Association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development.
OBJECTIVE
To determine whether amino acid mutations in the core region of hepatitis C virus (HCV) genotype 1 are associated with response to interferon (IFN) therapy and development of hepatocellular carcinoma (HCC).


METHODS
We followed up 361 patients (median duration, 121 months), and IFN monotherapy was administered to 275 (76%) [sustained virological response (SVR) rate, 26.5%]. Using pretreatment sera, mutations at core residues 70 and 91 were analyzed [double wild (DW)-type amino acid pattern: arginine, residue 70; leucine, residue 91].


RESULTS
A low aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and low HCV load were independently associated with SVR, but core mutations were not. During follow-up, 12 of 81 (14.8%) patients with the DW-type pattern and 52 of 216 (24.1%) patients with non-DW-type pattern developed HCC (p=0.06, Breslow-Gehan-Wilcoxon test). Multivariate analysis with the Cox proportional-hazards model revealed the following independent risk factors for HCC: male gender [p<0.0001; risk ratio (RR), 3.97], older age (p<0.05; RR, 2.08), advanced fibrosis (p<0.0001; RR, 5.75), absence of SVR (p<0.01; RR, 10.0), high AST level (p<0.01; RR, 2.08), high AST/ALT ratio (p<0.01; RR, 2.21), and non-DW-type pattern (p<0.05; RR, 1.96). In patients with F0-F2 fibrosis at entry, non-DW-type was likely to lead to cirrhosis (p=0.051).


CONCLUSIONS
In HCV genotype 1 patients, HCC risk could be predicted by studying core mutations, response to IFN, and host factors like age, gender, and liver fibrosis.
Nakamoto
Shingo
S
Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ward, Chiba City, Chiba 260-8670, Japan.
Imazeki
Fumio
F
Fukai
Kenichi
K
Fujiwara
Keiichi
K
Arai
Makoto
M
Kanda
Tatsuo
T
Yonemitsu
Yutaka
Y
Yokosuka
Osamu
O
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D016896:Treatment Outcome; D014758:Viral Core Proteins / Q000235:genetics*; D019562:Viral Load
D000998:Antiviral Agents; D014758:Viral Core Proteins; D007372:Interferons