Background: ABT-493 (NS3/4A protease inhibitor identified by AbbVie and Enanta) and ABT-530 (NS5A inhibitor) are next generation HCV direct-acting antiviral agents. Co-administration of ABT-493 and ABT-530 ± ribavirin for 12 weeks achieved high sustained virologic response (SVR) in patients with HCV GT1, GT2, or GT3 infection in the dose-ranging studies of SURVEYOR-I and -II. In this report, we characterize GT2 and GT3 variants detected in samples from SURVEYOR-II.
Methods: Population sequencing was performed on NS3 and NS5A genes from all baseline (BL) samples, and the first available sample after virologic failure (VF) with HCV RNA ≥1000 IU/mL. Sequences were examined for variants at positions where resistance to drugs in the protease or NS5A inhibitor class is known: NS3 positions 36, 56, 80, 155, 156, 166 (GT3 only), and 168, and NS5A positions 24, 28, 29, 30, 31, 32, 58, 92, and 93.
Results: For BL samples from GT2-infected patients (n= 74), 36 had M31 in NS5A, a common polymorphism that confers resistance to a number of NS5A inhibitors but not to ABT-530. In addition, 6 patients had other BL NS5A variants, 5 patients had a BL NS3 variant, and 2 patients had variants in both targets at BL. Irrespective of the presence of BL variants, all GT2-infected patients, except 1 lost to follow-up (LTFU), achieved SVR12. For GT3-infected patients (n= 121), 17 had NS3 variants, 19 had NS5A variants, and 5 had variants in both targets at BL. Seven GT3-infected patients experienced VF; only 1of these VFs (a relapse) occurred in a patient enrolled in an arm receiving the 300mg/120mg ABT-493/ABT-530 dose combination (n=30). For this patient, no NS3 variants and 1 NS5A variant (A30K) were detected at BL; a double NS3 variant (Y56H+Q168R) and a double NS5A variant (A30K+Y93H) were detected at VF. The other 6 VF patients were treated with lower combination doses; variant analysis will be presented.
Conclusion: All GT2-infected patients, except 1 LTFU, achieved SVR12 regardless of presence or absence of BL NS3 or NS5A variants. For GT3-infected patients, VF occurred in only 1 patient receiving 300mg/120mg ABT-493/ABT-530, the dose chosen for further studies. Evaluation of more GT3-infected patients receiving this dose to fully assess the impact of BL variants on treatment outcome is ongoing.