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Liz Highleyman
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In This Issue:
Hepatitis C
Host Genes and HCV
Viral Genes Matter, Too
HCV Treatment and Normal ALT
Host Genes and HCV
The 2002 National Institutes of Health
(NIH) consensus statement on the management of hepatitis C
recommended that more research should be conducted on the
role of genetic factors in the pathogenesis of HCV. Several
recent journal articles look at such genetic influences.
According to a study by Salim Khakoo, Mary Carrington, and
colleagues published in the August 6 issue of Science,
individuals with certain gene patterns may be more likely
to clear HCV without treatment. About 15-20% of people infected
with HCV spontaneously clear the virus; the rest develop chronic
hepatitis C. In previous studies of chimpanzees, animals that
spontaneously cleared HCV appeared to mount a stronger natural
killer (NK) cell response. Khakoo and colleagues analyzed
DNA from 1,037 HCV-infected subjects, 352 of whom cleared
the virus without treatment, examining the gene sequences
that code for “killer cell immunoglobulin-like receptors”?or
KIR receptors?on NK cells and their corresponding human leukocyte
antigen (HLA) molecules. KIR receptors are a type of inhibitory
receptor that suppresses the activity of NK cells. When the
immune system detects an invading virus, it must override
the KIR receptors in order for the NK cells to mount an attack.
The researchers found that individuals who spontaneously cleared
HCV were twice as likely to have a specific KIR/HLA combination
than those who developed persistent infection. The beneficial
combination appears to be “weaker,” and thus more
easily “turned off,” allowing NK cells to become
active against virus-infected cells. This apparent genetic
protection was only seen in individuals who were initially
infected with a relatively small amount of HCV (such as from
a needle-stick) and not in those who initially received a
large inoculum of virus (such as from a blood transfusion).
The results of this research raise the hope that gene therapy
or immune-based therapy may help prevent chronic HCV infection.
In an accompanying editorial, Peter Parham from Stanford University
pointed out that one type of leukemia is already treated by
releasing NK cells associated with a specific KIR receptor,
and suggested that a similar strategy may one day be developed
for hepatitis C. According to Carrington, “It’s
possible that if we could activate NK cells in the liver after
infection, maybe that could enhance clearance of the virus.”
Turning to existing therapies, Hermann
Wasmuth and colleagues reported in the August issue of Hepatology
that variants of the RANTES gene influence response to antiviral
treatment in patients with chronic HCV. RANTES is a chemokine
that attracts immune cells such as T cells and NK cells to
sites of inflammation. The researchers analyzed three linked
RANTES single nucleotide polymorphisms (genetic variants or
mutations)?403 G/A, In1.1 T/C, and 3’222 T/C?in 297
Caucasian HCV patients and 152 healthy control subjects. Haplotypes
(nucleotide combinations on a single chromosome) containing
these gene variants were then constructed. Haplotypes carrying
the In1.1C and 3’222C variants were seen more often
in nonresponders than in patients with a sustained response
to HCV therapy. This association was strongest in patients
with HCV genotypes 1 or 4, which respond less well to treatment
than genotypes 2 or 3. In laboratory studies, the In1.1C variant
has been shown to down-regulate RANTES activity; previous
research has found an association between this variant and
accelerated HIV progression as well, especially in people
of African descent. Wasmuth and colleagues concluded that
their analysis supports the hypothesis that nonresponders
to HCV therapy have a diminished Th1 type immune response.
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Viral Genes Matter, Too
Maria Pascu and colleagues from Berlin
reported in the September 2004 issue of Gut that
in patients with genotype 1b HCV, the number of mutations
within the “interferon sensitivity determining region”
of the viral NS5A gene?as its name suggests?has an impact
on how well patients respond to interferon-based therapy.
The researchers analyzed data from 1,230 genotype 1b chronic
HCV patients, mostly from Japan (655 subjects) or Europe (525
subjects). They found that the Japanese patients were about
twice as likely to have wild-type (nonmutated) ISDR sequences
(44% vs 25%), and also more likely to have highly mutant sequences
(18% vs 12%); the Europeans, however, were more likely to
have intermediate sequences (63% vs 38%). HCV that had more
mutations in the ISDR sequence was more susceptible to interferon,
and patients with more highly mutated virus were more likely
to achieve a sustained virological response (SVR), regardless
of geographical region. In the Japanese patients, however,
each additional ISDR mutation markedly increased the likelihood
of SVR; in the Europeans, this relationship was less pronounced.
Among patients with low pretreatment viral loads (less than
6.6 log copies/mL), Japanese subjects with ISDR mutant HCV
had an SVR rate of 97%?remarkably high for genotype 1 patients?compared
with 53% among Europeans. “These data support the concept
that mutant-type ISDR strains may represent a subtype within
genotype 1b with a more favorable response towards [interferon]
therapy,” the authors concluded.
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HCV Treatment and Normal ALT
In the August 2004 issue of Gastroenterology,
Andrew Holt and Stephen Zucker presented an overview of hepatitis
C treatment in patients with normal alanine transaminase (ALT)
levels, a group that comprises about 30% of patients with
chronic HCV. Although most such individuals appear to have
mild liver disease, some do progress to advanced fibrosis
and cirrhosis. Experts differ on whether patients with normal
ALT should routinely receive liver biopsies and HCV treatment.
The 1997 NIH hepatitis C consensus guidelines recommended
that individuals with persistently normal ALT should not receive
HCV therapy, because treatment with interferon monotherapy
was effective only in a minority of patients, prognosis without
therapy was generally good, and interferon was associated
with newly elevated ALT in some nonresponders (up to 25%).
The advent of more effective ribavirin combination therapy
and pegylated interferon, however, has led to reconsideration
of this recommendation. The 2002 consensus guidelines do not
recommend that patients with normal ALT either should or should
not be treated, concluding instead that all cases must be
considered on an individual basis.
Holt and Zucker commented on a report by C-K Hui and colleagues
in the November 2003 issue of Gut on the largest
study to date of patients with normal transaminase levels.
The researchers retrospectively evaluated the responses of
52 chronic HCV patients with normal ALT and 53 subjects with
elevated ALT, all treated with standard interferon plus ribavirin.
They found that SVR rates were similar in both groups (about
40%). In addition, the incidence of newly elevated ALT in
nonresponders who entered the study with normal levels was
uncommon, occurring in just three patients (9%). Holt and
Zucker note that with Hui’s study, “[t]he preponderance
of evidence” now indicates that HCV patients with normal
ALT are as likely to achieve a sustained response to interferon/ribavirin
as those with abnormal ALT, and that there is “a reasonably
low likelihood of disease exacerbation in those unfortunate
individuals who fail to respond.”
Nevertheless, the decision about whether to treat patients
with normal ALT remains “thorny.” Opponents argue
that given the side effects and cost of therapy, as well as
the small risk of worsening the underlying disease in nonresponders,
treatment should be reserved for those most likely to benefit.
Those who favor treatment note that some patients with normal
ALT do develop advanced liver damage, and with SVR rates now
in the range of 50% or better, all patients who might benefit
should be offered therapy. Holt and Zucker recommend that
when considering treatment of patients with normal ALT, “liver
biopsy would seem a prudent approach to help determine if
treatment is needed, and therapy should be offered to patients
with signs of progressive liver damage.”
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