Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study.

Hepatology Center, Saiseikai Suita Hospital, 1-2 Kawazonocho, Suita, 564-0013, Japan.
Journal of Gastroenterology (Impact Factor: 4.02). 07/2009; 44(9):952-63. DOI: 10.1007/s00535-009-0087-x
Source: PubMed

ABSTRACT Chronic hepatitis C (CHC) genotype 1b patients with high viral load are resistant to peginterferon (PEG-IFN) and ribavirin (RBV) combination therapy, especially older and female patients.
To elucidate the factors affecting early and sustained viral responses (EVR and SVR), 409 genotype 1b patients CHC with high viral loads who had received 48 weeks of PEG-IFN/RBV therapy were enrolled. The amino acid (aa) sequences of the HCV core at positions 70 and 91 and of the interferon sensitivity determining region (ISDR) were analyzed. Host factors, viral factors, and treatment-related factors were subjected to multivariate analysis.
Male gender, low HCV RNA load, high platelet count, two or more aa mutations of ISDR, and wild type of core aa 70 were independent predictive factors for SVR. In patients with over 80% adherences to both PEG-IFN and RBV, male gender, mild fibrosis stage, and wild type of core aa 70 were independent predictors for SVR.
Independent predictive factors for SVR were: no aa substitution at core aa 70, two or more aa mutations in the ISDR, low viral load, high values of platelet count, mild liver fibrosis and male gender.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.
    World Journal of Gastroenterology 06/2014; 20(24):7555-7569. · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pegylated interferon (PEG-IFN) plus ribavirin therapy is still recommended for elderly and/or cirrhotic patients. This study examined whether sustained virological response (SVR) to low-dose PEG-IFNα-2a plus ribavirin therapy for elderly and/or cirrhotic patients could be predicted based on viral reduction within 2 weeks after therapy initiation or interleukin (IL28B) polymorphism and viral mutations. Participants comprised 115 elderly (≥65 years) and/or cirrhotic patients with genotype-1b and high viral load. Reduced doses of PEG-IFN-α-2a (90 μg/kg/week) and ribavirin (400-800 mg/day) were administered for 48 to 72 weeks based on virological response of each patient. SVR was achieved in 34% (39/115), and treatment was discontinued in 15% (17/115). Univariate analysis identified age, α-fetoprotein, fibrosis marker, interferon sensitivity-determining region (ISDR), IL-28B polymorphism, and level of viral reduction within 2 weeks as factors contributing significantly to SVR. However, no significant differences were noted in core amino acid substitutions. Multivariate analysis identified age, hyaluronic acid, ISDR, and viral reduction as factors independently associated with SVR. Positive predictive value (PPV) and negative predictive value (NPV) of SVR based on the level of viral reduction at 2 weeks (cut-off level, 1.7 log) were 83% and 84%, respectively. The PPV of SVR based on IL-28B major and ISDR mutant was 70%, and the NPV of SVR based on IL-28B minor and wild-type ISDR was 89%. Evaluations of viral reduction at 2 weeks or both IL-28B and ISDR are useful to predict SVR to low-dose PEG-IFN-α-2a plus ribavirin therapy for elderly and/or cirrhotic patients.
    Antiviral therapy 10/2013; 19(1). · 3.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to clarify which or how factors could influence the probability of sustained virologic response (SVR) in 24-week telaprevir-based triple combination therapy for East Asian chronic hepatitis C patients infected with hepatitis C virus (HCV) genotype 1b. Of 140 patients who were enrolled in this study, 137 received 12-week telaprevir combined with 24-week pegylated interferon alpha-2b plus ribavirin and were subjected to the analysis. Factors associated with SVR were analyzed by multiple logistic regression analysis. Of the 137 patients, 112 (82%) achieved SVR. Of 87 patients with IL28B single nucleotide polymorphism (SNP) rs8099917 genotype TT, 84 (97%) achieved SVR. By contrast, 28 of 50 (56%) patients with the genotype TG/GG had SVR (p=3.29×10(-9) ). Fifty-three of 60 (88%) naïve patients and 50 of 54 (93%) prior relapsers achieved SVR. Nine of 13 (69%) prior partial responders and none of 10 (0%) prior null responders achieved SVR. Multivariable analysis identified four independent factors that were significantly associated with SVR: IL28B SNP rs8099917 genotype (p=6.90×10(-5) ), preexistence of cirrhosis (p=3.99×10(-3) ), prior treatment response (p=0.0126), and rapid virological response (p=0.0239). The IL28B SNP still remained informative as a predictor of SVR to 24-week telaprevir-based triple combination therapy for East Asian patients infected with HCV genotype 1b.
    Journal of Gastroenterology and Hepatology 10/2013; · 3.33 Impact Factor