Antiviral activity of dolutegravir in subjects with failure on an integrase inhibitor‐based regimen: week 24 phase 3 results from VIKING‐3

Abstract

Background VIKING-3 aimed to examine efficacy and safety of dolutegravir (DTG) 50 mg twice daily in patients with resistance to multiple ARV classes, including integrase inhibitors (INI). Methods RAL and/or EVG-resistant (current or historical) adult subjects with screening plasma HIV-1 RNA ]500 c/mL and resistance to ]2 other ART classes received open-label DTG 50 mg BID while continuing their failing regimen (without RAL/EVG). At Day 8 the background regimen was optimised and DTG continued. Activity of the optimized background regimen (OBR) was determined by Monogram Net Assessment. Primary endpoints were antiviral efficacy at Day 8 and Week 24. Results 183 subjects enrolled, 124 with INI-resistance at screening and 59 with historical (but no screening) resistance. Population was advanced: at BL, median CD4 140, prior ART 13 yrs, 56% CDC Class C; 79% had ����2 NRTI, 75% ����1 NNRTI, and 70% ����2 PI resistance-associated mutations, and 61% had non-R5 HIV detected. Of the 114 subjects who had the opportunity to complete 24 weeks on study before data cutoff, 72 (63%) had B50 c/mL RNA at Week 24 (SNAPSHOT algorithm). Mean HIV RNA declined   by 1.4 log10 c/mL (95% CI: 1.3, 1.5; p B 0.001) Primary INI mutations at BL N at Day 8; response differed by genotype pathway (Table). Mean HIV RNA (log10) Change from BL (SD) at Day 8 %����1 log HIV RNA decline of B50 c/mL at Day 8 82% 100% 96% 82% 69% 48% 75% 95% TOTAL 183 ����1.4 T66 1 ����1.9 (0.61) (0.42) (0.51) (0.51) (0.81) (0.76) (0.55) Y143 N155 Q148����51 secondary mutation# Q148����]2 secondary mutations# ]2 primary mutations No primary mutations 28 ����1.7 33 ����1.4 32 ����1.1 20 ����1.0 8 ����1.4 60 ����1.6 #Key secondary mutations comprised G140_ACS, L741, E138_AKT. In subjects with Q148 pathway mutations, virologic response decreased with increasing number of secondary mutations. Background overall susceptibility score (OSS) was not associated with Wk 24 response: % B50 c/mL were 83%, 63%, 59% and 69% for OSS 0, 1, 2 and ����2, respectively. Discontinuations due to adverse events were uncommon (6/183, 3%); the most common drug-related AEs were diarrhoea, nausea and headache, each reported in only 5% of subjects. Conclusion A majority of the highly treatment-experienced subjects in VIKING-3 achieved suppression with DTG-based therapy. Responses were associated with Baseline IN genotype but not OSS, highlighting the importance and independence of DTG antiviral activity. DTG had a low rate of discontinuation due to adverse events at 50 mg BID in this advanced patient population.