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

Abstract

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.

Resistance analysis and treatment outcomes in hepatitis C virus genotype 3‐infected patients within the Italian network VIRONET‐C

“…However, while baseline resistance testing is currently recommended for GT3 cirrhotic patients who are candidate for treatment with SOF + DCV or SOF/VEL, its clinical role before starting the G/P regimen is still poorly understood 37 . Overall, in our study, the natural prevalence of Y93H and A30K was similar to that reported in other studies 32,34,38 …”

“…In the context of GT3 infection, the presence of specific natural polymorphisms (particularly in NS5A) has been observed to reduce the SVR rates especially when combined with other negative predictive factors (eg treatment experience, cirrhosis or HCC) and in presence of short duration DAA treatments 12,13,32,33 . For this reason, this study also evaluated the prevalence of natural NS3, NS5A and NS5B‐RASs in a large cohort of DAA‐naïve GT3‐infected patients and the impact of baseline NS5A‐RASs on treatment outcome.…”

Efficacy and Safety of Sofosbuvir-Based Direct-Acting Antiviral Agents Treatment for Patients with Genotype 3/6 Hepatitis C Virus Infection

“…SVR of GT3 CHC patients was ideal in the era of combination treatment of peginterferon and Ribavirin before DAAs, as it reached about 70% (68.2-71.5%) and was much higher than that of GT1. However, SVR of GT3 CHC patients was not ideal in the era of SOF-based DAAs treatment, as it reached about 90% and was lower than that of other genotypes in several studies [12,[24][25][26][27]. GT3 is regarded as being more difficult to treat as it is a relatively aggressive genotype, associated with greater liver damage and cancer risk; some subgroups of patients with GT3 infection are less responsive to current licensed DAA treatments [12].…”

Efficacy and safety of sofosbuvir-based pangenotypic direct-acting antiviral agents for chronic hepatitis C patients without genotype determination

“…Advanced liver fibrosis or cirrhosis or baseline NS5A resistance-associated substitution Y93H may responsible for the failure of the virologic response, owing to its interference with responses to DAA therapy affect virological response to DAAs therapy. [ 29 , 30 ] Furthermore, SOF based pangenotypic DAAs therapy also achieved high SVR12 rate in CHC patients with hypertension or diabetes of our cohort. Another pangenotypic DAA, GLE/PIB also yield high SVR12 rates in CHC patients with HCV GT 1 to 6 with or without cirrhosis, ranging from 91% to 100%.…”