Week 96 resistance analyses of the once‐daily, single‐tablet regimen (STR) darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in adults living with HIV‐1 from the phase 3 randomized AMBER and EMERALD trials

Abstract

In AMBER and EMERALD, darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg demonstrated high virological response and low virological failure (VF) through week 96. Week 96 resistance analyses are presented. Post‐baseline samples for genotyping/phenotyping were analyzed from protocol‐defined‐VFs with viral load (VL) ≥ 400 copies/ml at failure/later time points. Post‐hoc analyses were deep sequencing (AMBER) and HIV‐1 proviral DNA sequencing from baseline samples (VL < 50 copies/ml) (EMERALD). Through week 96 across studies, no darunavir, primary protease inhibitor (PI), or tenofovir resistance‐associated‐mutations (RAMs) occurred in patients continuing (N = 1125) or switching to D/C/F/TAF (N = 715). M184I/V (emtricitabine RAM) was detected in one patient in each arm of AMBER. In EMERALD D/C/F/TAF patients with prior VF and baseline genoarchive data (N = 98), 4% had darunavir RAMs, 36% emtricitabine RAMs, mainly at position 184 (32%), 4% tenofovir RAMs, and 19% ≥3 thymidine‐analogue‐associated‐mutations at screening. The predicted phenotype showed 0% had reduced susceptibility to darunavir, 37% to emtricitabine, and 22% to tenofovir. All achieved VL < 50 copies/ml at week 96/prior discontinuation, with no VF. D/C/F/TAF has a high barrier to resistance; no darunavir, primary PI, or tenofovir RAMs occurred through 96 weeks in AMBER and EMERALD. In EMERALD, baseline archived darunavir, emtricitabine, and tenofovir RAMs in patients with prior VF did not preclude virologic response.

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1

“…As described previously, M184V was detected pretreatment at screening by deep sequencing as a minority variant (9%). 22 These results are consistent with previous DRV and D/C/F/TAF studies and the established high genetic barrier to resistance of DRV. 9,43,44 The lack of emergence of significant resistance mutations over time for virologically suppressed, treatment-experienced patients is important, particularly given concerns for re-emergence of archived RAMs in patients with prior VF.…”

“…There was no exclusion based on other PI or N(t)RTI RAMs, including FTC or TFV RAMs. 14,22,31 As such, ART-experienced, virologically suppressed patients with varied treatment histories, including history of VF, were allowed to enroll, so the population was more treatment-experienced than in most reported clinical switch studies. 14,22,31 In AMBER and EMERALD, D/C/F/TAF maintained high sustained virologic response rates at Week 96 across patient subgroups, ranging from 70% to 89% in ART-naïve patients in AMBER and 86% to 94% in ART-experienced, virologically suppressed patients in EMERALD.…”

“…14,22,31 As such, ART-experienced, virologically suppressed patients with varied treatment histories, including history of VF, were allowed to enroll, so the population was more treatment-experienced than in most reported clinical switch studies. 14,22,31 In AMBER and EMERALD, D/C/F/TAF maintained high sustained virologic response rates at Week 96 across patient subgroups, ranging from 70% to 89% in ART-naïve patients in AMBER and 86% to 94% in ART-experienced, virologically suppressed patients in EMERALD. Responses were comparable to Week 96 responses with STRs in overall populations of ART-naïve patients from previous Phase 3 trials (66% to 88%) [32][33][34][35][36][37][38][39][40] and other studies evaluating switching to integrase inhibitor-based regimens.…”

“…This patient had HIV-1 with transmitted NNRTI resistance at screening, and in a post-hoc analysis, M184V was detected pre-treatment as a minority variant (9%). 22 The patient had a baseline VL of 20,100 copies/mL, a CD4 þ cell count of 126 cells/mm 3 and was WHO clinical Stage 1.…”

High efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide in people with suppressed HIV and preexisting M184V/I

“…Recent data have shown that in addition to B/F/TAF, other three-drug regimens, such as DTG/ABC/3TC and cobicistat-boosted elvitegravir or darunavir with FTC/TAF also have high efficacy in virologically suppressed PWH with M184V/I who switch to these regimens [37,50–52]. Factors contributing to the efficacy of three-drug FTC or 3TC-containing regimens against M184V/I include third agents with high barriers to resistance, reduced replicative fitness and higher RT fidelity of HIV carrying M184V/I [10,53–56], and/or increased activity of tenofovir against M184V/I mutants [57,58].…”