Switch to single-tablet bictegravir-lenacapavir from a complex HIV regimen (ARTISTRY-1): a randomised, open-label, phase 3 clinical trial.

# Switch to single-tablet bictegravir–lenacapavir from a complex HIV regimen (ARTISTRY-1): a randomised, open-label, phase 3 clinical trial *The Lancet 2026* Articles Switch to single-tablet bictegravir–lenacapavir from a complex HIV regimen (ARTISTRY-1): a randomised, open-label, phase 3 clinical trial Chloe Orkin, Peter J Ruane, Malcolm Hedgcock, Cyril Gaultier, Marcelo H Losso, Benoit Trottier, Thomas Lutz, Mark O’Reilly, Mark Bloch, Jihad Slim, Moti Ramgopal, Simiso Sokhela, Karam Mounzer, Hung-Chin Tsai, Jorge Santana Bagur, Xu Zhang, Keith Aizen, Kwanza Price, Nicolas Margot, Jairo M Montezuma-Rusca, Peter Sklar, Martin Rhee, Pedro Cahn, on behalf of the ARTISTRY-1 Study Group Summary Background Single-tablet regimens (STRs) revolutionised HIV-1 treatment, improving adherence and clinical Lancet 2026; 407: 1249–58 outcomes; however, many people cannot take these due to resistance, contraindications, or drug–drug interactions, Published Online instead relying on complex multi-tablet regimens. Novel STRs are therefore needed. We aimed to evaluate the ecacy February 25, 2026 and safety of a novel STR, bictegravir–lenacapavir, in people with HIV-1. https://doi.org/10.1016/ S0140-6736(26)00307-7 See Comment page 1211 Methods ARTISTRY-1 was a randomised, open-label, active-controlled, non-inferiority phase 3 trial conducted at SHARE Collaborative, Blizard hospitals and clinics across 15 countries that enrolled people with HIV-1 with virological suppression on complex Institute, Faculty of Medicine regimens. Participants were randomly assigned (using interactive technology, 2:1, stratified by geographical region) to and Dentistry, Queen Mary switch to once-daily oral bictegravir–lenacapavir 75 mg/50 mg STR or continued complex regimen. The primary University of London, London, outcome was the proportion of participants with an HIV-1 RNA viral load of 50 copies per mL or higher at week 48 (US UK (Prof C Orkin MD); Ruane Clinical Research Group, Food and Drug Administration Snapshot algorithm), assessed in all randomly assigned participants who received any Los Angeles, CA, USA dose of assigned treatment. This trial (active; enrolment complete) was registered with ClinicalTrials.gov (NCT05502341). (P J Ruane MD); Spectrum Health, Vancouver, BC, Canada Findings Between Jan 29 and Sept 26, 2024, 729 participants were screened; 557 were randomly assigned and treated (M Hedgcock MD); BIOS Clinical Research, Palm Springs, CA, (bictegravir–lenacapavir n=371; complex regimen n=186). At baseline, median age was 60 years (range 22–84), HIV USA (C Gaultier MD); Emerging treatment duration was 28 years (IQR 22–32); participants were taking a median of three antiretroviral pills per day Diseases Research Unit, (range 2–11). At week 48, an HIV-1 RNA viral load of 50 copies per mL or higher was observed in three (1%) participants Hospital General de Agudos receiving bictegravir–lenacapavir and two (1%) receiving a complex regimen (dierence −0·3%; José María Ramos Mejía, Buenos Aires, Argentina 95·002% CI −2·3 to 1·8), meeting the non-inferiority margin of 4%. No resistance emerged. Adverse event rates (Prof M H Losso MD); Fundación were similar between groups. Six (2%) participants discontinued bictegravir–lenacapavir and one (1%) discontinued IBIS/CICAL, Buenos Aires, their complex regimen due to adverse events. There were five deaths in the bictegravir–lenacapavir group, none of Argentina (Prof M H Losso); which were deemed related to study drug. Participants reported increased treatment satisfaction after switching to Clinique de Médecine Urbaine du Quartier Latin, Montreal, bictegravir–lenacapavir. QC, Canada (B Trottier MD); Infektiologikum, Frankfurt, Interpretation Bictegravir–lenacapavir STR demonstrated non-inferior ecacy to complex regimens, with a similar Germany (T Lutz MD); East safety profile and increased treatment satisfaction. Bictegravir–lenacapavir oers new opportunities for HIV-1 Sydney Doctors, Darlinghurst, NSW, Australia treatment optimisation for people taking complex regimens. (M O’Reilly BMED); Taylor Square Private Clinic, Funding Gilead Sciences. Surry Hills, NSW, Australia (M O’Reilly); Holdsworth House Medical Practice, Darlinghurst, Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND NSW, Australia 4.0 license. (M Bloch MMed); Kirby Institute, University of Introduction Single-tablet regimens (STRs) have been standard of New South Wales, Kensington, Sydney, NSW, Australia People with HIV taking complex multi-tablet care for people with HIV-12,4 for almost two decades,5 (M Bloch); New York Medical antiretroviral therapy regimens face a substantial unmet oering simplicity, reduced pill burden, improved College, Valhalla, New York, NY, treatment need, often experiencing significant pill adherence, and better clinical outcomes compared with USA (J Slim MD); Saint Michael’s Medical Center, burden, adherence challenges, and diculties with complex multi-tablet regimens.6–8 A novel STR combining Newark, NJ, USA (J Slim); long-term HIV management.1 These individuals—often bictegravir, a global guideline-recommended integrase Midway Immunology and older adults diagnosed early during the HIV-1 epidemic strand-transfer inhibitor (INSTI) with a high resistance Research Center, Fort Pierce, FL, or people born with HIV-1, with decades of antiretroviral barrier,2,4,9–11 and lenacapavir, a first-in-class capsid USA (Prof M Ramgopal MD); Ezintsha, Faculty of Health therapy experience and a higher likelihood of inhibitor with no documented de novo resistance in the Sciences, University of the resistance—continue to rely on regimens consisting of absence of previous exposure,12–14 oers a promising Witwatersrand, Johannesburg, multiple pills and/or doses per day.2 These regimens treatment optimisation option for people with HIV-1 with South Africa (S Sokhela MBChB); usually require the use of pharmacological boosting virological suppression on a complex regimen who are Philadelphia FIGHT Community Health Centers, Philadelphia, agents and can result in higher drug concentrations.3 unable to use currently available STRs. The phase 2/3 Articles PA, USA (K Mounzer MD); Research in context School of Medicine, College of Medicine, National Yang Ming Evidence before this study enrolled in a registrational programme for HIV treatment to Chiao Tung University, Taipei City, Taiwan We searched PubMed on Feb 12, 2026, using the terms date, with a median participant age of 60 years. At baseline, (H-C Tsai MD); Division of “bictegravir AND lenacapavir” without language or date most participants had at least one comorbidity (54% had Infectious Diseases, restrictions. 