Dolutegravir (DTG) is a second generation InSTI that has shown in both preclinical and clinical studies to have a higher barrier to resistance than first generation InSTIs (RAL and EVG).To date, no InSTI resistance-associated mutations (RAMs) have been reported in ART-naïve persons receiving DTG through 144 weeks of follow-up in clinical trials and very few cases has been reported in INSTI-naïve subjects among pretreated individuals. Our objective was to identify and characterize different pathways of resistance in subjects failing a DTG-monotherapy (DTG-M) in four large clinical cohorts
This is an international, multi-cohort, retrospective study. All subjects with no prior InSTI virological failure (InSTI-VF) failing DTG-M were included in this analysis. Virological failure (VF) was defined as two plasma viral loads (VL) above 50 cp/mL. Genotypic resistance mutations could be detected by: (i) plasma population sequencing (PS); (ii) plasma ultra-deep sequencing test (UDS); peripheral blood mononuclear cell population sequencing (PBMC-PS); and PBMC-UDS
Three large clinical cohorts in Munich, Montreal and Barcelona were included in this analysis. A total of 178 ART-experienced subjects with no prior InSTI-VF changed from different ART-regimens to DTG monotherapy (DTG-M). Eleven (6.1%) had VF and 7 (3.9%) selected any InSTI-RAMs . Two of 7 were women, median (range) of previous VF 1 (0-8; 3: 0VF; 1:1VF; 3≥4). InSTI prior DTG was: 3 none, 3 RAL and 1 EGV. VL by the time of starting DTG-M was: 5= below the lower limits of detection (LLOD), 1=249 cp/mL and 1=21 cp/mL. Reasons for switch to DTG-M were: simplification (n=2), DDI (n=3), patient decision (n=3), toxicity (n=1), VF (n=1); 5 patients had at least one LLOD before VF. Median (range) time and first VL by the time of VF were 12 weeks (0-28) and 306 copies/mL (55-26180), respectively. Time to first detection of DTG-RAMs was 28 weeks (2-32). The three different pathways by the time of VF were: 148R/H in 3 patients, 155H in 2, and 118R in 2
Virological failure and selection of InSTI-RAMs are uncommon but they may exist in patients with no prior InSTI virological failure subjects on DTG-monotherapy. Different pathways, similar to first-generation InSTIs (RAL and EVG), 148R/H, 155H, and 118R were identified in these cases