Outcomes and Costs of Care in Hepatitis C: Combination TherapyScores Again

Editorial June 2000 Volume 95, Number 6 Pages 1392-1393

Outcomes and Costs of Care in Hepatitis C: Combination Therapy

Scores Again Raymond S. Koff, M.D.a

Prospective, multicenter, pharmaceutical company-sponsored, randomized clinical trials in the treatment of chronic hepatitis C have shown that clearance of hepatitis C virus (Hepatitis C Virus) is more likely in those treated with -interferons than in untreated patients. Sustained treatment-induced virological clearance is highly correlated with biochemical improvement, continued absence of circulating virus, improved histology, improvements in health-related quality of life, and most probably, a reduced risk of premature death from end-stage liver disease or cirrhosis-related hepatocellular carcinoma. The combination of interferon -2b plus ribavirin is even more likely to result in sustained virological clearance than is treatment with interferon -2b alone and has become the treatment of choice in previously untreated patients. Despite these observations, many questions remain unanswered about the natural history of the disease, and our ability to identify those patients most likely to develop advanced disease remains limited. Why so many patients do not have a virological response continues to be uncertain, and the impact of treatment on the course of the disease in virological nonresponders is still enigmatic. It should be recalled that hepatitis C is not invariably progressive, that the costs of treatment are high, and that long-term prospective studies of treated patients have been few in number. As a consequence, management strategies that are most favorable in the long term for the patient, the healthcare payer, and society require identification. Treatment strategies have become the subject of a large and growing number of "armchair" studies attempting to define better the value of treatment of chronic hepatitis C by developing decision analysis models of outcomes, identifying the costs of treatment (as well as the costs of nontreatment) and using these in Markov computer simulations of hypothetical cohorts of hepatitis C patients to assess cost-effectiveness. These have been undertaken, in large part, because the disease is now recognized as common, the potential clinical outcomes are serious for some patients, and both treatment and failure to treat are potentially expensive. In the 10 years since the first economic evaluation was published (1), the models have become more sophisticated, and more data from clinical trials and follow-up of treated patients have been incorporated into the decision analyses. With few exceptions, published analyses undertaken in the United States, specifically designed to relate the effectiveness of treatment of chronic hepatitis C to the costs of care, have suggested that treatment is indeed cost-effective but not cost-saving when compared to no treatment. In addition, despite the fact that combination therapy is more costly than interferon monotherapy, Wong et al. (2) now report in this issue that combination therapy is more cost-effective than interferon monotherapy.

This study, as well as one published recently by Younossi et al. (3) used published data about virological response rates from the large registration trials reported in late 1998. Despite differences in the models employed, both studies indicate that the most cost-effective strategy for previously untreated patients is the use of combination therapy. Adjustment of treatment duration based on genotype and possibly other favorable response features seems to improve cost-effectiveness. These observations support the not unanticipated premise that 48 wk of combination therapy is more cost-effective than 24 wk in patients with genotype 1, the predominant genotype in the US. However, in patients with non-genotype 1, in those with low viral loads, in younger patients, and in women, as well as in those with mild histology, shorter duration combination therapy makes economic and clinical sense. For patients who have genotypes 2 or 3 but in whom several less favorable response factors are present, 48 wk of therapy may be appropriate. A number of other economic analyses of management with combination therapy of chronic hepatitis C deserve mentioning, although most have been published as abstracts rather than full-length journal articles (4). These studies suggest that retreatment with combination therapy of the relapsed patient may be a cost-effective strategy, and that even retreatment of the nonresponding patient with interferon monotherapy, despite its relatively low success rate, may fall within an acceptable cost-effectiveness range.

Early combination treatment for the previously untreated patient with histologically mild disease may be more cost-effective than so-called "watchful waiting" with repeated biopsy and the treatment decision based on the finding of histological progression (5). Elsewhere it has been reported that empiric interferon monotherapy, without expensive virological studies and liver biopsy, is a reasonable strategy in the previously untreated patient (6). Based on the current evidence of the cost-effectiveness and improved response rate of the combination regimen, it seems very likely that combination therapy, with duration of therapy determined by genotyping alone and without pretreatment liver biopsy or Hepatitis C Virus RNA quantitation, is also likely to be a cost-effective approach. Some of us, persuaded by this argument, are now reserving liver biopsy for those patients who fail to respond to treatment. Of course, for many hepatologists, the concept of treating without a liver biopsy is an anathema; some traditions die hard. A number of questions are unresolved. These include determining the cost-effectiveness of combination treatment for the patient with chronic hepatitis C in whom persistently normal serum ALT levels are found pretreatment. Even more importantly, the clinical and economic benefits of monotherapy with the pegylated interferons, which are likely to induce sustained response rates comparable to or slightly better than that associated with today's combination therapy, even in patients with bridging fibrosis or cirrhosis, will be the next important topic for economic evaluation. Pegylated interferons are likely to be approved for the treatment of chronic hepatitis C quite soon, and it seems likely that ongoing trials will demonstrate an enhanced sustained virological response induced by the combination of pegylated interferon with ribavirin or with other adjunctive antiviral therapy. Assuming an even higher response rate and reasonable drug costs, these regimens will supplant today's combination therapy and should prove to be of even greater economic benefit.

aDivision of Digestive Diseases and Nutrition, Department of Medicine,

University of Massachusetts Medical School, Worcester, Massachusetts

References 1. Garcia de Ancos JL, Roberts JA, Dusheiko GM. An economic evaluation of the costs of alpha-interferon treatment of chronic active hepatitis due to hepatitis B or C virus. J Hepatol 1990;11:511-8.

2. Wong JB, Poynard T, Ling M-H, et al. Cost-effectiveness of 24 or 48 weeks of interferon -2b alone or with ribavirin as initial treatment of chronic hepatitis C. Am J Gastroenterol 2000;95:1524-30.

3. Younossi ZM, Singer ME, McHutchison JG, et al. Cost effectiveness of interferon alfa-2b combined with ribavirin for the treatment of chronic hepatitis C. Hepatology 1999;30:1318-24.

4. Koff RS. Cost-effectiveness of combined interferon and ribavirin versus interferon alone. Clin Liver Dis 1999;3:827-41.

5. Wong JB, Koff RS. The risks and benefits of biopsy managed care of histologically mild chronic hepatitis C versus initial combination therapy. Hepatology 1999;30:480A. 6. Wong JB, Bennett WG, Koff RS, et al. Pretreatment evaluation of chronic hepatitis C. Risks, benefits, and costs. JAMA 1998;280:2088-93.

Reprint requests and correspondence: Raymond S. Koff, M.D., Division of Digestive Diseases and Nutrition, UMass Memorial Medical Center, Shaw Building, SH-143, 55 Lake Avenue, North, Worcester, MA 01655. Received Feb. 19, 2000; accepted Feb. 23, 2000.