Hepatitis C Viral Evolution in Genotype 1 Treatment-Naïve and Treatment-Experienced Patients Receiving Telaprevir-Based Therapy in Clinical Trials

Kieffer, Tara L.; Meyer, Sandra De; Bartels, Doug J.; Sullivan, James C.; Zhang, Eileen Z.; Tigges, Ann M.; Dierynck, Inge; Spanks, Joan; Dorrian, Jennifer; Jiang, Min; Adiwijaya, Bambang S.; Ghys, A; Beumont, Maria; Kauffman, Robert S.; Adda, Nathalie; Jacobson, Ira M.; Sherman, Kenneth E.; Zeuzem, Stefan; Kwong, Ann D.; Picchio, Gastón

doi:10.1371/journal.pone.0034372

Cited by 80 publications

(104 citation statements)

References 27 publications

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“…Algorithm 2 integrates more mutations and was extracted from the website Geno2Pheno (http://hcv.geno2pheno.org/), developed by the Max-Planck-Institut für Informatik, Saarbrücken, Germany. Algorithm 3 was restricted to mutations that confer a Ͼ3-fold shift in HCV replicon activity (V36M plus T54S, V55A, R155K, and A156T/V) and has been used in clinical trials with boceprevir (1,(17)(18)(19). Table 1 summarizes the considered mutations for these three algorithms.…”

Section: Methodsmentioning

confidence: 99%

Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

et al. 2015

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The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC 50 ) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P ‫؍‬ 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.

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Section: Methodsmentioning

confidence: 99%

Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

et al. 2015

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“…HCV RNA ''<25 IU/mL, target not detected'' is also described as undetectable HCV RNA in the study. HCV RNA levels were measured at the following study visits: screening, baseline, day 3, weeks 1, 2, 4, 5,6,8,10,12,14,16,20,24, and 36, end of treatment (week 48 or time of early discontinuation), and at follow-up visits 4, 12, and 24 weeks after the end of treatment. HCV RNA levels were also assessed at week 72 for all patients, including those who discontinued early.…”

Section: Methodsmentioning

confidence: 99%

“…Substitutions considered to confer higher-level in vitro resistance to telaprevir (>25-fold increase in replicon IC 50 ) were A156T/V and the combination of V36MþR155K. 16 Other changes within the NS3Á4A region were also investigated.…”

Section: Methodsmentioning

confidence: 99%

“…[13][14][15] In HCV genotype 1-infected patients, the use of telaprevir was associated with the emergence of resistant variants at NS3 amino acid positions 36, 54, 155, and 156. 13,15,16 In addition to these positions, the use of boceprevir has been associated with the emergence of resistance at positions 55 and 170. 14 Here we report the findings from a subanalysis of the Phase 3 telaprevir REALIZE trial, in which treatment outcomes and the emergence of viral variants were further characterized in patients with prior peginterferon/ribavirin treatment failure who did not achieve an SVR with subsequent telaprevir-based therapy.…”

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confidence: 99%

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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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“…Szá-mos mutáció ismert, amely a proteázgátló gyógyszerek hatékonyságát csökkenti. Rezisztencia kialakulását figyelték meg, ha a 36, 54, 55, 155, 156, illetve 170-es pozícióban levő aminosav cseréje volt észlelhető [14,15]. A mutációs profi lt a szubtípus komolyan befolyásol-ta.…”

Section: Első Generációs Készítmények: Boceprevir éS Telaprevirunclassified

A hepatitis C-vírus-bázispolimorfizmus jelentősége a kezelésben

Tornai

2015

Orvosi Hetilap

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A krónikus C-vírus hepatitis kezelése az elmúlt huszonöt évben igen jelentős fejlődésen ment keresztül. Az 1-es genotípusú betegek gyógyulási aránya a pegilált interferon és ribavirin kettős kombinációval elérhető 40-50%-ról a direkt ható antivirális szerek bevezetésével szignifi kánsan növekedett. A direkt ható antivirális szerek három nagy csoportja ismert, amelyek a vírus szaporodásának különböző fázisában fejtik ki hatásukat, a vírus nem strukturális fehérjéinek működését gátolják (NS3/4A proteáz, NS5A protein és NS5B polimeráz). A hepatitis C-vírus rendkívül gyorsan szaporodik és ennek kapcsán folyamatosan képződnek mutánsok, amelyek rezisztensek lehetnek a direkt ható antivirális terápiára. Mivel a kezelés előtt ezek már jelen lehetnek, és a direkt ható antivirális kezelés alatt csak ezek képesek szaporodni, a szelekciós nyomás hatására a rezisztens vírus váltja fel a vad típust. Ez különösen megfi gyelhető volt monoterápia esetén, emiatt a direkt ható antivirális szereket kezdetben pegilált interferonnal kombinálták, majd mostanában teljesen interferonmentes kezeléseket fejlesztettek ki, amelyek két vagy három direkt ható antivirá-lis szer kombinációjából állnak. Az első generációs proteázgátló telaprevir és boceprevir mellett megfi gyelhető volt, hogy az 1a genotípusú betegek kedvezőtlenebbül reagálnak, magasabb a rezisztenciaarány, mint az 1b-betegekben. Hasonló jelenség megfi gyelhető a korszerűbb proteázgátlókkal is, de az NS5A-és NS5B-gátlók esetén is. Ennek hátterében az alacsonyabb genetikai korlát áll, azaz kevesebb mutáció is elegendő a rezisztencia kialakulásához az 1a genotípusban. A szelektálódó rezisztens mutánsok jelentik az egyik legfontosabb kihívást az interferonmentes kezelések során. Orv. Hetil., 2015, 156(21), 849-854.Kulcsszavak: hepatitis C-vírus, direkt ható antivirális szerek, rezisztencia, genotípus 1a és 1b Signifi cance of hepatitis C virus baseline polymorphism during the antiviral therapyThe treatment of chronic hepatitis C has developed signifi cantly during the last 25 years. In patients with genotype 1 infection 40-50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased signifi cantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the fi rst generation of direct...

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Hepatitis C Viral Evolution in Genotype 1 Treatment-Naïve and Treatment-Experienced Patients Receiving Telaprevir-Based Therapy in Clinical Trials

Cited by 80 publications

References 27 publications

Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin

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

A hepatitis C-vírus-bázispolimorfizmus jelentősége a kezelésben

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