16 articles were identified. None of these studies two or more select comorbidities) and 61% were taking Department of Medicine, compared a single-tablet regimen of bictegravir–lenacapavir two or more select concomitant medications. Median Kaohsiung Veterans General Hospital, Kaohsiung City, with complex regimens for treatment of HIV-1, with the duration of HIV treatment was 28 years, and a large Taiwan (H-C Tsai); School of exception of the phase 2 portion of the current trial. There is a percentage of participants (81%) were on a complex regimen Medicine, University of need for additional treatment options for people with HIV-1 due to antiretroviral resistance, demonstrating the treatment Puerto Rico, San Juan, who are unable to benefit from available single-tablet regimens challenges faced by this underserved population. Puerto Rico (Prof J Santana Bagur MD); due to resistance, intolerance, contraindications, or drug–drug Once-daily oral bictegravir–lenacapavir single-tablet regimen Gilead Sciences, Foster City, CA, interactions. Instead, these individuals—often older adults with demonstrated non-inferior efficacy to complex regimens, with USA (X Zhang PhD, multiple comorbidities, decades of antiretroviral therapy an HIV-1 RNA viral load of 50 copies per mL or higher in 1% of K Aizen MBChB, K Price MPH, N Margot MA, experience, and a higher likelihood of resistance—rely on participants receiving bictegravir–lenacapavir and 1% of J M Montezuma-Rusca MD, complex antiretroviral regimens, and frequently experience participants receiving a complex regimen at week 48 P Sklar MD, M Rhee MD); significant pill burden, adherence challenges, and difficulties (difference −0·3%; 95·002% CI −2·3% to 1·8%). No resistance Fundación Huésped, with long-term HIV management. A novel single-tablet emerged. There were similar rates of adverse events in both Buenos Aires, Argentina (P Cahn PhD) regimen of bictegravir and lenacapavir could offer a new treatment groups despite the open-label trial design, and treatment option for this population. The open-label, participants who switched to bictegravir–lenacapavir reported Correspondence to: Prof Chloe Orkin, Blizard randomised phase 2/3 ARTISTRY-1 trial evaluated the efficacy greater treatment satisfaction than those continuing a Institute, Faculty of Medicine and safety of switching to bictegravir–lenacapavir in people complex regimen. and Dentistry, Queen Mary with HIV-1 with virological suppression on a complex regimen. University of London, Implications of all the available evidence London E1 2AT, UK Two previously published phase 2 articles reported that These findings support the use of bictegravir–lenacapavir as a c.m.orkin@qmul.ac.uk bictegravir and lenacapavir maintained virological suppression new, optimised treatment option to maintain virological through 48 weeks and were well tolerated, including in people suppression in people with HIV-1 on complex regimens who with a history of antiretroviral resistance. Here we report have not benefitted from available single-tablet regimens due phase 3 data from ARTISTRY-1. to antiretroviral resistance or other reasons. In particular, Added value of this study bictegravir–lenacapavir could offer a more suitable long-term Phase 3 ARTISTRY-1 is the first randomised trial to investigate treatment option for an ageing population with comorbidities the novel single-tablet regimen of bictegravir–lenacapavir for and a greater risk of polypharmacy. treatment of HIV-1. It included the oldest study population ARTISTRY-1 trial evaluated the ecacy and safety of trial site (trial investigators and ethics approvals are listed See Online for appendix switching to bictegravir–lenacapavir STR in people with in the appendix [pp 3–5]). The protocol and statistical HIV-1 with virological suppression on complex regimens. analysis plan are provided in the appendix (p 25). A In phase 2, bictegravir and lenacapavir were well tolerated summary of important protocol amendments is also and maintained virological suppression through 48 weeks provided in the appendix (pp 6–7). The trial is active and in participants, most of whom had a history of closed to new participants. antiretroviral resistance.15 Here, we aimed to evaluate the 48-week ecacy and safety of bictegravir–lenacapavir Participants STR in people with HIV who switched from complex Eligible participants were aged 18 years or older, with regimens in the phase 3 study. plasma HIV-1 RNA concentrations below 50 copies per mL for at least 6 months before and at screening, Methods and on a complex regimen for at least 6 months due Study design to previous antiretroviral resistance, intolerance, or ARTISTRY-1 was a randomised, open-label, active- contraindication to existing STRs, with no resistance to controlled, non-inferiority phase 3 trial (GS-US-621-6289; bictegravir or previous exposure to lenacapavir. A complex ClinicalTrials.gov number NCT05502341), conducted at regimen was defined as (1) containing a boosted protease 90 hospitals and clinics across 15 countries or territories inhibitor (PI) or non-nucleoside reverse transcriptase (Australia, Argentina, Canada, Dominican Republic, inhibitor (NNRTI) plus one or more other third agent France, Germany, Italy, Japan, Puerto Rico, South Africa, from a class other than nucleos(t)ide reverse transcriptase South Korea, Spain, Taiwan, UK, and USA). The trial was inhibitor (NRTI), or (2) requiring two or more pills conducted in accordance with the Declaration of per day or one drug requiring more than once-daily Helsinki, and the protocol was approved by an dosing, or (3) containing a parenteral agent(s) as well as institutional review board or ethics committee at each oral agents (excluding a complete long-acting injectable 1250 Articles regimen). Participants were required to have an estimated at week 48, as determined by the US Food and Drug glomerular filtration rate (eGFR) by Cockroft–Gault Administration (FDA) Snapshot algorithm.16 Secondary equation of at least 15 mL/min and not be on renal endpoints included the proportion of participants with an replacement therapy. Those with chronic hepatitis B virus (HBV) infection, decompensated liver cirrhosis, or active tuberculosis infection were excluded. A complete list of A eligibility criteria is provided in the appendix (pp 8–9). Adults aged ≥18 years on a Week 0 Primary End of People with HIV were screened and recruited by complex multi-tablet endpoint randomised regimen* at week 48 treatment clinical investigators at hospitals and clinics. All Optional phase 3 • HIV-1 RNA <50 copies extension‡ participants provided written consent. Demographic data per mL on a stable complex Bictegravir–lenacapavir on sex at birth (male or female), gender (cisgender, multi-tablet regimen for STR once daily† ≥6 months before Bictegravir– transgender, non-binary or third gender, other, not screening Randomisation lenacapavir 2:1 disclosed), race (American Indian or Alaska Native, • No previous exposure to STR lenacapavir or resistance to Continued complex once daily Asian, Black, Native Hawaiian or Pacific Islander, White, bictegravir multi-tablet regimen Other, not permitted), and ethnicity (Hispanic or Latine, • No history of chronic HBV infection not Hispanic or Latine, not permitted) were collected • eGFR ≥15 mL/min; not on through self-reporting by study participants. renal replacement therapy Randomisation and masking B Following confirmation of eligibility, the investigator or 729 people with HIV and virological an appropriately trained designee randomly assigned suppression on a complex each participant to a treatment group using an interactive multi-tablet regimen screened response system (IXRS) in a 2:1 ratio stratified by for eligibility geographical region (appendix p 10). The randomisation sequence was obtained using block number and 149 screened but ineligible treatment allocation provided at each trial site by the 19 met eligibility criteria but were not randomly assigned interactive response system. There was no blinding of treatment allocation in this trial. 561 randomly assigned Procedures Eligible participants were randomly assigned in a 2:1 ratio either to switch to oral bictegravir–lenacapavir 373 assigned to bictegravir–lenacapavir 188 assigned to continue complex 75 mg/50 mg STR once daily, regardless of food intake, or 75 mg/50 mg STR multi-tablet regimen continue their complex regimen (figure 1A). Participants in the bictegravir–lenacapavir group received an oral 2 randomly assigned but not treated 2 randomly assigned but not treated pharmacokinetic loading dose of 600 mg lenacapavir on days 1 and 2 in addition to bictegravir–lenacapavir. Blood samples drawn for laboratory analyses, HIV-1 371 received bictegravir–lenacapavir and 186 continued to receive complex RNA, CD4 cell counts, and adverse event assessments were included in the FAS and SAS multi-tablet regimen and were included in the FAS and SAS were performed at day 1, weeks 4 and 12, and every 12 weeks thereafter. Resistance analysis was performed in confirmed cases of 17 discontinued bictegravir– 10 discontinued complex virological rebound (HIV-1 RNA ≥50 copies per mL at any lenacapavir multi-tablet regimen 6 adverse event 5 investigator’s discretion visit after day 1 followed by HIV-1 RNA ≥200 copies per mL 5 death 2 participant’s decision at the subsequent scheduled or unscheduled visit) or when 5 participant’s decision 2 loss to follow-up 1 investigator’s discretion 1 adverse event a participant had an HIV-1 RNA viral load of 200 copies per mL or higher at the last on-treatment visit through week 48 (including early discontinuation or loss to follow-up). 354 continued bictegravir–lenacapavir§ 176 continued complex multi-tablet Treatment satisfaction was assessed using HIV regimen¶ Treatment Satisfaction Questionnaire status version (HIVTSQs; at day 1 and weeks 4, 12, 24, and 48) and Figure 1: Study design and trial profile eGFR=estimated glomerular filtration rate. FAS=full analysis set. HBV=hepatitis B virus. SAS=safety analysis set. change version (HIVTSQc; at week 48; see appendix STR=single-tablet regimen. *Due to antiretroviral resistance, intolerance, drug–drug interactions, or pp 11–14 for copies of the questionnaires). contraindication to existing STRs. †Participants received an oral loading dose of lenacapavir 600 mg on days 1 and 2 of treatment. ‡Participants who switch from a complex regimen in the extension phase will take the oral Outcomes loading doses of lenacapavir. §Study was ongoing in 358 participants in the bictegravir–lenacapavir group; 13 participants discontinued the study (due to adverse event [n=6], death [n=5], or consent withdrawal [n=2]). The primary endpoint was the proportion of participants ¶Study was ongoing in 177 participants in the complex regimen group; nine participants discontinued the study with an HIV-1 RNA viral load of 50 copies per mL or higher (due to consent withdrawal [n=3], investigator’s discretion [n=3], loss to follow-up [n=2], or adverse event [n=1]). Articles HIV-1 RNA viral load of less than 50 copies per mL (US Bictegravir– Complex regimen Total (N=557) FDA Snapshot algorithm)16 at week 48, change from lenacapavir (n=371) (n=186) baseline in CD4 cell count at week 48, and the proportion Age, median (range), years 60 (22–84) 60 (24–75) 60 (22–84) of participants experiencing treatment-emergent adverse Age ≥55 years 288 (78%) 139 (75%) 427 (77%) events (TEAEs) through week 48. Vital signs (including Sex assigned at birth bodyweight) and laboratory analyses (including fasting Male 307 (83%) 150 (81%) 457 (82%) lipid concentrations) were performed throughout the Female 64 (17%) 36 (19%) 100 (18%) study. Adverse events were coded according to the Medical Gender identity Dictionary for Regulatory Activities. Adverse events and Cisgender 361 (97%) 179 (96%) 540 (97%) laboratory abnormalities were graded using the Division of Transgender 3 (1%) 1 (1%) 4 (1%) AIDS Toxicity Grading Scale, version 2.1. Patient-reported Non-binary or third gender 1 (<1%) 0 1 (<1%) treatment satisfaction was an exploratory endpoint. Other 2 (1%) 1 (1%) 3 (1%) Not disclosed 4 (1%) 5 (3%) 9 (2%) Statistical analysis Race* The week-48 primary analysis was conducted after all Asian 16 (4%) 9 (5%) 25 (4%) participants either completed their week-48 visit or prematurely discontinued study treatment. For the Black 64 (17%) 33 (18%) 97 (17%) primary endpoint, a sample size of 546 participants White 260 (70%) 124 (67%) 384 (69%) (randomly assigned in a 2:1 ratio to the bictegravir– Other† 12 (3%) 3 (2%) 15 (3%) lenacapavir or complex regimen group) was