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Liz Highleyman
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In This Issue:
Hepatitis C
Ribavirin and Anemia
Treatment Response in African Americans
HIV/HCV Coinfection
Impact of HAART
HAART Boosts HCV Diversity
Coinfection Treatment
HCV Associated with Lower Blood Lipids
Ribavirin
and Anemia
Hemolytic anemia related to ribavirin
is a common reason for discontinuation or modification of
HCV therapy. In the May issue of the Journal of Viral
Hepatitis, Sulkowski and colleagues reported on an analysis
of 677 HCV patients (not coinfected) receiving standard interferon
plus ribavirin (1000?2000 mg/day) in two separate studies.
More than half experienced a 30 g/L or greater decrease in
hemoglobin (Hb—an indication of anemia. Women were more
likely to experience Hb levels below 100 g/L, but men were
more likely to see a 30 g/L or greater drop. Ribavirin dose
reduction led to increases in Hb concentration of about 10
g/L.
However, lowering the dose or delaying
initiation of ribavirin does not seem to be a good strategy
for reducing anemia, since a full course of standard-dose
ribavirin appears to play an important role in preventing
HCV relapse. In fact, Bräu suggested that patients’
inability to tolerate a full course of ribavirin might help
account for the low SVR rates seen in his study. Instead,
use of erythropoietin (EPO, Procrit) to stimulate red blood
cell production may allow patients to remain on ribavirin
for the recommended 24—48 weeks. In the May 2004 issue
of Gastroenterology, Nezam Afdhal and colleagues
reported results of a controlled study of 185 HCV patients
who developed anemia while taking ribavirin. Patients received
40,000 IU of EPO or placebo once weekly. After eight weeks,
Hb levels rose and quality of life improved in the patients
receiving EPO. Use of EPO enabled 88% of patients in this
arm to stay on full-dose ribavirin, compared with 60% in the
placebo group.
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Treatment
Response in African Americans
Several studies have shown that African Americans respond
less well to HCV treatment than whites, although the reason
for this difference is not clear. In the May issue of the
American Journal of Gastroenterology, Richard Sterling
and colleagues reported data from a retrospective analysis
of 59 inmates (83% male, 55% Caucasian, 73% with genotype
1 HCV, 41% with advanced fibrosis) at prisons run by the Virginia
Department of Corrections. Subjects were treated with standard
interferon plus ribavirin. Overall sustained virological response
(SVR) rates were 41% in Caucasians and 28% in African Americans.
Looking only at those with genotype 1 HCV, however, the corresponding
SVR rates were 33% and 29—not a statistically significant
difference. The authors concluded, “HCV can be effectively
treated in the correctional setting with response rates similar
to, if not better than the published literature.” They
suggested that in the setting of directly observed therapy,
which ensures excellent adherence, similar SVR rates may be
achieved regardless of race.
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Impact
of HAART
Several recent reports have discussed the management of hepatitis
C in patients coinfected with HIV. The January 2 issue of
AIDS contained several articles on this topic, including
an overview by Vincent Soriano and colleagues of care of coinfected
patients. In the May 2004 issue of Clinical Gastroenterology
and Hepatology, Sterling and colleagues examined the
impact of highly active antiretroviral therapy for HIV (HAART)
on liver disease in coinfected individuals. Based on a retrospective
analysis of 101 coinfected patients and 302 with HCV alone,
the researchers found no significant differences in biochemical
(e.g., ALT level) or histological (liver tissue health) parameters
between the coinfected and HCV-monoinfected subjects. They
also observed no impact on liver disease due to protease inhibitors
(PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs),
although some drugs in both classes are known to be hard on
the liver. On the whole, the patients had well controlled
HIV disease and high CD4 cell counts, suggesting that effective
HAART may help slow liver disease progression.
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HAART
Boosts HCV Diversity
But HAART may also have negative effects that are not yet
well understood. According to a report in the April 15 issue
of the Journal of Infectious Diseases, anti-HIV therapy
appears to increase HCV genetic diversity. Jason Blackyard,
Raymond Chung, and colleagues assessed HCV quasispecies (viral
variants) in 11 coinfected patients in study ACTG 383. They
found that several HCV genetic sequences became more variable
after patients started HAART. For some sequences, diversity
was greater in subjects whose HCV viral load increased after
starting anti-HIV therapy (which happens about 25% of the
time), compared with those whose HCV levels remained stable.
The post-HAART increase in HCV viral load was not due to the
emergence of a dominant strain. The researchers suggested
that as HAART improves immunological function, the immune
system exerts greater selection pressure on HCV, causing it
to mutate more rapidly in an effort to evade the body’s
stronger immune defenses. It is not known how increases in
HCV viral load and genetic diversity might impact clinical
disease progression. But Chung sounded a note of caution:
“We need to be mindful that HCV RNA can actually increase
in some patients who are treated with HAART,” he told
Reuters Health News. “While we may be improving HIV
disease with HAART, we may unwittingly be [contributing to]
HCV-related liver disease.”
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Coinfection
Treatment
In the April issue of Hepatology, Norbert Bräu
and colleagues reported on a study of standard interferon
plus either full-course or delayed ribavirin in 107 HCV/HIV
coinfected patients. SVR rates were poor in both groups (about
11% with full-course ribavirin and about 6% with delayed ribavirin),
and more than half discontinued therapy prematurely. Anemia
occurred more often in the full-course group, and was more
common in patients who were also taking AZT (Retrovir). As
Mark Sulkowski noted in the same issue, standard interferon
is now considered substandard therapy; recent studies have
shown better SVR rates in coinfected patients receiving pegylated
interferon plus ribavirin (about 40% in the APRICOT study).
Indeed, in the January 2 AIDS, Robert Myers and colleagues
reported that coinfected patients who had previously failed
to respond or relapsed after treatment with standard interferon
(with or without ribavirin) had a SVR rate of 16% (9% for
genotype 1) when retreated with Peg-Intron plus ribavirin,
demonstrating that at least a portion of this hard-to-treat
population can be successfully treated with the best current
therapy.
Angel Luis Ballesteros and colleagues reported
in the same issue that coinfected patients who ultimately
achieved SVR experienced a very early decline in HCV viral
load, starting 24 hours after beginning treatment with pegylated
interferon plus ribavirin. A similar decline was not seen
in non-responders, suggesting that a lack of virological response
as early as week 4 might be used as an indicator of treatment
failure, allowing treatment discontinued and sparing patients
the side effects and cost of continued therapy.
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HCV Associated
with Lower Blood Lipids
While anemia may be a greater concern for coinfected patients
using AZT, another side effect associated with anti-HIV therapy—elevated
blood lipid (fat) level—seems to be less common in people
with hepatitis C. In a letter to the editor in the May 1,
2004 issue of the Journal of Acquired Immune Deficiency
Syndromes, Simona Di Giambenedetto and colleagues reported
that HCV coinfection was associated with a lower probability
of increased total cholesterol levels in patients treated
with PIs or NNRTIs; triglyceride levels, however, did not
differ by HCV status. Blood fat abnormalities are a growing
concern for people using HAART because they are associated
with increased risk of cardiovascular disease. It is not known
why cholesterol levels do not rise as much in coinfected individuals
treated with HAART, nor whether this effect will persist in
patients who achieve a sustained response to anti-HCV therapy.
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