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Ira S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD; Paul Martin, MD;
Marion G. Peters, MD |
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HEPATOLOGY WATCH® |
HIGHLIGHTS OF THE 54TH ANNUAL MEETING OF THE
AMERICAN ASSOCIATION FOR THE STUDY
OF LIVER DISEASES
NATURAL HISTORY OF CHRONIC HEPATITIS C VIRUS (HCV)
INFECTION AND FIBROSIS
Presence and spectrum of esophageal varices
(EVs). Arun Sanyal et al studied the
distribution and grade of EVs in patients with compensated chronic hepatitis C
who were virologic nonresponders to peginterferon plus ribavirin and enrolled
in the HALT-C trial. Among 486 patients
(208 with cirrhosis and 278 with bridging fibrosis) screened with endoscopy,
120 patients were found to have EVs (43% with cirrhosis and 11% with bridging
fibrosis). Independent predictors of EVs
were cirrhosis, race, splenomegaly, thrombocytopenia, increased bilirubin, and
increased INR. In patients with bridging
fibrosis, predictors of EVs were a lower platelet count, higher bilirubin
level, and higher INR. The small but
significantly increased INR and bilirubin values in patients with bridging fibrosis
suggest that these patients had more advanced liver disease than indicated by
liver biopsy. (Abstract 129)
Natural history of fibrosis. John Wong and Thierry Poynard developed a fibrosis-based
Markov model by using data from 2,313 liver biopsies obtained from patients
with chronic hepatitis C. They evaluated
the ability of the model to predict future outcomes by comparing cohort
simulation projections to published outcomes in the Kenny-Walsh (NEJM 1999) and Thomas (JAMA 2000) studies. Markov model projections of the likelihood of
developing Metavir fibrosis stages F0, F1, F2, F3, and F4 after a mean of 17
years were 50%, 36%, 10%, 2%, and 1.6%, respectively, compared with liver
biopsy results showing the same fibrosis stages in 49%, 34%, 10%, 5%, and 2%,
respectively. The model also predicted
that the incidence of cirrhosis would be 11% after 25 years and 30% after 35
years. Although men, injection drug use,
alcohol use and active inflammation all increased the rate of fibrosis
progression, duration of infection and older age at infection were the primary
determinants of fibrosis progression.
(Abstract 56)
Sexual transmission.
Norah
Terrault and colleagues studied the potential for sexual transmission of HCV
among 500 evaluable monogamous heterosexual couples. Anti-HCV persons with a monogamous
heterosexual partner for ³3 years were eligible. Exclusion criteria included HIV or HBV
coinfection and a history of injection drug use in either partner. Twenty partners (4%) tested positive for
anti-HCV (EIA and RIBA), and 12 had detectable HCV RNA. However, HCV genotypes/serotypes were
discordant in 6 (40%) of 15 couples tested to date. The low prevalence of positive anti-HCV in
both partners and the high rate of discordant HCV genotypes in those partners
who were both anti-HCV positive indicate that sexual transmission of HCV is
rare. (Abstract 58)
TREATMENT OF CHRONIC HCV INFECTION
Peginterferon (PEG-IFN) alfa-2a and ribavirin for
patients with normal ALT levels. Stefan Zeuzem and associates
conducted a multicenter study in which 491 chronic HCV patients with normal ALT
levels (ALT levels < ULN during the 18 months preceding baseline) were
randomized (3:3:1) to one of the following 3 treatment arms: PEG-IFN alfa-2a
180 ug/week plus ribavirin 800 mg/day for 24 weeks (n = 212); PEG-IFN alfa-2a
180 ug/week plus ribavirin 800 mg/day for 48 weeks (n = 210); and no treatment
(n = 69). The sustained virological
response (SVR) rates were 30% and 52% for the 24-week and 48-week treatment
groups, respectively, and 0% for the untreated group. For patients with genotype 1 infection, the
SVR rates were 13% and 40% when treated for 24 weeks and 48 weeks,
respectively. However, for HCV infection
due to genotypes 2 and 3, the SVR rates were similar between the 2 treatment
groups (72% vs. 78%). Only 2 patients
developed ALT flares (ALT levels >10 x ULN).
