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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.
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