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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”


Outcomes and Costs of Care in Hepatitis C: Combination Therapy Scores 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.