Switch to single-tablet regimen containing darunavir is safe, effective

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Switching to a once-daily, darunavir-based HIV regimen was non-inferior to continuing treatment with a boosted protease inhibitor plus emtricitabine and Viread, according to 48-week data from the EMERALD trial.

The once-daily, single-tablet regimen contains 800 mg of darunavir, 150 mg of Tybost (cobicistat, Gilead Sciences), 200 mg of emtricitabine and 10 mg of Vemlidy (tenofovir alafenamide, Gilead Sciences; D/C/F/TAF). Dr Joseph Eron, professor of medicine and director of the Clinical Core at the University of North Carolina Centre for AIDS Research, said at IDWeek 2017 that D/C/F/TAF was recently approved on Sept. 25 in Europe and is currently undergoing regulatory review for use in adults and children aged 12 years and older in the US.

For the phase 3 trial, Eron and colleagues randomly assigned 1,141 virologically suppressed patients receiving treatment on a boosted protease inhibitor (bPI) plus emtricitabine and Viread (tenofovir disoproxil fumarate, Gilead Sciences; F/TDF) to switch to D/C/F/TAF (n = 763) or continue treatment with bPI plus F/TDF (n = 378). The primary outcome was the proportion of patients with virological rebound at 48 weeks. The FDA established a noninferiority confidence interval of 4%.

“This is a very tight confidence interval, but I think it’s appropriate because people who are on therapy and are suppressed should stay suppressed,” Eron said.

The rate of virologic rebound was similar among patients in both treatment arms, occurring in 2.5% of those who switched to D/C/F/TAF and 2.1% in the control group. Among rebounding patients, 63% who switched therapy and 50% in the control group were re-suppressed without having to change therapy.

Overall, 94.9% of patients taking D/C/F/TAF and 93.7% in the control group were virologically suppressed at week 48, with virologic failure occurring in 0.8% and 0.5% of patients, respectively. There were no significant differences in treatment discontinuations (1.4% vs. 1.3%), grade 3 or 4 adverse events (6.8% vs. 8.2%) and serious adverse events (4.6% vs. 4.8%) among patients in the D/C/F/TAF and control arms. According to the researchers, there were no deaths in the study, and they did not detect resistance to any of the study drugs.

D/C/F/TAF was also assessed in treatment-naive patients enrolled in the phase 3 AMBER trial. Eron said results from this study will be presented at the European AIDS Conference, held from 25-27 October in Milan, Italy.

“The findings from the EMERALD study bring us one step closer to being able to offer those who live with HIV and struggle with adherence an option that combines the efficacy and high genetic barrier to resistance of darunavir with the demonstrated safety profile of TAF into a single tablet,” he said.

Abstract
Background: Simplified regimens with reduced pill burden and fewer side-effects are desirable for people living with HIV. We investigated the efficacy and safety of switching to a single-tablet regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide versus continuing a regimen of boosted protease inhibitor, emtricitabine, and tenofovir disoproxil fumarate.
Methods: EMERALD was a phase-3, randomised, active-controlled, open-label, international, multicentre trial, done at 106 sites across nine countries in North America and Europe. HIV-1-infected adults were eligible to participate if they were treatment-experienced and virologically suppressed (viral load <50 copies per mL for ≥2 months; one viral load of 50–200 copies per mL was allowed within 12 months before screening), and patients with a history of virological failure on non-darunavir regimens were allowed. Randomisation was by computer-generated interactive web-response system and stratified by boosted protease inhibitor use at baseline. Patients were randomly assigned (2:1) to switch to the open-label study regimen or continue the control regimen. The study regimen consisted of a fixed-dose tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, which was taken once per day for 48 weeks. The primary outcome was the proportion of participants with virological rebound (confirmed viral load ≥50 copies per mL or premature discontinuations, with last viral load ≥50 copies per mL) cumulative through week 48; we tested non-inferiority (4% margin) of the study regimen versus the control regimen in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02269917.
Findings: The study began on April 1, 2015, and the cutoff date for the week 48 primary analysis was Feb 24, 2017. Of 1141 patients (763 in the study group and 378 in the control group), 664 (58%) had previously received five or more antiretrovirals, including screening antiretrovirals, and 169 (15%) had previous virological failure on a non-darunavir regimen. The study regimen was non-inferior to the control for virological rebound cumulative through week 48 (19 [2·5%] of 763 patients in the study group vs eight (2·1%) of 378 patients in the control group; difference 0·4%, 95% CI −1·5 to 2·2; p<0·0001). No resistance to any study drug was observed. Numbers of discontinuations related to adverse events (11 [1%] of 763 patients in the study group vs four [1%] of 378 patients in the control group) and grade 3–4 adverse events (52 [7%] patients vs 31 [8%] patients) were similar between the two groups. There was a small non-clinically relevant but statistically significant (0·2 [SD 1·1] vs 0·1 [1·1], p=0.010) difference between the two groups in change from baseline in total cholesterol to HDL-cholesterol ratio. Only one serious adverse event (pancreatitis in the study group) was deemed as possibly related to the study regimen.
Interpretation: Our findings show the safety and efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide as a potential switch option for the treatment of HIV-1 infection in adults with viral suppression.

Authors
Chloe Orkin, Jean-Michel Molina, Eugenia Negredo, José R Arribas, Joseph Gathe, Joseph J Eron, Erika Van Landuyt, Erkki Lathouwers, Veerle Hufkens, Romana Petrovic, Simon Vanveggel, Magda Opsomer

Healio material
The Lancet HIV article summary


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