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: Evaluating long-term efficacy, safety and pharmacokinetics of long-acting cabotegravir + rilpivirine (CAB+RPV LA) in sub-Saharan African populations is important because of the region’s unique demographics and antiretroviral therapy resistance patterns. Objectives: To describe the 96-week efficacy, safety and pharmacokinetics of CAB+RPV LA in South African participants from the pooled FLAIR and ATLAS-2M Phase 3/3b randomised studies. Method: Primary endpoint: proportion of participants with plasma HIV-1 RNA levels ≥ 50 copies/mL at Week 96. Secondary endpoints: proportion of participants with plasma HIV-1 RNA levels 50 copies/mL, confirmed virological failure (CVF; two consecutive plasma HIV-1 RNA ≥ 200 copies/mL), adverse events and pharmacokinetics. Results: Sixty-six participants were included, (CAB+RPV LA, n = 49; current oral antiretroviral regimen [CAR], n = 17). Forty-five (92%) on CAB+RPV LA and 15 (88%) on CAR maintained HIV-1 RNA levels 50 copies/mL. At Week 96, two participants, one in each arm, had CVF. Ninety per cent on CAB+RPV LA and 76% on CAR of participants experienced an adverse event; six (12%) of which were drug-related (CAB+RPV LA: n = 6). Injection-site reactions were common (78% [Grade 1: 80%; Grade 2: 20%]). CAB and RPV trough plasma concentrations remained above respective in vitro protein-adjusted 90% inhibitory concentrations following all doses. Conclusion: This subgroup analysis of South African participants demonstrated durable efficacy, acceptable safety profile and pharmacokinetics of injectable CAB+RPV LA up to 96 weeks, consistent with long-term data from other regions and studies.

BACKGROUND:Cabotegravir + rilpivirine (CAB + RPV) administered via intramuscular gluteal injections is the first complete long-acting regimen for maintaining human immunodeficiency virus type 1 (HIV-1) virologic suppression. We present substudy results on short-term repeat intramuscular CAB + RPV long-acting thigh injections in participants with ≥3 years of experience with gluteal administration during the ATLAS-2M study. METHODS:Substudy phases included screening, thigh injection (day 1-week 16), and return to gluteal injection (week 16-week 24). The injection schedule was unchanged from the main study. Outcomes included pharmacokinetics, safety, tolerability, efficacy, and patient-reported outcomes. Pharmacokinetic parameters were determined using noncompartmental analysis and mixed-effects modeling. Population pharmacokinetic simulations were performed. RESULTS:There were 118 participants. In the arm that received injections every 2 months (Q2M), first CAB thigh injection including area under the concentration-time curve and maximum observed concentration (Cmax) and first RPV thigh injection Cmax and all last RPV thigh injection parameters were statistically higher vs gluteal injections (paired comparison). No significant differences occurred with once-monthly (QM) dosing. No participants had HIV-1 RNA ≥50 copies/mL after thigh injections. Overall, 4%-7% of injection site reactions (ISRs) were grade 3. Five participants withdrew due to an ISR or injection intolerability. Overall, 30% preferred thigh vs gluteal injections. Simulations demonstrated the potential for chronic/continuous QM or ≤2 consecutive Q2M thigh injections. CONCLUSIONS:These data demonstrate the potential use of chronic/continuous QM and rotational/short-term QM or Q2M (≤4 months of continuous dosing), CAB + RPV long-acting intramuscular thigh administration for HIV-1 treatment.

