolley JM, Consensus Interferon Study Group
CrossRef | Web of Science | Medline6
Ware JE, Bayliss MS, Mannocchia M, Davis GL. Health-related quality of life in chronic hepatitis C: impact of treatment and treatment response. Gastroenterology (in press).
Author/Editor Response
Drs. Newman and Clay both raise valid questions that cannot be easily answered. I agree that the two studies addressed only the short-term end point of response to treatment — that is, elimination of the virus and improvement in aminotransferase levels and histologic findings in the liver. Indeed, combination treatment with interferon and ribavirin has not been shown to slow the rate of progression to cirrhosis, liver failure, or death. However, a study of these long-term end points would require many years of follow-up and an enormous amount of resources and would most likely have unacceptably high rates of noncompliance and withdrawal. The slow rate of progression associated with hepatitis C–related liver disease is a formidable problem in any study designed to address the long-term effects of treatment.
Two lines of evidence support the beneficial effect of treatment with regard to long-term prognosis. First, a long-term follow-up study of patients with chronic non-A, non-B hepatitis (which was subsequently shown to be hepatitis C) who were treated successfully with interferon in the 1980s showed that there was no progression of liver disease, or even improvement in the condition.1 Second, several studies, including one published in 1995,2 have shown a reduced incidence of hepatocellular carcinoma among patients with chronic hepatitis C who are treated successfully with interferon. Notwithstanding the lack of long-term randomized, controlled studies, such findings support the substantial benefits of a sustained response to treatment in terms of morbidity and mortality. Although the naysayers may still argue that definitive proof is lacking, I see no reasons to withhold a reasonably effective treatment from those who are likely to benefit.
As physicians, we must be sensitive to the needs of our patients in a time of change. Nevertheless, I would like to underscore the importance of limiting treatment to patients whose liver disease is most likely to progress: those with persistently elevated aminotransferase levels, viremia, and findings of fibrosis and moderate inflammation on liver biopsy. Finally, physicians and patients must carefully weigh the risks (which are clinically significant in the case of treatment with interferon alfa-2b and ribavirin), the benefits (moderate in this instance), and the cost (substantial in this instance) of any treatment option for a disease that has emerged as an important public health problem.
2 ReferencesT. Jake Liang, M.D.
National Institutes of Health, Bethesda, MD 20892-18001
Lau DTY ,Kleiner DE ,Ghany MG ,Park Y ,Schmid P ,Hoofnagle JH . 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998;28:1121-1127
CrossRef | Web of Science | Medline2
Nishiguchi S ,Kuroki T ,Nakatani S , et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051-1055
CrossRef | Web of Science | Medline
