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Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy

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Abstract

Purpose

A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome.

Methods

The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored.

Results

Patients with SVR (n = 58) and with non-SVR (n = 20) differed significantly in pretreatment HCV RNA level (p = 0.002), fibrosis score (p = 0.047), and cumulative RBV dosage (p = 0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p = 0.01 for group 1, p = 0.004 for group 2, and p = 5E−05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258–2306 region were significantly high in SVR compared to non-SVR patients (p = 0.01 for group 1, p = 0.006 for group 2, and p = 0.0006 for combined). Multivariate analyses revealed that core aa 110 (p = 0.02), NS5A aa 2258–2306 (p = 0.03), and cumulative RBV dosage (p = 0.02) were identified as independent variables associated with the final outcome.

Conclusions

The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.

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Abbreviations

EVR:

Early virological response

IFN:

Interferon

IRRDR:

Interferon ribavirin resistance determinant region

ISDR:

Interferon sensitivity determinant region

ORF:

Open reading frame

PEG-IFN:

Pegylated-interferon

PePHD:

PKR-eIF2 phosphorylation homology domain

PKR-BD:

Double-stranded RNA-activated protein Kinase binding domain

RBV:

Ribavirin

RVR:

Rapid virological response

SVR:

Sustained virological response

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Acknowledgements

This study was supported in part by a grant-in-aid scientific research fund of the Ministry of Education, Science, Sports and Culture number 20390206 and in part by a grant-in-aid from the Ministry of Health, Labour, and Welfare of Japan (H19-kanen-002). We are grateful to Yamanashi Pegintron Ribavirin Study Group and Ochanomizu Liver Conference Group for their cooperation and advices. Especially, we thank Asuka Kanayama and Takako Ohmori for their technical assistance, and Takatoshi Kitamura and Shunichi Okada for their cooperation and advices.

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Authors and Affiliations

  1. First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan

    Makoto Kadokura, Shinya Maekawa, Ryota Sueki, Mika Miura, Kazuki Komase, Hiroko Shindo, Fumitake Amemiya, Tomoyoshi Uetake, Taisuke Inoue, Minoru Sakamoto & Nobuyuki Enomoto

  2. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, Tokyo, 113-8510, Japan

    Mina Nakagawa, Naoya Sakamoto & Mamoru Watanabe

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  1. Makoto Kadokura
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  2. Shinya Maekawa
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Correspondence to Shinya Maekawa.

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Kadokura, M., Maekawa, S., Sueki, R. et al. Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy. Hepatol Int 5, 789–799 (2011). https://doi.org/10.1007/s12072-011-9267-x

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  • DOI: https://doi.org/10.1007/s12072-011-9267-x

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