Prediction of Response to Pegylated Interferon and Ribavirin in Hepatitis C by Polymorphisms in the Viral Core Protein and Very Early Dynamics of Viremia

Akuta, Norio; Suzuki, Fumitaka; Kawamura, Yusuke; Yatsuji, Hiromi; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Arase, Yasuji; Ikeda, Kenji; Miyakawa, Yuzo; Kumada, Hiromitsu

doi:10.1159/000107707

Cited by 53 publications

(58 citation statements)

References 70 publications

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“…After multivariate analysis, EVR and adherence to peg-IFN were demonstrated to be associated with SVR. Of the baseline factors assessed before treatment, age, sex, WBC, α-feto protein level, γ-glutamyl transpeptidase, and LDL-cholesterol have been re por ted to be associated with a high SVR rate following peg-IFNα-2b plus RBV therapy in CHC Japanese patients [8,11,12] . The results of this study were very similar to those of our study.…”

Section: Discussionmentioning

confidence: 99%

“…The HCV strain and the efficacy of interferon treatment vary between races and countries [6,7] . Identification of the factors associated with treatment efficacy is extremely impor tant, however, few studies involving large populations have reported on the treatment of Japanese CHC patients with pegylated interferon alpha-2b (peg-IFNα-2b) plus RBV [8,9] . In this study, we evaluated the efficacy and safety of peg-IFNα-2b plus RBV therapy in CHC genotype Ib patients with a high viral load.…”

Section: Introductionmentioning

confidence: 99%

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Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

Kogure¹,

Ueno²,

Fukushima³

et al. 2008

WJG

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AIM:To evaluate the efficacy of pegylated interferon α-2b (peg-IFNα-2b) plus ribavirin (RBV) = 0.0102) were determined using univariate analysis, and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis. In the older patient group (> 56 years), SVR in females was significantly lower than that in males (17% vs 50%, P = 0.0262). EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR. CONCLUSION: Peg-IFNα-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%. Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFNα-2b is important in improving the SVR rate.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

Kogure¹,

Ueno²,

Fukushima³

et al. 2008

WJG

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“…The 8-kDa (p8) minicore protein was also detected in Huh-7.5 cells supporting full-length genotype 1b neomycin-selectable replicons. Expression of p8 was enhanced in replicons with a U271A mutation in codon 91 that confers clinically significant interferon resistance (1)(2)(3). Experiments with in vitro transcripts revealed that p8 synthesis is not dependent on the synthesis of the mature p21 core protein and occurs in 293T cells transfected with transcripts in which the AUG of the main reading frame has been replaced by a UAG stop codon.…”

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confidence: 99%

Internal Initiation Stimulates Production of p8 Minicore, a Member of a Newly Discovered Family of Hepatitis C Virus Core Protein Isoforms

Eng

Walewski

Klepper

et al. 2009

J Virol

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The hepatitis C virus (HCV) core gene is more conserved at the nucleic acid level than is necessary to preserve the sequence of the core protein, suggesting that it contains information for additional functions. We used a battery of anticore antibodies to test the hypothesis that the core gene directs the synthesis of core protein isoforms. Infectious viruses, replicons, and RNA transcripts expressed a p8 minicore containing the C-terminal portion of the p21 core protein and lacking the N-terminal portion. An interferon resistance mutation, U271A, which creates an AUG at codon 91, upregulated p8 expression in Con1 replicons, suggesting that p8 is produced by an internal initiation event and that 91-AUG is the preferred, but not the required, initiation codon. Synthesis of p8 was independent of p21, as shown by the abundant production of p8 from transcripts containing an UAG stop codon that blocked p21 production. Three infectious viruses, JFH-1 (2a core), J6/JFH (2a core), and H77/JFH (1a core), and a bicistronic construct, Bi-H77/JFH, all expressed both p8 and larger isoforms. The family of minicores ranges in size from 8 to 14 kDa. All lack the N-terminal portion of the p21 core. In conclusion, the core gene contains an internal signal that stimulates the initiation of protein synthesis at or near codon 91, leading to the production of p8. Infectious viruses of both genotype 1 and 2 HCV express a family of larger isoforms, in addition to p8. Minicores lack significant portions of the RNA binding domain of p21 core. Studies are under way to determine their functions.

