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Liz Highleyman
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In This Issue:
Hepatitis C
24-Week Treatment for Genotypes
2 and 3
Amantadine Efficacy and Safety
Natural History of Cirrhosis
Hepatocellular Carcinoma Risk Factors and Survival
24-Week Treatment for Genotypes 2 and 3
Given the side effects and cost of hepatitis
C therapy, HCV patients and their doctors have an interest
in limiting the length of treatment if this does not compromise
effectiveness. Data reported by Stefan Zeuzum and colleagues
in the June issue of the Journal of Hepatology confirm
that – as recommended in the June 2002 National Institutes
of Health HCV management guidelines – a 24-week course
of pegylated interferon plus ribavirin is adequate for patients
with HCV genotypes 2 or 3. Both genotypes respond better to
interferon-based therapy than genotype 1, and the two have
been grouped together in most studies. This trial, however,
revealed that after receiving Peg-Intron plus ribavirin (800-1400
mg/day depending on weight) for 24 weeks, the sustained virological
response (SVR) rate was higher in the 42 patients with genotype
2 compared with the 182 subjects with genotype 3 (93% vs 79%
in an intent-to-treat analysis). The researchers suggested
that the difference between the two genotypes may be due to
the presence of high baseline HCV viral load and steatosis
(fatty liver), both of which are associated with a lower likelihood
of achieving SVR, and both of which occurred more frequently
among the individuals with genotype 3 in this study. The authors
concluded that treatment for 24 weeks is sufficient for patients
with genotypes 2 or 3.
In an editorial in the same issue, Alfredo
Alberti noted that Zeuzem’s study “is important
in suggesting that HCV-2 and HCV-3 infected patients should
not be considered identical in relation to response to antiviral
therapy, as it has been customary to believe up to now.”
Future research may show that a longer course of therapy is
beneficial for genotype 3 patients with high viral loads and/or
steatosis. Another issue for future trials is whether 800
mg of ribavirin is sufficient for patients with genotypes
2 or 3 when used with Peg-Intron, as was seen in past studies
using Pegasys. And, suggested Alberti, it would be interesting
to explore whether an even shorter course of therapy or even
lower medication doses might still be effective for “easy
to treat” patients with genotypes 2 or 3, low HCV viral
load, and minimal liver damage.
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Amantadine Efficacy
and Safety
Given the limitations of current HCV treatment,
the need for new therapies is clear. In the June issue of
the American Journal of Gastroenterology, Jill Smith
and colleagues reported results of an open-label dose-escalation
study of amantadine (Symmetrel), a drug used to treat influenza
and Parkinson’s disease. Past research has demonstrated
that amantadine reduces ALT levels and may improve response
rates when combined with interferon plus ribavirin. One hundred
study participants received 200 mg daily doses of amantadine,
escalating to 500 mg. Elevated ALT levels normalized in 35%
of patients taking 200 mg, 49% of those taking 300 mg, 53%
of those taking 400 mg, and 56% of those taking 500 mg. Muscle
pain and fatigue improved as doses increased. However, toxic
blood levels of the drug (more than 1,600 ng/ml) also increased
with each 100 mg escalation, from 0% to 6% to 27% to 49%,
respectively. Side effects included erectile dysfunction,
mental confusion, hair loss, and hoarseness. Biochemical response
did not improve significantly at doses higher than 300 mg,
but toxicity did increase. The researchers therefore concluded
that the 300 mg dose offers the best combination of efficacy
and safety.
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Natural History
of Cirrhosis
Two recent studies examined the natural
history of liver cirrhosis in individuals with viral hepatitis.
In the May issue of Gut, L. Benvegnu and colleagues
investigated the progression and outcome of initially compensated
cirrhosis in a cohort of 312 Italian patients with hepatitis
B (43 patients), C (254 patients), or both (15 patients),
followed for an average of about eight years. Tests were performed
every six months to assess liver disease progression and identify
major complications. During the follow-up period, 102 patients
(about 33%) developed at least one complication. The most
common were hepatocellular carcinoma (HCC, a type of liver
cancer; about 21%), ascites (about 20%), gastrointestinal
bleeding (about 5%), and encephalopathy (about 2%). About
20% experienced liver disease progression as evidenced by
an increased Child-Pugh cirrhosis score. About 19% died from
liver disease during follow-up, most (70%) due to HCC. The
authors concluded that HCC was “the most frequent and
life-threatening complication, particularly in HCV positive
cases.”
The same month in the Journal of Hepatology, Ramon
Planas and colleagues from Spain reported on the natural history
of decompensated cirrhosis in patients with hepatitis C. Two
hundred patients were followed from their first hospitalization
for hepatic decompensation; average follow-up was about three
years. The most common initial complications related to decompensation
were ascites (48%), gastrointestinal bleeding (about 33%),
severe bacterial infection (about 15%), and encephalopathy
(5%). During follow-up, about 17% developed HCC and about
43% died. “Once decompensated HCV-related cirrhosis
was established,” the researchers concluded, “patients
showed not only a very high frequency of readmissions, but
also developed decompensations different from the initial
one.”
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Hepatocellular
Carcinoma Risk Factors and Survival
As Steedman Sarbah and colleagues reported in the May issue
of Digestive Diseases and Sciences, the incidence
of HCC appears to be increasing in the United States, likely
as a long-term consequence of hepatitis C that was contracted
years or decades ago, before current treatments were available.
Using medical records and patient databases, Sarbah’s
team examined the factors associated with the development
of liver cancer in 214 individuals with HCC and 516 controls
with cirrhosis but no HCC. Older age, male sex, and African
American or other non-Caucasian race/ethnicity were all independently
and significantly associated with an increased risk of developing
HCC.
Fortunately, according to a report by Angelo Sangiovanni and
colleagues in the April issue of Gastroenterology,
cirrhotic patients with HCC appear to be surviving longer
now than they did in the past. Following a cohort of more
than 400 outpatients with compensated cirrhosis for an average
of about 12 years, the researchers found that HCC developed
in 112 individuals, for a rate of 3.4% per year. They also
found that those who developed HCC during the most recent
five-year period of follow-up had a lower mortality rate than
those who developed liver cancer during the middle or the
earliest five-year period (10%, 37%, and 45%, respectively).
“Cirrhotic patients developing a HCC during the last
five years of surveillance survived longer than previously,
as a consequence of improved management of the tumor and complications
of cirrhosis,” the authors concluded.
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