Background:Modest weight and lipid changes have been observed in cabotegravir plus rilpivirine long-acting (CAB + RPV LA) phase 3/3b studies. The SOLAR study included standardized evaluations of weight and metabolic changes in people living with HIV switching to CAB + RPV LA dosed every 2 months (Q2M) vs. continuing bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).Setting:Phase 3b, randomized, open-label study conducted in 118 centers across 14 countries.Methods:Participants (n = 687) were randomized 2:1; 454 switched to CAB + RPV LA Q2M and 227 continued BIC/FTC/TAF. Participants who started lipid-modifying agents or underwent cosmetic procedures were excluded. We analyzed changes in body weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), muscle mass, body fat, and proportion with insulin resistance or metabolic syndrome at 1 year.Results:Median (interquartile range) change in body weight from baseline was -0.40 kg (-2.95 to +2.10) and +0.05 kg (-2.30 to +1.95) in the LA and BIC/FTC/TAF arm, respectively. Median (interquartile range) changes in WC and HC were +0.06 cm (-4.50 to 4.00) and +0.00 cm (-4.00 to 3.97) in the LA arm, and +1.14 cm (-3.00 to 5.09) and +0.13 cm (-3.10 to 4.00) in the BIC/FTC/TAF arm. There were no clinically relevant changes in WHtR, WHR, or the proportion with metabolic syndrome or insulin resistance in either arm.Conclusions:Standardized changes in weight, BMI, and body composition were minor and similar between participant switching to CAB + RPV LA Q2M or continuing BIC/FTC/TAF, with no clinically relevant changes in metabolic syndrome or insulin resistance.

OBJECTIVE:To evaluate subcutaneous anterior abdominal injections of long-acting cabotegravir plus rilpivirine (CAB + RPV LA) in participants with more than 3 years' experience with intramuscular injections in the Phase 3 FLAIR (NCT02938520) study. DESIGN:Substudy of a phase 3, randomized, open-label, multicenter, noninferiority study. METHODS:Substudy phases included screening/intramuscular gluteal injection, subcutaneous injection [day 1-week (W) 8], and return to gluteal injection (W12-W20). The injection schedule was unchanged from the main study (every 4 weeks). Outcomes included pharmacokinetics, safety, tolerability, efficacy, and patient-reported outcomes. RESULTS:Overall, 93 participants were enrolled and received subcutaneous injections; 19% were female (sex at birth). CAB and RPV plasma exposures were generally comparable between subcutaneous and intramuscular injections, with 90% confidence intervals of geometric least squares mean ratios all within 0.80-1.25 boundary of no difference. Pain (48%), nodules (34%), and erythema (26%) were the most frequently reported subcutaneous-related injection site reactions (ISRs). Median durations of nodule and induration were longer with subcutaneous vs. intramuscular administration. Five (5%) participants withdrew due to a subcutaneous-related ISR. Few participants (2%) had HIV-1 RNA at least 50 copies/ml after subcutaneous injections. Participants reported greater pain and lower acceptability of ISRs following subcutaneous vs. intramuscular administration; 59% of participants preferred intramuscular injections. CONCLUSION:Pharmacokinetics and efficacy were similar between CAB+RPV LA subcutaneous and intramuscular administration; however, due to the higher incidence and duration of ISRs, along with lower tolerability and acceptability of subcutaneous injections, subcutaneous administration with the current CAB LA and RPV LA formulations is not being evaluated further.

