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Utility of detection of telaprevir-resistant variants for prediction of efficacy of treatment of hepatitis C virus genotype 1 infection.

ABSTRACT: The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir-peginterferon (PEG-IFN)-ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of <1.3 ?g/kg of body weight, an IL28B rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of <5,000/mm(3) as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment.

SUBMITTER: Akuta N

PROVIDER: S-EPMC3911448 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Utility of detection of telaprevir-resistant variants for prediction of efficacy of treatment of hepatitis C virus genotype 1 infection.

Akuta Norio N Suzuki Fumitaka F Fukushima Taito T Kawamura Yusuke Y Sezaki Hitomi H Suzuki Yoshiyuki Y Hosaka Tetsuya T Kobayashi Masahiro M Hara Tasuku T Kobayashi Mariko M Saitoh Satoshi S Arase Yasuji Y Ikeda Kenji K Kumada Hiromitsu H

Journal of clinical microbiology 20131106 1

The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir-peginterferon (PEG-IFN)-ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis ident ...[more]

PMID: 24197875

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Project description:Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations.We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 ?g per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48.Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001).In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).

Project description:BackgroundThe use of pegylated interferon alpha and ribavirin (PegIFN/RBV) for the retreatment of chronic hepatitis C virus (HCV) infection without a sustained virological response (SVR) prior to PegIFN/RBV treatment has resulted in low success rates.AimsTo investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN/RBV in patients infected with HCV genotypes 1 and 4 who were previously treated with PegIFN/RBV and failed to achieve SVR.Study designMulti-center, retrospective, cross-sectional study.MethodsThe study included 111 patients: 80 prior relapsers, 25 prior null responders, and six prior partial responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-week PegIFN/RBV treatment; virological response results were assessed at weeks 4, 12, and 24. Treatment was discontinued in patients with HCV RNA >1000 IU/mL at week 4 or with negative RNA results at week 4 but >1000 IU/mL at week 12. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), and virological response at 24th week of treatment were evaluated. The side effects of combination therapy and the rates of treatment discontinuation were investigated.ResultsThe mean age of the patients was 56.02±9.96 years and 45.9% were male. Ninety-one percent of the patients were infected with viral genotype 1, 69.6% with the interleukin (IL) 28B genotype CT and 20.2% were cirrhotic. The RVR rate was 86.3% in prior relapsers, 56% in prior null responders, and 50% in prior partial responders (p=0.002). EVR rates in those groups were 91.3%, 56%, and 83.3%, respectively (p<0.001). eRVR rates were 83.8% in prior relapsers, 48% in prior null responders, and 50% in prior partial responders (<0.001). The virological response at the 24th week of treatment was found to be the highest in prior relapsers (88.8%); it was 56% in prior null responders and 66.7% in prior partial responders (p<0.001). Common side effects were fatigue, headache, anorexia, malaise, anemia, pruritus, dry skin, rash, dyspepsia, nausea, pyrexia, stomachache, and anorectal discomfort. All treatments were discontinued due to side effects in 9.9% of patients.ConclusionHigh virological response rates were obtained with TVR/PegIFN/RBV treatment. Although side effects were frequently observed, the discontinuation rate of combination therapy was low.

Dataset Information

Utility of detection of telaprevir-resistant variants for prediction of efficacy of treatment of hepatitis C virus genotype 1 infection.

Publications

Utility of detection of telaprevir-resistant variants for prediction of efficacy of treatment of hepatitis C virus genotype 1 infection.

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