Elsevier

The Lancet HIV

Volume 5, Issue 1, January 2018, Pages e23-e34
The Lancet HIV

Articles
Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial

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Summary

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.

Funding

Janssen.

Introduction

Since the advent of combination antiretroviral therapy (ART) for HIV, morbidity and mortality have significantly declined.1 However, incomplete adherence to ART and emergence of antiretroviral resistance can compromise the success of long-term treatment.2 Single-tablet HIV-1 regimens that are taken once per day are preferred by patients and might improve treatment adherence and satisfaction and virological outcomes.3

Treatment guidelines include darunavir and cobicistat combined with two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NRTIs) as a recommended,4 preferred,5 or alternative6 treatment option for treatment-naive patients with HIV-1 or a recommended option where protease inhibitor mutations exist (unless darunavir resistance is predicted).7 Darunavir can provide a durable virological response and a high genetic barrier to the development of antiviral resistance in a broad range of patients8, 9, 10 and had better tolerability than atazanavir in a comparative phase 3 study in treatment-naive patients.11 Ten years after its initial approval, a substantial amount of data on darunavir exists, supporting its position as the preferred protease inhibitor recommended in treatment guidelines.

Research in context

Evidence before this study

We searched PubMed for clinical trials of darunavir or protease inhibitors and cobicistat and tenofovir alafenamide for the treatment of HIV-1 infection. Our search terms included (“tenofovir alafenamide” OR “TAF”) AND (“darunavir” OR “protease inhibitor”) AND “cobicistat” AND “HIV” and we looked for manuscripts on randomised controlled trials published in English up to Sept 1, 2017. The once per day regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (the study regimen) has only been investigated in one exploratory phase 2 study in treatment-naive, HIV-1-infected adults. In that study the study regimen had virological efficacy similar to that of cobicistat-boosted darunavir given in combination with emtricitabine and tenofovir disoproxil fumarate at week 24 (US Food and Drug Administration [FDA]-snapshot analysis, primary endpoint), with improved bone and renal laboratory parameters and no resistance to any components of the regimen.

Added value of this study

The darunavir, cobicistat, emtricitabine, and tenofovir alafenamide regimen is the first and only single-tablet HIV-1 regimen in development that includes a protease inhibitor, darunavir. We report the first virological and safety outcomes in a phase 3 trial of switching to this regimen versus remaining on regimens of boosted protease inhibitor (darunavir or atazanavir boosted by either ritonavir or cobicistat or lopinavir and ritonavir) plus emtricitabine and tenofovir disoproxil fumarate (the control regimen) in adults with virologically suppressed HIV-1. In contrast with other switch studies, this study allowed enrolment of patients with a history of previous virological failure on non-darunavir-based regimens. Switching to the study regimen was non-inferior to continuing on the control regimen in terms of cumulative rebound rate through 48 weeks. Through 48 weeks no observed resistance was seen in either group, and both regimens were well tolerated. Patients who switched to the study regimen had improvements in measures of proteinuria and in bone mineral density. Overall, our findings show safety and efficacy of the study regimen as a potential switch option for the treatment of HIV-1.

Implications of all available evidence

The study regimen is a convenient and effective antiretroviral regimen that combines the high genetic barrier to resistance of darunavir with the renal and bone safety advantages of tenofovir alafenamide in virologically suppressed HIV-1-infected adults, including those with a history of virological failure on non-darunavir-based regimens.

A single-tablet once per day regimen combining darunavir with cobicistat, emtricitabine, and tenofovir alafenamide is under investigation in two international, randomised, phase 3 studies, EMERALD (NCT02269917) and AMBER (NCT02431247). Tenofovir alafenamide, the prodrug of tenofovir, provides comparable efficacy to tenofovir disoproxil fumarate at one-tenth of the dose, with lower risks of renal toxicity and changes in bone mineral density (BMD).12, 13, 14, 15 Tenofovir alafenamide is included as a preferred NRTI backbone in several guidelines.4, 5, 6, 7

In an exploratory phase 2 trial in 153 treatment-naive adults, the darunavir, cobicistat, emtricitabine, and tenofovir alafenamide regimen had virological efficacy similar to that of a regimen of darunavir and cobicistat combined with emtricitabine and tenofovir disoproxil fumarate at week 24 (US Food and Drug Administration [FDA]-snapshot analysis, primary endpoint, with a 12% margin for non-inferiority), with significantly improved renal and bone safety (NCT01565850; GS-US-299-0102).13 Importantly, no resistance to any of the compounds was observed.

The aim of the phase 3 EMERALD study was to assess efficacy and safety of switching to the darunavir, cobicistat, emtricitabine, and tenofovir alafenamide regimen versus remaining on a boosted protease inhibitor (darunavir and ritonavir or darunavir and cobicistat once per day, atazanavir and ritonavir or atazanavir and cobicistat once per day, or lopinavir and ritonavir twice per day) combined with emtricitabine and tenofovir disoproxil fumarate in virologically suppressed, treatment-experienced HIV-1-infected adults.

Section snippets

Study design and participants

EMERALD is a phase 3, randomised, active-controlled, open-label, international, multicentre, non-inferiority study. We did the trial in accordance with the International Conference on Harmonization guideline for Good Clinical Practice, principles of Good Clinical Practice, and the Declaration of Helsinki. The protocol was reviewed and approved by central or site-specific institutional review boards or independent ethics committees before the start of the study, and is available in the appendix.

Results

The study began on April 1, 2015, and the cutoff date for this week 48 primary analysis was Feb 24, 2017. Of the 1299 patients screened, 1141 underwent randomisation and were included in the intention-to-treat population, with 763 assigned to the study group and 378 assigned to the control group (figure 1).

Overall, 1087 (95%) of 1141 patients included in the intention-to-treat analysis completed week 48. During treatment, 34 participants discontinued from the study group and 20 discontinued

Discussion

In this phase 3, randomised, open-label trial, switching to the once-daily single-tablet regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide was non-inferior to remaining on a regimen of a boosted protease inhibitor combined with emtricitabine and tenofovir disoproxil fumarate in virologically suppressed, treatment-experienced HIV-1-infected adults, with respect to the proportion of patients with virological rebound cumulative through week 48.

The entry criteria for

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