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Liz Highleyman
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In This Issue: Hepatitis C
Hepatitis C Treatment
Interferon Improves Survival
HCV Screening Guidelines
Hepatitis C Treatment
In the March 2004 issue of Gastroenterology, Jean-Michel
Pawlotsky and colleagues reported on the antiviral action
of ribavirin in patients with chronic hepatitis C. Combining
ribavirin with interferon has been shown to improve virological
response and prevent relapse. Dr. Pawlotsky’s team studied
38 subjects with chronic genotype 1b hepatitis C receiving
various schedules of standard interferon and/or ribavirin,
plus seven untreated control subjects. Blood samples were
assessed frequently (every 4-12 hours for the first four days)
for HCV viral kinetics and ribavirin pharmacokinetics (how
the drug is metabolized and distributed in the body). They
found that four of the seven (57%) who received ribavirin
monotherapy experienced a “significant, moderate, early,
and transient” viral load decrease at days 2 and 3,
an effect associated with higher ribavirin blood concentrations
and slower drug clearance. The effect disappeared after four
days, and no patients who received ribavirin monotherapy completely
cleared HCV.
In combination therapy, ribavirin improved
the effectiveness of interferon, partially reducing viral
load rebound between injections in patients receiving interferon
three times weekly (this rebound was not seen in those receiving
daily interferon, so ribavirin did not play such an important
role). Patients receiving combination therapy went on to experience
a further “second phase” decline in HCV viral
load, which was not seen in those receiving ribavirin alone.
The researchers concluded that “[r]ibavirin exerts a
significant, moderate, and transient antiviral effect in a
significant proportion of patients with chronic hepatitis
C…and is partly responsible for the improved efficacy
of the combination of standard [interferon] and ribavirin
compared with [interferon] monotherapy.”
In the March 2, 2004 issue of the Annals
of Internal Medicine, Stephanos Hadziyannis and colleagues
with the Pegasys International Study Group reported results
of a trial of different doses and durations of combination
therapy with pegylated interferon-alpha-2a (Pegasys) plus
ribavirin. In this randomized study conducted at 99 international
centers, 1311 chronic hepatitis C patients (90% white, 65%
men, about 25% with compensated cirrhosis, all with elevated
ALT) were treated with once-weekly Pegasys plus either low-dose
(800 mg daily) or standard-dose (1000 or 1200 mg daily, depending
on weight) ribavirin, for either 24 or 48 weeks. The authors
found that among patients with HCV genotype 1, 48 weeks was
superior to 24 weeks, and standard-dose ribavirin worked better
than the lower dose. Among the genotype 1 subjects, sustained
virological response (SVR) was seen in 52% treated for 48
weeks with standard-dose ribavirin, 41% treated for 48 weeks
with low-dose ribavirin, 42% treated for 24 weeks with standard-dose
ribavirin, and 29% treated for 24 weeks with low-dose ribavirin.
In all groups, patients with lower initial HCV viral loads
responded better than those with higher viral loads. Among
patients with genotypes 2 or 3, however, SVR rates were not
significantly different based on ribavirin dose, treatment
duration, or initial viral load (about 80% in all groups).
Adverse side effects were more common in the longer-duration
and higher-dose ribavirin arms, and early discontinuation
due to insufficient response occurred more often in the lower-dose
arms. “Treatment with [Pegasys] and ribavirin may be
individualized by genotype,” the authors concluded.
“Patients with HCV genotype 1 require treatment for
48 weeks and a standard dose of ribavirin; those with HCV
genotypes 2 or 3 seem to be adequately treated with a low
dose of ribavirin for 24 weeks.”
Some recent research indicates that certain
“hard to treat” patients may benefit from a longer
course of therapy. For example, HCV/HIV coinfected individuals
appear to clear HCV more slowly, and may require longer treatment—perhaps
72 weeks for those with genotype 1 and 48 weeks for those
with genotypes 2 or 3. In the April 2004 issue of the Journal
of Hepatology, Johannes Brouwer and colleagues from Belgium
and the Netherlands reported on a study looking at whether
prolonging therapy could reduce relapse rates in patients
with chronic hepatitis C. Three hundred patients were randomly
assigned to receive 6-month treatment with standard interferon
plus ribavirin, 18-month treatment with interferon plus ribavirin,
or 18-month interferon monotherapy. At the end of treatment,
HCV viral load was undetectable in 55% and 49% of those on
6-month and 18-month combination therapy, respectively, compared
with 26% of those receiving monotherapy. Sustained response
rates in the three groups were 34%, 43%, and 16%, respectively.
