Prevalence of Sofosbuvir Resistance-Associated Variants in Brazilian and Worldwide NS5B Sequences of Genotype-1 HCV

Peres-da-Silva, Allan; Brandão‐Mello, Carlos Eduardo; Lampe, Elisabeth

doi:10.3851/imp3131

Cited by 13 publications

(7 citation statements)

References 22 publications

(29 reference statements)

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“…Previous studies have found variable prevalence of C316N in Brazil, from 3.85% (Peres-da-Silva et al, 2017) to 11.6% (Castillho et al, 2011), 16.3% (Noble et al, 2017), and 24% (Castilho et al, 2011), and higher prevalence in North America (16.81%), Europe (7.47%), and Asia (49.71%) (Peres-da-Silva et al, 2017). The higher prevalence of mutations in genotype 1b has been reported previously and it was due to the presence of C316N (Paolucci et al, 2013;Peres-da-Silva et al, 2017).…”

Section: Resultssupporting

confidence: 57%

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

Andrade

Rocha²,

Fontana-Maurell³

et al. 2020

Genet. Mol. Biol.

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Hepatitis C virus (HCV) infection is a worldwide health problem. Nowadays, direct-acting antiviral agents (DAAs) are the main treatment for HCV; however, the high level of virus variability leads to the development of resistance-associated variants (RAVs). Thus, assessing RAVs in infected patients is important for monitoring treatment efficacy. The aim of our study was to investigate the presence of naturally occurring resistance mutations in HCV NS3 and NS5 regions in treatment-naïve patients. Ninety-six anti-HCV positive serum samples from blood donors at the Center of Hematology and Hemotherapy of Santa Catarina State (HEMOSC) were collected retrospectively in 2013 and evaluated in this study. HCV 1a (37.9%), 1b (25.3%), and 3a (36.8%) subtypes were found. The frequency of patients with RAVs in our study was 6.9%. The HCV NS5b sequencing reveled 1 sample with L320F mutation and 4 samples with the C316N/R polymorphism. The analysis of the NS3 region revealed the D168A/G/T (3.45%), S122G (1.15%), and V55A (2.3%) mutations. All samples from genotype 3a (36.8%) presented the V170 I/V non-synonymous mutation. In conclusion, we have shown that mutations in NS3 and NS5b genes are present in Brazilian isolates from therapy-naïve HCV patients.

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Section: Resultssupporting

confidence: 57%

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

Andrade

Rocha²,

Fontana-Maurell³

et al. 2020

Genet. Mol. Biol.

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“…L159F is not associated with reduced sofosbuvir susceptibility, although this RAS was frequently detected with C316N. The high frequency of this double mutation was reported in untreated Brazilian patients infected with GT1b 53. The combination of L159F with C316N was also frequently found in GT1b-infected patients who failed to respond to sofosbuvir/ribvirin or other sofosbuvir-based regimens 54.…”

Section: Discussionmentioning

confidence: 96%

Computational analysis of naturally occurring resistance-associated substitutions in genes NS3, NS5A, and NS5B among 86 subtypes of hepatitis C virus worldwide