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“…Amino acid substitutions of core aa 70 and 91 and within the NS5A ISDR, as well as genetic polymorphisms in the host IL28B gene, encoding IFN--3 on chromosome 19, affect the outcome of interferon-based therapies for chronic hepatitis C patients (1,2,9,10,16,40,43). Even if only the amino acid substitution of a major variant were assumed, an accurate therapeutic effect would be impossible to predict.…”

Section: Discussionmentioning

confidence: 99%

Use of Illumina Deep Sequencing Technology To Differentiate Hepatitis C Virus Variants

et al. 2012

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Hepatitis C virus (HCV) is a positive-strand enveloped RNA virus that shows diverse viral populations even in one individual. Though Sanger sequencing has been used to determine viral sequences, deep sequencing technologies are much faster and can perform large-scale sequencing. We demonstrate the successful use of Illumina deep sequencing technology and subsequent analyses to determine the genetic variants and amino acid substitutions in both treatment-naïve (patient 1) and treatmentexperienced (patient 7) isolates from HCV-infected patients. As a result, almost the full nucleotide sequence of HCV was detectable for patients 1 and 7. The reads were mapped to the HCV reference sequence. The coverage was 99.8% and the average depth was 69.5؋ for patient 7, with values of 99.4% (coverage) and 51.1؋ (average depth) for patient 1. In patient 7, amino acid (aa) 70 in the core region showed arginine, with methionine at aa 91, by Sanger sequencing. Major variants showed the same amino acid sequence, but minor variants were detectable in 18% ( . The single open reading frame encodes a polyprotein of 3,011 amino acids (aa) that is cleaved by viral and cellular proteases into 10 different proteins. The three structural proteins, which constitute the viral particle, include the core protein and the envelope glycoproteins E1 and E2. Two regions in E2, known as hypervariable regions 1 and 2, are reported to have extreme sequence variability. The seven nonstructural components include the p7 polypeptide, the NS2-3 protease, the NS3 serine protease and RNA helicase, the NS4A polypeptide, the NA4B and NS5A proteins, and the NS5B RNA-dependent RNA polymerase (RdRp) (29). At both ends of the open reading frame lie the 5=-and 3=-untranslated regions (5=-UTR and 3=-UTR). The nucleotide sequence of the 5=-UTR is relatively well conserved among different HCV genotypes. The HCV 5=-UTR contains an internal ribosome entry site (IRES) that directs the cap-independent initiation of virus translation and forms on four characteristic stem-loop structures (17, 18). HCV displays very high genetic variability both in populations and within infected individuals, where it exists as a cluster of closely related but distinct variants, termed "quasispecies," as occurs in many other RNA viruses with a polymerase enzyme lacking proofreading ability (6,8,26).Current standard treatment of chronic HCV infection is based on the combination of pegylated alpha interferon (peg-IFN-␣) and ribavirin (RBV). However, patients with a high load of genotype 1b virus (Ͼ1 ϫ 10 5 log IU/ml) do not achieve high sustained virological response (SVR) rates (Ͻ50%), even when the most effective combination treatment (IFN plus RBV) is administered for 48 weeks (14,25). Some investigations concerning therapeutic prediction based on virological features revealed that substitutions of arginine for glutamine at amino acid (aa) 70 and/or leucine for methionine at aa 91 in the core region are independent and significant factors associated with SVR or that patients whose viruses ...

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Prediction of Response to Pegylated Interferon and Ribavirin in Hepatitis C by Polymorphisms in the Viral Core Protein and Very Early Dynamics of Viremia

Cited by 53 publications

References 70 publications

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

Internal Initiation Stimulates Production of p8 Minicore, a Member of a Newly Discovered Family of Hepatitis C Virus Core Protein Isoforms

Use of Illumina Deep Sequencing Technology To Differentiate Hepatitis C Virus Variants

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