estimated to Ethnicity‡ provide at least 90% power to detect non-inferiority, Hispanic or Latine 80 (22%) 42 (23%) 122 (22%) assuming that 2% of participants in both treatment Not Hispanic or Latine 270 (73%) 128 (69%) 398 (71%) groups had an HIV-1 RNA viral load of 50 copies per mL HIV-1 RNA ≥50 copies per mL§ 13 (4%) 7 (4%) 20 (4%) or higher at week 48, a non-inferiority margin of 4% for CD4 count, median (IQR), cells per µL 626 (457–836); 579 (450–747); 612 (456–809); n=366 n=185 n=551 a 0·025 one-sided significance level. To account for multiplicity (two interim analyses for the primary CD4 count <200 cells per µL 12 (3%) 5 (3%) 17 (3%) endpoint were performed before this analysis), the History of AIDS 43 (12%) 24 (13%) 67 (12%) primary ecacy endpoint analysis alpha level was Duration of HIV treatment, median 28·3 (21·6–32·3); 28·3 (21·4–31·8); 28·3 (21·6–32·1); (IQR), years n=358 n=183 n=541 adjusted to 0·04998 (95·002% CI). If the upper bound of Historical resistance mutations¶|| the two-sided 95·002% CI of the treatment dierence in NRTI 247 (67%) 128 (69%) 375 (67%) proportion of participants with an HIV-1 RNA viral load NNRTI 203 (55%) 104 (56%) 307 (55%) of 50 copies per mL or higher at week 48 was less PI 151 (41%) 77 (41%) 228 (41%) than 4%, non-inferiority of bictegravir–lenacapavir to INSTI 1 (<1%) 2 (1%) 3 (1%) complex regimens was established. The proportion of Reasons for receiving complex regimen¶ participants with an HIV-1 RNA viral load of 50 copies per mL or higher at week 48 was summarised by History of antiretroviral resistance 297 (80%) 153 (82%) 450 (81%) treatment group and by visit using missing=failure and Intolerance to components of STRs 89 (24%) 39 (21%) 128 (23%) missing=excluded approaches, as detailed in the Contraindication to STRs 23 (6%) 10 (5%) 33 (6%) appendix (p 15). Safety data were reported descriptively. Number of antiretroviral pills per day, 3·0 (2·0–11·0) 3·0 (2·0–9·0) 3·0 (2·0–11·0) median (range) Ecacy outcomes were analysed in the full analysis Number of antiretroviral pills per day set, which included all randomly assigned participants 2 152 (41%) 74 (40%) 226 (41%) who received any dose of assigned treatment; 3 96 (26%) 48 (26%) 144 (26%) participants were grouped according to the treatment 4 40 (11%) 23 (12%) 63 (11%) they were assigned to. Safety outcomes were analysed in ≥5 83 (22%) 41 (22%) 124 (22%) the safety analysis set, which included all randomly assigned participants who received any dose of assigned Number of antiretrovirals in complex 2·0 (2·0–5·0) 3·0 (2·0–6·0) 3·0 (2·0–6·0) regimen, median (range)** treatment; participants were grouped according to the Highest dosing frequency treatment they received. Adverse events were reported Daily 219 (59%) 120 (65%) 339 (61%) throughout the study period non-systematically and Twice daily 152 (41%) 66 (35%) 218 (39%) were reviewed by an Independent Safety Monitoring Select comorbidities¶†† Committee. TEAEs were summarised by the number Dyslipidaemia 244 (66%) 133 (72%) 377 (68%) and percentage of participants who experienced at least Hypertension 190 (51%) 90 (48%) 280 (50%) one TEAE. No statistical comparisons were performed Hyperglycaemia or diabetes 91 (25%) 42 (23%) 133 (24%) for safety. Analyses were conducted using SAS, version 9.4. Chronic kidney disease 49 (13%) 29 (16%) 78 (14%) Details of statistical analyses, including handling of (Table 1 continues on next page) missing data, are included in the appendix (pp 15–16). 1252 Articles Role of the funding source Bictegravir– Complex regimen Total (N=557) The study sponsor, Gilead Sciences (Foster City, CA, lenacapavir (n=371) (n=186) USA), played a role in the study design; data collection, (Continued from previous page) analysis, and interpretation; decision to publish; and Number of select comorbidities preparation of the manuscript. 1 95 (26%) 53 (28%) 148 (27%) Results ≥2 202 (54%) 96 (52%) 298 (54%) Select concomitant medications‡‡ Between Jan 29 and Sept 26, 2024, 729 participants were Antidiabetic agents 84 (23%) 44 (24%) 128 (23%) screened (figure 1B); 557 were randomly assigned and received at least one dose of study treatment: 371 switched Antihypertensive agents 203 (55%) 101 (54%) 304 (55%) to bictegravir–lenacapavir and 186 continued their Lipid-lowering agents 262 (71%) 134 (72%) 396 (71%) complex regimen and were included in the full analysis Antidiabetic and antihypertensive 58 (16%) 36 (19%) 94 (17%) agents set and safety analysis set. Two participants in each study Antidiabetic, antihypertensive, and 50 (13%) 32 (17%) 82 (15%) group were randomly assigned but not treated and were lipid-lowering agents excluded from the analysis. Baseline characteristics were Number of select concomitant medications balanced between groups (table 1). At baseline, median 1 62 (17%) 50 (27%) 112 (20%) age was 60 years (range 22–84), 100 (18%) of 557 participants ≥2 237 (64%) 102 (55%) 339 (61%) were assigned female at birth, 97 (17%) were Black, and Creatinine clearance, median (IQR), 82·9 (66·4–103·2) 82·4 (65·4–100·2) 82·8 (66·0–102·6) 122 (22%) were Hispanic or Latine; 377 (68%) had mL/min dyslipidaemia, 280 (50%) hypertension, 133 (24%) hyper- >15 to ≤30 3 (1%) 3 (2%) 6 (1%) glycaemia or diabetes, and 78 (14%) chronic kidney >30 to <60 56 (15%) 26 (14%) 82 (15%) disease; 298 (54%) had two or more of these comorbidities ≥60 312 (84%) 157 (84%) 469 (84%) and 339 (61%) were taking two or more concomitant Data are n (%) unless otherwise specified. ATC=Anatomical Therapeutic Chemical Medical Class Level. INSTI=integrase medications. Median duration of HIV treatment was strand-transfer inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleos(t)ide reverse 28 years (IQR 22–32). Baseline complex regimen transcriptase inhibitor. PI=protease inhibitor. STR=single-tablet regimen. *Local regulators did not allow the collection consisted of a median of three antiretroviral pills per day of race information for 36 participants (19 in the bictegravir–lenacapavir group and 17 in the complex regimen group). †Category includes American Indian or Alaska Native, Native Hawaiian, Pacific Islander, and other. ‡Local regulators did (range 2–11), and 218 (39%) participants were taking not allow the collection of ethnicity information for 37 participants (21 in the bictegravir–lenacapavir group and 16 in antiretroviral pills twice daily. The most common reason the complex regimen group). §Participants had screening HIV-1 RNA <50 copies per