Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients

Paolucci, Stefania; Fiorina, L; Piralla, Antonio; Gulminetti, Roberto; Novati, Stefano; Barbarini, Giorgio; Sacchi, Paolo; Gatti, Marta; Dossena, Luca; Baldanti, Fausto

doi:10.1186/1743-422x-9-245

Cited by 77 publications

(78 citation statements)

References 31 publications

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“…Further, position 98 is located between two positions coordinating the zinc ion, and changes might influence NS3P stability (9,81,82). A98T was identified in HCV genotype 3 patients, either treatment naïve or failing telaprevir therapy without apparent resistance (55,78). Interactions between residues 155 and 168 have been described previously (83,84), and substitutions at position 168 might compensate for the loss of replication induced by substitutions at position 155 by restoring such interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Substitutions at position 18 might influence the positioning of the NS3P active site on the membrane and thus NS3P activity, or they might induce conformational changes influencing interactions with NS4A and/or NS3H. Substitutions might increase HCV fitness across genotypes, since changes at position 18 were observed in genotype (isolate) 1a (TN), 2a (J6), and 5a (SA13) boceprevir escape variants, in treatment-naïve HCV genotype 1 or 4 patients (78), and in HCV genotype 1 patients with linear-PI treatment failure (38,79,80). Further, position 98 is located between two positions coordinating the zinc ion, and changes might influence NS3P stability (9,81,82).…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle

Serre

Jensen

Ghanem

et al. 2016

Antimicrob Agents Chemother

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bHepatitis C virus (HCV) NS3 protease inhibitors (PIs) are important components of novel HCV therapy regimens. Studies of PI resistance initially focused on genotype 1. Therefore, knowledge about the determinants of PI resistance for the highly prevalent genotypes 2 to 6 remains limited. Using Huh7.5 cell culture-infectious HCV recombinants with genotype 1 to 6 NS3 protease, we identified protease positions 54, 155, and 156 as hot spots for the selection of resistance substitutions under treatment with the first licensed PIs, telaprevir and boceprevir. Treatment of a genotype 2 isolate with the newer PIs vaniprevir, faldaprevir, simeprevir, grazoprevir, paritaprevir, and deldeprevir identified positions 156 and 168 as hot spots for resistance; the Y56H substitution emerged for three newer PIs. Substitution selection also depended on the specific recombinant. The substitutions identified conferred cross-resistance to several PIs; however, most substitutions selected under telaprevir or boceprevir treatment conferred less resistance to certain newer PIs. In a single-cycle production assay, across genotypes, PI treatment primarily decreased viral replication, which was rescued by PI resistance substitutions. The substitutions identified resulted in differential effects on viral fitness, depending on the original recombinant and the substitution. Across genotypes, fitness impairment induced by resistance substitutions was due primarily to decreased replication. Most combinations of substitutions that were identified increased resistance or fitness. Combinations of resistance substitutions with fitness-compensating substitutions either rescued replication or compensated for decreased replication by increasing assembly. This comprehensive study provides insight into the selection patterns and effects of PI resistance substitutions for HCV genotypes 1 to 6 in the context of the infectious viral life cycle, which is of interest for clinical and virological HCV research. With more than 100 million chronic infections causing approximately 500,000 deaths annually, hepatitis C virus (HCV) is a major global health and economic burden (1, 2). The six epidemiologically important genotypes differ in ϳ30% of their sequence and in their sensitivity to antiviral regimens (3-6). In Europe, the Americas, Asia, and Australasia, genotypes 1, 2, and 3 are most prevalent. While genotypes 4, 5, and 6 are more restricted to specific geographical regions in Africa and Asia, they account for 20% of global HCV infections and have spread beyond these primary geographical locations (1, 2, 7).The development of directly acting antivirals (DAAs) has revolutionized HCV therapy. The main components of interferonfree regimens introduced in the clinic are inhibitors of the HCV nonstructural (NS) proteins NS3 protease (NS3P), NS5A,8,9). Even though DAA-based therapy regimens could cure most patients in clinical trials, failure rates of 5 to 10% are to be expected in real life, due primarily to the development of DAA resistance (4,8). Given the large ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle

Serre

Jensen

Ghanem

et al. 2016

Antimicrob Agents Chemother

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“…Several groups have reported the detection of HCV variants with natural NS3/4A polymorphisms that are associated with protease inhibitor resistance in PR treatment-naive and/or protease inhibitor-naive patients, in particular polymorphisms at NS3 codon 80 (12)(13)(14)(15)(16)(17)(18)(19)(20). It is not clear how these baseline polymorphisms impact response to treatment.…”

mentioning

confidence: 99%

Baseline Hepatitis C Virus (HCV) NS3 Polymorphisms and Their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

Berger

Triki

Cartier

et al. 2014

Antimicrob Agents Chemother

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A challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%; P ‫؍‬ 0.47) or treatment naive (62% compared to 66%; P ‫؍‬ 0.72).

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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.…”

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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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Naturally occurring mutations to HCV protease inhibitors in treatment-naïve patients

Cited by 77 publications

References 31 publications

Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle

Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle

Baseline Hepatitis C Virus (HCV) NS3 Polymorphisms and Their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

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

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