SUBTYPE ANALYSIS AND RESISTANCE ASSOCIATED VARIANTS IN NAÏVE HCV GT1 CARRIERS IN ISRAEL

Yael Gozlan ¹ Ziv Ben Ari ² Roy Moscona ¹ Avia Rakovsky ¹ Michal Michaeli ¹ Yael Sandak ² Avishag Hassid ² Keren Tsaraf ² Ella Weizmann ² Ella Mendelson ^1,3 Zippi Kra-Oz ⁵ Yonat Shemer ⁴ Licita Schreiber ⁶ Orna Mor ¹

¹Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel
²Liver Disease Center, Sheba Medical Center, Ramat-Gan, Israel
³Public School of Health, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
⁴Infectious Diseases Institute, Ben-Gurion University of the Negev, Beer-Sheva, Israel
⁵Virology Laboratory, Rambam Medical Center, Haifa, Israel
⁶Virology Department, Maccabi HealthCare Services, Central Laboratory, Rehovot, Israel

Background and aims: Treatment with the new antiviral agents is HCV subtype dependent and can be compromised by resistance mutations in the NS3/4A (NS3), NS5B and NS5A proteins. Subtyping of GT1, the most prevalent HCV genotype, performed by either 5’ UTR sequencing or commercial assays inefficiently differentiates between GT1 subtypes. Using HCV population sequencing of NS3, NS5A and NS5B genes we re-determined GT1 subtypes and retrospectively investigated the prevalence of baseline resistance variants (RAVs) in a cohort of DDAs naïve HCV patients. The impact of the identified RAVs on subsequent therapy outcome was also assessed.

Methods: Baseline NS3 (n=169), NS5A (n=64) and NS5B (n=42) sequences from 180 GT1 DAA naïve patients were analyzed. Geno2Pheno and bio Africa tools were used for subtype determination and RAVs were identified based on the IAS-USA 2012 list.

Results: Sequencing revealed that most (77.2%) presented with GT1b; 20% with GT1a, 1.67% with GT1d and 0.56% with GT1m. NS3 RAVs were identified in 36.7% and 2.94% of GT1a (n=30) and GT1b (n=136) patients, respectively. NS5A (17%) and NS5B (3%) RAVs were identified only in GT1B patients. The three GT1d and the GT1m pateint all had RAVs in NS3 (NS5A RAVs were not assessed). SVR24 was achieved in 92% (42/45) of the only 45 GT1b treated patients, irrespective of the baseline NS3 RAVs. 2/49 were lost to follow up, 1/49 stopped treatment and 1/49 relapsed and treatment-emergent resistance mutations were identified following the relapse.

Conclusions: Although GT1b NS3 RAVs did not affect treatment success, NS5A RAVs may abrogate treatment outcome. Sequencing should be performed for subtype determination in non-conclusive cases. Effect of RAVs in subtypes other than 1a and 1b should be explored.