These results are comparable to those obtained in chronic HCV patients
with elevated ALT levels treated with antiviral therapy. (Abstract 106)
Response of genotype 1 infection in African-American
(AA) vs. Caucasian (Ca) patients. Lennox Jeffers et al enrolled 78 AA
and 28 Ca patients with previously untreated chronic HCV genotype 1 infection
into a study to receive PEG-IFN alfa-2a 180 ug/week plus ribavirin 1,000 to
1,200 mg/day for 48 weeks. High viral
loads were detected in 45 AA patients and in only 12 Ca patients. An SVR was achieved in 26% and 39% of AA and
Ca patients, respectively. Fibrosis
improvement was seen in 13 (25%) of 53 AA patients and 1 (6%) of 16 Ca
patients. These data indicate that
response rates to antiviral therapy are lower in AA compared to Ca patients
with chronic HCV, but demonstrate the highest response rate yet reported in
this population. (Abstract 71)
Protease inhibitors.
BILN
2061 (Boehringer Ingelheim) is a novel HCV serine protease inhibitor that has
previously demonstrated activity against HCV genotype 1 infection. Markus Reiser and colleagues randomized 10
patients with HCV of other than genotype 1 infection in a double-blind manner
to receive 500 mg of BILN 2061 (n = 8) or placebo (n = 2) twice daily for 2
days. The viral load decreased by 1 log10
units in 4 of the 8 BILN 2061-treated patients and returned to baseline levels
within 1-7 days. BILN 2061 was well
tolerated and no adverse events were reported.
These findings showed that BILN 2061 has antiviral activity against
non-genotype 1 HCV, but in a less uniform and pronounced manner than in
genotype 1 patients. (Abstract 136).
VX-950 (Vertex Pharmaceuticals Inc) is a newly developed protease
inhibitor. Kai Lin et al incubated HCV
replicon cells with concentrations of VX-950 or BILN 2061 that were fixed
multiples (10X and 50X) of their respective IC50s. The rate of inhibition of HCV replicon RNA
was similar for both drugs after 2 days of incubation. However, at later time points (12-15 days),
VX-950 suppressed HCV replicon RNA by 1-2 log10 greater than BILN
2061. (Abstract 137)
NATURAL HISTORY AND TREATMENT OF CHRONIC HBV
Association of genotype F with hepatocellular
carcinoma (HCC) in
Adefovir dipivoxil (ADV) therapy in HBeAg-negative
chronic hepatitis B. Stefanos Hadziyannis et al.
evaluated the benefits of 96 weeks of ADV therapy. In this study of 185 HBeAg-negative patients
with HBV infection, patients were randomized in a 2:1 ratio to receive ADV 10
mg or placebo. At 48 weeks, placebo
patients (n = 60) were crossed over to ADV 10 mg and ADV-treated patients were
re-randomized (2:1 ratio) to ADV 10 mg (n = 80) or placebo (n = 40). After 96 weeks of ADV therapy, HBV DNA levels
were <1,000 copies/mL in 71%, ALT levels normalized in 75%, and biopsy
improvement occurred in 79%. (Abstract
241)
ADV treatment of liver transplantation (LT) patients
with lamivudine (LAM)-resistant HBV. Christopher Westland et al studied
114 LT patients with LAM-resistant HBV who had been treated with ADV for 96
weeks. The ADV resistance mutation
rtN236T was found in only 2 (1.8%) patients at week 96. The emergence of rtN236T was associated with
a rebound rise in serum HBV DNA and ALT levels in both patients. Retreatment with LAM in addition to ADV
treatment resulted in a >2.9 log10 copies/mL reduction in HBV
DNA. Thus, ADV-resistant HBV clones that
emerge are sensitive to LAM. (Abstract
10) Eugene Schiff et al performed a
retrospective analysis of 100 pre-LT patients with LAM-resistant HBV infection
who were treated with ADV. At week 48 of
ADV therapy, the mean decrease in serum HBV DNA levels was 4.1 log10
copies/mL, and ALT, albumin, bilirubin, and prothrombin time had normalized in
78%, 81%, 50%, and 83% of patients, respectively. ADV therapy had improved the clinical
condition of 38 patients, allowing them to undergo subsequent LT. In 20 other patients, ADV resulted in
