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Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women.

ABSTRACT: Hepatitis C virus (HCV) non-nucleoside inhibitors (NNIs) target the viral RNA-dependent RNA polymerase encoded by the NS5B gene. Several NNIs share a similar allosteric binding site, and their antiviral efficacy is attenuated by a cysteine-to-tyrosine mutation at amino acid 316 (C316Y). In the current study, we assessed NS5B resistance mutations in treatment-naive individuals from a prospective natural history study of viral infections in women.Partial NS5B sequences from HCV-positive women were amplified by RT-PCR. Additionally, subcloning was performed to evaluate intrapatient variability in selected samples.HCV NS5B genotypes were 45 genotype 1a (57.0%), 11 genotype 1b (13.9%), 5 genotype 2a (6.3%), 3 genotype 2b (3.8%), 9 genotype 3a (11.4%) and 6 genotype 4a (7.6%). One HCV genotype 1a-infected patient was found to have the C316Y mutation (1.3%). Clonal analysis further revealed that all NS5B sequences from this individual--representing three serum samples collected 4 years apart--contained the C316Y mutation. In contrast, the S282T resistance mutation was not found in any samples.The C316Y polymerase resistance mutation was found in 1.3% of samples from HCV-infected women. The presence of this mutation over time suggests significant replicative fitness of this variant and has implications for development of new specifically targeted antiviral therapies against HCV (STAT-C) targeting this region.

SUBMITTER: Dryer PD

PROVIDER: S-EPMC2766823 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women.

Dryer Peter D PD Limketkai Berkeley N BN Martin Christina M CM Ma Gang G Sherman Kenneth E KE Taylor Lynn E LE Mayer Kenneth H KH Jamieson Denise J DJ Blackard Jason T JT

The Journal of antimicrobial chemotherapy 20090918 5

<h4>Objectives</h4>Hepatitis C virus (HCV) non-nucleoside inhibitors (NNIs) target the viral RNA-dependent RNA polymerase encoded by the NS5B gene. Several NNIs share a similar allosteric binding site, and their antiviral efficacy is attenuated by a cysteine-to-tyrosine mutation at amino acid 316 (C316Y). In the current study, we assessed NS5B resistance mutations in treatment-naive individuals from a prospective natural history study of viral infections in women.<h4>Methods</h4>Partial NS5B seq ...[more]

PMID: 19767319

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Project description:IntroductionTreatment of HCV infection with peginterferon and ribavirin results in a low sustained virologic response rate, but has a number of undesirable adverse effects. Direct-acting antivirals (DAAs) offer a high efficacy, low risk, and a short treatment time. However, the existence of resistance-associated mutations, particularly in the NS5B polymerase, can attenuate the efficacy of DAAs. The objective of this study was to identify amino acid changes in the NS5B gene linked to DAA resistance in treatment-naive Vietnamese chronic hepatitis C patients.MethodsBlood samples and treatment data were collected from 100 HCV-infected patients hospitalized at the National Hospital for Tropical Diseases between January and December 2020; the plasma was then isolated and stored at -80°C for molecular analysis. The NS5B gene fragments of 100 samples were amplified with specified primers and the nucleotide sequences were obtained using the Sanger sequencing system. The nucleotide sequences were then analyzed and compared to identify substitutions in the NS5B region.ResultsA total of 100 HCV isolates from patients were classified into three genotypes, including genotypes 1, 3, and 6. The NS5B sequence analysis revealed many amino acid mutations in all genotypes, although these mutations were not strongly associated with resistance to DAAs like S282T. Analytical data on ribavirin-resistance mutations revealed that Q309R was predominantly found in genotype 1a, D310N was mostly found in genotype 1b, and N244I, T329I, A333E were not observed. The following mutations were shown to be related with DAAs resistance: E237G, S282R, L320F, V321A, and V321I. Furthermore, NS5B-resistance mutations were not associated with clinical characteristics, long-term virological response, or improvements in clinical parameters (liver enzymes or liver fibrosis index).ConclusionAlthough NS5B mutations were found in treatment-naive Vietnamese patients, changes in the NS5B gene did not appear to be highly correlated with HCV ribavirin and DAA antiviral resistance.

Project description:Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo.Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

Project description:BACKGROUND:It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen (HBsAg) are associated with nucleoside/nucleotide analog resistance. AIM:To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations. METHODS:In total, 19440 patients with chronic hepatitis B virus infection, who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017, were enrolled. As determined by sequence analysis, 6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations. Phenotypic analyses were performed to evaluate HBsAg production, replication capacity, and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V. RESULTS:The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations. In particular, these mutations were sQ101H/K/R, sS114A/L/T, sT118A/K/M/R/S/V, sP120A/L/Q/S/T, sT/I126A/N/P/S, sM133I/L/T, sC137W/Y, sG145A/R, and sA159G/V. Among these, sA159V was detected in 1.95% (136/6982) of patients with resistance mutations and 1.08% (134/12,458) of patients lacking resistance mutations (P < 0.05). The coexistence of sA159V with lamivudine (LAM) and entecavir (ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance. HBsAg production was significantly lower and the replication capacity was significantly higher, without a significant difference in LAM/ETV susceptibility, in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts. CONCLUSION:In summary, we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations. sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.

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Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women.

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Screening for hepatitis C virus non-nucleotide resistance mutations in treatment-naive women.

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