67 Molecular Characterization of HCV Resistance to Telaprevir by Means of Ultra-Deep Pyrosequencing: Preexisting Resistant Variants and Dynamics of Resistant Populations

Chevaliez, Stéphane; Rodríguez, C.; Soulier, A.; Ahmed–Belkacem, Abdelhakim; Hézode, C.; Pawlotsky, Jean‐Michel

doi:10.1016/s0168-8278(11)60069-x

Cited by 29 publications

(26 citation statements)

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“…[19][20][21] Also in line with other studies, 20,22,23 the presence of resistant variants at baseline does not necessarily preclude successful treatment (i.e., SVR) in all patient groups, especially in prior relapsers. However, there might have been an effect in prior null responders.…”

Section: Discussionsupporting

confidence: 56%

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

et al. 2012

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In the Phase 3 REALIZE study, 662 genotype 1 hepatitis C virus (HCV)-infected patients with prior peginterferon/ribavirin treatment failure (including relapsers, partial, and null responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 weeks of peginterferon/ribavirin (lead-in T12/PR48), or 12 weeks of placebo (PR48), combined with a total of 48 weeks of peginterferon alfa-2a/ribavirin. Sustained virologic response (SVR) rates were 64% (T12/PR48), 66% (lead-in T12/PR48), and 17% (PR48). This analysis aimed to characterize treatment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR. HCV NS3Á4A population sequencing was performed at baseline, during treatment, and follow-up. Telaprevir-resistant variants were classified into lower-level (3-to 25-fold 50% inhibitory concentration [IC 50 ] increase: V36A/M, T54A/S, R155I/K/M/T, and A156S) and higher-level (>25-fold IC 50 increase: V36M1R155K and A156T/V) resistance. Resistant variants were uncommon at baseline. Overall, 18% (52%, 19%, and 1% of prior null and partial responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic failure, with no significant difference with or without a lead-in. Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase was associated with higher-or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months) in 58% of non-SVR patients. Conclusion: In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, resistant variants became undetectable over time. (HEPATOLOGY 2012;56:2106-2115

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Section: Discussionsupporting

confidence: 56%

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

et al. 2012

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“…Nonetheless, the available pre-clinical and clinical data indicate that drug-resistant variants emerge during treatment or are already present before start of therapy [10,11]. In addition, these new combination therapies induce considerable side effects and in liver transplant patients their use will be complicated because of complex drug-drug interactions [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice

Lacek

Vercauteren

Grzyb

et al. 2012

Journal of Hepatology

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“…In PROVE2 trial amino acid substitutions known to confer resistance to TVR were found at baseline in all 28 patients [36]. While no enrichment in TVR-resistant viral population was observed in the control group (n=5), in TVR-failures, the viral population at the time of failure was considerably enriched in TVR-resistant variants.…”

Section: Resistant Variants Detectable At the Baseline: Are They Impomentioning

confidence: 97%

Resistance-Associated Variants in Chronic Hepatitis C Patients Treated with Protease Inhibitors

Gambarin‐Gelwan

Jacobson

2011

Curr Gastroenterol Rep

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Direct-acting antiviral agents in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) significantly improve sustained virologic response rate and reduce duration of therapy among both treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C. One of the most important considerations with both boceprevir and telaprevir is the potential development of resistant variants with therapy. Patients with poor intrinsic responsiveness to interferon, and those with incomplete virological suppression on protease inhibitor therapy, appear to be at higher risk for resistance. In this article we will define antiviral resistance and review the data on both in vitro and in vivo resistance to protease inhibitors, concentrating on data on boceprevir and telaprevir. We will also explore the significance of resistant variants present at the baseline, as well as the fate of the resistant variants and the ways to minimize the development of resistance to protease inhibitors.

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67 Molecular Characterization of HCV Resistance to Telaprevir by Means of Ultra-Deep Pyrosequencing: Preexisting Resistant Variants and Dynamics of Resistant Populations

Cited by 29 publications

References 0 publications

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice

Resistance-Associated Variants in Chronic Hepatitis C Patients Treated with Protease Inhibitors

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