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HEPATOLOGY WATCH® |
Editorial Board: Emmet B. Keeffe, MD
(Chair); M. Eric Gershwin, MD; Ira S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD; Paul
Martin, MD; Marion G. Peters, MD |
HIGHLIGHTS OF THE 56TH
ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
CHRONIC HEPATITIS C VIRUS (HCV) INFECTION
Corrected estimate of the number of infected persons in the
Use of epoetin (EPO) alfa to reduce the need for ribavirin
(RBV) dose reduction. RBV dose reduction during the treatment of patients with
chronic hepatitis C is associated with a significant decrease in the sustained
virologic response (SVR) rate. Shiffman and others studied whether the addition
of EPO to combination peginterferon (PegIFN) alfa-2b
plus RBV therapy would reduce the frequency of RBV-induced anemia and thereby
decrease the need to lower the RBV dose. A total of 150 patients with HCV
genotype 1 were randomized to receive PegIFN alfa-2b 1.5
μg/kg/wk plus RBV 13.3 mg/kg/day (group 1), RBV
13.3 mg/kg/day and EPO 40,000 U/wk (group 2), or RBV 15.2 mg/kg/day plus EPO
(group 3). EPO was titrated to maintain the hemoglobin level between 12 and 15
g/dL. While early and end-of-treatment VR rates were comparable among groups,
the SVR rate was greater in group 3 than in groups 1 and 2 (45% vs 27% and 24%;
P = 0.05) due to a lower relapse rate.
Thus, an increase in SVR rate can result from using EPO to allow higher doses
of RBV to be given to patients with HCV genotype 1 disease. (Abstract 55)
Shorter treatment duration for early responders. Ferenci
and coworkers are conducting a prospective, randomized trial in which the
duration of antiviral therapy for patients with HCV treated with PegIFN alfa-2a plus RBV is determined by VR at weeks 4 and
12. In the current report, data for patients who achieved undetectable HCV RNA
serum levels at week 4 are presented. These patients were assigned to receive
only 20 more weeks of therapy. The SVR rate for this patient group was 67%, and
only 6% of patients were lost to follow-up. These early findings indicate that a
shorter duration of treatment (24 weeks) provides substantial clinical benefit
to early responders ("super-responders") to PegIFN
alfa-2a plus RBV. (Abstract 56)
Acute infection. Loomba and associates
described the clinical features of 25 patients with acute HCV infection who
presented to the
Clinical features of patients with normal ALT levels. Vandeli and
colleagues reported the clinical features of 207 anti-HCV–positive patients who
had normal ALT levels at diagnosis. The majority of patients had genotype 1
disease, and 189 patients were HCV RNA–positive at presentation. Baseline liver
biopsies revealed severe hepatitis with or without cirrhosis in 33.8%, moderate
hepatitis in 40.6%, minimal changes in 24.2%, and no lesions in 1.4% of
patients. A deterioration of liver histology was detected in 15 (20.8%) of 72
patients with persistently normal alanine aminotransferase (ALT) levels who
underwent a second liver biopsy. These findings indicate that normal ALT levels
are not predictive of disease activity or the degree of liver fibrosis. (Abstract
90)
New therapies. Three studies report promising results for new antiviral
therapies in patients with HCV failing PegIFN-containing
treatments. In the first study, SCH 503034 (an orally active HCV protease
inhibitor) demonstrated dose-dependent antiviral activity against patients with
HCV-1 infection. A second study showed that SCH 503034 plus PegIFN
has potent antiviral activity in HCV-1 nonresponders to PegIFN.
In the third study, the combination of valopicitabine
plus PegIFN produced significantly greater
suppression of HCV replication than retreatment with Peg IFN and RBV. Finally,
VX-950, another protease inhibitor, was studied in naïve patients and shown to
rapidly decrease HCV RNA by ³2 log copies/mL in all patients and
>3 log copies/mL in 93% of patients. (Abstracts 94, 95, 96, and 201)
Responses in African Americans (AAs)
and White Americans (WAs). Conjeevaram and coworkers analyzed data obtained from a
study of 196 AAs and 205 WAs
with previously untreated genotype 1 HCV infection. All patients received Peg
IFN alfa-2b plus RBV therapy, and demographic features were similar between the
two patient groups. However, both early VR and SVR were achieved significantly
more frequently in the WA group than the AA group. No factor accounting for the
racial differences in VR have been identified. Analyses of other clinical,
viral, immunologic, and genetic differences between responders and
non-responders are ongoing. (Abstract 199)
Weight-based RBV dosing. Jacobson and others randomized 4913
patients with HCV to receive 48 weeks of treatment with Peg IFN alfa-2b and a
flat dose (FD) of RBV (800 mg/day) or weight-based dose (WBD) (<65 kg, 800
mg/day; 65 to <85 kg, 1000 mg/day; 85 to <105 kg, 1200 mg/day; 105 to 125
kg, 1400 mg/day). The SVR rate was greater and the relapse rate lower in the
WBD group. While the WBD group developed anemia more frequently than the FD
group, the discontinuation rate was similar. In addition, 24 weeks of treatment
was as effective as 48 weeks in patients with genotype 2 or 3 disease. (Abstract
LB05)
CHRONIC HEPATITIS B VIRUS INFECTION (HBV)
Response to adefovir (ADV) in orthotopic liver transplant
(OLT) patients. Lok and colleagues report data from 68 patients in the NIH HBV-OLT
study who received ADV and underwent ≥6 months of follow-up to determine
rates of VR and ADV resistance. Fifty-seven patients had prior lamivudine
therapy and 45 patients received a combination of ADV plus lamivudine. The mean
duration of follow-up was 18 months (range, 6 to 41 months), and ADV was
initiated prior to OLT in 51 patients. Of 61 patients with detectable serum HBV
DNA levels at the start of ADV, 54% of patients achieved VR (serum HBV DNA
<4 log copies/mL after 6 months of treatment). ADV-resistant mutations were
detected in four patients and were associated with switching to ADV monotherapy
after lamivudine resistance had developed and with genotype D disease. These
findings indicate that new therapies are needed because nearly half the
patients with OLT did not meet VR criteria, and combination therapy should be
considered in all patients with OLT to prevent sequential antiviral resistance.