mL, but baseline HIV-1 RNA for receiving a complex regimen was a history of ≥50 copies per mL. ¶Categories are not mutually exclusive. ||Investigators were asked to document previous resistance resistance (450 [81%] participants), followed by data from available historical HIV-1 genotype and/or phenotype reports. No resistance testing was performed at baseline; NRTI, NNRTI, PI, and INSTI data were not available for 75, 79, 78, and 197 participants in the bictegravir– intolerance to components of currently available STRs lenacapavir group, and 44, 46, 50, and 100 participants in the complex regimen group, respectively. **Multiple (128 [23%]) and contraindications to STRs (33 [6%]). The reported antiretroviral therapies were counted only once per participant for each drug name and each drug class. proportion of participants randomly assigned by country ††Grouped terms on standardised Medical Dictionary for Regulatory Activities query narrow search. ‡‡Antidiabetic agents included drugs with WHO ATC2 “drugs used in diabetes”; antihypertensive agents included drugs with WHO was balanced between treatment groups according to the ATC2 “agents acting on the renin–angiotensin system”, “antihypertensives” (excluding ATC3 “other stratification by geographical region (appendix p 18). antihypertensives”), “beta-blocking agents”, “calcium channel blockers”, or “diuretics”; lipid-lowering agents included Participants were receiving a broad range of complex drugs with WHO ATC2 “drugs used in diabetes”. regimens at baseline (figure 2); 427 (77%) of 557 were Table 1: Demographic and clinical characteristics of participants at baseline (safety analysis set) taking a regimen that included a PI. The most common regimen was PI plus INSTI, either alone (166 [30%]) or with an NRTI (135 [24%]). contributed to this category; neither were deemed related At week 48, three (1%) participants in the bictegravir– to study drug; the one discontinuation in the complex lenacapavir group and two (1%) in the complex regimen regimen group in this category was due to an adverse group had an HIV-1 RNA viral load of 50 copies per mL event); five (1%) participants in the bictegravir– or higher (dierence −0·3% [95·002% CI −2·3 to 1·8]; lenacapavir group and eight (4%) participants in the table 2). These results met the prespecified non- complex regimen group also discontinued due to other inferiority criteria for the primary endpoint. At week 48, reasons but with last available HIV-1 RNA viral load 356 (96%) participants in the bictegravir–lenacapavir below 50 copies per mL; one participant in the complex group and 174 (94%) in the complex regimen group had regimen group had missing data during the analysis an HIV-1 RNA viral load of less than 50 copies per mL. window but was still on study drug. Results were Data were not available in the week-48 analysis window consistent when using missing=excluded and for a total of 12 (3%) participants in the bictegravir– missing=failure analyses (table 2). CD4 cell count lenacapavir group and ten (5%) participants in the remained stable in both groups; median change in CD4 complex regimen group. Of these, seven (2%) count from baseline to week 48 was +18 cells per µL participants in the bictegravir–lenacapavir group and (IQR −72 to 98) in the bictegravir–lenacapavir group one (1%) participant in the complex regimen group and −12 (−82 to 93) in the complex regimen group discontinued study drug due to adverse events or death (dierence in change +19·0 [95% CI −11·6 to 49·5]; (two deaths in the bictegravir–lenacapavir group p=0·22; appendix p 19). Articles 30% 24% 13% 12% (n=166) (n=135) (n=70) (n=69) INSTI + NNRTI (± NRTI) PI + INSTI + NNRTI (± NRTI) (eg, bictegravir + doravirine + emtricitabine + (eg, darunavir + etravirine + raltegravir + tenofovir alafenamide) ritonavir) 7% 4% 3% (n=41) (n=23) (n=17) PI+ INSTI+ EI (± NRTI) PI + NNRTI (± NRTI) (eg, darunavir + dolutegravir + (eg, darunavir + maraviroc + ritonavir) etravirine + ritonavir) 4% 3% (n=20) (n=16) INSTI + EI (±N RTI) (eg, lamivudine + PI + INSTI + NRTI Other* INSTI+ EI+ NNRTI (± NRTI) abacavir + PI +I NSTI (eg, cobicistat+ darunavir + dolutegravir + (eg, darunavir + etravirine + (eg, etravirine + maraviroc + dolutegravir + (eg, cobicistat + darunavir +d olutegravir) emtricitabine + tenofovir alafenamide) maraviroc +r itonavir) raltegravir) maraviroc) Figure 2: Diversity of complex regimens at baseline (safety analysis set) Most commonly used regimen is noted in parentheses. EI=entry inhibitor. INSTI=integrase strand-transfer inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleos(t)ide reverse transcriptase inhibitor. PI=protease inhibitor. *List of regimens comprising “Other” category is provided in the appendix (p 17). Bictegravir– Complex regimen Difference for Difference for lenacapavir (n=371) (n=186) bictegravir–lenacapavir bictegravir–lenacapavir vs complex regimen vs complex regimen (95·002% CI) (95% CI) US Food and Drug Administration Snapshot algorithm (full analysis set)* HIV-1 RNA ≥50 copies per mL 3 (1%) 2 (1%) −0·3% (−2·3 to 1·8) ·· HIV-1 RNA <50 copies per mL 356 (96%) 174 (94%) 2·4% (−1·8 to 6·6) ·· No virological data 12 (3%) 10 (5%) ·· ·· Discontinued due to adverse event or death 7 (2%)† 1 (1%)‡ ·· ·· Discontinued study due to other reasons§ and last 5 (1%) 8 (4%) ·· ·· available HIV-1 RNA was <50 copies per mL Had missing data during the analysis window but was 0 1 (1%) ·· ·· still on study drug Missing=excluded analysis (full analysis set with non-missing HIV-1 RNA value at week-48 visit, while on treatment)* HIV-1 RNA <50 copies per mL 356/359 (99%) 174/176 (99%) ·· 0·3% (−1·9 to 2·5) HIV-1 RNA ≥50 copies per mL 3/359 (1%) 2/176 (1%) ·· ·· 50 to <200 copies per mL 2/359 (1%) 1/176 (1%) ·· ·· 200 to <1000 copies per mL 1/359 (<1%) 1/176 (1%) ·· ·· Missing=failure analysis (full analysis set, while on treatment)* HIV-1 RNA <50 copies per mL 356/371 (96%) 174/186 (94%) ·· 2·4% (−1·8 to 6·6) HIV-1 RNA ≥50 copies per mL 3/371 (1%) 2/186 (1%) ·· ·· 50 to <200 copies per mL 2/371 (1%) 1/186 (1%) ·· ·· 200 to <1000 copies per mL 1/371 (<1%) 1/186 (1%) ·· ·· Missing data 12/371 (3%) 10/186 (5%) ·· ·· Data are n (%) or n/N (%) unless otherwise specified. *Differences in percentages of participants between treatment groups (bictegravir–lenacapavir minus complex regimen) and two-sided CIs were constructed based on Mantel–Haenszel stratum weights and Koch variance estimator and adjusted by geographical region (USA vs non-USA). †Category included two deaths (neither were related to study drug) and five adverse events. ‡Categoryi ncluded one adverse event. §Other reasons included discontinuation of study drug due to investigator’s discretion, participant’s decision, loss to follow-up, non-compliance with study drug, protocol violation, pregnancy, and study termination by sponsor. Table 2: Efficacy outcomes at week 48 1254 Articles Of the three participants in the bictegravir–lenacapavir Bictegravir– Complex regimen group and two in the complex regimen group with a lenacapavir (n=371) (n=186) confirmed HIV-1 RNA viral load of 50 copies per mL or Adverse event—any grade 305 (82%) 157 (84%) higher by week 48, two had a viral load below 200 copies Grade ≥3 adverse event 51 (14%) 26 (14%) per mL and did not qualify for resistance testing. DRAE—any grade 53 (14%) 3 (2%) Three met the criteria for protocol-defined confirmed Grade ≥3 DRAE 2 (1%)* 0 virological rebound (two in the bictegravir–lenacapavir Serious adverse event 52 (14%) 22 (12%) group and one in the complex regimen group) and Serious DRAE 1 (<1%)† 0 qualified for resistance testing. No treatment-emergent resistance mutations to study drugs were detected in Adverse event leading to discontinuation of study drug 6 (2%)‡ 1 (1%)§ either treatment group. Adverse event occurring in ≥5% of participants in either group Treatment satisfaction at baseline was similar between Upper respiratory tract infection 34 (9%) 24 (13%) groups (mean HIVTSQs total score at baseline was 55 Nasopharyngitis 26 (7%) 17 (9%) [SD 10·4] in the bictegravir–lenacapavir group Diarrhoea 22 (6%) 11 (6%) and 55 [9·4] in the complex regimen group; available Headache 28 (8%) 4 (2%) range 0 to 66; appendix p 20). At week 48, participants in Cough 18 (5%) 11 (6%) the bictegravir–lenacapavir group reported improvement Arthralgia 19 (5%) 8 (4%) from baseline in treatment satisfaction (mean change in Hypertension 21 (6%) 6 (3%) HIVTSQs total score, +7 [SD 10·6]), while those in the COVID-19 20 (5%) 6 (3%) complex regimen group reported no change (0 [9·6]; Death¶ 5 (1%)|| 0 appendix p 20). After switching to bictegravir–lenacapavir, Data are n (%). Median duration of exposure was 65·9 weeks (IQR 56·6–74·0) for the bictegravir–lenacapavir group and mean HIVTSQc total score at week 48 was +27 (SD 9·1; 65·9 weeks (55·6–73·9) for the complex regimen group. Includes all randomly assigned participants who received any available range −33 to 33). dose of assigned treatment grouped according to the treatment they received. DRAE=drug-related adverse event. HBV=hepatitis B virus. *Diabetes and maculopapular rash. †Newly diagnosed diabetes on day 76 in a participant with a Overall, the incidence of adverse events was similar in high baseline fasting glucose concentration (100 mg/dL); resolved on day 173 after switching back to baseline regimen both groups (bictegravir–lenacapavir: 305 [82%] of 371; of efavirenz plus ritonavir-boosted darunavir on day 103. ‡One participant experienced nausea, dizziness, headache, complex regimen: 157 [84%] of 186), with the majority alopecia, and worsening fatigue; one participant experienced headache and hypoaesthesia; one participant experienced erectile dysfunction and worsening hypertension; and one participant experienced each of the following: being mild or moderate in severity (grade 1 or 2; table 3). cerebrovascular accident, diabetes, and HBV viraemia; all but hypoaesthesia, HBV viraemia, and cerebrovascular 51 (14%) participants in the bictegravir–lenacapavir accident were deemed related to study drug. §Due to pulmonary embolism; this was not deemed related to study drug. group and 26 (14%) in the complex regimen group ¶Includes any that occurred during the study. ||Due to unknown cause (n=2; one participant had a history of arterial experienced a grade 3 or worse adverse event. Drug- hypertension and one a history of hypercholesterolaemia; no autopsy was performed on these participants), cardiac arrest (n=1), metastatic neoplasm (n=1), and respiratory failure (n=1); no deaths were deemed related to study drug. related adverse events (DRAEs) were reported by 53 (14%) participants in the bictegravir–lenacapavir Table 3: Safety (safety analysis set) group and three (2%) participants in the complex regimen group (table 3 and appendix p 21). Of these, two (1%) and zero participants, respectively, reported occurred during the study in the bictegravir–lenacapavir grade 3 or worse DRAEs. One participant in the group (one due to each of the following: liver failure bictegravir–lenacapavir group with high fasting secondary to metastatic cancer, sudden cardiac arrest, concentrations of glucose and lipase, and grade 1 and oropharyngeal cell carcinoma; two due to unknown triglyceride concentration, at baseline, experienced a cause); none were deemed related to bictegravir– serious DRAE of newly diagnosed diabetes. This lenacapavir. No dierence in the overall safety profile was participant had switched from efavirenz plus ritonavir- observed for participants by level of renal function, and boosted darunavir; the event resolved after switching renal-related adverse events were infrequent (appendix back to original treatment regimen. Six (2%) participants p 22). discontinued bictegravir–lenacapavir due to adverse Laboratory abnormalities occurred in 341 (92%) of events; one participant experienced nausea, 371 participants in the bictegravir–lenacapavir group and dizziness, headache, alopecia, and worsening fatigue; 178 (96%) of 186 participants in the complex regimen one experienced headache and hypoaesthesia; group (appendix p 23); most were grade 1 or 2 in severity. one experienced erectile dysfunction and worsening The most common grade 3 or worse abnormalities in hypertension; and one experienced each of the following: both groups were decreased creatinine clearance and cerebrovascular accident, diabetes (same participant as increased direct bilirubin concentration, which were above), and HBV viraemia; all except the cerebrovascular mostly transient and not clinically relevant. Vital signs accident, HBV viraemia, and hypoaesthesia were deemed were unchanged through 48 weeks. related to study drug. One (1%) participant discontinued At week 48, fasting total cholesterol, triglyceride, and their complex regimen due to an adverse event of LDL cholesterol concentrations, and total cholesterol:HDL pulmonary embolism (due to interaction of boosted PI cholesterol