Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies

Barnard, Richard; Howe, John A.; Ogert, Robert A.; Zeuzem, Stefan; Poordad, Fred; Gordon, Stuart C.; Ralston, Robert; Tong, Xiao; Sniukiene, Vilma; Strizki, Julie; Ryan, Desmon̄d; Long, Jianmin; Qiu, Ping; Brass, Clifford A.; Albrecht, Janice K.; Burroughs, Margaret; Vuocolo, Scott; Hazuda, Daria J.

doi:10.1016/j.virol.2013.06.029

Cited by 61 publications

(61 citation statements)

References 28 publications

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“…Nodes are shown in green when at least one mutation was detected (according to algorithm 3) and the patient achieved an SVR, in yellow when a mutation was detected and the patient did not achieve an SVR, and in red when no mutation was detected and the patient did not achieve an SVR. ered in the analysis (5,12). In our HCV-infected cohort restricted to poor IFN-RBV responders, we observed no relationship between the presence of baseline NS3 RAVs and protease inhibitorbased triple-therapy outcomes.…”

Section: Figmentioning

confidence: 56%

“…It included real-life patients treated with either telaprevir (54%) or boceprevir (46%). The significant disequilibrium in SVR according to the protease inhibitor used (36% with boceprevir and 64% with telaprevir; P ϭ 0.008) might explain the discrepancy with the boceprevir clinical trial results described by Barnard et al (12). Indeed, of 16 patients in our study presenting with baseline RAVs according to the same algorithm as that of Barnard et al (12), 5/8 treated with telaprevir achieved an SVR, whereas only 3/8 treated with boceprevir did.…”

Section: Figmentioning

confidence: 75%

“…In pooled phase II and III boceprevir studies, a lower SVR rate was observed in poor IFN responders with baseline RAVs than in those without baseline RAVs (23% versus 34%, respectively; P ϭ 0.002). In this population, the presence of mutations conferring a Ͼ3-fold shift in the concentration needed to inhibit HCV replication by 50% in vitro (IC 50 ) for telaprevir or boceprevir (V36M, T54S, V55A, or R155K) at baseline was associated with non-SVR in boceprevir-treated patients (12). Moreover, in the RE-ALIZE study with telaprevir, no prior null responders with the preexisting variants T54S or R155K achieved an SVR (13).…”

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confidence: 92%

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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: Figmentioning

confidence: 56%

Section: Figmentioning

confidence: 75%

mentioning

confidence: 92%

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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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“…Az első generációs NS3/4A proteázgátlók esetén a hármas kombináció sikerének és a rezisztencia kialakulá-sának az egyik kulcstényezője a peg-IFN-re adott válasz. Amennyiben a beteg a kettős kombinációra gyengébben reagált, korábbi nullreszponder vagy aktuálisan a negyedik heti vírusválasz <1 log 10 , a rezisztencia kialakulásának a valószínűsége jelentősen magasabb, mint a jól reagá-lókban [17].…”

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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“…Many uncertainties exist regarding the clinical impact of RAVs, making interpretation of HCV genotypic drug resistance a challenge. Some naturally occurring polymorphisms or treatment-associated substitutions have been shown to impact treatment response only in the context of specific HCV genotypes or subtypes (Barnard et al, 2013;Sarrazin et al, 2007;Sullivan et al, 2013;Susser et al, 2009). How polymorphisms are influencing therapy outcome depends also on the viral genetic sequence and drug context.…”

Section: Introductionmentioning

confidence: 99%

Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning

Cuypers

Libin

Schrooten

et al. 2017

Infection, Genetics and Evolution

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Resistance-associated variants (RAVs) have been shown to influence treatment response to direct-acting antivirals (DAAs) and first generation NS3/4A protease inhibitors (PIs) in particular. Interpretation of hepatitis C virus (HCV) genotypic drug resistance remains a challenge, especially in patients who previously failed DAA therapy and need to be retreated with a second DAA based regimen. Bayesian network (BN) learning on HCV sequence data from patients treated with DAAs could provide insight in resistance pathways against PIs for HCV subtypes 1a and 1b, in a similar way as applied before for HIV. The publicly available 'Rega-BN' tool chain was developed to study associative analyses for various pathogens. Our first analysis, comparing sequences from PI-naïve and PIexperienced patients, determined that NS3 substitutions R155K and V36M arise with PI-exposure in HCV1a infected patients, and were defined as major and minor resistance-associated variants respectively. NS3 variant 174H was newly identified as potentially related to PI resistance. In a second analysis, NS3 sequences from PInaïve patients who cleared the virus during PI therapy and from PI-naïve patients who failed PI therapy were compared, showing that NS3 baseline variant 67S predisposes to treatment-failure and variant 72I to treatment success. This approach has the potential to better characterize the role of more RAVs, if sufficient therapy annotated sequence data becomes available in curated public databases. In addition, polymorphisms present in baseline sequences that predispose patients to therapy failure can be identified using this approach.

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Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies

Abstract: We detected no association between the presence of baseline amino acid variants at boceprevir resistance-associated loci and outcome in the context of good IFN response.

Cited by 61 publications

References 28 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

A hepatitis C-vírus-bázispolimorfizmus jelentősége a kezelésben

Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning

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