Natural Prevalence of Hepatitis C Virus Variants with Decreased Sensitivity to NS3·4A Protease Inhibitors in Treatment‐Naive Subjects

Bartels, Doug J.; Zhou, Yi; Zhang, Eileen Z.; Marcial, Michelle; Byrn, Randal A.; Pfeiffer, Thomas; Tigges, Ann M.; Adiwijaya, Bambang S.; Lin, Chao; Kwong, Ann D.; Kieffer, Tara L.

doi:10.1086/591141

Cited by 196 publications

(176 citation statements)

References 33 publications

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“…Thus, The present study showed that the frequency of mutations associated with resistance was 18.9%, which is inconsistent with the results of previous studies. However, when only individual frequencies of a mutation are considered, including T54A, T54S, V55A, R155K (2.7%) and A156T (5.4%), the results are similar to those reported in the literature (Bartels et al 2008, Kuntzen et al 2008, Peres-da-Silva et al 2010.…”

Section: Discussionsupporting

confidence: 85%

“…Although some studies have reported a frequency of resistance mutations of less than 1% (Lu et al 2007, Bartels et al 2008, Cubero et al 2008, others have demonstrated a frequency that oscillates between 0.3-2.8% (Kuntzen et al 2008). Few studies have been conducted in Brazil and currently, there is only one study, which was conducted in Rio de Janeiro (RJ), that has reported the presence of a subtype 1a virus with a T54S mutation at a frequency of 4.1%.…”

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confidence: 98%

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Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Zeminian

Padovani

Corvino

et al. 2013

Mem. Inst. Oswaldo Cruz

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The goal of treatment of chronic hepatitis C is to achieve a sustained virological response, which is defined as exhibiting undetectable hepatitis C virus (HCV) RNA levels in serum following therapy for at least six months. However, the current treatment is only effective in 50% of patients infected with HCV genotype 1, the most prevalent genotype in Brazil. Inhibitors of the serine protease non-structural protein 3 (NS3) have therefore been developed to improve the responses of HCV-infected patients. However, the emergence of drug-resistant variants has been the major obstacle to therapeutic success. The goal of this study was to evaluate the presence of resistance mutations and genetic polymorphisms in the NS3 genomic region of HCV from 37 patients infected with HCV genotype 1 had not been treated with protease inhibitors. Plasma viral RNA was used to amplify and sequence the HCV NS3 gene. The results indicate that the catalytic triad is conserved. A large number of substitutions were observed in codons 153, 40 and 91; the resistant variants T54A, T54S, V55A, R155K and A156T were also detected. This study shows that resistance mutations and genetic polymorphisms are present in the NS3 region of HCV in patients who have not been treated with protease inhibitors, data that are important in determining the efficiency of this new class of drugs in Brazil.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 98%

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Zeminian

Padovani

Corvino

et al. 2013

Mem. Inst. Oswaldo Cruz

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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: 60%

“…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%

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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“…Using population sequence analysis (i.e., direct sequencing), baseline RAVs against NS3/4A protease inhibitors (PIs) telaprevir and boceprevir have been detected in 2 to 28% of treatment-naive patients in previous studies (1,(5)(6)(7)(8)(9)(10)(11). During triple therapies combining pegIFN and ribavirin with telaprevir or boceprevir, the presence of preexisting RAVs at baseline did not decrease the sustained virological response (SVR) rates (rates of infection cure) in patients who naturally responded to pegIFN-ribavirin; however, lower SVR rates have been observed in patients with baseline RAVs who were also poor pegIFN-ribavirin responders.…”

mentioning

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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Natural Prevalence of Hepatitis C Virus Variants with Decreased Sensitivity to NS3·4A Protease Inhibitors in Treatment‐Naive Subjects

Cited by 196 publications

References 33 publications

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

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

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

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