Thus, the relapse rate was 38% for both the 6-month combination
therapy and 18-month monotherapy arms, compared with just
13% for the 18-month combination therapy arm. While this study
showed that six months of treatment is not adequate for many
patients, it did not answer whether 18 months is superior
to the typical 12-month course of therapy for genotype 1 HCV.
References:
Pawlotsky, J. et al. Antiviral action of ribavirin in chronic
hepatitis C. Gastroenterology 126: 703-14. March
2004.
Hadziyannis, S. et al (PEGASYS International Study Group).
Peginterferon-alpha2a (Pegasys) and ribavirin combination
therapy in chronic hepatitis C: a randomized study of treatment
duration and ribavirin dose. Annals of Internal Medicine
140 (5): 346-355. March 2, 2004.
Brouwer, J. et al. Reduction of relapse rates by 18-month
treatment in chronic hepatitis C: A Benelux randomized trial
in 300 patients. Journal of Hepatology 40 (4): 689-695.
April 2004.
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Interferon
Improves Survival
A. Kasahara and colleagues from Japan reported in the March
2004 issue of the Journal of Viral Hepatitis that
interferon improves survival in hepatitis C patients who respond
well to therapy. In a long-term study of nearly 2954 patients
with chronic hepatitis C patients (2698 treated with interferon
and 256 untreated), death due to liver-related disease occurred
in 68% of the treated patients and 81% of the untreated patients.
In addition, the risk of death from all causes was lower for
treated compared with untreated patients. Broken down by treatment
response status, patients who achieved a sustained virological
response had a significantly lower liver-related disease mortality
rate than untreated patients, but this was not true for patients
who achieved only a transient virological response. However,
both sustained and transient biochemical responders (but not
biochemical nonresponders) had a significantly lower liver-related
death rate than untreated patients. The researchers concluded
that “interferon treatment improved survival in chronic
hepatitis C patients showing a biochemical as well as a virological
response by preventing liver-related deaths.”
Reference:
Kasahara, A. et al. Interferon treatment improves survival
in chronic hepatitis C patients showing biochemical as well
as virological responses by preventing liver-related death.
J. Viral Hepatitis 11 (2): 148-156. March 2004.
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HCV
Screening Guidelines
The latest recommendations of the U.S. Preventive Services
Task Force (USPSTF) concerning screening for HCV were published
in the March 16, 2004 issue of the Annals of Internal
Medicine. Although antibody tests can accurately identify
people with HCV, infection rates are low among people without
known risk factors (e.g., injection drug use, pre-1990 blood
transfusion, occupational exposure), and most infected individuals
never develop severe liver disease (although some 75% do become
chronically infected). After reviewing available evidence,
the USPSTF found no studies showing that the benefits of widespread
screening of low-risk individuals outweigh the risks (including
anxiety, possible complications of biopsies, and side effects
and cost of treatment if a person is found to be infected).
Therefore, the task force recommended against routine HCV
screening of individuals with no known risk factors and no
symptoms of liver disease. The task force declined to take
a position either for or against routine screening even of
adults with specific risk factors, again citing insufficient
evidence.
In an accompanying article in the same issue, Roger Chou,
Elizabeth Clark, and Mark Helfand reviewed the available evidence
and concluded that “data are inadequate to accurately
weigh the overall benefits and risks of screening in otherwise
healthy asymptomatic adults.” The recommendations are
controversial, and some studies suggest that limiting HCV
screening to those with known risk factors will miss many
infections. For example, a Scottish study published in the
April 2004 issue of Gut found that risk-based screening
identified only one-quarter of previously undetected infections
among more than 30,000 pregnant women.
References:
U.S. Preventive Services Task Force. Screening for hepatitis
C virus infection in adults: recommendation statement. Annals
of Internal Medicine 140 (6): 462-464. March 16, 2004.
Chou, R. et al. Screening for hepatitis C virus infection:
a review of the evidence for the U.S. preventive services
task force. Annals of Internal Medicine 140 (6):
465-479. March 16, 2004.
Hutchinson, S. et al. Hepatitis C virus among childbearing
women in Scotland: prevalence, deprivation, and diagnosis.
Gut 53: 593-598. April 2004.
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