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Liz Highleyman
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In This Issue:
Hepatitis C
HCV/HIV Coinfection
HCV Liver Transplant Outcomes
Post-Transplant HCV Recurrence
Hepatocellular Carcinoma News
HCV/HIV Coinfection
A small Spanish study reported in the September
3 issue of AIDS produced the highest sustained virological
response (SVR) yet seen in an HCV/HIV coinfected cohort with
genotype 1 HCV. Montserrat Laguno and colleagues from Barcelona
randomly assigned 95 coinfected subjects to receive either
standard interferon three times weekly or pegylated interferon
alfa-2b (Peg-Intron), both with weight-adjusted ribavirin.
Subjects with genotypes 1 or 4 were treated for 48 weeks,
while those with genotypes 2 or 3 were treated for 24 weeks.
The overall SVR rates were 44% for Peg-Intron/ribavirin and
21% for standard interferon/ribavirin. Among those with genotypes
1 or 4, the corresponding SVR rates were 38% and 7%; among
subjects with genotypes 2 or 3, 53% and 47%, respectively,
achieved SVR. In the recent APRICOT study, which used pegylated
interferon alpha-2a (Pegasys), the SVR rate for genotype 1
subjects was 29%. The recent RIBAVIC study, using Peg-Intron,
found an SVR rate of just 15% among genotype 1 patients. (These
two studies did not analyze genotypes 1 and 4 together; some
recent research suggests genotype 4 may be easier to treat
than previously believed.) Side effects were generally similar
to those seen in other studies of interferon-based therapy;
however, nine subjects developed signs of mitochondrial toxicity,
a potential concern when ribavirin is used with certain nucleoside
analog HIV drugs including d4T (Zerit) and ddI (Videx). The
researchers recommended that concomitant use of ribavirin
and these HIV medications “should be cautioned against
or not recommended.”
In other coinfection news, a study
reported in the September 2004 issue of Human Pathology
confirms that fibrosis progression tends to be more severe
in HCV/HIV confected individuals than in those with HCV alone.
A. Rullier and colleagues conducted a prospective study of
33 coinfected patients and 33 control subjects with HCV alone.
They found that while disease activity and HCV viral load
were similar in the two groups, fibrosis was “more marked”
in the coinfected subjects. In addition, coinfected patients
had fewer CD4 white blood cells than those with HCV alone
(although all of the HIV patients had at least 250 CD4 cells/mm3,
indicating low-level immune suppression). “Our data
confirm the need to treat [coinfected] patients against HCV,
and suggest that HIV infection could favor fibrosis via the
modulation of the intrahepatic immune response,” the
authors concluded.
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HCV Liver Transplant Outcomes
Long-term transplant outcomes are similar
in patients with hepatitis C and those with liver failure
due to other causes, according to a study in the September
issue of Liver Transplantation. Michael Charlton,
MD, from the Mayo Clinic and colleagues analyzed the medical
records of 165 patients with HCV, part of the Liver Transplantation
Database maintained by the National Institutes of Diabetes
and Digestive and Kidney Diseases (NIDDK). Subjects were followed
for up to 12 years. The most common cause of transplant failure
or death among these patients was recurrence of hepatitis
C. HCV almost always infects the new liver after a transplant,
and appears to progress more rapidly in patients taking immune-suppressing
drugs to prevent organ rejection after the procedure. Nevertheless,
in this study, 10-year outcomes in the hepatitis C patients
were similar to those in patients undergoing liver transplants
for other reasons. After 10 years, liver graft survival rates
were 64% for HCV positive individuals, compared with 51% for
patients without hepatitis C. Poor outcomes were associated
with older age of both the recipient and the donor, high HCV
viral load, and antibodies against cytomaglovirus (CMV), all
of which, the research suggested, are indications of decreased
immune function. “Long-term outcomes, specifically patient
and liver graft survival, are as good for patients with hepatitis
C as they are for patients with almost any other cause of
liver disease. This is contrary to the findings of less complete
and rigorous data sets,” Charlton told Reuters Health.
