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Liz Highleyman
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In This Issue:
Hepatitis C
HCV/HIV Coinfection Results Published
BILN 2061 and Genotype
Normal-Protein Diet for Hepatic
Encephalopathy
HCV/HIV Coinfection Results Published
In Roche’s APRICOT trial, Francesca
Torriani and colleagues randomly assigned 868 HCV/HIV coinfected
patients to receive standard interferon plus ribavirin, pegylated
interferon (Pegasys) monotherapy, or Pegasys plus ribavirin
for 48 weeks. After 72 weeks, 40% of patients treated with
Pegasys/ribavirin achieved a sustained virological response
(SVR), compared with 20% of those receiving Pegasys monotherapy
and 12% of those receiving standard interferon/ribavirin.
Among patients with genotype 1 HCV (about two-thirds), the
corresponding rates were 29%, 14%, and 7%; for those with
genotypes 2 or 3, the rates were 62%, 36%, and 20%. These
Pegasys/ribavirin SVR rates are the highest yet seen in a
coinfected population.
In study ACTG 5071, Raymond Chung and colleagues (New
England Journal of Medicine July 29, 2004, Vol 351) randomly
assigned 133 participants to receive standard interferon or
Pegasys, both with escalating doses of ribavirin. After 72
weeks, the overall SVR rates were 27% for Pegasys/ribavirin
and 12% for standard interferon/ribavirin. Among subjects
with genotype 1 (about three-quarters), SVR rates were 14%
in the Pegasys arm and 6% in the standard interferon arm;
for those with genotypes 2 or 3, the rates were 73% and 33%,
respectively. Upon liver biopsy, 35% of patients without virological
clearance still showed evidence of histological response.
It is unclear why the SVR rates were lower for ACTG 5071 compared
with APRICOT. In ACTG 5071, the relapse rate during the post-treatment
follow-up period was high in the Pegasys arm, perhaps due
to the low initial ribavirin dose. Also, ACTG 5071 included
more African Americans (about 33%) than APRICOT (about 10%),
a group that responds less well to HCV treatment.
In an editorial in the same issue, Jean-Michel Pawlotsky discussed
the treatment of hepatitis C in “difficult to treat”
patients including those with HIV. The studies by Torriani
and Chung, he wrote, “show that a sustained virologic
response can be achieved with pegylated interferon alfa and
ribavirin therapy in a substantial proportion of coinfected
patients.” Although SVR rates for HCV/HIV coinfected
patients remain lower than those for patients with HCV alone,
“[t]hese results, together with the poor prognosis for
HIV-positive patients with HCV infection, justify broad use
of antiviral therapy in the treatment of coinfected patients.”
Pawlotsky suggested that the availability of new classes of
hepatitis C drug—including HCV polymerase, helicase,
and protease inhibitor—could provide renewed hope for
patients who do not respond to current therapies.
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BILN 2061
and Genotype
Research clearly shows that genotype 1
HCV is harder to treat with interferon-based therapy, and
that sustained response rates are high—twice as high
in some studies—in people with genotypes 2 or 3. But
a new HCV protease inhibitor may help reverse this imbalance.
In the July 2004 issue of the Journal of Virology,
Diane Thibeault and colleagues from Boehringer Ingelheim reported
on a study of the sensitivity of the NS3 serine proteases
from different genotypes of HCV to the experimental protease
inhibitor BILN 2061. Laboratory sensitivity studies showed
that BILN 2061 has less affinity for (in other words, is less
likely to bind to and deactivate) proteases from genotype
2 and 3 HCV compared with genotype 1. The researchers substituted
residues near the inhibitor-binding site of genotype 1b protease
with residues from genotype 2b or 3a, to determine which residues
account for the difference. They found that five residues
(at positions 78, 79, 80, 122, and 132) account for most of
the reduced sensitivity of genotype 2b, while a single residue
(168) accounts for the reduced sensitivity of genotype 3a.
Despite this lower sensitivity, however, the researchers concluded
that BILN 2061 “remains a potent inhibitor of these
non-genotype-1 NS3-NS4A proteins,” suggesting that “there
is potential for BILN 2061 as an antiviral agent for individuals
infected with non-geno type-1 HCV.”
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Normal-Protein
Diet for Hepatic Encephalopathy
Traditionally, restriction of protein
in the diet has been recommended for the management of hepatic
encephalopathy (HE). This condition occurs in patients with
cirrhosis whose livers can no longer filter out neurotoxic
substances such as ammonia. Symptoms range from mild cognitive
impairment to lethargy, personality changes, and coma. (Note:
the “brain fog” often described by people with
HCV is not a sign of HE). Ammonia is produced in the intestines
when amino acid—the building blocks of protein—are
broken down, and thus it was thought that limiting the amount
of dietary protein could improve encephalopathy. However,
protein restriction has fallen out of favor for patients with
chronic HE because it can worsen the malnutrition and muscle
wasting often seen in individuals with advanced liver disease.
Protein restriction during intermittent encephalopathy episodes
or flare-ups remains controversial, and there has been surprisingly
little clinical research on the subject. In the July issue
of the Journal of Hepatology, Juan Córdoba
and colleagues from Barcelona reported results from a study
of dietary protein in patients with episodic HE. Thirty cirrhotic
patients hospitalized for episodes of encephalopathy were
randomly assigned to receive either a normal-protein diet
(1.2gm/kg/day) or a low-protein diet for 14 days. The patients
were also treated with other standard measures (e.g., lactulose
enemas, antibiotics) to reduce the amount of ammonia in the
blood. The researchers found that HE outcomes did not differ
significantly between the two groups. During the study period,
the two arms had similar levels of protein synthesis (muscle
building), but the low-protein group had greater protein breakdown
(muscle wasting). “Diets with a normal content of protein,
which are metabolically more adequate, can be administered
safely to cirrhotic patients with episodic hepatic encephalopathy,”
the researchers concluded. “Restriction of the content
of protein of the diet does not appear to have any beneficial
effect for cirrhotic patients during an episode of encephalopathy.”
In an editorial in the same issue, Kevin Mullen and Srinivasan
Dasarathy lauded Córdoba and colleagues for undertaking
this challenging study. “We now have for the first time
some data that suggests that early introduction of oral protein
at levels of 1.2gm/kg/day along with adequate oral calories
does not delay recovery from HE,” they wrote. “The
rationale for low protein diets in the short and long-term
management of HE seems questionable based on the data presented
in this manuscript….Not only do expert opinions indicate
protein restriction should not be employed in the management
of HE, but some data also supports these opinions.”
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