Unfortunately, knowledge of chronic hepatitis C and its sequelae is not yet complete, and highly effective therapy has not been available. The natural history of HCV infection is still uncertain. In fact, rates of progression of chronic hepatitis C to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and death are not completely understood. Chronic hepatitis C seems to be an indolent, slowly progressive disease usually accompanied by little, if any, evidence of illness or death during the first two decades after infection. Progression is related to age at the time of infection; duration of infection; sex; concomitant alcohol use; and, possibly, the immunocompetence of the infected person. The degree of hepatic inflammation, as assessed by liver biopsy, may be a predictor of progression; the stage of hepatic fibrosis may be an even better predictor. The importance of such viral factors as viral load, specific HCV genotypes, and the development and complexity of closely related HCV quasispecies also remains uncertain. Consequently, predicting progression in the individual patient is not yet possible.

Uncertainty about disease progression, coupled with the fact that available treatment is successful in only a minority of patients, has made management decisions difficult. Randomized, controlled trials of interferon- therapy have demonstrated efficacy in just a small proportion of treated patients [2]. Typically, only 10% to 20% of treated patients with a spectrum of histologic severity have had sustained biochemical (normalization of serum alanine aminotransferase levels) and virologic (clearance of circulating HCV RNA) responses when studied at least twice 6 or more months after completing a 6-month or 12-month course of treatment. Histologic improvement is shown in most of these persons with a sustained response. Even the highly promising adjunctive treatment program combining interferon- and ribavirin is thought to produce a sustained response in fewer than half of treated patients. In addition, none of the identified predictors of a sustained response to treatment (for example, the absence of cirrhosis, the presence of HCV genotypes other than type 1, and HCV RNA levels less than 1 million copies/mL) are sufficiently reliable to be useful in making clinical decisions for the individual patient.

Further complicating decision making is the fact that long-term follow-up studies of treated patients have been limited. Because claims of sustained responses have often been based on single observations made 6 months after completion of therapy, and because relapses may occur even after this 6-month period, many clinicians have questioned whether treatment truly makes a difference even if a "sustained" response occurs. The actual long-term durability of such sustained responses has been undefined. Equally critical is the question of whether this response reduces the likelihood of future development of HCV-related cirrhosis, end-stage liver disease, hepatocellular carcinoma, or death.

In this era of managed care, concerns about the most appropriate use of resources have prompted another question about interferon- treatment of chronic hepatitis C. Simply framed, that question asks whether current interferon- treatment regimens are worth their costs. More specifically, is treatment cost-effective compared with no treatment? Even more specifically, is interferon- cost-effective in patients with histologically mild disease and no cirrhosis, in whom the rate of progression is believed to be slow?

Three articles in this issue begin to answer these questions. In the study by Marcellin and colleagues [3], 80 [18%] of 450 French patients with chronic hepatitis C treated with 3 to 5 million U of interferon- three times weekly for 6 to 12 months were followed for 1 to 7.6 years. Each of these 80 patients showed a sustained response to therapy, which was defined as 1) normal serum alanine aminotransferase levels measured monthly during the first 6 months after discontinuation of interferon- therapy and 2) a negative result on testing for serum HCV RNA 6 months after the end of therapy. During the follow-up period, the rates of sustained biochemical and virologic response were 93% and 96%, respectively. Histologic improvement occurred in 94% of persons with a sustained response, and no hepatic HCV RNA could be detected in any patient in whom this marker was measured in follow-up liver biopsy samples. Of note, and as anticipated, few patients with a sustained response had cirrhosis shown on the initial biopsy. In addition, more than 60% of the patients with a sustained response were 40 years of age or younger, 60% had had infection for no more than 10 years, about 70% had low pretreatment HCV RNA levels, and genotype 1 was underrepresented.

These results are encouraging. They permit us to begin to think about applying the term "cure" to patients with sustained response. The striking improvement in liver histologic findings and the absence of detectable HCV RNA on follow-up liver biopsy are especially promising observations that need confirmation in a larger series of prospectively followed patients with treatment response. Readers should be concerned about the possibility of false-negative HCV RNA results as a consequence of sampling error [which seems unlikely] and the possibility that the assay used in the study was not sufficiently sensitive to detect residual HCV RNA in hepatocytes. Of course, if further follow-up for a longer period indicates that 1) circulating HCV RNA remains undetectable, 2) alanine aminotransferase levels are within normal limits, and 3) histologic and clinical progression is halted, then the presence or absence of residual hepatic HCV becomes an academic question. Decades-long clearance of HCV from hepatic and extrahepatic sites may be the requisite criterion for "cure." Because such data are not yet available, it may be premature to talk about "cures." Nonetheless, it is an exciting proposition.