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Post-Transplant HCV Recurrence
Post-transplant hepatitis C recurrence
is more severe and may follow a more aggressive course when
using transplanted livers from living donors rather than cadavers,
according to a Spanish study published in the September issue
of Hepatology. Montserrat Garcia-Retortillo, Xavier
Forns, and colleagues from Barcelona analyzed 116 consecutive
patients undergoing liver transplantation for end-stage cirrhosis
or hepatocellular carcinoma between March 2000 and August
20003. After a median follow-up of 22 months (range 3-44),
severe hepatitis C recurrence (defined as the development
of biopsy-proven cirrhosis or clinical symptoms of liver decompensation)
occurred in 22% of patients overall. But the rate of severe
recurrence differed significantly based on the source of the
donated liver: 18% (17 of 95 cases) among those who received
cadaver livers, compared with 41% (9 of 22 cases) among those
who received livers from living donors. The researchers could
not say with certainty what factors accounted for this difference,
but suggested that higher rates of biliary complications might
contribute to fibrosis, or that liver regeneration when using
a graft from a living donor might promote HCV replication
in hepatocytes. In an accompanying editorial in the same issue,
Mark Russo and Roshan Shrestha of the University of North
Carolina note that other similar studies have not found the
same difference between living donor and cadaver transplants.
“The benefits of living donor liver transplantation
should not be overlooked,” they wrote, arguing against
making “a premature decision about the risk of recurrent
hepatitis C with living donor liver transplantation.”
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Hepatocellular
Carcinoma News
Viral hepatitis, heavy alcohol consumption,
and diabetes together increase the risk of developing hepatocellular
carcinoma (HCC, a type of liver cancer) more than the separate
factors alone, according to a study published in the September
1 issue of Cancer. Jian-Min Yuan from the University
of Southern California and colleagues analyzed risk factors
in 295 HCC patients and 435 cancer-free control subjects.
As expected, hepatitis C and B both increased the risk of
developing HCC, but hepatitis C had a stronger effect. While
heavy alcohol use significantly increased the risk of HCC,
moderate drinkers, surprisingly, had a lower risk of liver
cancer. Having diabetes increased the HCC risk three-fold.
When considered together, subjects who were both heavy alcohol
users and diabetic had a 17-fold greater risk of developing
HCC. The combination of viral hepatitis plus either heavy
drinking or diabetes increased liver cancer risk by about
48-fold.
In related news, Mindie Nguyen from Stanford university and
colleagues reported in the September issue of Clinical
Gastroenterology and Hepatology that Asians may have
a four-fold greater risk, and African-American men a two-fold
greater risk, of HCC compared with whites. The researchers
analyzed medical records and pathology reports from 207 patients
with chronic HCV and cirrhosis and 257 control subjects. After
controlling for confounding factors, Asian men were 4.3 times
as likely and Asian women were 4.6 times more likely to have
HCC than whites. African-American men were 2.4 times as likely,
but the risk was not significantly greater for African-American
women. The researchers said that their findings need to be
confirmed in larger studies of racially varied populations.
In other HCC news, Monica Anzola presented an overview of
how hepatitis C and B contribute to liver cancer in the September
issue of the Journal of Viral Hepatitis. HBV is a
DNA virus that integrates itself into the human host cell
genome. This process is believed to be carcinogenic (cancer-causing),
perhaps because the virus interferes with the cells’
normal growth and division. HBV also encodes a protein called
HBx, which is known to contribute to the development of HCC.
HCV, in contrast, is an RNA virus that does not integrate
into the genetic material of the host cell. It likely promotes
liver cancer “through host protein interactions or via
the inflammatory response to the virus,” according to
Anzola, since proteins encoded by HCV (including the core
proteins NS3 and NS5A) interfere with cellular communication.
A better understanding of how HCV and HBV proteins function,
Anzola suggests, could lead to the development of strategies
to reduce the carcenogenicity of these viruses.
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