(Editorial)
About 4 million people in the United States and probably more
than 100 million people worldwide are infected with the hepatitis C
virus (HCV). (1) The majority have no symptoms, although they can
transmit this blood-borne virus to others. People who have been
infected for decades may first come to medical attention because of
complications related to advanced liver disease. Ironically, the
public health implications of HCV infection have only recently been
widely appreciated, as a result of epidemiologic studies that
pointed out the magnitude of infection and an alarming increase in
morbidity and mortality due to HCV-related disease. In the United
States, the rate of death from hepatitis C is increasing and may
approach or even surpass the number of deaths from AIDS in the next
few years. (1,2) This change reflects the advent of improved
treatments for the human immunodeficiency virus (HIV) and an
anticipated increase in the number of people with end-stage liver
disease as a result of chronic hepatitis C. Recent studies of the
natural history of HCV infection indicate that the majority of
people with chronic infection have relatively mild disease with
slow progression, and many of them will probably die with the
infection rather than of it. (3) Nonetheless, the proportion of
people with more serious liver disease -- that is, those who
require medical treatment -- is expected to increase.
Currently, treatment is recommended for patients with
persistently elevated aminotransferase concentrations, HCV viremia,
and findings of fibrosis and moderate inflammation on liver biopsy.
(4) For other groups of patients, the indications for treatment are
less clear and decisions should be made on an individual basis.
Even before the virus was identified, treatment for what was
then known as non-A, non-B hepatitis relied on the antiviral
effects of interferon. Treatment with the standard dose of
interferon alfa (3 million U three times a week for 12 months)
normalizes aminotransferase concentrations and leads to the
disappearance of HCV RNA from serum in approximately 40 percent of
patients with chronic hepatitis C. (5) However, this response is
transient in the majority of patients; only 10 to 15 percent have a
sustained response after treatment is stopped. Although longer
duration (18 to 24 months) of treatment, higher doses of interferon
alfa (up to 30 million U per week), and treatment with other types
of interferon may improve the response, many patients still
relapse. Moreover, these alternatives are costly or poorly
tolerated. (6,7,8)
Two studies in this issue of the Journal address the role of
interferon alfa-2b in combination with ribavirin for the treatment
of chronic hepatitis C. McHutchison et al. (9) studied the effect
of this combination as an initial treatment, and Davis et al. (10)
as a treatment after relapse. The findings of both studies indicate
that this combination therapy represents an important advance.
These large multicenter, randomized, controlled trials expanded on
the findings of earlier, small studies that the combination of
interferon and ribavirin was more efficacious than interferon
alone. (11,12) Both studies reported impressive rates of sustained
virologic response, defined as the absence of serum HCV RNA 24
weeks after treatment was completed, with combination therapy. The
rate was 31 to 38 percent when combination therapy was used as the
initial treatment and 49 percent when it was used for the treatment
of relapse. These rates are 5 to 10 times as high as those achieved
with monotherapy. The rates of histologic response were similar to
the rates of virologic and biochemical response. The factors
associated with a response to combination therapy were similar to
those that predict a response to treatment with interferon alone: a
low viral titer before treatment, an HCV genotype other than 1
(there are at least six genotypes), and the absence of cirrhosis
before treatment. (5)
An interesting paradox emerges from these studies. In patients
treated with interferon alone, early clearance of the virus (after
4 or 12 weeks of treatment) has been associated with a sustained
virologic response. (13,14) Davis et al. also found this to be true
with the use of interferon and ribavirin for the treatment of
relapse. In contrast, McHutchison et al. reported that in at least
50 percent of patients with a sustained response after initial
treatment with interferon and ribavirin for either 24 or 48 weeks,
HCV RNA was not cleared from serum until after week 12 or 24 of
therapy. Surprisingly, there was also no significant association
between early viral clearance and a sustained virologic response
among patients treated with interferon alone; up to 52 percent of
such patients had late viral clearance and a sustained response.
Therefore, the recommendation that an early virologic response
should be used as a guide to the duration of therapy (4) should be
reevaluated.
Why is the combination of interferon and ribavirin much more
effective than interferon alone for the treatment of chronic
hepatitis C, and what is the mechanism of action? Unfortunately,
there are no readily available answers. Ribavirin is a synthetic
guanosine analogue with activity against a broad spectrum of DNA
and RNA viruses, but its molecular mechanism of action remains
unclear. (15) Like other nucleoside analogues, ribavirin may have a
direct antiviral effect, but it may also have an immunomodulatory
effect. (16) Treatment with ribavirin alone has no effect on serum
HCV RNA levels, although it does lead to a transient decrease in
aminotransferase concentrations. (17) Therefore, ribavirin may
enhance the effect of interferon, leading to a more vigorous immune
response against HCV.
The chief and most frequent side effect of ribavirin is
hemolytic anemia, which in rare instances can be severe enough to
require the discontinuation of treatment. (17) This side effect, in
conjunction with the bone marrow suppression that is commonly
observed with interferon treatment, excludes as candidates for
combination therapy many patients at risk for heart disease. How
ribavirin causes hemolytic anemia is not known; therefore, this
side effect cannot be predicted or prevented. In addition,
ribavirin is teratogenic and must be used with caution in women of
childbearing age.
The study by McHutchison et al., as well as other reports, (18)
makes a compelling argument for the use of the combination of
interferon and ribavirin as the initial treatment for hepatitis C.
However, some questions require further study before a clear
recommendation can be made. For example, should all patients be
treated for 48 weeks, or should the duration of therapy be based on
established prognostic factors? McHutchison et al. found that the
difference in the overall rates of sustained response between the
group treated with 24 weeks of combination therapy and the group
treated with 48 weeks was barely significant. The patients who
would benefit the most from 48 weeks of therapy are probably those
with factors that are associated with a poor response, including
HCV genotype 1 and high viral titers and cirrhosis before
treatment. In addition, both medications, especially when given in
combination for more than 24 weeks, have clinically significant
side effects. In the study by McHutchison et al., 21 percent of the
patients assigned to combination therapy for 48 weeks discontinued
treatment because of severe side effects. Since the studies by
McHutchison et al. and Davis et al. were carefully monitored
clinical trials in tertiary academic centers and the patients were
presumably highly motivated, the use of this combination in routine
practice may be associated with a lower rate of efficacy, more
severe side effects, and greater noncompliance. Moreover, the
promising results of these studies should not alter the current
recommendations regarding the initiation of treatment. (4) The role
of treatment earlier in the course of HCV infection remains to be
established.
It is often the case that for the treatment of viral infections,
two antiviral drugs are better than one; HCV infection is no
exception. Many other antiviral compounds in addition to interferon
and ribavirin may soon be available for the treatment of hepatitis
C. Many of these new drugs are likely to be the result of molecular
engineering, based on incremental increases in our understanding of
the molecular virology and pathogenesis of HCV infection and
targeted to specific virally encoded functions. As has been true in
the search for the best therapy for HIV infection, it will be a
daunting challenge to develop the most effective and least costly
combination therapies for HCV infection.
T. Jake Liang, M.D.; National Institutes of Health; Bethesda,
MD 20892
SOURCE: The New England Journal of Medicine -- November 19, 1998
-- Volume 339, Number 21
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