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Liz Highleyman
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In This Issue: Hepatitis C
Hepatitis C Treatment in Nonresponders
Fibrosis Progression
HCV/HBV Coinfection
Hepatitis C Treatment in Nonresponders
Hepatitis C Treatment in Nonresponders
In the April 2004 issue of Gastroenterology, Mitchell
Shiffman and colleagues reported the first results from the
Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis
(HALT-C) trial, ongoing at 10 centers in the U.S. The study
evaluated 604 patients with chronic hepatitis who did not
respond to previous treatment with standard interferon, with
or without ribavirin; all subjects had bridging fibrosis or
cirrhosis —the most difficult population to treat. The
primary endpoint of the study was whether therapy delayed
or stopped the progression of cirrhosis. Participants were
retreated with pegylated interferon-alpha-2a (Pegasys) 180
µg/week plus ribavirin 1000–1200 mg/day (depending
on weight). Patients who showed an early response (undetectable
HCV viral load at 20 weeks) continued treatment for 48 weeks
and were followed for an additional 24 weeks.
At 20 weeks, 35% of patients had undetectable
HCV viral load. At the end of treatment the response rate
was 32%, and at the end of follow-up (72 weeks) 18% achieved
sustained virological response (SVR). Among those who achieved
an early virological response (EVR) by 12 weeks, 34% went
on to achieve SVR, but only three patients (1%) who did not
achieve EVR later achieved SVR. The SVR rate was 14% for patients
with genotype 1, 65% for genotype 2, and 54% for genotype
3. Consistent with other studies, African-Americans had lower
sustained response rates (6% compared with 20% for whites),
as did patients over age 60. Other predictors of sustained
response were a lower AST to ALT ratio and absence of cirrhosis.
Patients previously treated with standard interferon monotherapy
were more likely to respond to the new regimen than those
who previously received standard interferon plus ribavirin.
Subjects who received a lower initial dose of ribavirin during
the first 20 weeks (due to intolerance) were less likely to
achieve SVR, confirming other research showing that ribavirin
helps prevent relapse. However, when the dose of Pegasys or
ribavirin was reduced after 20 weeks (when HCV viral load
was already undetectable) the SVR was not significantly different.
The researchers concluded that “[s]elected nonresponders
to previous interferon-based therapy can achieve SVR following
retreatment with [Pegasys] and ribavirin.” The patients
who still did not respond will enter a maintenance phase of
the trial to see whether lower-dose, long-term (3.5 years)
interferon therapy can help delay or prevent liver disease
progression even in the absence of virological response.
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Fibrosis
Progression
In the March 2004 issue of Gut, S.D. Ryder and colleagues
from the Trent Hepatitis C Study Group reported data from
a study of fibrosis progression in patients with chronic hepatitis
C. The researchers prospectively studied the rate of fibrosis
progression by looking at the results of repeat liver biopsies
in patients who did not receive treatment between the two
procedures. The study included more than 200 HCV-infected
patients (about 60% men; median age 36 years), most with mild
liver disease. The median interval between biopsies was 2.5
years. One-third of the patients showed progression of at
least 1 point in their Ishak fibrosis scores, while about
25% had increases of two or more points. Patients who were
older at the time of the first biopsy and those who showed
some fibrosis on the earlier biopsy were more likely to progress.
In contrast to some previous studies, fibrosis progression
was not independently associated with duration of HCV infection,
alcohol consumption, ALT level, coinfection with hepatitis
B virus (HBV), HCV genotype, iron levels, steatosis (fatty
liver), or degree of necroinflammation (liver inflammation
and cell death). These data indicate that even mild fibrosis
can progress significantly over 30 months in patients with
untreated hepatitis C. The researchers concluded that their
results “suggest that HCV infection will place an increasing
burden on health care services in the next 20 years,”
making a case for early treatment to prevent or retard fibrosis
progression.
In other fibrosis news, Armelle Poujol-Robert
and colleagues reported in the March 2004 issue of the American
Journal of Gastroenterology that fibrosis and cirrhosis
are associated with several factors that promote blood clotting,
or thrombosis (deficiency of protein C and elevated levels
of factor VIII and homocysteine), possibly because these
factors affect microcirculation in the liver. And in the April
2004 issue of the Journal of Hepatology (which contained
several reports on mechanisms of liver damage), Pedro Lorenzo
Majano and colleagues reported that in a laboratory study
of human hepatocytes (liver cells), the antioxidant N-acetyl-cysteine
(NAC) altered NF-kappa-B activity and reduced levels of an
enzyme that generates nitric oxide, suggesting that it may
help protect the liver from inflammatory damage. NAC has been
touted as a complementary therapy for fibrosis, and is used
to prevent liver damage due to acetaminophen overdose.
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HCV/HBV
Coinfection
Although coinfection with hepatitis C and HIV has received
a great deal of attention in recent years, HCV/ HBV coinfection
has been less studied—even though it appears to be quite
common. In the April 2004 issue of Gastroenterology,
Yun-fan Liaw and colleagues from Taiwan (where hepatitis B
is endemic and usually acquired perinatally or by age 2) looked
at the impact of HCV superinfection in patients with HBV.
(Strictly speaking, “coinfection” refers to simultaneous
infection with more than one pathogen, while “superinfection”
refers to infection with a second pathogen at a later time;
however, “coinfection” is often used to refer
to both).
The study showed that among patients
already infected with HBV, HCV superinfection can cause acute
icteric (characterized by jaundice) hepatitis, similar to
that seen in patients with HBV/HDV (hepatitis D, which only
occurs in conjunction with hepatitis B). In this study, 34%
of 93 HCV superinfected patients rapidly developed hepatic
decompensation (e.g., blood clotting problems, ascites, encephalopathy),
11% experienced liver failure, and 10% died. The long-term
effects of superinfection with HCV are worse than those of
HDV. About half of the untreated HBV/HCV coinfected patients
in this study developed cirrhosis after 10 years of follow-up,
higher than the rates seen in people with chronic hepatitis
C alone, chronic active hepatitis B alone, or HBV/HDV coinfection.
Rates of hepatocellular carcinoma (HCC, a type of liver cancer)
were also higher among the HBV/HCV patients: 14% at 10 years,
21% at 15 years, and 32% at 20 years. Interestingly, clearance
of HBV surface antigen (HbsAg) occurred earlier and more often
in those superinfected with HCV, a phenomenon the researchers
called “HBV displacement”; past research has shown
that HBV superinfection also seems to suppress HCV. The researchers
concluded that “the long-term prognosis following acute
HCV superinfection is much worse in terms of cirrhosis or
HCC development and associated mortality than that following
acute HDV superinfection or active hepatitis B.” Hepatitis
B or A superinfection in patients who already have hepatitis
C can also cause severe liver disease; for this reason, all
HCV-infected people should consider hepatitis A and B vaccination.
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