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Sequence heterogeneity in NS5A of hepatitis C virus genotypes 2a and 2b and clinical outcome of pegylated-interferon/ribavirin therapy.

ABSTRACT: Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic variations within the NS5A and core regions of other genotypes, HCV-2a and HCV-2b, on PEG-IFN/RBV treatment outcome. Pretreatment sequences of NS5A and core regions were analyzed in 112 patients infected with HCV-2a or HCV-2b, who were treated with PEG-IFN/RBV for 24 weeks and followed up for another 24 weeks. The results demonstrated that HCV-2a isolates with 4 or more mutations in IRRDR (IRRDR[2a]?4) was significantly associated with rapid virological response at week 4 (RVR) and sustained virological response (SVR). Also, another region of NS5A that corresponds to part of the IFN sensitivity-determining region (ISDR) plus its carboxy-flanking region, which we referred to as ISDR/+C[2a], was significantly associated with SVR in patients infected with HCV-2a. Multivariate analysis revealed that IRRDR[2a]?4 was the only independent predictive factor for SVR. As for HCV-2b infection, an N-terminal half of IRRDR having two or more mutations (IRRDR[2b]/N?2) was significantly associated with RVR, but not with SVR. No significant correlation was observed between core protein polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a or HCV-2b infection.The present results suggest that sequence heterogeneity of NS5A of HCV-2a (IRRDR[2a]?4 and ISDR/+C[2a]), and that of HCV-2b (IRRDR[2b]/N?2) to a lesser extent, is involved in determining the viral sensitivity to PEG-IFN/RBV therapy.

SUBMITTER: El-Shamy A

PROVIDER: S-EPMC3271109 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Sequence heterogeneity in NS5A of hepatitis C virus genotypes 2a and 2b and clinical outcome of pegylated-interferon/ribavirin therapy.

El-Shamy Ahmed A Shoji Ikuo I Kim Soo-Ryang SR Ide Yoshihiro Y Imoto Susumu S Deng Lin L Yoon Seitetsu S Fujisawa Takashi T Tani Satoshi S Yano Yoshihiko Y Seo Yasushi Y Azuma Takeshi T Hotta Hak H

PloS one 20120202 2

<h4>Unlabelled</h4>Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic ...[more]

PMID: 22319571

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Project description:Patients receiving therapy for chronic hepatitis C virus (HCV) infection frequently experience cytopenias and weight loss. We retrospectively assessed the pharmacodynamic effects of pegylated interferon (PEG-IFN) alfa-2a and ribavirin by evaluating the relationship between changes in hematologic parameters, body weight, and virologic response. Patients with HCV genotypes 1, 4, 5, or 6 receiving 24 or 48 weeks of PEG-IFN alfa-2a and ribavirin therapy were pooled from four phase 3/4 trials. Maximum decreases in hemoglobin level, neutrophil count, platelet count, and weight during therapy were assessed according to virologic response category (sustained virologic response [SVR], relapse, breakthrough, and nonresponder) and race/ethnicity. Of 1,778 patients analyzed, more than half were male, non-Hispanic Caucasian, and infected with HCV genotype 1; had a baseline HCV RNA >800,000; and had alanine aminotransferase levels ?3 × the upper limit of normal. Virologic responders (SVR, relapse, and breakthrough) experienced greater maximum decreases from baseline in hemoglobin level, neutrophil count, platelet count, and weight compared with nonresponders; however, no clear trend was observed between SVR, relapse, and breakthrough. After adjusting for drug exposure and treatment duration, only decreases in neutrophil count remained associated with virologic response. Significantly greater declines in neutrophil (P < 0.0001) and platelet (P < 0.005) count were observed at weeks 4, 12, and 24 of therapy in virologic responders compared with nonresponders. This difference between responders and nonresponders was also observed among racial/ethnic groups, although statistical significance was not consistent across all groups.This post hoc analysis of HCV patients treated with PEG-IFN alfa-2a and ribavirin shows that maximum decreases from baseline in hematologic parameters and weight loss were associated with virologic response. However, after adjusting for drug exposure and accounting for duration of therapy, only neutropenia was independently associated with virologic response.

Project description:To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection.Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group?I?included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493).Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well.Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted.

Dataset Information

Sequence heterogeneity in NS5A of hepatitis C virus genotypes 2a and 2b and clinical outcome of pegylated-interferon/ribavirin therapy.

Publications

Sequence heterogeneity in NS5A of hepatitis C virus genotypes 2a and 2b and clinical outcome of pegylated-interferon/ribavirin therapy.

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