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Fixed-Dose Combination Bictegravir, Emtricitabine, and Tenofovir

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Fixed-Dose Combination Bictegravir, Emtricitabine, and Tenofovir Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials Chloe Orkin, Edwin DeJesus, Paul E Sax, Jose R Arribas, Samir K Gupta, Claudia Martorell, Jeffrey L Stephens, Hans-Jurgen Stellbrink, David Wohl, Franco Maggiolo, Melanie A Thompson, Daniel Podzamczer, Debbie Hagins, Jason A Flamm, Cynthia Brinson, Amanda Clarke, Hailin Huang, Rima Acosta, Diana M Brainard, Sean E Collins, Hal Martin, on behalf of the GS-US-380-1489 and GS-US-380-1490 study investigators Summary Background In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and Lancet HIV 2020; 7: e389–400 tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. See Comment page e374 We report week-144 efficacy and safety results from these studies. Queen Mary University of London, London, UK Methods We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly (Prof C Orkin MD); Barts Health NHS Trust, Royal London assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir Hospital, Ambrose King Centre, 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir London, UK (Prof C Orkin); 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, Orlando Immunology Center, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir Orlando, FL, USA (E DeJesus MD); Division of Infectious Diseases, alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 Brigham and Women’s Hospital secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, and Harvard Medical School, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were Boston, MA, USA registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. (Prof P E Sax MD); Infectious Diseases Unit, Hospital Universitario La Paz, Findings 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and IdiPaz Madrid, Spain tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, (Prof J R Arribas MD); emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, Department of Medicine, Division of Infectious Diseases, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens Indiana University School of for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the Medicine, Indianapolis, IN, USA bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and (Prof S K Gupta); The Research lamivudine group (difference −2·6%, 95% CI −8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma Institute, Springfield, MA, USA (C Martorell MD); Department HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and of Internal Medicine, Mercer 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference −1·9%, University School of Medicine, −7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All Macon, GA, USA (Prof J L Stephens MD); treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug Department of Internal discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide Medicine, Infectious Diseases, group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in University of Hamburg, the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, Hamburg, Germany (Prof H-J Stellbrink MD); and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median Department of Medicine, changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs Institute of Global Health and 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (–0·1 vs –0·3; p=0·007) at week 144; no differences were Infectious Diseases, University observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no of North Carolina at Chapel Hill, Chapel Hill, NC, USA differences in median changes from baseline in weight at week 144 for either study. (Prof D Wohl MD); Unit of HIV-related Diseases and Interpretation These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, Experimental Therapies, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy (F Maggiolo MD); AIDS Research Funding Gilead Sciences. Consortium of Atlanta, Atlanta, GA, USA (M A Thompson MD); Infectious Disease Department, Hospital Universitari de Bellvitge, Barcelona, Spain Research in context (D Podzamczer MD); Georgia Department of Public Health, Evidence before this study other guidelines-recommended treatment regimens Coastal Health District, Data on bictegravir regimens for HIV treatment extend to a (dolutegravir, abacavir, and lamivudine; and dolutegravir plus Chatham Care Center, maximum follow-up time of 96 weeks. We searched PubMed co-formulated emtricitabine and tenofovir alafenamide), Savannah, GA, USA for randomised clinical trials of bictegravir in people with HIV, co-formulated bictegravir, emtricitabine and tenofovir (D Hagins MD); Department of Adult and Family Medicine, with title and abstract search terms of “bictegravir” and alafenamide showed non-inferior efficacy at week 144. No Kaiser Permanente Medical “randomised” or “randomized”. We used internet search participants on any regimen failed with emergent resistance, Group, Sacramento, CA, USA engines to identify governmental, non-governmental, and further showing the high barrier to resistance of the study (J A Flamm MD); Central Texas professional medical society practice guidelines relevant to regimens. We found less nausea and fewer drug-related Clinical Research, Austin, TX, USA (C Brinson MD); bictegravir. Searches were limited to publications in English adverse effects in those treated with co-formulated Elton John Centre, Royal Sussex between Jan 1, 1997, and Nov 1, 2019. Our search yielded bictegravir, emtricitabine, and tenofovir alafenamide County Hospital, 14 publications, of which we excluded nine because they compared with those who received dolutegravir, abacavir, and Brighton & Sussex University lamivudine. Bone mineral density, glomerular filtration rate, Hospitals NHS Trust, reported results from switch studies in virologically Brighton, UK (A Clarke MD); and suppressed adults with HIV, meta-analyses, systemic analyses, and biomarkers of renal tubular function were similar between Department of Biometrics phase 1, or patient-reported outcomes. The remaining five bictegravir, emtricitabine, and tenofovir alafenamide and (H Huang PhD), Department of reports summarised outcomes from weeks 48 or 96 from dolutegravir, abacavir, and lamivudine. These studies provide Virology (R Acosta BS), Department of HIV Clinical three phase 2 and phase 3 studies of bictegravir, emtricitabine, evidence of the durable efficacy, continued tolerability, and Research (S E Collins MD, and tenofovir alafenamide in treatment-naive adults. Across no treatment-emergent resistance for participants taking D M Brainard MD, H Martin MD), these reports, bictegravir, emtricitabine, and tenofovir bictegravir, emtricitabine, and tenofovir alafenamide. Gilead Sciences, alafenamide was non-inferior to standard-of-care regimens, Foster City, CA, USA Implications of all the available evidence including those containing dolutegravir. Bictegravir, Correspondence to: Data from these analyses confirm findings from reports emtricitabine, and tenofovir alafenamide had a similar renal, Dr Sean E Collins, MD, Gilead from weeks 48 and 96 from randomised studies comparing bone, and lipid safety profile to that of the comparators. Sciences, Foster City, CA 94404, bictegravir, emtricitabine, and tenofovir alafenamide with USA Bictegravir, emtricitabine, and tenofovir alafenamide became standard-of-care regimens, including those containing [email protected] a guidelines-recommended regimen for the initial treatment dolutegravir. Co-formulated bictegravir, emtricitabine, and of adults with HIV on the basis of week-48 data; longer-term tenofovir alafenamide can be administered once daily, does data are needed to inform clinical care. not require HLA B*5701 testing, and provides Added value of this study guideline-recommended therapy for people with HIV and with These randomised, blinded, phase 3 studies provide evidence HIV–hepatitis B virus co-infection. Together, these studies of the long-term safety and efficacy of bictegravir, provide long-term
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