sufficient clinical improvement to allow either the removal from the LT
waitlist or a downgrading of the patient's status from a high to a low
priority. (Abstract 11)
Effects of LAM on disease progression in advanced
chronic hepatitis B. Yun-Fan Liaw and coworkers randomized (2:1 ratio) 651 patients with
compensated HBV-cirrhosis in a double-blind manner to receive either LAM 100
mg/day or placebo for up to 5 years. The
study was terminated at the second interim analysis at the recommendation of
the Data Safety Monitoring Board due to significant differences in outcomes
between the treatment groups. Disease
progression had developed in 8% of LAM-treated patients compared to 18% of
placebo-treated patients. In addition,
HCC had occurred in 4% of patients on LAM versus 6% of patients on placebo. This large trial demonstrates that LAM
therapy delays disease progression in advanced HBV. (Abstract 220)
Peginterferon (PEG-IFN) alfa-2a therapy. Patrick Marcellin and others conducted a double-blind phase
III study of PEG-IFN alfa-2a in 537 chronic HBV patients who were
HBeAg-negative and anti-HBe-positive for at least 6 months. Patients were randomized to receive 48 weeks
of therapy with PEG-IFN alfa-2a plus placebo, PEG-IFN alfa-2a plus LAM 100
mg/day, or LAM 100 mg/day alone. At 24
weeks post-treatment (week 72), PEG-IFN alfa-2a monotherapy treatment group had
higher ALT and HBV DNA response rates than patients treated with LAM
alone. Furthermore, the addition of LAM
to PEG-IFN alfa-2a did not improve response rates compared to those achieved
with PEG-IFN alfa-2a alone. This study
demonstrated that PEG-IFN alfa-2a monotherapy is effective treatment for
patients with HBeAg-negative/anti-HBe-positive chronic hepatitis B. (Abstract
1181)
NATURAL HISTORY OF NONALCOHOLIC FATTY LIVER DISEASE
(NAFLD)
Characteristics of children with obesity-associated
steatohepatitis. Ruben Quiros-Tejeira and associates
found that aminotransferase levels were elevated in 52 (15.7%) of 332 obese
children identified at the Texas Children's Hospital from 2001 to 2003. Liver biopsies were obtained from these 52
children, and portal fibrosis was present in 35 (87.5%) of those with elevated
aminotransferase levels. Grade 3
macrovesicular steatosis, grade 3 fibrosis, and early cirrhosis were documented
by liver biopsy in 9, 8, and 2 children, respectively. A high incidence of elevated ALT levels and a
high prevalence of fibrosis were detected in these obese children, suggesting
that obesity-associated steatohepatitis may be a progressive liver
disease. (Abstract 91) Leon Adams and coworkers reviewed the
clinical courses of 100 patients with NAFLD seen at the Mayo Clinic between
January 1990 and December 2000. These
patients underwent a mean of 2.3 liver biopsies (range, 2-4 biopsies), and the
mean follow-up interval was 36 months (range, 9-288 months). Cirrhosis was identified on the initial
biopsy in 17 patients. Stable fibrosis
was observed in 55% of patients, while 29% had progression of fibrosis and 16%
had improvement. Univariate linear
regression identified the rate of fibrosis progression to be associated with a
lower fibrosis stage on initial biopsy.
These data showed that liver fibrosis remained stable in the majority of
patients with NAFLD. (Abstract 104) Eduardo Fassio and colleagues identified 22 NASH
patients who had undergone a second liver biopsy at least 3 years after the
initial liver biopsy. Fibrosis
progression was found to occur in 7 (31.8%) patients and no progression of
liver disease was seen in the remaining 15 (68.2%) patients. The patients with progression of fibrosis had
a higher body mass index (BMI) at baseline.
This study showed that fibrosis progression occurred in > 30% of NASH
patients and that higher BMI at baseline was predictive of fibrosis
progression. (Abstract 157)
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