Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis.
We showed previously that amino acid (aa) substitutions in hepatitis C virus core region (HCV-CR) are negative predictors of virologic response to pegylated interferon (IFN) plus ribavirin therapy. HCV-CR induces hepatocellular carcinoma in transgenic mice, but the clinical impact is still unclear. To evaluate the impact of aa substitutions in HCV-CR on hepatocarcinogenesis, we performed a follow-up study on 313 noncirrhotic consecutive naïve patients infected with HCV genotype 1b who received IFN monotherapy. The median follow-up was 14.7 years. A sustained virologic response (SVR) after the first IFN was achieved by 65 patients (20.8%) (group A). Of 248 patients (79.2%) of non-SVR after first IFN, 112 (35.8%) did not receive additional IFN (group B), and the remaining 136 (43.5%) received multicourse IFN monotherapy (group C). As a whole, cumulative hepatocarcinogenesis rates in double wild-type (arginine at aa 70/leucine at aa 91) of HCV-CR were significantly lower than those in nondouble wild-type. Multivariate analyses identified 3 parameters (fibrosis stage 3, nondouble wild-type of HCV-CR, and group B) that tended to or significantly influenced hepatocarcinogenesis independently. With regard to hepatocarcinogenesis rates in group C according to HCV-CR and the mean alanine aminotransferase (ALT) during IFN-free period, significantly higher rates were noted in patients of nondouble wild-type with ALT levels of more than 1.5 times the upper limit of normal (25.7%) compared with the others (2.4%).


CONCLUSIONS
Amino acid substitutions in the HCV-CR are the important predictor of hepatocarcinogenesis. In multicourse IFN therapy to nondouble wild-type, we emphasize the importance of reducing the risk of hepatocarcinogenesis by mean ALT during an IFN-free period below 1.5 times the upper limit of normal.
Department of Hepatology, Toranomon Hospital, Tokyo, Japan. akuta-gi@umin.ac.jp
Norio
N
Akuta
Fumitaka
F
Suzuki
Yusuke
Y
Kawamura
Hiromi
H
Yatsuji
Hitomi
H
Sezaki
Yoshiyuki
Y
Suzuki
Tetsuya
T
Hosaka
Masahiro
M
Kobayashi
Mariko
M
Kobayashi
Yasuji
Y
Arase
Kenji
K
Ikeda
Hiromitsu
H
Kumada
D000293:Adolescent; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000821:virology*; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000627:therapeutic use; D007564:Japan / Q000453:epidemiology; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016896:Treatment Outcome; D014758:Viral Core Proteins / Q000235:genetics*
D000998:Antiviral Agents; D014758:Viral Core Proteins; D007372:Interferons; D000410:Alanine Transaminase