Long-acting cabotegravir pharmacokinetics with and without oral lead-in for HIV PrEP.

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-IC90) and 50% achieving 8× PA-IC90. Observed trough concentrations (Cτ) were similar with and without OLI (P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection Cτ 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-IC90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC90 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.

Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the vastus lateralis (lateral thigh) muscles of healthy adult participants.

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/m2. 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.

Practical dosing guidance for the management of clinician-administered injections of long-acting cabotegravir and rilpivirine.

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-1 Cabotegravir (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.

Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.

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.

Expanded Multivariable Models to Assist Patient Selection for Long-Acting Cabotegravir + Rilpivirine Treatment: Clinical Utility of a Combination of Patient, Drug Concentration, and Viral Factors Associated With Virologic Failure.

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.

Long-Acting Cabotegravir and Rilpivirine Dosed Every 2 Months in Adults With Human Immunodeficiency Virus 1 Type 1 Infection: 152-Week Results From ATLAS-2M, a Randomized, Open-Label, Phase 3b, Noninferiority Study.

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.

Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine in clinical trials.

BACKGROUND: Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long-acting (LA) with live births, are presented. METHODS: Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare-sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post-last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians. RESULTS: As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non-pregnant women. CONCLUSION: In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non-pregnant women. Pregnancy surveillance within ViiV Healthcare-sponsored clinical trials is ongoing, with dedicated pregnancy studies planned.

Perspectives of people living with HIV-1 on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings: results from the CUSTOMIZE hybrid III implementation-effectiveness study.

INTRODUCTION: The CUSTOMIZE hybrid III implementation-effectiveness study evaluated implementation of once-monthly long-acting (LA) cabotegravir + rilpivirine in diverse US healthcare settings. Here, we report patient participant perspectives after 12 months in CUSTOMIZE. METHODS: CUSTOMIZE was a phase IIIb, 12-month study conducted from July 2019 to October 2020 at eight diverse US HIV clinics that enrolled virologically suppressed people living with HIV-1 (PLHIV) on a stable oral regimen to receive monthly cabotegravir + rilpivirine LA injections after a 1-month oral lead-in. Participants were administered quantitative surveys before injections at months 1 (baseline), 4 and 12. A randomly selected subset of participants was interviewed at baseline and month 12. Data collection at month 12 was completed by October 2020 (during the COVID-19 pandemic). RESULTS: At baseline, 109 and 34 participants completed surveys and interviews, respectively; 87% were male; 35% were Black or African American. All participants who remained in the study at month 12 (n = 102) maintained HIV-1 RNA <50 copies/ml; two participants withdrew due to injection-related reasons. Mean total scores measuring acceptability and appropriateness of cabotegravir + rilpivirine LA were high at baseline (4.5-4.6 out of 5) and month 12 (4.7-4.9). At month 12, 74% of participants reported nothing interfered with receiving LA injections; injection pain or soreness was the most common concern (15%). Time spent in the clinic and coming to the clinic for monthly injections was very or extremely acceptable after 12 months for most participants (93% and 87%, respectively), with 64% reporting having spent ≤30 minutes in the clinic for injection visits. At month 12, 92% of participants preferred LA injections to daily oral tablets (3%); 97% plan to continue LA treatment going forward. In month 12 interviews, 24 (77%) of 31 participants reported the COVID-19 pandemic did not impact their ability to receive treatment. CONCLUSIONS: Once-monthly cabotegravir + rilpivirine LA was highly acceptable among PLHIV who were virologically suppressed on a stable antiretroviral regimen and interested in trying LA therapy, with few participants reporting challenges receiving LA injections. Implementation data from CUSTOMIZE suggest that monthly LA injections provide a convenient and appealing treatment option for PLHIV.

Perspectives of healthcare providers on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings from a Hybrid III Implementation-effectiveness study (CUSTOMIZE).

