A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients

Abstract

Objectives:To investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults.Design:Phase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247).Methods:Seven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin).Results:At week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI −1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (−22.42 vs. −10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. −2.73%, P < 0.0001 (hip), −0.68 vs. −2.38%, P = 0.004 (lumbar spine), and −0.26 vs. −2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036.Conclusion:D/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.

Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

“…No grade 3/4 or serious AEs, deaths, or discontinuations due to AEs occurred. The tolerability profile is consistent with earlier studies, with the most commonly reported AEs during the studies, headache and nausea, reported previously for studies of DRV, COBI, FTC, and TAF and in the ongoing phase 3 studies …”

“…Consistent with other DRV formulations, it is recommended that D/C/F/TAF be taken with food. Also in the ongoing phase 3 studies, the recommended intake for the D/C/F/TAF single‐tablet regimen and other DRV‐containing regimens is with food …”

Impact of Splitting or Crushing on the Relative Bioavailability of the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single‐Tablet Regimen

“…Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF; 800/150/200/10 mg) is an oral once‐daily single‐tablet regimen that is approved in Europe, Canada, and the United States. Studies of the protease inhibitor darunavir have demonstrated a durable virologic response, long‐term safety, and a high barrier to the development of resistance .…”

“…The efficacy and safety of D/C/F/TAF were demonstrated in 2 pivotal phase 3 clinical trials . In AMBER, D/C/F/TAF was noninferior (10% margin) to darunavir/cobicistat plus emtricitabine/tenofovir disoproxil fumarate in treatment‐naive adults after 48 weeks, with virologic suppression rates of 91.4% and 88.4%, respectively .…”

“…In EMERALD, which enrolled treatment‐experienced, virologically suppressed adults, switching to D/C/F/TAF was noninferior (4% margin) to continuing boosted protease inhibitor plus emtricitabine/tenofovir disoproxil fumarate through 48 weeks, with cumulative virologic rebound rates of 2.5% and 2.1%, respectively; virologic response rates in week 48 were 94.9% and 93.7%, respectively . In both AMBER and EMERALD, the safety and tolerability profiles of D/C/F/TAF were improved relative to the comparator, particularly for renal and bone safety parameters …”