Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, ph

Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch. In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries. Eligible participants were aged 18 years or older, had an estimated glomerular filtration rate of 50 mL per min or higher, had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 6 months or more before screening, and were on a regimen consisting of boosted atazanavir or darunavir plus either emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated once-daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg), herein known as the bictegravir group, or to remain on their baseline boosted protease inhibitor regimen, herein known as the boosted protease inhibitor group, for 48 weeks. Randomisation was stratified by use of tenofovir disoproxil fumarate or abacavir at screening. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (by US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 4%. Efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting patients and is registered with ClinicalTrials.gov, number NCT02603107. Between Dec 2, 2015, and July 15, 2016, 578 participants were randomly assigned and 577 were treated (290 in the bictegravir group and 287 in the boosted protease inhibitor group). At week 48, five participants (2%) in the bictegravir group and five (2%) in the boosted protease inhibitor group had plasma HIV-1 RNA of 50 copies per mL or higher (difference 0·0%, 95·002% CI -2·5 to 2·5), thus switching to the bictegravir regimen was non-inferior to continued boosted protease inhibitor therapy. The overall incidence and severity of adverse events was similar between groups, although headache occurred more frequently in the bictegravir group than in the boosted protease inhibitor group. 233 (80%) participants in the bictegravir group and 226 (79%) in the boosted protease inhibitor group had an adverse event. Only two (1%) participants in the bictegravir group and one (<1%) in the boosted protease inhibitor group discontinued treatment because of adverse events. 54 participants (19%) in the bictegravir group had drug-related adverse events compared with six (2%) in the protease inhibitor group. Fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide might be a safe and efficacious alternative to continued boosted protease inhibitor therapy in adults with HIV-1 infection. Gilead Sciences.

Daar ES ，DeJesus E ，Ruane P ，Crofoot G ，Oguchi G ，Creticos C ，Rockstroh JK ，Molina JM ，Koenig E ，Liu YP ，Custodio J ，Andreatta K ，Graham H ，Cheng A ，Martin H ，Quirk E ... -  《Lancet HIV》

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, phas

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. 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. 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. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection. Gilead Sciences.

Molina JM ，Ward D ，Brar I ，Mills A ，Stellbrink HJ ，López-Cortés L ，Ruane P ，Podzamczer D ，Brinson C ，Custodio J ，Liu H ，Andreatta K ，Martin H ，Cheng A ，Quirk E ... -  《Lancet HIV》

Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.

Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per μL, 50-199 cells per μL, or ≥200 cells per μL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference -0·6%, 95·002% CI -4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001). At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. Gilead Sciences.

Gallant J ，Lazzarin A ，Mills A ，Orkin C ，Podzamczer D ，Tebas P ，Girard PM ，Brar I ，Daar ES ，Wohl D ，Rockstroh J ，Wei X ，Custodio J ，White K ，Martin H ，Cheng A ，Quirk E ... -  《-》

Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-infer

The single-tablet regimen consisting of bictegravir, emtricitabine, and tenofovir alafenamide is recommended for treatment of HIV-1 infection on the basis of data from 48 weeks of treatment. Here, we examine the longer-term efficacy, safety, and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with dolutegravir plus co-formulated emtricitabine and tenofovir alafenamide at week 96. This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 126 outpatient centres in ten countries. We enrolled treatment-naive adults (aged ≥18 years) with HIV-1 infection who had an estimated glomerular filtration rate of at least 30 mL/min and sensitivity to emtricitabine and tenofovir. People with chronic hepatitis B or C infection, or both, and those who had used antivirals previously for prophylaxis were allowed. We randomly assigned participants (1:1) to receive treatment with either co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or dolutegravir 50 mg with co-formulated emtricitabine 200 mg and tenofovir alafenamide 25 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607956. Between Nov 13, 2015, and July 14, 2016, we screened 742 individuals, of whom 657 were enrolled. 327 participants were assigned to the bictegravir group and 330 to the dolutegravir group. Of these, 320 in the bictegravir group and 325 in the dolutegravir group received at least one dose of study drug. At week 96, HIV-1 RNA less than 50 copies per mL was achieved by 269 (84%) of 320 participants in the bictegravir group and 281 (86%) of 325 in the dolutegravir group (difference -2·3%, 95% CI -7·9 to 3·2), demonstrating non-inferiority of the bictegravir regimen compared with the dolutegravir regimen. Both treatments continued to be well tolerated through 96 weeks; 283 (88%) of 320 participants in the bictegravir group and 288 (89%) of 325 in the dolutegravir group had any adverse event and 55 (17%), and 33 (10%) had any serious adverse event. The most common adverse events were diarrhoea (57 [18%] of 320 in the bictegravir group vs 51 [16%] of 325 in the dolutegravir group) and headache (51 [16%] of 320 vs 48 [15%] of 325). Deaths were reported for three (1%) individuals in each group (one cardiac arrest, one gastric adenocarcinoma, and one hypertensive heart disease and congestive cardiac failure in the bictegravir group and one unknown causes, one pulmonary embolism, and one lymphoma in the dolutegravir group); none were considered to be treatment related. Adverse events led to discontinuation in six (2%) participants in the bictegravir group and five (2%) in the dolutegravir group; one of these events in the bictegravir group versus four in the dolutegravir group occurred between weeks 48 and 96. Study drug-related adverse events were reported for 64 (20%) participants in the bictegravir group and 92 (28%) in the dolutegravir group. These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with chronic HIV. Gilead Sciences, Inc.

Stellbrink HJ ，Arribas JR ，Stephens JL ，Albrecht H ，Sax PE ，Maggiolo F ，Creticos C ，Martorell CT ，Wei X ，Acosta R ，Collins SE ，Brainard D ，Martin H ... -  《Lancet HIV》

Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-i

Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1. We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791. We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per μL) and total lymphocyte counts (mean change -0·20 × 109/L) were decreased at 48 weeks. Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). Merck Sharp & Dohme, a subsidiary of Merck & Co.

Mills AM ，Rizzardini G ，Ramgopal MN ，Osiyemi OO ，Bogner JR ，Hagins DP ，Paredes R ，Reynes J ，Rockstroh JK ，Carr A ，Su FH ，Klopfer SO ，Eves K ，Plank RM ，Correll T ，Fox MC ... -  《Lancet HIV》