INTRODUCTION: CUSTOMIZE evaluated the implementation of long-acting (LA) cabotegravir + rilpivirine, a novel healthcare provider-administered injectable antiretroviral therapy regimen, in diverse US healthcare settings. Findings from staff-study participants (SSPs) through 12 months of implementation are reported. METHODS: CUSTOMIZE was a phase IIIb, 12-month, single-arm, hybrid III implementation-effectiveness study conducted from July 2019 to October 2020 at eight US clinics of five clinic types: private practice (n = 2), federally qualified health centre (n = 2), university (n = 2), AIDS Healthcare Foundation (n = 2) and health maintenance organization (n = 1). Eligible patient participants received monthly cabotegravir + rilpivirine LA injections after a 1-month oral lead-in. At baseline, month 4 and month 12, SSPs (n = 3 each per clinic), including physicians, nurses or injectors, and administrators, completed quantitative surveys and semi-structured interviews to assess implementation outcomes (acceptability, appropriateness and feasibility of intervention measures), programme sustainability and SSP perceptions of, attitudes towards, and expectations for cabotegravir + rilpivirine LA. Month 12 data collection occurred during the COVID-19 pandemic. RESULTS: In surveys, SSPs reported high mean total scores for acceptability, appropriateness and feasibility of cabotegravir + rilpivirine LA implementation at baseline (4.43, 4.52 and 4.38 of 5, respectively) and month 12 (4.45, 4.61 and 4.46 of 5, respectively), regardless of clinic type. At month 12, SSPs were positive about the implementation sustainability (mean Program Sustainability Assessment Tool score, 5.83 out of 7). At baseline, SSPs' top concern was patients' ability to maintain monthly appointments (81%); at month 12, 39% had this concern. The proportion of SSPs reporting patient injection pain or soreness as a barrier was consistent at month 12 versus baseline (48% vs. 46%). Most (78%) SSPs reported optimal implementation of cabotegravir + rilpivirine LA in their clinics was achieved in 1-3 months. In interviews, SSP-reported strategies for successful implementation included teamwork, using a web-based treatment planner and having a designated person to track appointment scheduling. In month 12 interviews, SSP-reported structural changes needed for implementation included changing clinic hours and purchasing refrigerators. CONCLUSIONS: In CUSTOMIZE, cabotegravir + rilpivirine LA was successfully implemented across a range of US healthcare settings. Barriers were mitigated with minor process adjustments.

Population pharmacokinetics of cabotegravir following administration of oral tablet and long-acting intramuscular injection in adult HIV-1-infected and uninfected subjects.

AIM: To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability. METHODS: Analyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P < .01) and backward elimination (P < .001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction-corrected visual predictive checks. RESULTS: The model-building dataset included 23 926 plasma concentrations from 1647 adult HIV-1-infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10-60 mg, long-acting [LA] intramuscular injection 200-800 mg). A two-compartment model with first-order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KALA ) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KALA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model-building dataset. CONCLUSIONS: A cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended.

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

BACKGROUND: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. METHODS: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-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 in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. FINDINGS: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported. INTERPRETATION: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. FUNDING: National Institute of Allergy and Infectious Diseases, 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 provided pharmaceutical support.

Long-Term Efficacy, Safety, and Durability of Cabotegravir and Rilpivirine as 2-Drug Oral Maintenance Therapy After 6 Years of Study.

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.

Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 µg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 µg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).

Impact of Integrase Sequences from HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine.

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine versus daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

Multiparametric magnetic resonance imaging to characterize cabotegravir long-acting formulation depot kinetics in healthy adult volunteers.

AIM: Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. METHODS: Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic-guided injection targeting the gluteal muscles. MRI was performed to determine injection-site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue and combined IM/SC compartments, and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3 and 8. Linear regression analysis examined correlations between MRI-derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax ) and partial area under the concentration-time curve (AUC) through Weeks 4 and 8. RESULTS: Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n = 2), combined IM/SC compartments (n = 4), SC compartment (n = 1) and retroperitoneal cavity (n = 1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax and partial AUC through Weeks 4 and 8. CONCLUSION: MRI clearly delineated cabotegravir LA injection-site location and depot kinetics in healthy adults. Although injection-site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution.