ratio improved from baseline in the component of regimen with anticoagulants); this was not bictegravir–lenacapavir versus the complex regimen deemed related to the complex regimen. Five deaths group. Median changes from baseline to week 48 in the Articles bictegravir–lenacapavir versus complex regimen groups interactions and requiring active management. were: total cholesterol, −15 mg/dL versus +2 mg/dL Additionally, the lenient eGFR cuto of 15 mL/min (nominal p<0·0001); LDL cholesterol, −9 mg/dL versus (six [1%] had eGFR ≤30 mL/min and 88 [16%] had eGFR +2 mg/dL (nominal p<0·0001); triglycerides, −15 mg/dL <60 mL/min) provides confidence in bictegravir– versus +4 mg/dL (nominal p=0·0008); total lenacapavir for those with chronic kidney disease. cholesterol:HDL cholesterol ratio, −0·3 mg/dL versus Bictegravir–lenacapavir was well tolerated, and similar 0 mg/dL (nominal p<0·0001). HDL cholesterol remained numbers of adverse events and serious adverse events stable in both groups (appendix p 24). Reductions in were reported in both groups. Although the frequency of total cholesterol, LDL cholesterol, and triglyceride DRAEs was higher in the bictegravir–lenacapavir group concentrations, and total cholesterol:HDL cholesterol than in the complex regimen group, this is consistent ratio, with bictegravir–lenacapavir compared with with an open-label trial design involving switching away complex regimens were observed from the first from a long-standing familiar regimen.19,22,23 Moreover, assessment at week 12 onwards. Bodyweight remained only one serious adverse event was considered related to stable in both treatment groups through 48 weeks bictegravir–lenacapavir, a newly diagnosed case of diabetes (median change from baseline +0·6 kg [IQR −1·1 to 2·6] in a participant with hyperglycaemia at baseline. Only and 0·0 kg [−2·0 to 2·4] in the bictegravir–lenacapavir two DRAEs in the bictegravir–lenacapavir group were and complex regimens groups, respectively). grade 3 or worse; rates of discontinuation due to adverse events were low overall. Switching to bictegravir– Discussion lenacapavir improved fasting lipid concentrations in a Treatment optimisation is widely recognised as the best population in whom approximately 70% had a diagnosis way to ensure adherence and treatment success when of dyslipidaemia at baseline and over half of participants managing chronic conditions such as HIV. For had two or more comorbidities associated with increased two decades, this has remained an unmet need for people cardiovascular risk. These observations might indicate a not suitable for currently available STRs due to potential beneficial eect of bictegravir–lenacapavir in antiretroviral resistance. Here, we show that once-daily people with HIV and metabolic or cardiovascular risk oral bictegravir–lenacapavir was non-inferior to complex factors. regimens in maintaining virological suppression Participants who switched to bictegravir–lenacapavir through 48 weeks, with similarly high suppression rates, from a complex regimen reported greater treatment similar adverse event rates in both groups, and increased satisfaction than those continuing a complex regimen. treatment satisfaction through 48 weeks. Hence, the This confirms that participants found multi-tablet novel STR of bictegravir–lenacapavir oers an alternative treatment regimens more challenging. These challenges treatment option for people on complex regimens. could over time jeopardise adherence (enhanced With a median participant age of 60 years, this is the adherence has been reported with STRs)2,6–8 and retention oldest study population ever enrolled in a registrational in care, which are both necessary to maintain virological programme for HIV treatment.17–20 This is particularly suppression and avoid emergent resistance. Switching relevant given that advances in antiretroviral therapy to bictegravir–lenacapavir STR reduced the pill burden have allowed people with HIV to have near-normal life (a third of participants were taking four or more expectancies; consequently, most people with HIV in antiretroviral pills per day, with a maximum of 11 pills high-resource countries are aged 50 years or older.2,21 The per day) and thereby the risk of drug–drug interactions. median treatment duration of 28 years, high level of Taken together, this highlights the importance of historical antiretroviral resistance (67% with NRTI continuing to optimise treatment in the face of previous resistance), and high proportion of participants on a resistance, comorbidities, and preferences. complex regimen because of antiretroviral resistance This trial had limitations. This was an open-label trial, (81%) is consistent with their extensive HIV-1 treatment but, given the wide range of antiretrovirals included in experience and underscores why optimisation to the complex regimens and the importance of patient currently available STRs has not been possible thus far. satisfaction for regimen optimisation, a blinded design In addition, the study population was generally was impractical. A separate blinded phase 3 trial representative of people with HIV receiving complex (NCT06333808) comparing outcomes after switching regimens in routine care, reflecting the diverse race and from bictegravir–emtricitabine–tenofovir alafenamide to ethnicity of the participating countries. bictegravir–lenacapavir is ongoing. Longer-term ecacy Most participants had at least one comorbidity at and safety outcomes of bictegravir–lenacapavir will be baseline (14% had chronic kidney disease and 50% had assessed through continued follow-up. However, hypertension), 81% were taking concomitant medications bictegravir has an established safety profile in both for these comorbidities, three-quarters were on a complex clinical and real-world studies with bictegravir– regimen that included a PI, and a third were taking emtricitabine–tenofovir alafenamide10,24–27 and lenacapavir four or more antiretroviral tablets per day, all contributing has been studied extensively in individuals receiving pre- to an increased risk of clinically significant drug–drug exposure prophylaxis.28,29 Of note, participants with 1256 Articles previous or chronic HBV infection were excluded; MB received payment or honoraria for lectures, presentations, speakers’ vaccination and routine surveillance should be conducted bureaus, manuscript writing, or educational events from Gilead according to current guidelines for individuals