NS3 Protease Polymorphism and Natural Resistance to Protease Inhibitors in French Patients Infected with HCV Genotypes 1–5

Vallet, Sophie; Viron, Florent; Henquell, Cécile; Guillou‐Guillemette, Hélène Le; Lagathu, Gisèle; Abravanel, Florence; Trimoulet, Pascale; Soussan, Patrick Ben; Schvoerer, Évelyne; Rosenberg, Arielle R.; Gouriou, S.; Colson, Philippe; Izopet, Jacques; Payan, Christopher

doi:10.3851/imp1900

Cited by 51 publications

(52 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 99%

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Three 1a mutants were generated with the single NS3 substitutions V36M and R155K and the T54A-plus-A156T double substitution. All the mutants were amplifiable with the NS3G1FI-M13 and NS3G1RI-M13 primers (12). It is also possible to amplify the samples with the primers Mars F3 and Mars R2 (16), except for the two 1a mutations (V36M [QC3] and T54A plus A156T [QC4]).…”

Section: Methodsmentioning

confidence: 99%

“…The dilutions were made under RNase-free conditions; 0.5 U/l of RNasin was added to each mutant sample dilution (recombinant RNasin RNase inhibitor; Promega, Charbonnières, France). Each sample of the panel was aliquoted in 500 l and subjected to NS3 genotyping according to the recommended protocol (12).…”

Section: Methodsmentioning

confidence: 99%

“…These variants most often preexist in very low proportions and are detectable only by means of next-generation sequencing (NGS) (4-7), whereas they can sometimes be present as major viral populations detectable by means of population sequencing (8)(9)(10)(11). In a previous multicenter study, we described the natural genetic variability of the NS3 protease and the presence of variants resistant to protease inhibitors in patients infected with the HCV genotype 1 to 5 strains that are circulating in France in the absence of specific antiviral pressure (12). Although genotyping of HCV resistance to NS3 protease inhibitors has not found a clear indication in clinical practice in the context of the triple combination of pegylated alpha interferon, ribavirin, and either telaprevir or boceprevir, such genotyping is mandatory in clinical trials and cohort studies where these molecules are used, and it might find utility in the coming era of interferon-free regimens.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Multicenter Quality Control of Hepatitis C Virus Protease Inhibitor Resistance Genotyping

Vallet¹,

Larrat²,

Laperche³

et al. 2013

J Clin Microbiol

Self Cite

View full text Add to dashboard Cite

ccHepatitis C virus (HCV) protease inhibitor resistance-associated substitutions are selected during triple-therapy breakthrough. This multicenter quality control study evaluated the expertise of 23 French laboratories in HCV protease inhibitor resistance genotyping. A panel of 12 well-defined blinded samples comprising two wild-type HCV strains, nine transcripts from synthetic NS3 mutant samples or from clinical strains, and one HCV RNA-negative sample was provided to the participating laboratories. The results showed that any laboratory with expertise in sequencing techniques should be able to provide reliable HCV protease inhibitor resistance genotyping. Only a 0.7% error rate was reported for the amino acid sites studied. The accuracy of substitution identification ranged from 75% to 100%, depending on the laboratory. Incorrect results were mainly related to the methodology used. The results could be improved by changing the primers and modifying the process in order to avoid cross-contamination. This study underlines the value of quality control programs for viral resistance genotyping, which is required prior to launching observational collaborative multicenter studies on HCV resistance to direct-acting antiviral agents. H epatitis C virus (HCV) resistance-associated variants have been shown to emerge rapidly with the use of direct-acting antiviral (DAA) agents with a low-to-moderate barrier to resistance when used as monotherapies (1). Despite significant viral load reductions during administration of the two most advanced protease inhibitors, telaprevir and boceprevir, viral breakthroughs often occur as a result of the outgrowth of variants bearing a number of well-identified amino acid substitutions that confer resistance to these agents (2, 3). The very early selection of resistant viral populations in patients receiving protease inhibitors is in keeping with the preexistence of such variants in most HCVinfected patients before the initiation of treatment. These variants most often preexist in very low proportions and are detectable only by means of next-generation sequencing (NGS) (4-7), whereas they can sometimes be present as major viral populations detectable by means of population sequencing (8-11). In a previous multicenter study, we described the natural genetic variability of the NS3 protease and the presence of variants resistant to protease inhibitors in patients infected with the HCV genotype 1 to 5 strains that are circulating in France in the absence of specific antiviral pressure (12). Although genotyping of HCV resistance to NS3 protease inhibitors has not found a clear indication in clinical practice in the context of the triple combination of pegylated alpha interferon, ribavirin, and either telaprevir or boceprevir, such genotyping is mandatory in clinical trials and cohort studies where these molecules are used, and it might find utility in the coming era of interferon-free regimens. In particular, the impact of such

show abstract

“…When RAVs are present at baseline, either as major viral population or as minority variants, they could greatly affect viral response to treatment, particularly in monotherapy, determining a suboptimal viral decay and thus further increasing in resistance level [14,[19][20][21][22][23][24][25][26]. This point should be taken into account to fully determine the kinetics of HCV-RNA decay.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus RNA levels at week-2 of telaprevir/boceprevir administration are predictive of virological outcome

Cento

Paolo

Carlo

et al. 2015

Digestive and Liver Disease

View full text Add to dashboard Cite

a b s t r a c tBackground: Triple therapy with telaprevir/boceprevir + pegylated-interferon + ribavirin can achieve excellent antiviral efficacy, but it can be burdened with resistance development at failure. Aims: To evaluate kinetics of hepatitis C virus (HCV) RNA decay and early resistance development, in order to promptly identify patients at highest risk of failure to first generation protease inhibitors. Methods: HCV-RNA was prospectively quantified in 158 patients receiving pegylatedinterferon + ribavirin + telaprevir (N = 114) or + boceprevir (N = 44), at early time-points and during per protocol follow-up. Drug resistance was contextually evaluated by population sequencing. Results: HCV-RNA at week-2 was significantly higher in patients experiencing virological failure to triple-therapy than in patients with sustained viral response (2.3 [1.9-2.8] versus 1.2 [0.3-1.7] log IU/mL, p < 0.001). A 100 IU/mL cut-off value for week-2 HCV-RNA had the highest sensitivity (86%) in predicting virological success. Indeed, 23/23 (100%) patients with undetectable HCV-RNA reached success, versus 26/34 (76.5%) patients with HCV-RNA < 100 IU/mL, and only 11/31 (35.5%) with HCV-RNA > 100 IU/mL (p < 0.001). Furthermore, differently from failing patients, none of the patient with undetectable HCV-RNA at week-2 had baseline/early resistance. Cento et al. / Digestive and Liver Disease xxx (2014) xxx-xxx Conclusions: With triple therapy based on first generation protease inhibitors, suboptimal HCV-RNA decay at week-2 combined with early detection of resistance can help identifying patients with higher risk of virological failure, thus requiring a closer monitoring during therapy.

show abstract

NS3 Protease Polymorphism and Natural Resistance to Protease Inhibitors in French Patients Infected with HCV Genotypes 1–5

Abstract: We have developed an HCV protease NS3 inhibitor resistance genotyping tool suitable for use with HCV genotypes 1-5. Polymorphism data is valuable for interpreting genotypic resistance profiles in cases of failure of anti-HCV NS3 protease treatment.

Cited by 51 publications

References 50 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

Multicenter Quality Control of Hepatitis C Virus Protease Inhibitor Resistance Genotyping

Hepatitis C virus RNA levels at week-2 of telaprevir/boceprevir administration are predictive of virological outcome

Contact Info

Product

Resources

About