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HEPATOLOGY, May 1998, p. 1443-1444, Vol. 27, No. 5
SEE ARTICLE 1435
Editorial
Hepatitis C: Somber Views of Natural History and Optimistic
Views of Interferon Treatment?
Hepatitis C is a slow and silent killer, which, after a period
of considerable controversy, is now clearly recognized as a cause
of excess mortality. The most convincing evidence of serious nature
of Hepatitis C virus (HCV) infection is provided by a study from
the United Kingdom of a cohort of hemophiliacs in which 25 years
of infection was associated with a seventeen-fold increased risk
of death from liver disease and a sixfold increased risk of liver
cancer compared with those without infection.1 Also,
national mortality data from Europe suggest a dramatic increase
in primary liver cancer. 2,3 In France between 1979 and
1994, the period concurrent with the French epidemic of Hepatitis
C, death caused by primary liver cancer increased fourfold in males
and twofold in females. 4,5 This evidence of excess mortality
brings a sense of urgency to the assessment of the efficacy of treatment,
particularly in patients with HCV-associated cirrhosis. To date,
only one randomized study of interferon (IFN) has been published
which shows a significant difference in the incidence of hepatocellular
carcinoma (HCC) between treated and untreated patient6;
however, this study is isolated and is imperfect in design, with
concerns being raised regarding the small sample size and the relatively
short duration of therapy. Clearly, further studies are needed to
assess the effect of interferon on major clinical endpoints (ie,
the development of complications of cirrhosis such as HCC and hepatic
decompensation) and on development of death.
Two nonrandomized studies which address the possible beneficial
role of interferon, one from Japan7 and one from France,8
are published in this issue of HEPATOLOGY. Although very different
in design, both emphasize the risk of HCC in patients with cirrhosis,
independent of genotype, and both suggest a possible beneficial
effect of IFN in reducing the incidence of HCC.
The paper by Kasahara et al.7 describes a multi-center
study of patients treated for Hepatitis C, most of whom do not have
cirrhosis. Its strengths are as follows: a large sample size (1022
patients treated with IFN); a largely prospective study design;
the inclusion of data on genotype and viral load; the exclusion
of patients receiving low doses of IFN that is less than a total
of 200 MU, which corresponds to the standard regimen of 3 MU TIW
for 6 months.
The low prevalence of cirrhosis (less than 3%) present in the study
population initially may explain the relatively large amounts of
IFN which could be administered (500 MU), as patients with cirrhosis
are typically less tolerant of IFN than those without cirrhosis.
Moreover, these increased doses may also explain the 30% rate of
sustained response, a percentage which is higher than that traditionally
observed with standard doses of IFN. There are a number of limitations
of this study, however, including the following: the lack of a prospective
control group, lack of details concerning the timing of tests such
as ultrasonography, -fetoprotein levels, histological assessment,
inadequate information concerning alcohol consumption, and lack
of detail regarding the type of IFN used. Finally, the period of
follow-up at 39 months was relatively short for a non-cirrhotic
population. The message for the clinician is that there appears
to be a relationship between the response to IFN and the reduced
incidence of HCC. The benefit of interferon was observed both in
transient and sustained responders but not in non-responders. This
study strongly supports the use of 3 MU TIW for 12 months, for a
total administered dose of approximately 500 MU.
The benefit of IFN may be secondary to a decrease in progression
of liver disease to cirrhosis in responders compared with non-responders.
Meta-analyses of randomized trials 9,10 have shown that
IFN significantly reduces the grade of inflammatory activity and
stage of fibrosis in non-cirrhotic patients, particularly in those
who respond to treatment. A recent randomized trial has also demonstrated
that an aggressive IFN regimen reduces the incidence of cirrhosis
despite a very low sustained virological response rate.11
In the study of Kasahara et al.,7 the progression of
fibrosis was not assessed by follow-up biopsy. The correlation between
the degree of fibrosis present initially and the development of
HCC was almost significant at P = .052. By univariate analysis,
HCC developed more frequently in patients with advanced liver fibrosis
than in patients with mild fibrosis (P = .0008). Even in
those who did not respond to IFN, a treatment benefit could exist,
although the lack of an untreated control group makes the determination
of any effect difficult. In the non-responders, the incidence of
HCC was 3.7% per year, compared with 5% to 7% per year observed
in Japanese patients with cirrhosis. In the absence of an adjustment
for the incidence of cirrhosis, this difference is impossible to
evaluate.
In the second study in this issue of HEPATOLOGY, Serfaty et al.
evaluated retrospectively the effects of IFN in a selected population
of HCV-positive patients with compensated cirrhosis. The strengths
of this study are as follows: 1) criteria for inclusion were clearly
defined; 2) treatment was with either interferon alpha 2a or 2b;
3) only 3% of patients were lost to follow-up; 4) an untreated comparison
group was included; and 5) most importantly, all complications of
liver disease such as variceal hemorrhage, hepatic insufficiency,
need for liver transplantation as well as development of HCC were
evaluated. Its weaknesses include the following: a lack of randomization
as well as omission of several potentially relevant details which
may influence rate of development of complications and/or mortality,
such as duration of follow-up; use of screening ultrasonography
and -fetoprotein levels; quantitation of alcohol consumption; and
administration of adjunctive therapy, such as beta-blockers or endoscopic
sclerotherapy for portal hypertension. Moreover, the total dose
of IFN received and the duration of treatment in non-responders
was not provided. The principal message for the clinician from this
second study is that, at about 3% per year, the incidence of HCC
in patients with Hepatitis C cirrhosis is similar worldwide, an
incidence which is higher than previous estimates, and that this
risk is independent of genotype responsible for infection.12
Results from this study also suggest that IFN may even benefit patients
with HCV cirrhosis who traditionally rarely achieve a sustained
virological response rate. These data are consistent with the results
of a randomized trial from our group, in which histological improvement
was observed in 80% of cirrhotics who received long-term IFN compared
with only 24% in patients who were treated for only 6 months.13
Serfaty et al. also point out the need for markers of disease progression,
suggesting that serum albumin could be a useful predictor of future
hepatic decompensation.
Thierry Poynard, M.D., Ph.D
Pierre Opolon, M.D.
Service Hepato-Gastroenterologie
Groupe Hospitalier Pitie Salpêtrière
Paris, France
Footnotes
Abbreviations: HCV, Hepatitis C virus; IFN, interferon;
HCC, hepatocellular carcinoma.
From the Service Hepato-Gastroenterologie, Groupe Hospitalier
Pitie Salpêtrière, Paris, France
Received January 16, 1998; accepted March 3, 1998.
REFERENCES
Copyright © 1998
by the American Association for the Study of Liver Diseases.
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