The second article describes a decision analysis model projecting the long-term benefits and costs of 6 months of interferon- therapy for histologically mild chronic hepatitis C [4]. Bennett and colleagues show that treatment increases life expectancy and does so with a marginal cost-effectiveness well within the acceptable range for medical interventions in the United States. The authors performed a meta-analysis of primary data from five studies to determine rates of treatment response, reviewed the literature and used the assessment of an expert panel to estimate the natural history of chronic hepatitis C, and used a Markov model computer simulation to estimate lifelong clinical and economic outcomes. The critical assumptions in this analysis are that HCV RNA negativity at 6-month follow-up equals "cure" and that "cure" restores full life expectancy. Marcellin and coworkers' follow-up observations [3] provide a firm foundation for the first assumption. Only further follow-up will determine whether the second assumption is valid.

In an independent Markov simulation presented in the third paper in this issue, Kim and colleagues [5] compared the cost-effectiveness of 12 months or 6 months of interferon- therapy with that of no treatment in four hypothetical age-specific cohorts (30, 40, 50, and 60 years of age). Although the model's details on natural history, the initial disease state, rates of response to interferon-, and cost data differ somewhat from those in Bennett and colleagues' model, the two analyses share many assumptions, including the notion that sustained remission equals "cure" and fully restores life expectancy. Kim and colleagues' well-described and carefully considered analysis clearly indicates that 12 months of interferon- therapy, although more efficacious than the shorter treatment regimen, was only minimally less cost-effective. In fact, the marginal cost-effectiveness for 12 months of treatment was $5000 per quality-adjusted life-year gained compared with $4000 for the 6-month course. Kim and colleagues conclude that with the possible exception of patients older than 60 years of age, interferon- treatment is justifiable from a societal cost-effectiveness perspective.

Both Bennett and Kim and their colleagues adhered closely to recently established recommendations for the study and reporting of cost-effectiveness analyses [6, 7]. For example, in addition to using the 5% discounting rate that has been the standard in these analyses, Bennett and coworkers used the newer 3% rate. Kim and associates also used the 3% annual rate.

Although the articles by Bennett and Kim and their colleagues collectively seem to be the most comprehensive and best-conducted economic evaluations of the cost-effectiveness of interferon- therapy for chronic hepatitis C, a few caveats are worth mentioning. These include the lack of prospectively collected data on the cost of the actual use of interferon- in a community-setting clinical practice and the use of quality-of-life assessment done by physicians or a nurse rather than patients. In addition, the sensitivity analyses did not determine whether changes in more than one variable at a time might alter the robustness of the reported results. Whether either of these models can be applied to the patient with mild chronic hepatitis C and normal serum aminotransferase levels is unknown.

The duration of interferon- treatment used in Bennett and colleagues' analysis (6 months) is currently out of fashion [8]. In patients who achieve a biochemical and virologic therapeutic response after 12 weeks of treatment, therapy is now being continued for 12 months because this duration seems to be associated with a higher rate of sustained response [2]. Many physicians are administering treatment for even longer periods. Kim and colleagues' simulation indicates that 12-month regimens will be economically acceptable [8]. As Marcellin and co-workers indicate, however, treatment that lasts 12 months or longer is sometimes unnecessary because biochemical recovery, viral clearance, and histologic improvement are sustained for years after therapy ends in some patients receiving only 6 months of therapy. How to determine which responding patients will remain in remission after discontinuation of treatment at 6 months is still uncertain.

Despite the progress reported in these three articles, several questions remain unanswered. Will the sustained response described by Marcellin and colleagues continue beyond 7 years? Will the histologic improvement continue and will progression to cirrhosis be halted? Does a sustained response in patients with HCV-related cirrhosis alter the natural history of that disease, reducing the long-term risk for decompensation, hepatocellular cancer, and death? What is the marginal cost-effectiveness of therapy in patients with HCV-related cirrhosis?

In summary, Marcellin and colleagues' observational data provide convincing support for the notion that initial favorable treatment outcomes assessed 6 months after treatment may be sustainable for years. The decision analysis models of Bennett and Kim and their colleagues indicate that achieving these outcomes in patients with histologically mild disease and no cirrhosis is justifiable in terms of cost. Thus, interferon- therapy for chronic hepatitis C is both beneficial and affordable.

Raymond S. Koff, MD

Columbia MetroWest Medical Center; Framingham, MA 01702