iconstar paper   HIV Articles  
Back grey arrow rt.gif
 
 
Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial
 
 
  Download the PDF here
 
HIV Lancet July 2018 - Jean-Michel Molina, Douglas Ward, Indira Brar, Anthony Mills, Hans-Jürgen Stellbrink, Luis López-Cortés, Peter Ruane, Daniel Podzamczer, Cynthia Brinson, Joseph Custodio, Hui Liu, Kristen Andreatta, Hal Martin, Andrew Cheng, Erin Quirk
 
Summary
 
Background

 
Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection.
 
Methods
 
In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120.
 
Findings
 
Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI −1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group.
 
Interpretation
 
The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection.
 
Funding
 
Gilead Sciences.
 
Introduction

 
Bictegravir is a novel, potent, unboosted integrase strand transfer inhibitor (INSTI) with a high in-vitro barrier to resistance and low potential for drug interactions.1, 2 Three large phase 3 studies3, 4, 5 in previously untreated or virologically suppressed adults with HIV-1 infection compared bictegravir (plus emtricitabine and tenofovir alafenamide) with dolutegravir (plus abacavir and lamivudine or emtricitabine and tenofovir alafenamide) or boosted protease inhibitor regimens. The bictegravir regimen was well tolerated and showed high rates of HIV-1 suppression, without virological failure resulting from treatment-emergent resistance. Therefore, fixed-dose, combination bictegravir, emtricitabine, and tenofovir alafenamide might be a potent, convenient, tolerable, and practical regimen for long-term treatment in many patients with HIV-1 infection.
 
Research in context
 
Evidence before this study

 
We searched PubMed for randomised clinical trials comparing bictegravir with dolutegravir in individuals with HIV-1 using the search terms "bictegravir" and "dolutegravir" or "randomised" or "randomized". Searches were limited to articles published in English between Jan 1, 1997, and Nov 1, 2017. Our search yielded three articles, all of which summarised results from phase 2 or 3 studies of bictegravir with emtricitabine and tenofovir alafenamide compared with dolutegravir given with either emtricitabine and tenofovir alafenamide or abacavir and lamivudine in treatment-naive adults with HIV-1. Both treatments showed high efficacy and were well tolerated through 48 weeks. Bictegravir was non-inferior to dolutegravir in all trials, most notably in the two phase 3 studies, which were randomised, double blinded, and active controlled.
 
Added value of this study
 
Integrase strand transfer inhibitors (INSTIs) are recommended for first-line antiretroviral therapy in combination with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). Virologically suppressed individuals with HIV-1 might switch from their existing regimen because of safety or tolerability concerns, for regimen simplification, or because of other reasons. To our knowledge, this study is the first phase 3 clinical trial to investigate switching to the fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine. We found that co-formulated, fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine in maintaining virological suppression (plasma HIV-1 RNA <50 copies per mL) through 48 weeks, and had a similar safety and tolerability profile. Fewer participants in the dolutegravir group discontinued treatment because of adverse events, but fewer treatment-related adverse events were reported in the bictegravir group. To our knowledge, this study is also the first to combine an unboosted INSTI with the guideline-recommended NRTI backbone of emtricitabine and tenofovir alafenamide, which is recognised for its potency and safety advantages, particularly with respect to bone and renal measures, compared with tenofovir disoproxil fumarate. This NRTI backbone does not require testing for HLA-B*5701 before treatment and does not have any known association with cardiovascular events.
 
Implications of all the available evidence
 
Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide might be an effective alternative to dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1, potentially avoiding the neuropsychiatric adverse events associated with dolutegravir and the cardiovascular adverse events linked to abacavir. Additionally, our results complement those from phase 2 and 3 studies of bictegravir, emtricitabine, and tenofovir alafenamide in treatment-naive adults, suggesting that this regimen could be a safe and efficacious option for initial or ongoing treatment of HIV-1 infection.
 
Switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine has the potential to maintain high rates of suppression while avoiding the potential side-effects of abacavir, such as cardiovascular events.6, 7, 8 Additionally, this switch might avoid adverse effects on the CNS and treatment discontinuation, which have been reported more frequently with dolutegravir in clinical practice and cohort studies than in published results of clinical trials.9, 10, 11 This regimen also contains two NRTIs with activity against hepatitis B virus (HBV), and the tablet is less than half the size of co-formulated abacavir, lamivudine, and dolutegravir, which might improve acceptability among patients.12, 13, 14, 15
 
In this study, we investigated the efficacy and safety of switching to fixed-dose, combination bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection.

 
 
 
 
  iconpaperstack View Older Articles   Back to Top   www.natap.org