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IL28B genotype effects during early treatment with peginterferon and ribavirin in difficult-to-treat hepatitis C virus infection.

ABSTRACT: BACKGROUND:Mathematical models of hepatitis C virus (HCV) during therapy may elucidate mechanisms of action for antiviral therapy. In genome-wide association studies, IL28B gene polymorphisms are highly predictive of therapeutic clearance of HCV. METHODS:We collected sera from 20 chronically infected HCV participants at 13 points during the first 28 days of therapy. We assessed the presence of the C allele at single-nucleotide polymorphism rs12979860 using the ABI TaqMan allelic discrimination kit. We estimated dynamic parameters from the entire population using the Neumann model for HCV infection. Statistical methods for repeated nonlinear measures compared model parameters by established predictors of response. RESULTS:The frequencies of IL28B genotypes were 6 (C/C), 11 (C/T), and 3 (T/T). The mean log decline in HCV RNA from 0 to 48 hours was more rapid among C/C genotype participants compared with C/T or T/T genotype participants (1.4 vs 0.7; P = .07), and from 2 days to 14 days (1.6 vs 0.7; P = .04). In the multivariate model, the C/C genotype predicted a steeper second-phase decline when adjusted for race (P = .01). CONCLUSIONS:The presence of the C/C genotype at IL28B rs12979860 exerts its antiviral effect by increasing the infected hepatocyte death rate. This suggests that an immune-mediated mechanism is responsible.

SUBMITTER: Scott J

PROVIDER: S-EPMC3132139 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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IL28B genotype effects during early treatment with peginterferon and ribavirin in difficult-to-treat hepatitis C virus infection.

Scott John J Holte Sarah S Urban Thomas T Burgess Caitlin C Coppel Erica E Wang Chia C Corey Larry L McHutchison John J Goldstein David D

The Journal of infectious diseases 20110801 3

<h4>Background</h4>Mathematical models of hepatitis C virus (HCV) during therapy may elucidate mechanisms of action for antiviral therapy. In genome-wide association studies, IL28B gene polymorphisms are highly predictive of therapeutic clearance of HCV.<h4>Methods</h4>We collected sera from 20 chronically infected HCV participants at 13 points during the first 28 days of therapy. We assessed the presence of the C allele at single-nucleotide polymorphism rs12979860 using the ABI TaqMan allelic d ...[more]

PMID: 21742841

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Project description:BACKGROUND:This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon ?-2a (PegIFN?-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients. METHODS:Patients who had failed PegIFN?/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFN?/RBV. Eight patients in the Phase 1 group received short-term (?14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFN?-2a/RBV for 12 weeks followed by PegIFN?-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). RESULTS:Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies. CONCLUSIONS:The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFN?-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted. TRIAL REGISTRATION:NCT01323244 . (date of registration: March 24, 2011).

Dataset Information

IL28B genotype effects during early treatment with peginterferon and ribavirin in difficult-to-treat hepatitis C virus infection.

Publications

IL28B genotype effects during early treatment with peginterferon and ribavirin in difficult-to-treat hepatitis C virus infection.

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