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Relationship
Between HCV Genotypes and Disease Progression in HIV-HCV Coinfected
Patients
The
following editorial by Marina Nunez and Vincent Soriano comments
on the article by Yoo and others
regarding the effect of hepatitis C virus genotype 1 on HCV and HIV disease. Both the editorial and the article appear in
the current (January 1, 2005) issue of The Journal of Infectious Diseases.
“Six major hepatitis C virus (HCV) genotypes have been described, and HCV
genotypes 1-4 are the predominant circulating
genotypes in Western countries. These genotypes show a distinct geographic distribution, as well
as a different susceptibility to interferon
(IFN)-based therapies.
“Only
recently have other differences between HCV genotypes been appreciated. For example, patients carrying
HCV genotype 2 and with normal levels of transaminases are at higher risk for experiencing alanine aminotransferase (ALT) flares; however, they have the
best response to IFN-based therapies. On the
other hand, patients infected with HCV genotype
3 show the highest rate of spontaneous clearance
but may show faster liver-fibrosis
progression, often accompanied by liver
steatosis; however, they tend to respond
well to IFN-based therapies.
“Finally,
chronic infection seems to be more frequent
in patients after acute
infection with HCV genotype 4, and these
patients tend to respond less well to IFN-based
therapies.
“In
North America, Japan, and western Europe,
HCV genotype 1 is by far the predominant HCV
genotype. Since the introduction of HCV serological
tests in the early 1990s, HCV transmission
through blood transfusions and other medical interventions has declined sharply, and, currently, needle sharing
among injection drug users (IDUs) represents
the major mechanism of acquisition of HCV in
the developed world. Given that HCV and HIV share routes of transmission, it is not surprising that the IDU population is largely coinfected with both
viruses.
“In
this issue of The Journal of Infectious Diseases,
Yoo et al. suggest that coinfection with HCV
genotype 1 might have a more deleterious effect
on the progression of HIV-1
disease than does coinfection with other
HCV genotypes.
“Since
the introduction of highly active antiretroviral therapy (HAART),
liver-related
complications have emerged as an important cause of hospital
admission and death
in HIV-infected individuals in the developed world. Classical opportunistic
infections are now less frequent, and, conversely, complications
of end-stage liver disease-mainly due to HCV infection-are on the
rise.
“There is
no doubt that this is due, in part, to the faster progression
to liver cirrhosis seen in HIV/HCV-coinfected patients. This accelerated course of hepatitis
C and the higher risk for liver toxicity after beginning to take antiretroviral drugs in HIV/HCV-coinfected
patients are the 2 main reasons
why HCV therapy is now considered to be a
priority in this population.
“What
is not so clear is whether HCV infection influences HIV disease progression. Initial reports claimed
that there is an increased risk for progression
to clinical AIDS in HIV/HCV-coinfected patients, but
this finding has not been confirmed by more-recent
studies. Some studies have shown significantly lower
CD4+ T cell counts in HIV/HCV-coinfected patients,
compared with those in HIV-monoinfected patients, despite similar HIV RNA levels, but another
study failed to show any difference.
“Disagreement
also exists when assessment is made of the
ability of the immune system to recover after
antiretroviral therapy. Although initial studies underlined
that increases in CD4+ T cell counts
might be blunted in HIV/HCV-coinfected patients, similar
increases in CD4+ T cell counts,
compared with those in HIV-monoinfected patients, have been observed by other studies.
“Yoo
et al. have reported lower CD4+
T cell counts in HIV-1/HCV coinfected hemophiliacs
carrying HCV genotype 1 than in those carrying
other HCV genotypes, despite comparable HIV-1
RNA levels.
“Although
details on the use of antiretroviral drugs, which
might have influenced those differences, were not provided, the finding of Yoo et al. is of
interest. HCV RNA levels were also higher in
the HIV-1/HCV genotype 1-coinfected participants, confirming
the findings of previous studies . Higher
HCV-RNA levels in liver
biopsy specimens have been found in patients
infected with HCV genotype 1, compared with those
in patients infected with HCV
genotype 3.
“In
addition, an inverse correlation between HCV RNA
levels and survival has been found in hemophiliacs.
In Yoo et al.'s study, do the lower CD4+
T cell counts have anything to do with the higher HCV RNA levels observed in the HIV-1/HCV genotype 1coinfected participants?
Unfortunately, the authors did not provide
information on this aspect, and it warrants further
study.
“Why
might patients coinfected with HIV and HCV
genotype 1 have lower CD4+ T cell counts?
Immune activation driven by chronic HCV infection might favor HIV transcription within CD4+
T cells, leading to a more rapid destruction
of these cells. In a study from the Swiss
Cohort, persistent CD4+ T cell apoptosis
was found to be associated with poor CD4+
T cell recovery, despite the use of maximal
suppressive HAART.
Alternatively,
direct HCV infection of CD4+ T cells might increase their destruction. Fas-mediated apoptosis of peripheral-blood mononuclear cells (PBMCs) has
been shown to be increased in HIV/HCV-coinfected
patients, and we have recently shown significantly
higher markers of apoptosis in PBMCs derived from
HIV/HCV-coinfected patients than in those derived from HIV-monoinfected patients.
“That
HCV genotype 1 coinfection has a more deleterious
effect on HIV disease progression, compared
with that of coinfection with other genotypes, was
originally reported in the mid 1990s. Contrary
to Yoo et al.'s findings, however, that study
did not find lower CD4+ T cell counts
in HIV/HCV-coinfected hemophiliacs.
“Why Yoo
et al.'s study would find that HCV genotype
1 coinfection has a more deleterious effect
on AIDS-related mortality is not completely clear, because the association was weaker after adjustment
for HIV-1 and HCV RNA levels.
“The
issue of a worsened AIDS-related mortality in HIV/HCV
genotype 1coinfected patients has important clinical implications. It provides
further reason for treating hepatitis C in
HIV/HCV genotype 1-coinfected patients, even though sustained virological response rates are achieved
in <30% of HIV/HCV genotype 1-coinfected patients receiving pegylated IFN and ribavirin.
“Currently, longer courses of anti-HCV therapy are being proposed, to improve treatment outcome in these difficult-to-treat
patients.
See
also the article
by Yoo and others.
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
12/08/04
Reference
M Nunez and V Soriano. Hepatitis C Virus (HCV) Genotypes and Disease Progression in HIV/HCV-Coinfected Patients. The Journal of Infectious Diseases
191(1): 1-3. January 1, 2005.
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