Mutations in hepatitis C virus NS3 protease domain associated with resistance to specific protease inhibitors in antiviral therapy naïve patients

Peres-da-Silva, Allan; Almeida, Adílson José de; Lampe, Elisabeth

doi:10.1007/s00705-010-0642-z

Cited by 28 publications

(39 citation statements)

References 24 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%

“…The substitution T54S, which had a frequency of 2.7%, was previously reported at a frequency of 4.1% in HCV subtype 1a variants in RJ (Peres-da-Silva et al 2010), suggesting that this substitution is already present in Brazilian variants even in the absence of selective drug pressure.…”

Section: Discussionmentioning

confidence: 68%

“…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%. Although a V170I substitution has not yet been associated with resistance, it was detected in 98% of samples (Peres-da-Silva et al 2010).…”

mentioning

confidence: 95%

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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%

Section: Discussionmentioning

confidence: 68%

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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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“…and amplification of viral RNA -Onestep RT-PCR followed by a second round of PCR (RTnested PCR) was used to amplify the NS3 protease region of HCV using specific oligonucleotide primers for each subtype, as previously described (Peres-da-Silva et al 2010). For the RT-PCR reactions, the reagents from the Superscript ™ III One-Step RT-PCR system (Life Technologies, Invitrogen, Carlsbad, CA, USA) were used.…”

Section: Reverse-transcription (Rt)-nested Polymerase Chain Reaction mentioning

confidence: 99%

“…To date, several specific NS3-4A S protease inhibitors, such as VX-950, SCH6, SCH503034, ITMN-191 and TMC435350, have been designed and are currently being evaluated in clinical trials (López-Labrador 2008). However, given the high level of variability of HCV, which is a result of the error-prone nature of RNA-dependent RNA polymerase, variants resistant to a number of protease inhibitors have been identified (Peres-da-Silva et al 2010, Vermehren & Sarrazin 2011) and represent a current challenge for therapy with DAAs.…”

mentioning

confidence: 99%

Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

Peres-da-Silva

Almeida

Lampe

2012

Mem. Inst. Oswaldo Cruz

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Protease inhibitor resistance mutations in untreated Brazilian patients infected with HCV: Novel insights about targeted genotyping approaches

et al. 2014

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Several new direct-acting antiviral (DAA) drugs are being developed or are already approved for the treatment of chronic hepatitis C virus (HCV) infection. HCV variants presenting drug-resistant phenotypes were observed both in vitro and during clinical trials. The aim of this study was to characterize amino acid changes at positions previously associated with resistance in the NS3 protease in untreated Brazilian patients infected with HCV genotypes 1a and 1b. Plasma samples from 171 untreated Brazilian patients infected with HCV were obtained from the Department of Gastroenterology of Clinics Hospital (HCFMUSP) in São Paulo, Brazil. Nested PCR and Sanger sequencing were used to obtain genetic information on the NS3 protein. Bioinformatics was used to confirm subtype information and analyze frequencies of resistance mutations. The results from the genotype analysis using non-NS3 targeted methods were at variance with those obtained from the NS3 protease phylogenetic analyses. It was found that 7.4% of patients infected with HCV genotype 1a showed the resistance-associated mutations V36L, T54S, Q80K, and R155K, while 5.1% of patients infected with HCV genotype 1b had the resistance-associated mutations V36L, Q41R, T54S, and D168S. Notably, codons at positions 80 and 155 differed between samples from Brazilian patient used in this study and global isolates. The present study demonstrates that genotyping methods targeting the NS3 protein showed a difference of results when compared to mainstream methodologies (INNO-LiPA and polymerase sequencing). The resistance mutations present in untreated patients infected with HCV and codon composition bias by geographical location warrant closer examination.

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Mutations in hepatitis C virus NS3 protease domain associated with resistance to specific protease inhibitors in antiviral therapy naïve patients

Cited by 28 publications

References 24 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

Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

Protease inhibitor resistance mutations in untreated Brazilian patients infected with HCV: Novel insights about targeted genotyping approaches

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