levovirin-valinate-hydrochloride and Hepatitis-C--Chronic

Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial.. The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control.. Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable.. Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.

Topics: Adult; Antiviral Agents; Cell Line, Tumor; DNA Mutational Analysis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Monosaccharides; Mutagens; Mutation; Replicon; Retrospective Studies; Ribavirin; RNA, Viral; Time Factors; Triazoles; Viral Nonstructural Proteins

In vitro and in vivo data indicate multiple, but contradictory effects of interferon on pituitary hormone secretion. We therefore investigated prospectively basal and stimulated pituitary hormone secretion in 21 patients with chronic hepatitis C virus (HCV) infection before and during antiviral therapy.. Twenty-one patients received pegylated interferon-alpha plus either ribavirin or levovirin. Baseline and stimulated growth hormone (GH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and thyroid-stimulating hormone (TSH) responses were measured using standard pituitary function tests, before therapy in all and during therapy in 17 out of the 21 patients.. Before therapy 17 patients (81%) had severe GH insufficiency and 9 of these had low insulin-like growth factor-1 (IGF-1) concentrations. Basal and stimulated GH concentrations increased significantly during therapy, reducing the number of patients with severe GH insufficiency to four, but IGF-1 remained low. Basal PRL and TSH concentrations were normal before and during therapy, while thyroid-releasing hormone (TRH)-stimulated concentrations increased significantly during therapy. The adrenocorticotropic hormone (ACTH)/cortisol axis, basal and stimulated gonadotropin, and testosterone concentrations were normal throughout. Neither the HCV RNA level nor transaminases correlated with hormone concentrations before or during therapy.. GH insufficiency is common in patients with chronic HCV infection. While GH secretion improves during antiviral therapy, IGF-1 remains low, indicating persistent GH resistance of hepatocytes. Whether improvement in GH secretion during treatment is due to a direct drug effect or related to the suppression of viral load could not be differentiated, as most patients demonstrated a positive virologic response.

Topics: Adult; Aged; Antiviral Agents; Drug Therapy, Combination; Female; Growth Hormone; Hepatitis C, Chronic; Humans; Insulin-Like Growth Factor Binding Protein 1; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Monosaccharides; Pituitary Function Tests; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Ribavirin; Statistics, Nonparametric; Treatment Outcome; Triazoles