Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study

Abstract

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen.

Methods: EMERALD patients were virologically suppressed (viral load [VL] < 50 copies/mL for ≥ 2 months at screening). Prior non-darunavir virologic failure (VF) was allowed. Primary endpoint was proportion of patients with virologic rebound (confirmed VL ≥ 50 copies/mL) cumulative through week 48. Virologic response was VL < 50 copies/mL (FDA snapshot). Safety was assessed by adverse events, renal proteinuria markers, and bone mineral density. Outcomes were examined for prespecified subgroups by age (≤/> 50 years), gender, race (black/non-black), prior number of antiretrovirals used (4/5/6/7/> 7), prior VF (0/≥ 1), baseline bPI (darunavir/atazanavir or lopinavir), and baseline boosting agent (ritonavir/cobicistat).

Results: Among 1141 patients in the D/C/F/TAF (n = 763) and control (n = 378) arms, virologic rebound rates (2.5% and 2.1%, respectively) were similar, and this was consistent across all subgroups. Virologic response rates ranged from 91 to 97% (D/C/F/TAF) and 89 to 99% (control) across all subgroups, with differences between treatment arms of 0 and 6%. Adverse event rates were low in both arms and across subgroups. Improvements in renal and bone parameters were observed with D/C/F/TAF across demographic subgroups.

Conclusions: For treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI. Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://ichgcp.net/clinical-trials-registry/NCT02269917.

Keywords: Antiretroviral; Darunavir; HIV-1; Protease inhibitor; Single-tablet regimen; Switch study.

Conflict of interest statement

GDH has received research or grant support from Gilead, ViiV, Janssen, Proteus, and the US National Institutes of Health; he has also served as a consultant to Janssen, Gilead, and ViiV. JJE received research grants from Janssen, Gilead, and ViiV; and has served as a consultant to Bristol-Myers Squibb, Merck, Janssen, Gilead, and ViiV. P-MG has received grant/research support from Merck; served on advisory committees or review panels for Merck, Roche, ViiV, Gilead, and Janssen; and served as a speaker/teacher for Merck and Tibotec. CO has received speaker honoraria or consulting fees for attending speakers bureaus or advisory boards for, and has received research grants from, Janssen, Merck, ViiV, and Gilead. J-MM has received honoraria for participation in advisory boards for Gilead and Merck; and has received a research grant from Merck. EDJ has participated in a speaker bureau for Gilead, and advisory boards for Gilead, Janssen, and Theratechnologies. RP is a former contractor for Janssen. DL, EVL, EL, REN, KB, and EYW are full-time employees of Janssen.

Figures

Fig. 1

Virologic rebound rates through week 48 by subgroup. D/C/F/TAF darunavir/cobicistat/emtricitabine/tenofovir alafenamide, ARV antiretroviral, VF virologic failure, bPI boosted protease inhibitor, CI confidence interval. *Differences (95% CI) in virologic rebound rate between treatment arms are reported above the brackets. The total number of patients in each treatment arm for each subgroup is reported below the x-axis labels. †For patients ≤ 50 years without polypharmacy, virologic rebound rates were 2.5% (11/436) with D/C/F/TAF and 2.9% (6/206) with control; for patients > 50 years with polypharmacy, these rates were 0% (0/108) with D/C/F/TAF and 2.0% (1/50) with control. ‡Data are not reported for the 1 patient who had used 3 prior ARVs. §Darunavir with ritonavir or cobicistat, atazanavir with ritonavir or cobicistat, and lopinavir with ritonavir. ¶Ritonavir with darunavir, atazanavir, or lopinavir; and cobicistat with darunavir or atazanavir

Fig. 2

Virologic response and VF rates at week 48 by subgroup. VF virologic failure, D/C/F/TAF darunavir/cobicistat/emtricitabine/tenofovir alafenamide, ARV antiretroviral, bPI boosted protease inhibitor, CI confidence interval, FDA Food and Drug Administration. *Differences (95% CI) in virologic response rate between treatment arms are reported above the brackets. The total number of patients in each treatment arm for each subgroup is reported below the x-axis labels. †For each subgroup, patients with missing virologic data (per FDA snapshot) in the D/C/F/TAF and control arms, respectively, were as follows: 4% and 6% for those ≤ 50 years, 6% and 6% for those > 50 years, 4% and 6% for men, 5% and 6% for women, 4% and 7% for those who are non-black/African American, and 7% and 4% for those who are black/African American. ‡For patients ≤ 50 years without polypharmacy, rates of HIV-1 RNA < 50 copies/mL were 96% (419/436) with D/C/F/TAF and 94% (193/206) with control; for patients > 50 years with polypharmacy, these rates were 93% (100/108) with D/C/F/TAF and 92% (46/50) with control. §For each subgroup, patients with missing virologic data (per FDA snapshot) in the D/C/F/TAF and control arms, respectively, were as follows: 3.5% and 3.1% of those who used 4 prior ARVs, 5.1% and 8.9% of those who used 5 prior ARVs, 4.3% and 3.3% of those who used 6 prior ARVs, 4.3% and 10.0% of those who used 7 prior ARVs, 5.2% and 7.9% of those who used > 7 prior ARVs, 4.6% and 5.5% of those with 0 prior VFs, and 2.6% and 7.5% of those with ≥ 1 prior VF. ¶Data are not reported for the 1 patient who used 3 prior ARVs. #For each subgroup, patients with missing virologic data (per FDA snapshot) in the D/C/F/TAF and control arms, respectively, were as follows: 3% and 5% for the darunavir group, 7% and 8% for the atazanavir or lopinavir group, 4% and 7% for the ritonavir group, 4% and 2% for the cobicistat group. **Darunavir with ritonavir or cobicistat, atazanavir with ritonavir or cobicistat, and lopinavir with ritonavir. ††Ritonavir with darunavir, atazanavir, or lopinavir; and cobicistat with darunavir or atazanavir

Fig. 3

Changes from baseline to week 48 in renal laboratory parameters based on demographic characteristics. D/C/F/TAF darunavir/cobicistat/emtricitabine/tenofovir alafenamide, SE standard error, RBP retinol binding protein. *The total number of patients in each treatment arm for each subgroup is reported at the bottom of the figure

Fig. 4

Changes from baseline in BMD over time (hip and lumbar spine) based on demographic characteristics. BMD bone mineral density, D/C/F/TAF darunavir/cobicistat/emtricitabine/tenofovir alafenamide, SE standard error. *Data are from the bone investigation substudy, which included 209 patients in the D/C/F/TAF arm and 108 patients in the control arm. The total number of substudy patients in each treatment arm for each subgroup is reported in the legends