Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection
ABSTRACT Pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin (RBV) therapy is currently the de-facto standard treatment for hepatitis C virus (HCV) infection. The aims of this study were to analyze the clinical and virological factors associated with a higher rate of response in patients with HCV genotype 1b infection treated with combination therapy.
We analyzed, retrospectively, 239 patients with chronic hepatitis C-1b infection who received 48 weeks of combination therapy. We assessed clinical and laboratory parameters, including age, gender, pretreatment hemoglobin, platelet counts, HCV RNA titer, liver histology, the number of interferon sensitivity determining region (ISDR) mutations and substitutions of the core amino acids 70 and 91. Drug adherence was monitored in each patient. We carried out univariate and multivariate statistical analyses of these parameters and clinical responses.
On an intention-to-treat (ITT) analysis, 98 of the 239 patients (41%) had sustained virological responses (SVRs). Patients with more than two mutations in the ISDR had significantly higher SVR rates (P<0.01). Univariate analyses showed that stage of fibrosis, hemoglobin, platelet counts, ISDR mutations, serum HCV RNA level, and adherence to PEG-IFN plus RBV were significantly correlated with SVR rates. Multivariate analysis in subjects with good drug adherence extracted the number of ISDR mutations (two or more: odds ratio [OR] 5.181).
The number of mutations in the ISDR sequence of HCV-1b (>or=2) is the most effective parameter predicting a favorable clinical outcome of 48-week PEG-IFN plus RBV therapy in patients with HCV genotype 1b infection.
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ABSTRACT: Pegylated interferon lambda-1a (Lambda) is currently in clinical development for the treatment of chronic hepatitis C virus (HCV) infection. To gain insight into the potential mechanisms of non-responsiveness that may occur in patients treated with Lambda, HCV subgenomic replicon cell-lines with impaired susceptibility to the unpegylated recombinant (r) form of interferon (IFN) lambda-1 (rIFNλ) were isolated and characterized. The selected replicon cell populations showed a defect in the activation of the IFN-dependent JAK-STAT signaling pathway. Reduced phosphorylation of STAT proteins and lower expression levels of the cellular janus kinases Jak1 and Tyk2 were observed in these cell populations, which may account for the impaired JAK-STAT signaling and reduced antiviral responses to rIFNλ. Overall, this in vitro study provides molecular insights into the possible mechanism of viral evasion to rIFNλ in the HCV replicon cell system.Virology 07/2013; 444(1-2). DOI:10.1016/j.virol.2013.07.005 · 3.28 Impact Factor
12/2012; Agency for Healthcare Research and Quality.
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ABSTRACT: Cell culture produced hepatitis C virus (HCV) has been subjected to up to 100 serial passages in human hepatoma cells in the absence or presence of different doses of interferon-α (IFN-α). Virus survival, genetic changes, fitness levels and phenotypic traits have been examined. While high initial IFN-α doses (increasing from 1 to 4 IU/ml) did not allow HCV survival beyond passage 40, a gradual exposure (from 0.25 to 10 IU/ml) allowed the virus to survive for at least 100 passages. The virus passaged in the presence of IFN-α acquired IFN-α resistance as evidenced by enhanced progeny production and viral protein expression in an IFN-α environment. A partial IFN-α resistance was also noted in populations passaged in the absence of IFN-α. All lineages acquired adaptative mutations, and multiple, non-synonymous mutations scattered throughout the genome were present in IFN-α-selected populations. Comparison of consensus sequences indicates a dominance of synonymous versus non-synonymous substitutions. IFN-α-resistant populations displayed decreased sensitivity to a combination of IFN-α and ribavirin. A phenotypic trait common to all assayed viral populations is the ability to increase shut-off of host cell protein synthesis, accentuated in infections with IFN-α-selected populations carried out in the presence of IFN-α. The trait was associated with enhanced phosphorylation of PKR and eIF2α, although other contributing factors are likely. The results suggest that multiple, independent mutational pathways can confer IFN-α resistance to HCV, and might explain why no unified picture has been obtained regarding IFN-α resistance in vivo.Journal of Virology 05/2013; 87(13). DOI:10.1128/JVI.02824-12 · 4.65 Impact Factor