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.