Worldwide Prevalence of Baseline Resistance-Associated Polymorphisms and Resistance Mutations in HCV against Current Direct-Acting Antivirals

Palanisamy, Navaneethan; Kalaghatgi, Prabhav; Akaberi, Dario; Lundkvist, Åke; Chen, Zhiwei; Hu, Peng; Lennerstrand, Johan

doi:10.3851/imp3237

Cited by 16 publications

(14 citation statements)

References 36 publications

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“…( 35 ) This difference may reflect geographic variations in baseline RAS prevalence as we have previously observed a 4% prevalence of H58 RAS among untreated Australian patients with genotype 1a ( 36 ) compared to 0%‐2% in global and European patients. ( 16,37 ) In contrast to the wide range of RASs for genotype 1a, patients with genotype 3a were more likely to have a single NS5A RAS, with Y93H found in 72%. This is similar to the 66% prevalence in the European study ( 30 ) and may reflect a relatively high baseline prevalence of Y93H (9%) among patients with genotype 3a who are treatment naive.…”

Section: Discussionmentioning

confidence: 99%

“…This is similar to the 66% prevalence in the European study ( 30 ) and may reflect a relatively high baseline prevalence of Y93H (9%) among patients with genotype 3a who are treatment naive. ( 37 ) The very high prevalence of Y93H among treatment failures is clinically important as Y93H confers high levels of resistance against most NS5A inhibitors, with a 3,500‐fold reduction in half‐maximal effective concentration (EC50) for daclatasvir and over 700‐fold reduction in EC50 for velpatasvir. ( 38 )…”

Section: Discussionmentioning

confidence: 99%

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Impact of an Open Access Nationwide Treatment Model on Hepatitis C Virus Antiviral Drug Resistance

et al. 2020

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Direct acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) treatment, but drug resistance could undermine proposed global elimination targets. Real-world studies are needed to inform the impact of widespread DAA treatment on antiviral resistance in the community. The prevalence and range of posttreatment resistance-associated substitutions (RASs) was determined in Australian patients with open access to DAAs through a wide range of prescribers. NS3, NS5A, and NS5B regions were amplified by polymerase chain reaction and analyzed by population sequencing. Clinically relevant RASs were identified using online databases (ReCALL and Geno2Pheno[hcv]). Of 572 samples, 60% were from genotype 3 and 27% from genotype 1a. Ninety-two percent of people failed a DAA regimen containing an NS5A inhibitor, including 10% with a pangenotype regimen. NS5A RASs were detected in 72% of people with genotype 1 and 80% with genotype 3. For genotype 1, there was a range of RASs across the NS5A region, while for genotype 3, the Y93H RAS predominated (72%). The prevalence of NS3 RASs was higher in people exposed to an NS3 inhibitor (35% vs. 3.9%; P < 0.0001). NS5B resistance was rare, with a single case of sofosbuvir resistance. Multiclass drug resistance was found in 33% of people exposed to both NS3 and NS5A inhibitors. Conclusion: The high prevalence of NS5A RASs among people failing DAA therapy reinforces the importance of specific retreatment regimens, ideally guided by resistance testing. The impact of multiclass drug resistance on retreatment in people exposed to both NS3 and NS5A inhibitors needs to be assessed in real-world studies. Surveillance for increasing antiviral resistance during treatment scale-up is essential to maintain the efficacy of current DAA regimens. (Hepatology Communications 2020;4:904-915).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of an Open Access Nationwide Treatment Model on Hepatitis C Virus Antiviral Drug Resistance

et al. 2020

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“…The NS5A RAS Y93H mutation/polymorphism is found quite often (5-10%) at baseline in DAA-treatment-naïve patients with GT 3 (with regard to subtype 3a) using the population sequencing method [15]. This RAS possesses a high fold in vitro resistance of >2000 to daclatasvir (DCV) and >700 to velpatasvir (VEL) used for treatment of GT 3 infection [16][17][18]. This was further revealed in clinical studies, the ALLY-3 study showed that 33% without liver cirrhosis and 75% with liver cirrhosis of the GT 3 patients with baseline RAS Y93H failed 12-week treatment with DCV plus sofosbuvir (SOF) [19].…”

Section: Introductionmentioning

confidence: 99%

Effect of the baseline Y93H resistance-associated substitution in HCV genotype 3 for direct-acting antiviral treatment: real-life experience from a multicenter study in Sweden and Norway

