BACKGROUND:Randomized trials of long-acting injectable antiretroviral therapy (ART) in persons with human immunodeficiency virus (HIV) who face challenges with adherence to oral medication are lacking. METHODS:We conducted an open-label, randomized trial involving persons with HIV who had inadequate adherence to ART (a persistent HIV-1 RNA level of >200 copies per milliliter or loss to follow-up). Participants received up to 24 weeks of adherence support, conditional economic incentives, and standard care with oral ART (step 1). Participants who had an HIV-1 RNA level of 200 copies per milliliter or lower in step 1 were randomly assigned in a 1:1 ratio to either continue standard care or switch to monthly injections of long-acting cabotegravir plus rilpivirine with or without oral lead-in therapy (step 2). The primary outcome was regimen failure, defined as confirmed virologic failure (two consecutive HIV-1 RNA measurements of >200 copies per milliliter) or treatment discontinuation during step 2. RESULTS:In step 1 of the trial, we enrolled 453 participants; the median age was 40 years, 63% were Black, and 29% had been assigned female sex at birth. In step 2, a total of 306 participants underwent randomization; 152 were assigned to receive cabotegravir-rilpivirine and 154 to receive standard care. Step 2 randomization was stopped early on the basis of the superiority of cabotegravir-rilpivirine to standard care in secondary outcomes at a prespecified analysis performed after a median follow-up of 48 weeks. The cumulative incidence of regimen failure by week 48 was 22.8% in the cabotegravir-rilpivirine group and 41.2% in the standard-care group (difference, -18.4 percentage points; 98.4% confidence interval [CI], -32.4 to -4.3; P = 0.002). The cumulative incidence of an adverse event was 43.5% in the cabotegravir-rilpivirine group and 42.4% in the standard-care group (difference, 1.1 percentage points; 95% CI, -12.7 to 15.0). Resistance-associated mutations developed in 2 participants with confirmed virologic failure in each group. CONCLUSIONS:Monthly injections of long-acting cabotegravir-rilpivirine were superior to standard oral ART in reducing the risk of regimen failure among persons with HIV who had adherence challenges. (Funded by the National Institute of Allergy and Infectious Diseases; LATITUDE ClinicalTrials.gov number, NCT03635788.).

Background: Safe and effective long-acting HIV prevention agents are needed for women. Methods: HPTN 084 was a phase III randomised double-blind, double-dummy, active-controlled superiority trial. HIV-uninfected women were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Participants were prescribed five weeks of daily oral product followed by intramuscular injections every eight weeks after an initial four-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF/FTC for 48 weeks. The primary endpoints of the study were incident HIV infection and ≥grade 2 clinical and laboratory events. Findings: The study enrolled 3224 participants at 20 sites in sub-Saharan Africa. Median age was 25 years (interquartile range 22, 30); 55% (1755/3209) had two or more partners in the preceding month. Forty incident infections were observed over 3898 person-years (py) (HIV incidence 1.0%, 95% confidence intervals [CI] 0.73, 1.40); four in the CAB group (HIV incidence 0.2/100 py; 95% CI 0.06 to 0.52) and 36 in the TDF/FTC group (1.85/100 py; 95% CI 1.3 to 2.57) (hazard ratio 0.12, 95% CI 0.05 to 0.31; p-value <0.0001). In a random subset of 405 TDF/FTC participants, 42% (812/1929) of plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of py. Adverse event rates were similar across both groups, apart from injection site reactions (ISRs) which were more frequent among CAB compared to TDF/FTC recipients (38% [577/1519] vs. 11% [162/1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1.3 per 100 py (95% CI 0.9, 1.7); no congenital birth anomalies were reported.Interpretation: While both HIV prevention products were generally safe, well tolerated and effective, CAB was superior to TDF/FTC in preventing HIV infection in women. Funding: National Institute of Allergy and Infectious Diseases (NIAID), USA; ViiV Healthcare; and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences, Inc provided pharmaceutical support. Declaration of Interest: The authors have no competing interests to declare, except PLA has received fees from Merck, ViiV and Gilead, and research support from Gilead paid to his institution.Ethical Approval: The protocol was reviewed and approved by national drug authorities and local research ethics committees in each of the participating 20 sites in seven countries in sub-Saharan Africa where the burden of HIV in women is high. All participants provided written consent in a language of their choice prior to any study procedures.

BACKGROUND:Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed. METHODS:DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA <50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of -12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304. FINDINGS:Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3-20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than -12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p<0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2-4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders. INTERPRETATION:When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment. FUNDING:ViiV Healthcare.

OBJECTIVES To expand understanding of the virological potency of initial dolutegravir plus lamivudine dual therapy (dolutegravir/lamivudine), we compared the viral decay seen in the pilot ACTG A5353 study with the decay observed with dolutegravir plus two NRTIs in the SPRING-1 and SINGLE studies, while also exploring the impact of baseline viral load (VL). METHODS Change in VL from baseline was calculated for timepoints shared by A5353 (n = 120, including 37 participants with pretreatment VL >100 000 copies/mL), SPRING-1 (n = 51) and SINGLE (n = 417). The 95% CIs of change from baseline were determined for each observed week, using the mean log10-transformed VL, and compared between the dolutegravir/lamivudine and triple therapy groups using the Wilcoxon Rank Sum test for non-inferiority (δ = 0.5). To assess the impact of baseline VL on viral decay, we examined a bi-exponential non-linear mixed-effect model. RESULTS The mean VL change from baseline to week 24 was -2.9 log10 copies/mL for dolutegravir/lamivudine versus -3.0 log10 copies/mL for dolutegravir-based three-drug therapy (P < 0.001). In the decay model, baseline VL >100 000 copies/mL was associated with a slower initial decay rate (d1). A faster initial decay rate was seen with dolutegravir/lamivudine, which was partially offset when baseline VL was >100 000 copies/mL as indicated by a significant interaction between baseline VL and drug therapy group. The secondary decay rate (d2) was not significantly different from zero, with no significant associations. CONCLUSIONS Viral decay with dolutegravir/lamivudine was comparable to viral decay with dolutegravir-based triple therapy, even in individuals with higher pretreatment VL (>100 000 copies/mL).

PS1/1 Outcomes for women in phase 3 trials of long-acting cabotegravir + rilpivirine: pooled ATLAS and FLAIR week 48 results R Quercia, C Orkin, R D’Amico, J Mrus, S Wu, A Cutrell, K Chow, J Polli, D Margolis, P Williams, A de Ruiter, K Smith and W Spreen ViiV Healthcare, Brentford, UK Queen Mary University, London, UK ViiV Healthcare, Research Triangle Park, USA GlaxoSmithKline, Collegeville, USA GlaxoSmithKline, Mississauga, Canada Janssen Research & Development, Beerse, Belgium