(Abstract 91)
Telbivudine (LdT) therapy (GLOBE Trial). Lai and
others present two reports of data from a large phase III study (GLOBE Trial)
in which 1367 patients with chronic hepatitis B (hepatitis B surface antigen [HBsAg]-positive;
HBV DNA >6 log10 copies/mL; ALT, 1.3 to 10 times the upper limit
of normal, and compensated liver disease) were randomized (double-blind) to
receive LdT 600 mg/day orally or standard lamivudine
100 mg/day. For the primary efficacy end point of therapeutic response (defined
as HBV DNA <5 log10 copies/mL with hepatitis B e antigen [HBeAg]
loss or ALT normalization) at week 52, LdT was
superior to lamivudine in HBeAg-positive patients but not HBeAg-negative
patients. Undetectable serum levels of HBV DNA (by polymerase chain reaction)
were achieved in a greater percentage of LdT-treated
patients than lamivudine-treated patients in both HBeAg-positive and -negative
groups. In addition, patients in both the LdT and
lamivudine groups who achieved low HBV DNA levels at week 24 of therapy had a
greater chance of having VR at week 52. (Abstracts 92 and LB01)
Clevudine; a new therapeutic agent. Clevudine is a pyrimidine analog
that has demonstrated potent anti-HBV activity preclinically. Yoo and coworkers conducted a multicenter, double-blind
trial in which 243 patients with HBeAg-positive chronic HBV were randomized to
receive clevudine 30 mg once daily orally or placebo for 24 weeks. At week 24
serum HBV DNA levels were undetectable in 59% of clevudine-treated patients
compared with 0% of placebo patients. Clevudine was well tolerated and showed
durable viral suppression activity associated with ALT normalization. (Abstract
186)
AUTOIMMUNE HEPATITIS (AIH) AND PRIMARY SCLEROSING CHOLANGITIS (PSC)
Role of magnetic resonance cholangiography (MRC) in
screening for AIH and PSC overlap. While large bile duct injury is a known variant in
children with AIH, bile duct abnormalities are not thought to be a feature of
AIH in adults. In the current study, Abdalian and
colleagues used MRC to screen 55 consecutive patients with AIH and identified
20 patients with large bile duct changes. Ten of these patients had findings
consistent with PSC. Only two of the 10 patients with overlapping PSC were
found to have evidence of biliary strictures by ultrasonography. No disease
parameters surveyed, including alkaline phosphatase/aspartate aminotransferase
ratio, correlated with the severity of duct changes seen on MRC. These findings
suggest the prevalence of PSC in adult patients with AIH is higher than
expected and MRC has a role to identify coexistent PSC in these patients. (Abstract
31)
VARICEAL BLEEDING
Esophageal capsule endoscopy. de Franchis and others conducted a study in which 32 patients
undergoing upper endoscopy (EGD) to screen for varices and portal hypertensive
gastropathy (PHG) were also asked to undergo PillCam™
ESO. For the detection of esophageal varicies, PillCam ESO had a sensitivity of 100%, a specificity of
89%, a positive predictive value (PPV) of 96%, and a negative predictive value
(NPV) of 100%. For the detection of PHG, PillCam ESO
had a sensitivity of 100%, a specificity of 77%, a PPV of 87%, and a NPV of
100%. There were no complications associated with PillCam
ESO. These test characteristics indicate that PillCam
ESO is comparable to EGD for detecting esophageal varices and PHG. (Abstract
37)
HEPATOCELLULAR CARCINOMA (HCC)
SVR is associated with a lower risk. Bruno and colleagues
developed a database including all patients with HCV-related cirrhosis treated
with interferon monotherapy between January 1992 and December 1997 (n = 1214). The
incidence of HCC was 0.7% in patients who achieved an SVR compared with 2.2% in
patients who did not. Cox regression analysis identified the lack of SVR as
well as male gender and age >58 years to be significantly correlated with
HCC occurrence. Overall mortality in the SVR group was less than that in the
non-SVR group (5.5% vs 16.7%). These data indicate that antiviral therapy
should be aimed at viral eradication. (Abstract 85)
Risk of HCC patients with combined HCV and HBV infection. Huang and others are following a
cohort of 11,973 Taiwanese men to assess the cumulative HCC incidence
associated with chronic HCV and HBV infection. Between 1991 and 2003 there were
230 cases of HCC. After adjustment for age, ALT level, cigarette smoking, and
alcohol use, subjects who were anti-HCV–positive and HBeAg-positive were at the
highest risk for HCC. (Abstract 86)
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