without Sciences, GSK, and ViiV Healthcare; received support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare; and HBV immunity.2,4,11 Future work might be required to participated on data safety monitoring or advisory boards for Gilead study how dierent approaches to delivery of clinical care Sciences, GSK, and ViiV Healthcare. JS received payment or honoraria (eg, across dierent health-care systems) have impacted for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Gilead Sciences, Merck, Thera, and ViiV these findings. Healthcare. MRa received consulting fees from Gilead Sciences, In this phase 3 trial, once-daily oral bictegravir– Shionogi, and ViiV Healthcare; and received payment or honoraria for lenacapavir was non-inferior to complex regimens in lectures, presentations, speakers’ bureaus, manuscript writing, or maintaining HIV-1 suppression. Bictegravir–lenacapavir educational events from AbbVie, Gilead Sciences, and ViiV Healthcare. SS received research grants and support for clinical trials (paid to her was generally well tolerated, led to improvement in the institution) from Janssen, Merck, and the South African Medical lipid profile, and provided greater treatment satisfaction Research Council; received payment or honoraria for lectures, among participants who switched from a complex presentations, speakers’ bureaus, manuscript writing, or educational regimen. This STR could present the first opportunity to events from ViiV Healthcare; received support for attending meetings and/or travel from Merck; received a drug donation to her institution optimise treatment while maintaining virological from ViiV Healthcare; and participated on an advisory board for AbbVie. suppression in people taking complex regimens who KM received payment or honoraria for lectures, presentations, speakers’ have not benefitted from available STRs due to bureaus, manuscript writing, or educational events from, and served on antiretroviral resistance or other reasons. In particular, an advisory board for, Epividian, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. H-CT received honoraria for a lecture at an bictegravir–lenacapavir could oer a more suitable international congress, and travel and registration support for attending long-term treatment option for an ageing population an international meeting, from Gilead Sciences. JSB received research with cardiometabolic comorbidities, declining GFR, and grants or contracts from Chem Bio Diagnostics, Gilead Sciences, and a greater risk of polypharmacy. Moderna; and consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational Contributors events from AbbVie. XZ, KA, KP, NM, JMM-R, PS, and MRh are CO, PJR, MH, CG, MHL, BT, TL, MO, MB, JS, MRa, SS, KM, H-CT, JSB, employees of Gilead Sciences and own employee stock grants. and PC contributed to data collection. JMM-R and PS contributed to PC received research grants and payment or honoraria for lectures, study design and data analysis or interpretation. CO, XZ, KA, KP, NM, presentations, speakers’ bureaus, manuscript writing, or educational and MRh contributed to data analysis or interpretation. All authors events from ViiV Healthcare; and consulting fees from Gilead Sciences, contributed to drafting or revising of the manuscript, approved the final Merck, and ViiV Healthcare. version for submission, and agree to be accountable for all aspects of the Data sharing work. CO, XZ, KA, JMM-R, and PS directly accessed and verified the study data. All authors had full access to the study data and shared final Gilead Sciences shares anonymised individual patient data upon request or as required by law or regulation with qualified external researchers responsibility for the decision to submit the manuscript for publication. based on submitted curriculum vitae and reflecting non-conflict of Declaration of interests interest. The request proposal must also include a statistician. Approval CO received grants (paid to her institution) from Gilead Sciences, of such requests is at Gilead Sciences’ discretion and is dependent on MSD, and ViiV Healthcare; received consulting fees for advisory boards the nature of the request, the merit of the research proposed, the and payment or honoraria for lectures, presentations, speakers’ bureaus, availability of the data, and the intended use of the data. Data requests manuscript writing, or educational events from Bavarian Nordic, Gilead should be sent to DataSharing@gilead.com. The clinical study protocol Sciences, GSK, MSD, and ViiV Healthcare; received support for and statistical analysis plan are provided in the appendix available with attending meetings and/or travel from Bavarian Nordic, Gilead Sciences, the online version of the article. and ViiV Healthcare; and is a governing council member of the Acknowledgments International AIDS Society (unpaid). PJR received payment or honoraria This study was funded by Gilead Sciences (Foster City, CA, USA). for lectures, presentations, speakers’ bureaus, manuscript writing, We thank all participants and their families, participating sites, or educational events from Gilead Sciences and ViiV Healthcare. investigators, and trial sta. We also thank Jared Baeten (Gilead MH received payment or honoraria for lectures, presentations, speakers’ Sciences, Foster City, CA, USA) for his critical review of the manuscript. bureaus, manuscript writing, or educational events, and support for Medical writing support, including development of a draft outline and attending meetings and/or travel from, and participated on advisory subsequent drafts in consultation with the authors, collating author boards for, Gilead Sciences, Merck, and ViiV Healthcare. CG received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare; and comments, copyediting, fact checking, and referencing, was provided by Joanna Nikitorowicz-Buniak and Anna Chapman-Barnes of Aspire received payment or honoraria for lectures, presentations, speaker’s Scientific (Manchester, UK). Funding for medical writing support for bureaus, manuscript writing, or educational events from Gilead Sciences this article was provided by Gilead Sciences (Foster City, CA, USA). and ViiV Healthcare. MHL received research grants (paid to his institution) from Gilead Sciences, and participated on advisory boards Editorial note: The Lancet Group takes a neutral position with respect to for Gilead Sciences and ViiV Healthcare. 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