Geng

Chi

et al. 2019

IDR

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Background and objectiveDirect-acting antivirals (DAA) facing resistance continue to be used in some areas worldwide. Thus, identifying hepatitis C virus (HCV) genotypes/subtypes and loci with certain prevalent resistance-associated substitutions (RASs) deserves attention. We investigated the global and regional frequencies of naturally occurring RASs among all confirmed HCV subtypes (n=86) and explored co-occurring and mutually exclusive RAS pairs within and between genes NS3, NS5A, and NS5B.MethodsA total of 213,908 HCV sequences available as of July 10, 2019 were retrieved from the NCBI nucleotide database. After curation, 17,312 NS3, 8,478 NS5A, and 25,991 NS5B sequence fragments from DAA-naïve patients were screened for RASs. MEGA 6.0 was used to translate aligned nucleotide sequences into amino acid sequences, and RAS pairs were identified by hypergeometric analysis.ResultsRAS prevalence varied significantly among HCV subtypes. For example, D168E, highly resistanct to all protease inhibitors except voxilaprevir, was nearly absent in all subtypes except in 43.48% of GT5a sequences. RASs in NS3 exhibiting significantly different global distribution included Q80K in GT1a with the highest frequency in North America (54.49%), followed by in Europe (22.66%), Asia (6.98%), Oceania (6.62%), and South America (1.03%). The prevalence of NS3 S122G in GT1b was highest in Asia (26.6%) and lowest in Europe (2.64%). NS5A L28M, R30Q, and Y93H in GT1b, L31M in GT2b, and NS5B C316N in GT1b was most prevalent in Asia. A150V in GT3a, associated with sofosbuvir treatment failure, was most prevalent in Asia (44.09%), followed by Europe (31.19%), Oceania (24.29%), and North America (19.05%). Multiple mutually exclusive or co-occurring RAS pairs were identified, including Q80K+R155K and R155K+D168G in GT1a and L159F+C316N and R30Q (NS5A)+C316N (NS5B) in GT1b.ConclusionOur data may be of special relevance for those countries where highly effective antivirals might not be available. Considering the specific RASs prevalence will help the clinicians to make optimal treatment choices. The RASs pairs would benefit anti-HCV drug development.

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“…(2017) [33] and Peres-da-Silva A. et al . (2017) [15] whose prevalence was 14.2% (8/56) and 25% (13/52), respectively. The occurrence of these RASs did not appear to have influenced therapeutic response after treatment, since all HCV GT 1b-monoinfected patients has achieved SVR.…”

Section: Discussionmentioning

confidence: 99%

Treatment of chronic HCV infection with DAAs in Rio de Janeiro/Brazil: SVR rates and baseline resistance analyses in NS5A and NS5B genes

et al. 2019

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The selection of viral strains with resistance-associated substitutions at hepatitis C virus (HCV) NS5A and NS5B genes is considered one of the limiting factors for achieving sustained virologic response (SVR) to combination of direct-acting antivirals daclatasvir (DCV) and sofosbuvir (SOF). Since 2015, this interferon-free regimen has been available in Brazilian clinical routine for treating mono- and HCV/HIV-coinfected patients chronically infected with genotypes 1 and 3. Our aim was to assess SVR rate for Brazilian patients chronically infected with genotypes 1 and 3 after DCV/SOF therapy and the frequency of baseline RASs in HCV NS5A and NS5B genes. Serum samples were collected from 107 monoinfected patients and 25 HCV/HIV co-infected patients before antiviral therapy with DCV/SOF. Genetic diversity of NS5A and NS5B genes was assessed by direct nucleotide sequencing. Overall, SVR rate was 95.4% (126/132), and treatment failure occurred in five monoinfected and one HCV/HIV co-infected patient. NS5A RASs frequency was higher for HCV/HIV patients (28%) than monoinfected patients (16.8%). No difference was evidenced between mono- and HCV/HIV-coinfected groups (15% vs. 16%) regarding NS5B gene. Genotype (GT) 1b strains had significantly more baseline substitutions in NS5A (31.6%) than GT 1a and 3a. At least one primary NS5A RAS described in literature at loci 28, 30, 31 or 93 was identified in HCV GTs 1 strains for both groups. As for NS5B, RASs at positions 159 and 316 was observed only in GT 1b strains. This study highlighted that SVR rate in clinical routine in Brazil was similar to randomized clinical trials (89–98%). Our research provided genetic data about the circulation of resistant variants in Brazil. Despite its presence, most of identified baseline mutations did not negatively impact treatment outcome. Genetic diversity of circulating strains suggested that most of the Brazilian HCV chronic carriers are susceptible to new therapeutic regimens including recently approved DAAs.

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Prevalence of Sofosbuvir Resistance-Associated Variants in Brazilian and Worldwide NS5B Sequences of Genotype-1 HCV

Cited by 13 publications

References 22 publications

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil

<p>Computational analysis of naturally occurring resistance-associated substitutions in genes <em>NS3</em>, <em>NS5A</em>, and <em>NS5B</em> among 86 subtypes of hepatitis C virus worldwide</p>

Treatment of chronic HCV infection with DAAs in Rio de Janeiro/Brazil: SVR rates and baseline resistance analyses in NS5A and NS5B genes

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