Kjellin

Kileng

Akaberi

et al. 2019

Scandinavian Journal of Gastroenterology

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Background: The NS5A resistance-associated substitution (RAS) Y93H is found quite frequently (5-10%) at baseline in direct-acting antiviral agents (DAA) treatment-naïve genotype (GT) 3a patients when studied by the population-sequencing method (cut-off 20%). This RAS may impair HCV DAA treatment response, since it possesses a high fold in vitro resistance to daclatasvir (DCV) and velpatasvir (VEL) in GT 3. We investigated the effect of baseline Y93H in patients with GT 3a infection on treatment outcome, with or without resistance-based DAA-treatment during 2014-2017. Patients/Methods: Treatment in the intervention group (n ¼ 130) was tailored to baseline resistancefindings by population-sequencing method. Detection of baseline Y93H above 20% prompted a prolonged treatment duration of NS5A-inhibitor and sofosbuvir (SOF) and/or addition of ribavirin (RBV). Patients without baseline Y93H in the intervention group and all patients in the control group (n ¼ 78) received recommended standard DAA-treatment. Results: A higher sustained virologic response rate (SVR) in the intervention group was shown compared to the control group at 95.4% (124/130) and 88.5% (69/78), respectively (p ¼ .06). All five patients with baseline Y93H in the intervention group achieved SVR with personalised treatment based on results from resistance testing; either with the addition of RBV or prolonged treatment duration (24w). In the control group, 2/4 patients with Y93H at baseline treated with ledipasvir/SOF/RBV or DCV/SOF without RBV, failed treatment. Conclusion: The results from this real-life study are in accordance with the findings of the randomised controlled trials in 2015 and the EASL-guidelines of 2016, thus, baseline Y93H impacts on DCV and VEL treatment outcome.

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“…High prevalence of variants C445F, A553V and S556G were found in both GTs 2b and 3a. The variants C445F and S556G have also been previously reported as baseline polymorphisms with natural prevalence ranging from 96 to 100% for GT 2 and from 97.1 to 100% for GT 3 [7,42,45,46]. Additionally, the natural prevalence of the variant A553V was reported to be 96% for GT 2 and 97.1% for GT 3[46].…”

Section: Discussionmentioning

confidence: 97%

“…The variants C445F and S556G have also been previously reported as baseline polymorphisms with natural prevalence ranging from 96 to 100% for GT 2 and from 97.1 to 100% for GT 3 [7,42,45,46]. Additionally, the natural prevalence of the variant A553V was reported to be 96% for GT 2 and 97.1% for GT 3[46]. The variant A553V is associated with a high level (> 100-fold increase in effective concentration 50 ) of resistance against dasabuvir in GT 1b replicon assay [20].…”

Section: Discussionmentioning

confidence: 99%

Baseline dasabuvir resistance in Hepatitis C virus from the genotypes 1, 2 and 3 and modeling of the NS5B-dasabuvir complex by thein silicoapproach

Akaberi

Bergfors

Kjellin

et al. 2018

Infection Ecology & Epidemiology

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Background: Current combination treatments with direct-acting antiviral agents (DAAs) can cure more than 95% of hepatitis C virus (HCV) infections. However, resistance-associated substitutions (RASs) may emerge and can also be present in treatment-naïve patients. Methods, results and discussion: In this study, a semi-pan-genotypic population sequencing method was developed and used to assess all NS5B amino acid variants between residue positions 310 and 564. Our method successfully sequenced more than 90% of genotype (GT) 1a, 1b, 2b and 3a samples. By using the population sequencing method with a cut-off of 20%, we found the dasabuvir RASs A553V and C445F to be a baseline polymorphism of GT 2b (8 out of 8) and GT 3a (18 out of 18) sequences, respectively. In GT 1a and 1b treatment-naïve subjects (n=25), no high-fold resistance polymorphism/RASs were identified. We further predicted dasabuvir’s binding pose with the NS5B polymerase using the in silico methods to elucidate the reasons associated with the resistance of clinically relevant RASs. Dasabuvir was docked at the palm-I site and was found to form hydrogen bonds with the residues S288, I447, Y448, N291 and D318. The RAS positions 316, 414, 448, 553 and 556 were found to constitute the dasabuvir binding pocket.

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Worldwide Prevalence of Baseline Resistance-Associated Polymorphisms and Resistance Mutations in HCV against Current Direct-Acting Antivirals

Cited by 16 publications

References 36 publications

Impact of an Open Access Nationwide Treatment Model on Hepatitis C Virus Antiviral Drug Resistance

Impact of an Open Access Nationwide Treatment Model on Hepatitis C Virus Antiviral Drug Resistance

Effect of the baseline Y93H resistance-associated substitution in HCV genotype 3 for direct-acting antiviral treatment: real-life experience from a multicenter study in Sweden and Norway

Baseline dasabuvir resistance in Hepatitis C virus from the genotypes 1, 2 and 3 and modeling of the NS5B-dasabuvir complex by thein silicoapproach

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