Kjellin M (1), Kileng H (2), Akaberi D (1), Duberg A.S (3), Danielsson A (4), Gangsoy M (5), Aleman S (6), Gutteberg T (2), Lannergård A (1), Lennerstrand J (1)

Affiliates

1. Dept of Medical Science, Uppsala University, Uppsala, Sweden. 2. Tromsö University Hospital, Tromsö, Norway. 3. Örebro University Hospital, Örebro, Sweden. 4. Falun Hospital, Falun, Sweden. 5. Bodö Hospital, Bodö, Norway. 6. Karolinska University Hospital, Stockholm, Sweden

Abstract

Background: Resistance associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAA) in hepatitis C virus (HCV) treatment. The NS5A-RAS Y93H is found quite frequently (5 – 9 %) at baseline for DAA-treatment-naïve genotype (GT) 3a patients with population sequencing (cut-off 20%). This RAS possesses a high fold in vitro resistance to daclatasvir > 2000 fold and velpatasvir >700 fold. We investigated the effects of baseline Y93H on treatment outcome in patients with HCV GT 3 infection receiving a personalised treatment regime based on results from NS5A resistance testing. This multi-center study was carried out between 2014 and 2017.
Patients/Methods: Treatment in the intervention group n=135 (Uppsala and Tromsö) was tailored to baseline resistance (population sequencing method). Detection of baseline Y93H led to a prolonged treatment duration (during 2014-16 daclatasvir + sofosbuvir and 2017 velpatasvir + sofosbuvir (Epclusa) and/or addition of ribavirin at the responsible MD’s discretion. Patients without baseline Y93H in the intervention group and all patients in the control group n=80 (Örebro, Falun, Bodö and Stockholm) received recommended standard DAA-treatment.
Results: Preliminary data show a higher sustained virologic response rates (SVR) in the intervention compared to control groups with 95.6% (129/135) and 88.8% (71/80), respectively (p=0.058). A similar trend towards higher SVR-rate in cirrhotic patients (p=0.27) can be noticed in the intervention group compared to the control group with SVR-rates 92.5% (49/53) and 85.7% (42/49), respectively. All five patients with baseline Y93H in the intervention group achieved SVR with personalised resistance-based treatment. In the control group, 2/4 patients with Y93H at baseline treated with 12 weeks ledipasvir+sofosbuvir and daclatasvir+sofosbuvir, respectively, failed treatment.
Conclusion: In line with the findings of the ALLY-3 and ASTRAL-3 trials and the EASL-guidelines 2018, baseline Y93H appeared to have an impact on daclatasvir/velpatasvir treatment outcome. This could also have implications for the recently approved regimes (Maviret and Vosevi) which are more potent against Y93H.