Multicompartmental pharmacokinetic evaluation of long-acting cabotegravir in healthy adults for HIV preexposure prophylaxis.

AIMS: Cabotegravir is an integrase strand transfer inhibitor in clinical development as long-acting (LA) injectable HIV preexposure prophylaxis. METHODS: This phase I study assessed pharmacokinetics of cabotegravir in plasma and anatomical sites associated with sexual HIV-1 transmission after repeated oral and single intramuscular (IM) LA dosing in healthy adults. Following a 28-day oral lead-in period of cabotegravir 30 mg and a washout period of 14-42 days, participants were administered a single ultrasound-guided gluteal IM cabotegravir LA 600-mg injection. The study objective was to characterize cabotegravir concentrations in plasma, cervical, vaginal and rectal tissues, and cervicovaginal and rectal fluids and up to Week 12 after IM injection. RESULTS: Nineteen participants enrolled and 16 completed the study through Week 52. Cabotegravir was detected in plasma and all tissues and fluids. Median plasma cabotegravir concentrations exceeded the in vitro protein-adjusted 90% maximal inhibitory concentration through Week 12. Median tissue- and fluid-to-plasma cabotegravir concentration ratios across all visits were 0.32 for rectal fluid and 0.08-0.16 for other tissues and fluids. Adjusted R2 coefficients between cabotegravir concentrations in plasma and cervical, vaginal and rectal tissues were 0.78, 0.79 and 0.90, respectively. Injection-site reactions were common (88% of participants) and were mostly grade 1 in intensity (82%). Two participants reported 11 non-drug-related serious adverse events. CONCLUSION: Concentrations of cabotegravir in tissues and fluids were proportional to plasma over time, with strong correlations between tissue and plasma concentrations. Cabotegravir LA tissue-to-plasma ratios may be important for understanding its use as preexposure prophylaxis.

Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy.

OBJECTIVES: Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809). DESIGN: A Phase 2b, multicenter, open-label, rollover study. METHODS: LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed. RESULTS: Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV. CONCLUSION: CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from simian HIV acquisition by long-acting cabotegravir in macaques.

OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women. DESIGN: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. METHODS: The first study (n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis. Six animals were CAB-LA treated and five were controls. The second study (n = 9) included a triple STI model with repeated exposures to C. trachomatis, T. vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared with untreated controls over time. RESULTS: All six CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, while the untreated animals became SHIV-infected after a median of two challenges (log-rank P < 0.001) or one challenge (log-rank P = 0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers, and seroconversion. CONCLUSION: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA.

Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment.

BACKGROUND: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented. METHODS AND DESIGN: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm). Endpoints assessed at W 96 included proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, incidence of confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/ml), safety and tolerability, pharmacokinetics, and patient-reported outcomes. RESULTS: Most participants completing the Maintenance Phase transitioned to ATLAS-2M (88%, n = 502/572). Overall, 52 participants were included in the W 96 analysis of ATLAS; of these, 100% (n = 23/23) and 97% (n = 28/29) in the Long-acting and Switch arms had plasma HIV-1 RNA less than 50 copies/ml at W 96, respectively. One participant had plasma HIV-1 RNA 50 copies/ml or higher in the Switch arm (173 copies/ml). No participants met the CVF criterion during the Extension Phase. No new safety signals were identified. All Switch arm participants surveyed preferred long-acting therapy to their previous daily oral regimen (100%, n = 27/27). CONCLUSION: In this subgroup of ATLAS, 98% (n = 51/52) of participants at the Extension Phase W 96 analysis maintained virologic suppression with long-acting therapy. Safety, efficacy, and participant preference results support the therapeutic potential of long-acting CAB+RPV treatment for virologically suppressed people living with HIV-1.

Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study.

BACKGROUND: Previous work established non-inferiority of switching participants who were virologically suppressed from daily oral standard of care to monthly long-acting intramuscular injections of cabotegravir plus rilpivirine over 96 weeks following a cabotegravir plus rilpivirine oral lead-in. Here, we report an evaluation of switching participants from standard of care oral regimens to long-acting cabotegravir plus rilpivirine via direct-to-injection or oral lead-in pathways. METHODS: This study reports the week 124 results of the FLAIR study, an ongoing phase 3, randomised, open-label, multicentre (11 countries) trial. Antiretroviral therapy (ART)-naive participants who were virologically suppressed (HIV-1 RNA <50 copies per mL) during the 20-week induction phase with standard of care were randomly assigned (1:1) to continue the standard of care oral regimen or switch to long-acting cabotegravir plus rilpivirine (283 per group) in the 100-week maintenance phase. Randomisation was stratified by sex at birth and baseline (pre-induction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL). Participants randomly assigned to long-acting therapy at baseline received a cabotegravir (30 mg) plus rilpivirine (25 mg) once daily oral lead-in for at least 4 weeks before first injection and could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw. At week 100, participants in the oral comparator ART group, in discussion with the investigator, could elect to switch to long-acting therapy (extension switch population), either direct-to-injection or with a 4 week oral lead-in (oral lead-in group), or withdraw. Week 124 endpoints included plasma HIV-1 RNA 50 or more copies per mL and less than 50 copies per mL (US Food and Drug Administration [FDA] Snapshot), confirmed virological failure (two consecutive HIV-1 RNA ≥200 copies per mL), and safety and tolerability. The study is registered at ClinicalTrials.gov, NCT02938520. FINDINGS: Screening occurred between Oct 27, 2016, and March 24, 2017. At week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 [48%] in the direct-to-injection group and 121 [52%] in the oral lead-in group; extension switch population). 243 (86%) of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. One (<1%) participant in each extension switch group had 50 or more HIV-1 RNA copies per mL; 110 (99%) participants in the direct-to-injection group and 113 (93%) participants in the oral lead-in group remained suppressed (HIV-1 RNA <50 copies per mL) at the week 124 Snapshot. The lower suppression rates in the oral lead-in group were driven by non-virological reasons. For participants in the randomly assigned long-acting group, 227 (80%) of 283 participants remained suppressed; at the week 124 Snapshot, 14 (5%) participants had HIV-1 RNA 50 or more copies per mL, including five additional participants since the week 96 analysis. The remaining 42 (15%) participants in the randomly assigned long-acting group had no virological data. Adverse events leading to withdrawal were infrequent, occurring in three (1%) participants in the extension switch population (one in the direct-to-injection group and two in the oral lead-in group) after 24 weeks of cabotegravir plus rilpivirine therapy, and 15 (5%) participants in the randomly assigned long-acting group up to 124 weeks of therapy. No deaths occurred in the extension phase. Overall, cabotegravir plus rilpivirine adverse event type, severity, and frequency were similar across all groups. Injection site reactions were the most common adverse event, occurring after 914 (21%) of 4442 injections in the extension switch population and 3732 (21%) of 17 392 injections in the randomly assigned long-acting group. Injection site reactions were mostly classified as mild-to-moderate in severity and decreased in incidence over time. Four (2%) of 232 participants in the extension switch population and seven (2%) of 283 in the randomly assigned long-acting group withdrew due to injection-related reasons. INTERPRETATION: After 24 weeks of follow-up, switching to long-acting treatment with or without an oral lead-in phase had similar safety, tolerability, and efficacy, supporting future evaluation of the simpler direct-to-injection approach. The week 124 results for participants randomly assigned originally to the long-acting therapy show long-acting cabotegravir plus rilpivirine remains a durable maintenance therapy with a favourable safety profile. FUNDING: ViiV Healthcare and Janssen Research & Development.