3 New Hepatitis C Abstracts

April 18, 2011

Hepatology. 2011 Apr 12. doi: 10.1002/hep.24350. [Epub ahead of print]

Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression and

steatosis in chronic hepatitis C.

Trépo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, Gustot T, Lemmers A,

Berthillon P, Amininejad L, Chevalier M, Devière J, Manns M, Trépo C, Sninsky J,

Wedemeyer H, Franchimont D, Moreno C.

Department of Gastroenterology, Hepatopancreatology and Digestive Oncology,

Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of

Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.

Abstract

Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis and

fibrosis progression remains highly unpredictable. A recent genome-wide

association study identified a genetic variant in the PNPLA3 gene (rs738409 C>G)

associated with steatosis, that was further demonstrated to influence severity

of fibrosis in non-alcoholic fatty liver disease. Our aim was to study the

impact of this polymorphism on histological liver damage and response to

antiviral therapy in CHC. 537 Caucasian CHC patients were recruited from 3

European centers (Brussels, Belgium [n=229], Hannover, Germany [n=171] and Lyon,

France [n=137]) and were centrally genotyped for the PNPLA3 (rs738409 C>G)

polymorphism. We studied the influence of rs738409 and other variants in the

PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and

longitudinal manner. Nine others variants previously associated with fibrosis

progression were included. Finally, we explored the impact of rs738409 on

response to standard antiviral therapy using the IL28B rs12979860 C>T variant

both as a comparator and as a positive control. After adjustment for age,

gender, body mass index, alcohol consumption and diabetes, rs738409 mutant G

allele homozygote carriers remained at higher risk for steatosis (odds ratio

[OR]=2.55, 95% confidence interval [CI]=1.08-6.03, p=0.034), fibrosis (OR=3.13,

95%CI=1.50-6.51, p=0.002) and fibrosis progression (OR=2.64, 95%CI=1.22-5.67

p=0.013). Conversely, rs738409 was not independently associated with treatment

failure (OR=1.07, 95%CI=0.46-2.49, p=0.875) and did not influence clinical or

biological variables. CONCLUSION: The PNPLA3 (rs738409 C>G) polymorphism favors

steatosis and fibrosis progression in CHC. This polymorphism may represent a

valuable genetic predictor and a potential therapeutic target in CHC liver

damage. (HEPATOLOGY 2011.).

PMID: 21488075 [PubMed - as supplied by publisher]

Related citations

Hepatology. 2011 Apr 12. doi: 10.1002/hep.24342. [Epub ahead of print]

Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in

genotype 1 infected patients.

Wagner F, R, Kantaridis C, Simpson P, Troke PJ, Jagannatha S,

Neelakantan S, Purohit VS, Hammond JL.

Charité Research Organisation, Charité Universitätsmedizin Berlin, Berlin,

Germany.

Abstract

More effective and better tolerated therapies are needed for chronic hepatitis C

virus (HCV) infection. Among the direct-acting anti-HCV agents in development is

the non-structural 5B protein (NS5B-polymerase) non-nucleoside inhibitor (NNI)

filibuvir. We investigated the antiviral activity, pharmacokinetics, safety and

tolerability of multiple doses of filibuvir in treatment-naïve and

treatment-experienced patients chronically infected with HCV genotype 1 in two

Phase 1b clinical studies (Study 1 was a randomized, placebo-controlled dose

escalation study and Study 2 was a non-randomized, open-label study). The

filibuvir doses evaluated ranged from 200 mg to 1400 mg daily, and the duration

of dosing ranged from 3 to 10 days. Genotypic changes in the NS5B nucleotide

sequence following short-term filibuvir therapy were also assessed. Filibuvir

potently inhibited viral replication in a dose-dependent manner. Mean maximum

HCV RNA change from baseline ranged from -0.97 log(10) IU/mL with filibuvir 100

mg BID to -2.30 log(10) IU/mL with filibuvir 700 mg BID in treatment-naïve

patients. In treatment-experienced patients, an HCV RNA reduction of 2.20

log(10) IU/mL was achieved with filibuvir 450 mg BID. Filibuvir was well

tolerated in both studies. Adverse events were mild or moderate in severity. No

discontinuations, serious adverse events or deaths were reported. NS5B

sequencing identified residue 423 as the predominant site of mutation following

filibuvir dosing. Conclusions: Filibuvir administration resulted in significant

reductions in HCV RNA concentrations at doses that were well tolerated in HCV

genotype 1-infected patients. Filibuvir is currently being evaluated in

combination with pegylated interferon alfa 2a plus ribavirin in treatment-naïve

patients. (HEPATOLOGY 2011.).

PMID: 21488067 [PubMed - as supplied by publisher]

Hepatology. 2011 Apr;53(4):1237-45. doi: 10.1002/hep.24207.

Impact of radiation and hepatitis virus infection on risk of hepatocellular

carcinoma.

Ohishi W, Fujiwara S, Cologne JB, Suzuki G, Akahoshi M, Nishi N, Tsuge M,

ma K.

Department of Clinical Studies, Hiroshima, Japan. nwaka@....

Abstract

In cohort studies of atomic bomb survivors and Mayak nuclear facility workers,

radiation-associated increases in liver cancer risk were observed, but hepatitis

B virus (HBV) and hepatitis C virus (HCV) infections were not taken strictly

into account. We identified 359 hepatocellular carcinoma (HCC) cases between

1970 and 2002 in the cohort of atomic bomb survivors and estimated cumulative

incidence of HCC by radiation dose. To investigate contributions of radiation

exposure and hepatitis virus infection to HCC risk, we conducted a nested

case-control study using sera stored before HCC diagnosis in the longitudinal

cohort of atomic bomb survivors. The study included 224 HCC cases and 644

controls that were matched to the cases on gender, age, city, and time and

method of serum storage, and countermatched on radiation dose. The cumulative

incidence of HCC by follow-up time and age increased significantly with

radiation dose. The relative risk (RR) of HCC for radiation at 1 Gy was 1.67

(95% confidence interval: 1.22-2.35) with adjustment for alcohol consumption,

body mass index (BMI), and smoking habit, whereas the RRs for HBV or HCV

infection alone were 63 (20-241) and 83 (36-231) with such adjustment,

respectively. Those estimates changed little when radiation and hepatitis virus

infection were fit simultaneously. The RR of non-B, non-C HCC at 1 Gy was 1.90

(1.02-3.92) without adjustment for alcohol consumption, BMI, or smoking habit

and 2.74 (1.26-7.04) with such adjustment. Conclusion: These results indicate

that radiation exposure and HBV and HCV infection are associated independently

with increased HCC risk. In particular, radiation exposure was a significant

risk factor for non-B, non-C HCC with no apparent confounding by alcohol

consumption, BMI, or smoking habit. (HEPATOLOGY 2011;53:-).

PMID: 21480328 [PubMed - in process]

April 18, 2011