Prevalence of polymorphisms with significant resistance to NS5A inhibitors in treatment-naive patients with hepatitis C virus genotypes 1a and 3a in Sweden

Lindström, I.; Kjellin, Midori; Palanisamy, Navaneethan; Bondeson, Kåre; Wesslén, Lars; Lannergård, Anders; Lennerstrand, Johan

doi:10.3109/23744235.2015.1028097

Cited by 33 publications

(30 citation statements)

References 27 publications

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“…In the United States, it has been described a prevalence ranging 9‐12% for G1a . In Europe, recent studies have reported rates of prevalence ranging from 1.6% in Sweden to 12.5% in Italy . In Spain, Calleja et al and Palladino et al described rates of prevalence around 6%.…”

Section: Discussionmentioning

confidence: 97%

Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies

Grandal

Pernas

Tabernilla

et al. 2018

Journal of Medical Virology

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The presence of resistance-associated substitutions (RASs) at NS5A region might compromise the efficacy of Direct Acting Antiviral agents (DAAs). HCV resistance at NS5A region is mainly focused on patients with hepatitis C virus (HCV) genotypes 1a (G1a) and 3 (G3) with other factors of poor treatment response (ie cirrhosis, prior treatment-exposure, or HCV-RNA >800 000 IU/mL). Herein, we evaluated in a cohort of HCV G1a and G3 infected patients the prevalence of RASs at domain I NS5A using population-based sequencing and the impact of RASs on the optimization of current therapeutic strategies. The RASs considered as clinically relevant were: M28A/G/T, Q30D/E/H/G/K/L/R, L31M/V/F, H58D, and Y93C/H/N/S for G1a and Y93H for G3. A total of 232 patients naïve to NS5A inhibitors were included (166 G1a, 66 G3). The overall prevalence of NS5A RASs for G1a and G3 patients was low (5.5%) or null, respectively. A high proportion of patients harbored, at least, one factor of poor response (78.9% for G1a, and 75.8% for G3). Overall, the rates of patients harboring NS5A RASs in combination with any of the other factors were low and the vast majority of patients (G1a> 94% and G3 100%) could be treated with standard treatments of 12 weeks without ribavirin. In conclusion, testing NS5A RASs in specific HCV-infected populations (ie G1a & G3, cirrhosis, prior treatment experienced, HCV-RNA >800 000 IU/mL) might be useful to optimize current NS5A-based therapies avoiding ribavirin-related toxicities, and shortening treatment duration in the majority of patients.

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Section: Discussionmentioning

confidence: 97%

Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies

Grandal

Pernas

Tabernilla

et al. 2018

Journal of Medical Virology

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“…With the exception of NS5B nucleoside analogues, the current DAAs target the NS3, as well as the allosteric sites of NS5B and NS5A, which all have a low threshold of resistance[10,18]. Data from both replicon analysis and from clinical trials have consistently identified viral mutations that can be associated with antiviral treatment failure[19].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms and resistance mutations of hepatitis C virus on sequences in the European hepatitis C virus database

Kliemann¹,

Tovo²,

Veiga³

et al. 2016

WJG

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AIMTo evaluate the occurrence of resistant mutations in treatment-naïve hepatitis C virus (HCV) sequences deposited in the European hepatitis C virus database (euHCVdb).METHODSThe sequences were downloaded from the euHCVdb (). The search was performed for full-length NS3 protease, NS5A and NS5B polymerase sequences of HCV, separated by genotypes 1a, 1b, 2a, 2b and 3a, and resulted in 798 NS3, 708 NS5A and 535 NS5B sequences from HCV genotypes 1a, 1b, 2a, 2b and 3a, after the exclusion of sequences containing errors and/or gaps or incomplete sequences, and sequences from patients previously treated with direct antiviral agents (DAA). The sequence alignment was performed with MEGA 6.06 MAC and the resulting protein sequences were then analyzed using the BioEdit 7.2.5. for mutations associated with resistance. Only positions that have been described as being associated with failure in treatment in in vivo studies, and/or as conferring a more than 2-fold change in replication in comparison to the wildtype reference strain in in vitro phenotypic assays were included in the analysis.RESULTSThe Q80K variant in the NS3 gene was the most prevalent mutation, being found in 44.66% of subtype 1a and 0.25% of subtype 1b. Other frequent mutations observed in more than 2% of the NS3 sequences were: I170V (3.21%) in genotype 1a, and Y56F (15.93%), V132I (23.28%) and I170V (65.20%) in genotype 1b. For the NS5A, 2.21% of the genotype 1a sequences have the P58S mutation, 5.95% of genotype 1b sequences have the R30Q mutation, 15.79% of subtypes 2a sequences have the Q30R mutation, 23.08% of subtype 2b sequences have a L31M mutation, and in subtype 3a sequences, 23.08% have the M31L resistant variants. For the NS5B, the V321L RAV was identified in 0.60% of genotype 1a and in 0.32% of genotype 1b sequences, and the N142T variant was observed in 0.32% of subtype 1b sequences. The C316Y, S556G, D559N RAV were identified in 0.33%, 7.82% and 0.32% of genotype 1b sequences, respectively, and were not observed in other genotypes.CONCLUSIONHCV mutants resistant to DAAs are found in low frequency, nevertheless they could be selected and therapy could fail due resistance substitutions in HCV genome.

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“…Resistance to either drug correlated inversely with treatment success and compromised both. While baseline viral polymorphisms to many current DAAs have been well known, their clinical significance have often been unclear [Palanisamy et al, ; Lindström et al, ]. For example, global analyses of data from phase 3 trials of ledipasvir/sofosbuvir identified slight to substantial impact of baseline NS5A RAVs on SVR rate, with a greater impact from variants conferring a high degree of resistance in vitro [Afdhal et al, ,; Kowdley et al, ].…”

Section: Future Directionsmentioning

confidence: 99%

Hepatitis C-A clinical review

2016

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With an estimated prevalence of about 170 million people worldwide, chronic hepatitis C is an important cause of chronic liver disease associated with a substantial risk of cirrhosis and hepatocellular carcinoma. The recent past has borne witness to remarkable advancements in the treatment of chronic hepatitis C with the development of novel, effective, and well tolerated medications that have resulted in paradigm shifts in treatment approaches and may potentially affect the natural history of the disease. We provide a clinical review of current concepts and future developments in the management of chronic hepatitis C to aid in the understanding and individualization of chronic hepatitis C treatment. J. Med. Virol. 88:1844-1855, 2016. © 2016 Wiley Periodicals, Inc.

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Prevalence of polymorphisms with significant resistance to NS5A inhibitors in treatment-naive patients with hepatitis C virus genotypes 1a and 3a in Sweden

Abstract: Using this method, baseline resistance can be examined and the data could have a potential role in selecting the optimal and cost-efficient treatment for the patient.

Cited by 33 publications

References 27 publications

Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies

Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies

Polymorphisms and resistance mutations of hepatitis C virus on sequences in the European hepatitis C virus database

Hepatitis C-A clinical review

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