Introduction Les injections intramusculaires (IM) du cabotégravir (CAB) seul à longue durée d'action (LA) dans le muscle fessier (MF) sont approuvées pour la prophylaxie avant exposition (PrEP) du VIH-1 et en combinaison avec la rilpivirine pour le traitement. Le muscle vastus lateralis (latéral) de la cuisse est un autre site d'administration potentiel en cas de fatigue de l'injection dans le muscle fessier ou d'obstruction physique. Nous avons cherché à caractériser la pharmacocinétique (PK) de CAB et son association avec les données démographiques après administration dans la cuisse versus dans le MF à l'aide d'une analyse PK de la population (pop PK). Matériels et méthodes L'analyse des concentrations de CAB a été faite sur les données de quatorze participants (pts) négatifs au VIH ayant reçu une injection unique de 600 mg dans la cuisse dans l'étude de phase I 208832 et 118 pts positifs au VIH-1 ayant reçu des injections dans la cuisse (400 mg par mois [QM] x 4 ou 600 mg tous les 2 mois (Q2M) x 2) après plus de 3 ans d'injections dans le MF dans l'étude de phase IIIb 207966 (ATLAS-2M). Un modèle établi de pop PK dans le MF a été adapté aux données PK après des injections dans le MF et dans la cuisse, permettant une comparaison intra-patient chez les pts de l'étude ATLAS-2M. Les paramètres relatifs au MF ont été fixés. Les paramètres relatifs à la cuisse, y compris la constante du taux d'absorption (KA-cuisse) et la biodisponibilité (F-cuisse), ont été estimés. Les profils PK CAB suite à des injections administrées en QM et Q2M d'une façon chronique ou intermittente dans la cuisse ont été simulés et comparés aux injections dans le muscle fessier. L'objectif PK était que 95 % des pts maintiennent des concentrations > 0,45 pg/mL, soit le 5e percentile de la concentration minimale de CAB observée après l'injection d'initiation dans le muscle fessier dans les études de phase III. Résultats 1 254 concentrations issues de 366 injections dans la cuisse et 2 022 concentrations issues de 1 631 injections dans le MF ont été analysées. Comme pour l'administration dans le MF, la KA-cuisse était corrélée au sexe et à l'IMC.La KA-cuisse était corrélée et généralement plus rapide que la KA-fessier, selon la relation linéaire additive : KA-cuisse = KA-fessier + 0,000253 h-1. La demi-vie de l'administration dans la cuisse était de 26 % (homme) et 39 % (femme) plus courte que pour l'administration dans le muscle fessier. La F-cuisse représentait 90 % de celle dans le muscle fessier. La cible PK a été maintenue après des injections chroniques QM dans la cuisse ou des injections alternées cuisse-fessier pour les schémas QM ou Q2M, mais pas après des injections chroniques Q2M dans la cuisse. Conclusion La modélisation et la simulation pop PK soutiennent l'administration chronique de CAB LA QM dans la cuisse et les injections intermittentes dans la cuisse pour les schémas QM et Q2M. Cependant, l'administration chronique Q2M simulée dans la cuisse n'a pas maintenu la cible PK établie dans les essais pivots et n'est donc pas recommandée.Liens d'intérêts déclarés :Boards d'experts : Gilead, MSD, Janssen, ViiV Healthcare Grants : MSD Travel : Gilead, MSD

ABSTRACT Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m 2 . One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.

SOLAR (NCT04542070; registered 2020–09-09) is a Phase 3b study that demonstrated the noninferior virological efficacy of switching to cabotegravir + rilpivirine long-acting (CAB + RPV LA) dosed every 2 months vs. continuing daily oral bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) over 12 months. Participants were randomised (2:1) to switch to CAB + RPV LA or to continue BIC/FTC/TAF. Patient-reported endpoints included treatment preference, treatment satisfaction (12-item HIV Treatment Satisfaction Questionnaire status version), acceptability of injections (Perception of Injection questionnaire [acceptability domain]) and three single-item questions exploring psychological challenges related to HIV treatment (fear of disclosure, adherence-related anxiety and reminder of HIV status). Of 670 participants, 447 participants switched to CAB + RPV LA and 223 continued BIC/FTC/TAF. Overall, 18

AbstractStudies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We document full suppression in all animals during treatment (4-12 months) and no virus rebound after treatment discontinuation (1.5-2 years of follow up) despite CD8 + T cell depletion. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation.

ABSTRACT Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with ( n = 278) or without ( n = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI ( n = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084. Cabotegravir pharmacokinetic profiles were simulated in three populations (assigned-male-at-birth, 50%-assigned-female-at-birth, and assigned-female-at-birth) under three scenarios: first injection given (A) 1 or (B) 3 days after final OLI dose (OLI-injection gap) or (C) without OLI. The PK objective was 80% of participants achieving 4× in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC 90 ) and 50% achieving 8× PA-IC 90 . Observed trough concentrations ( C τ ) were similar with and without OLI ( P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection C τ remained above PK objective. Approximately 1–2 weeks after the first injection, simulated PK profiles became nearly identical among all scenarios. Without OLI, it was predicted that 80% of participants achieve 4× PA-IC 90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC 90 in 1.4, 2.1, and 3.8 days, respectively. Observed long-acting cabotegravir exposure was similar with or without OLI, supporting optional OLI use. Cabotegravir exposure was predicted to remain above PK objective for OLI-injection gaps of ≤3 days and rapidly achieve PK objective after first injection without OLI. Findings are consistent between assigned-male-at-birth and assigned-female-at-birth populations. This study is registered with ClinicalTrials.gov as NCT02720094 .

