Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients

Abstract

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in AMBER (NCT02431247). Methods: Treatment-naive, HIV-1-positive adults [screening plasma viral load ≥1000 copies/ml; CD4+ cell count >50 cells/μl) were randomized (1 : 1) to D/C/F/TAF (N = 362) or D/C plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) (N = 363) over at least 48 weeks. After week 48, patients could continue on or switch to D/C/F/TAF in an open-label extension phase until week 96. Results: At week 96, D/C/F/TAF exposure was 626 patient-years (D/C/F/TAF arm) and 109 patient-years (control arm post switch), week 96 virologic suppression (viral load <50 copies/ml; FDA-Snapshot, from baseline) was 85.1% (308/362) (D/C/F/TAF) and 83.7% (304/363) (control). Week 96 virologic failure (viral load ≥50 copies/ml; FDA-Snapshot) was 5.5% (20/362) and 4.4% (16/363), respectively. No darunavir, primary protease inhibitor or tenofovir resistance-associated mutations (RAMs) were observed post baseline. In one patient in each arm, an M184I and/or V RAM was detected. Few adverse event-related discontinuations (3% D/C/F/TAF; <1% control post switch) and no deaths occurred on D/C/F/TAF. Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the control arm post switch. Increases in total-cholesterol/high-density-lipoprotein--cholesterol rtio at week 96 were +0.25 versus baseline (D/C/F/TAF) and +0.24 versus switch (control). Conclusion: At week 96, D/C/F/TAF resulted in high virologic response and low virologic failure rates, with no resistance development to darunavir or TAF/TDF. Bone, renal and lipid safety were consistent with known D/C/F/TAF component profiles. Control arm safety post switch was consistent with the D/C/F/TAF arm. AMBER week 96 results confirm the efficacy, high barrier to resistance and bone/renal safety benefits of D/C/F/TAF for treatment-naive patients.

Pooled resistance analyses of darunavir once-daily regimens and formulations across 10 clinical studies of treatment-naïve and treatment-experienced patients with human immunodeficiency virus-1 infection

“…These clinical trials were conducted over more than a 10-year span, providing 5291 patientyears of experience with this regimen. 20,21,23,30 A limitation of the analysis is that the studies did not include integrase inhibitor-based regimens, which were not available at the time that some of the studies in this analysis took place. Additionally, the analysis reported here only includes data from controlled clinical trials and does not include real-world data.…”

“…Methodological details for the seven clinical studies included in the previous analysis have been described. 6,[10][11][12][13][14][15][16] Detailed methods for the three recent studies of the D/C/F/TAF STR have also been reported [19][20][21][22][23] and are briefly summarized here. Key study design information for all 10 studies is shown in Supplemental Figure S1.…”

“…Of the 725 enrolled patients, 362 initiated treatment with D/C/F/TAF at baseline ("D/C/F/TAF" group) and 363 initiated treatment with a control regimen (darunavir/cobicistat þ emtricitabine/tenofovir disoproxil fumarate [TDF]) and subsequently switched to D/C/F/ TAF after the Week 48 primary analysis time point ("darunavir/cobicistat þ emtricitabine/TDF switch to D/C/F/TAF" group); all 725 patients were included in the current analysis. 19,20 DIAMOND was a 48-week, single-arm study of treatment-naïve adults who rapidly initiated treatment with D/C/F/TAF within 2 weeks of HIV-1 infection diagnosis, prior to the availability of baseline laboratory assessments, including resistance test results. All 109 patients from DIAMOND were included in the current analysis.…”

“…Details of the resistance analyses performed in the 10 studies have been described. 6,[19][20][21][22][23] Post-baseline resistance testing was performed for patients who experienced protocol-defined virologic failure (PDVF; i.e. nonresponse, virologic rebound, and/or viremic at endpoint).…”

“…3,18 Reported here is an extension of a previous evaluation of post-baseline HIV-1 resistance data from seven phase 2 or 3 clinical studies (1686 patients) of darunavir 800 mg QD-based ARV regimens. 6 The current analysis incorporates post-baseline findings from three recent studies of the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/ 200/10 mg QD STR [19][20][21][22][23] to evaluate resistance across a total of 10 clinical studies of darunavir 800 mg QDbased regimens.…”