Human
Genetic Variation Predicts Sustained Treatment Response in HIV-HCV Coinfected
Patients
By
Liz Highleyman  The
pathogenesis of hepatitis C virus (HCV) infection
is not completely understood -- especially in HIV-HCV
coinfected individuals -- but it is increasingly clear that various viral
and host factors interact to influence HCV's activity and the immune system's
response.
In
a presentation at the 16th Conference on Retroviruses and
Opportunistic Infections (CROI 2009) this week in Montreal, German researchers
described a study looking at the role of a specific human genetic variation, or
polymorphism, on spontaneous HCV clearance and response to treatment
of hepatitis C.
Outbreaks of apparently sexually transmitted HCV infection
have been reported in recent years among HIV positive gay/bisexual men in several
European cities. Acute hepatitis C may resolve spontaneously without treatment
in approximately 25% of all cases, but this is less likely in people coinfected
with HIV.
The present study focused on cytotoxic T-lymphocyte antigen-4
(CTLA4), a co-receptor expressed by activated T-cells that binds to CD80 and CD86
on antigen-presenting cells, thereby down-regulating T-cell proliferation and
dampening T-cell function.
It was recently demonstrated, the researchers
noted as background, that the single nucleotide polymorphism (SNP) CTLA4 +49A>G
-- that is, a single change replacing adenine (A) with guanine (G) at position
49 -- is associated with better response to interferon/ribavirin.
HCV
monoinfected people with the G/G variation have a higher rate of spontaneous HCV
clearance and better response to treatment, but it is unknown whether this also
holds true for HIV-HCV coinfected individuals.
The investigators assessed
the influence of CTLA4 genotype on HCV response in a cohort of 139 HIV-HCV coinfected
patients, of whom 84 had acute and 55 had chronic hepatitis C. They evaluated
rates of sustained virological response (SVR) to interferon/ribavirin therapy,
that is continued undetectable HCV RNA 24 weeks after completion of treatment.
Results
The CTLA4 +49 G/G genotype was similarly distributed among HCV monoinfected individuals,
HIV-HCV coinfected patients, and healthy control subjects with neither virus.
There was a trend toward a higher likelihood of spontaneous clearance of acute
HCV infection in coinfected patients with the G/G genotype, but the numbers were
too low to reach statistical significance.
Looking at all HIV-HCV coinfected patients (acute and chronic), 78% of those with
the G/G genotype achieved SVR, compared to 31% with other genotypes (A/A or A/G).
Among coinfected patients with acute HCV, the SVR rates for G/G patients and those
with other genotypes were 75% and 41%, respectively.
Among coinfected patients with chronic HCV, the corresponding SVR rates were 100%
and 19%, respectively.
In a multivariate analysis, the G/G genotype was a significant predictor of sustained
response (odds ratio 20.3; P = 0.005).
"The
CTLA4 +49 G/G genotype might be associated with spontaneous clearance of HCV in
coinfected patients," the investigators concluded. "The CTLA4 +49 G/G
genotype is a predictor of response to HCV therapy in [HIV-HCV coinfected] patients
with acute (and chronic) hepatitis C."
"This study underlines
the role of an efficient T-cell response and sheds light on the influence of genetic
host factors for successful treatment," they added.
2/13/09 Reference
H
Nischalke, M Vogel, B Kraemer, and others. Influence of the CTLA4 +49 A>G Polymorphism
on Response to Hepatitis C Virus-specific Therapy in HIV+ Patients with Acute
Hepatitis C. 16th Conference on Retroviruses and Opportunistic Infections (CROI
2009). Montreal, Canada. February 8-11, 2009. Abstract 104. |
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