Cabotegravir intramuscular gluteal injection is approved for HIV treatment (with rilpivirine) and prevention. Thigh muscle is a potential alternative injection site. We aim to characterize cabotegravir pharmacokinetics and its association with demographics following intramuscular thigh injection in comparison with gluteal injection using population pharmacokinetic (PPK) analysis. Fourteen HIV-negative participants received 600 mg single thigh injection in phase 1 study 208832 and 118 participants with HIV received thigh injections 400 mg monthly 4x or 600 mg once-every-2-months 2x after >= 3 years of gluteal injections in phase 3b study ATLAS-2M provided 1,249 cabotegravir concentrations from 366 thigh injections and 1,998 concentrations from 1,618 gluteal injections. The established gluteal PPK model was modified by adding thigh injection compartment and fit to pharmacokinetic data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M. Gluteal parameters were fixed. Similar to the gluteal absorption rate constant (KAgluteal), the thigh absorption rate constant (KAthigh) was slower in females than males and in participants with higher BMI. KAthigh was strongly correlated with KAgluteal (correlation coefficient 0.766), best described by the additive linear relationship KAthigh = KAgluteal + 0.0002527 h-1. Terminal half-life of thigh injection was 26% (male) and 39% (female) shorter than gluteal injection. Relative bioavailability of thigh to gluteal was estimated to be 89.9%. The impact of covariates on cabotegravir exposure following thigh injections was <= 35%. In conclusion, cabotegravir absorption following thigh injection was correlated with, faster than, and 10% less bioavailable than gluteal injection, and correlated with sex and BMI. The cabotegravir thigh PPK model can inform dosing strategies and future study design.

Cabotegravir (CAB) and rilpivirine (RPV) is the first complete long-acting (LA) injectable regimen recommended by treatment guidelines for the maintenance of HIV-1 virologic suppression in people with HIV-1 who are virologically suppressed on a stable antiretroviral regimen that is administered monthly (Q1M) or every 2 months (Q2M). As an alternative regimen to lifelong daily oral antiretroviral therapy, Q1M or Q2M dosing schedules are associated with increased patient satisfaction and treatment preference. In addition, it may address challenges associated with daily oral dosing, including fear of treatment disclosure or stigma, anxiety related to oral dosing adherence, and the daily reminder of HIV disease status. Cabotegravir + RPV LA is administered by clinical staff as two intramuscular injections dosed Q1M or Q2M. In this review, we share practical dosing guidance for CAB+RPV LA injectable therapy, including how to initiate therapy, schedule injection visits, manage dosing interruptions due to missed or delayed injection visits, manage errors in dosing, and transition to alternative antiretroviral therapy after discontinuation. Practical guidance on the clinical management of CAB+RPV LA dosing, including a detailed discussion using case-based scenarios that may be encountered in clinical practice, is provided. The clinician-administered CAB+RPV LA regimen has dosing management considerations that are flexible and considerate of the patient and has the potential to provide a highly desirable and efficacious alternative to daily oral antiretroviral therapy for many people with HIV-1. Guidance for clinicians on the management of long-acting Cabotegravir and Rilpivirine Injectable Therapy for HIV-1Cabotegravir (CAB) and rilpivirine (RPV) is the first long-acting (LA) injectable therapy for people with HIV-1 who previously achieved undetectable virus levels using other HIV-1 medications. People with HIV-1 receive CAB+RPV LA as two injections given by their clinician every 1 month or every 2 months, providing an alternative treatment option to lifelong daily oral medications. People with HIV-1 receiving CAB+RPV LA every 1 or 2 months have higher levels of treatment satisfaction and often prefer CAB+RPV LA compared with daily oral medications. Cabotegravir+RPV LA may also address challenges associated with daily oral medications, including fear of inadvertently sharing HIV status, anxiety related to taking daily medications, and having a daily reminder of HIV. In this review, we provide guidance for clinicians on how to administer CAB+RPV LA injectable therapy, including how to start patients on CAB+RPV LA injections, schedule injection visits, manage missed or delayed injection visits, manage dosing errors, and switch patients to a different treatment if CAB+RPV LA is discontinued. This review also includes a detailed discussion of potential scenarios related to the administration and scheduling of CAB+RPV LA injections that may occur in clinical practice. Overall, this review serves as a practical guide for managing CAB+RPV LA injectable therapy in clinical practice that will be useful for HIV clinicians.

Abstract Background Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. Methods Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population—baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). Results Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. Conclusions The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.

Abstract Background Cabotegravir (CAB) + rilpivirine (RPV) dosed intramuscularly monthly or every 2 months is a complete, long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Here, we report the antiretroviral therapy as long acting suppression (ATLAS)-2M study week 152 results. Methods ATLAS-2M is a phase 3b, randomized, multicenter study assessing the efficacy and safety of CAB+RPV LA every 8 weeks (Q8W) versus every 4 weeks (Q4W). Virologically suppressed (HIV-1 RNA <50 copies/mL) individuals were randomized to receive CAB+RPV LA Q8W or Q4W. Endpoints included the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL and <50 copies/mL, incidence of confirmed virologic failure (CVF; 2 consecutive measurements ≥200 copies/mL), safety, and tolerability. Results A total of 1045 participants received CAB+RPV LA (Q8W, n = 522; Q4W, n = 523). CAB+RPV LA Q8W demonstrated noninferior efficacy versus Q4W dosing, with 2.7% (n = 14) and 1.0% (n = 5) of participants having HIV-1 RNA ≥50 copies/mL, respectively, with adjusted treatment difference being 1.7% (95% CI: 0.1–3.3%), meeting the 4% noninferiority threshold. At week 152, 87% of participants maintained HIV-1 RNA <50 copies/mL (Q8W, 87% [n = 456]; Q4W, 86% [n = 449]). Overall, 12 (2.3%) participants in the Q8W arm and 2 (0.4%) in the Q4W arm had CVF. Eight and 10 participants with CVF had treatment-emergent, resistance-associated mutations to RPV and integrase inhibitors, respectively. Safety profiles were comparable, with no new safety signals observed since week 48. Conclusions These data demonstrate virologic suppression durability with CAB+RPV LA Q8W or Q4W for ∼3 years and confirm long-term efficacy, safety, and tolerability of CAB+RPV LA as a complete regimen to maintain HIV-1 virologic suppression.

BACKGROUND:Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV. METHODS:SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing. FINDINGS:837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18-74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3-29·5). At month 11-12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI -0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2. INTERPRETATION:These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment. FUNDING:ViiV Healthcare.

Background In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine. Methods LATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1. After a 24-week induction phase with cabotegravir + 2 NRTIs, participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL were randomized to receive cabotegravir (10, 30, or 60 mg) + rilpivirine (25 mg) in the maintenance phase through Week 96 and switched to cabotegravir 30 mg + rilpivirine 25 mg in the open-label phase through Week 312. Results Of 160 participants who entered the maintenance phase, 111 completed the study at Week 312. At Week 312, 105 (66%) participants maintained HIV-1 RNA <50 copies/mL, 15 (9%) had HIV-1 RNA >= 50 copies/mL, and 40 (25%) had no virologic data. Eight participants met protocol-defined virologic failure criteria through Week 312, 2 of whom met protocol-defined virologic failure criteria after Week 144. Six participants developed treatment-emergent resistance to 1 or both agents during the study, 3 of whom developed integrase inhibitor resistance substitutions. Two participants (1%) reported drug-related serious adverse events. Few adverse events led to withdrawal during the open-label phase (n = 5, 3%). Conclusions Oral cabotegravir + rilpivirine demonstrated efficacy in the majority of participants and an acceptable safety profile through 6 years of treatment, demonstrating its durability as maintenance therapy for HIV-1. Oral cabotegravir + rilpivirine maintained virologic suppression in the majority of participants and demonstrated an acceptable safety profile through 6 years of treatment, supporting its use as a flexible treatment strategy in people with HIV-1 receiving long-acting cabotegravir + rilpivirine.