Efficacy, Safety, and Pharmacokinetics by Body Mass Index Category in Phase 3/3b Long-Acting Cabotegravir Plus Rilpivirine Trials.

BACKGROUND: Cabotegravir plus rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of human immunodeficiency virus-1 (HIV-1) virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among phase 3/3b trial participants. METHODS: Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2M were pooled through week 48. Data beyond week 48 were summarized by study (FLAIR through week 96 and ATLAS-2M through week 152). HIV-1 RNA <50 and ≥50 copies/mL, confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥200 copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30 kg/m2, lower; ≥30 kg/m2, higher). RESULTS: Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30 kg/m2. At week 48, 92% versus 93% of participants with lower versus higher BMI had HIV-1 RNA <50 copies/mL, respectively. Including data beyond week 48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least 1 other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV-1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories. CONCLUSIONS: CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category. CLINICAL TRIALS REGISTRATION: NCT02938520, NCT02951052, and NCT03299049.

Asian participants' experience in phase 3/3b studies of long-acting cabotegravir and rilpivirine: Efficacy, safety, pharmacokinetic, and virological outcomes through week 96.

OBJECTIVES: Cabotegravir + rilpivirine (CAB + RPV) dosed monthly or every 2 months is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virological suppression. This post hoc analysis summarizes outcomes for Asian participants through week 96. METHODS: Data from Asian participants naive to CAB + RPV randomized to receive dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) in the FLAIR (NCT02938520) and ATLAS-2M (NCT03299049) phase 3/3b studies were pooled. The proportion of participants with plasma HIV-1 RNA ≥50 and <50 copies/mL (per FDA Snapshot algorithm), incidence of confirmed virological failure (CVF; two consecutive HIV-1 RNA ≥200 copies/mL), pharmacokinetics, safety, and tolerability through week 96 were assessed. RESULTS: Overall, 41 Asian participants received CAB + RPV (Q8W, n = 17; Q4W, n = 24). At week 96, 83% (n = 34/41) of participants maintained HIV-1 RNA <50 copies/mL, none had HIV-1 RNA ≥50 copies/mL, and 17% (n = 7/41) had no virological data. No Asian participant met the CVF criterion. Drug-related adverse events occurred in 44% (n = 18/41) of participants; none were Grade ≥3. All injection site reactions were Grade 1 or 2; median duration was 2 days and most resolved within 7 days (90%, n = 390/435). CAB and RPV trough concentrations remained well above their respective protein-adjusted 90% inhibitory concentrations (CAB, 0.166 µg/mL; RPV, 12 ng/mL) through week 96. CONCLUSIONS: CAB + RPV LA demonstrated high efficacy, with no participants having CVF, and an acceptable safety profile in Asian participants through week 96. These data support CAB + RPV LA as a complete regimen for the maintenance of HIV-1 virological suppression in Asian individuals.

Cabotegravir + Rilpivirine Long-Acting: Overview of Injection Guidance, Injection Site Reactions, and Best Practices for Intramuscular Injection Administration.

Background: Cabotegravir (CAB) + rilpivirine (RPV) dosed monthly or every 2 months is a complete long-acting (LA) regimen for the maintenance of human immunodeficiency virus type 1 virologic suppression. Across the phase 3/3b trials, the most frequently reported adverse events were injection site reactions (ISRs). Methods: We present pooled ISR characteristics and outcomes for participants receiving CAB + RPV LA through week 96 of the FLAIR and ATLAS-2M studies, and survey results from healthcare providers (HCPs) giving injections (eg, injectors) in the ATLAS, FLAIR, and ATLAS-2M studies to determine optimal injection techniques. Surveys were anonymous, self-administered online questionnaires that queried provider demographics, injection experience, and techniques to minimize pre-/postinjection discomfort. Data were summarized using descriptive statistics. Results: Overall, 8453 ISRs were reported by 801 participants receiving ≥1 injection of CAB LA/RPV LA. Most ISRs were mild to moderate in severity (grade 1-2, 99%), with a median duration of 3 days (interquartile range, 2-4 days), and rarely led to withdrawal (2%). Surveys were completed by 181 HCPs across 113 sites. Pushing the intramuscular injection at slow speed (66%), bringing the medication to room temperature (58%), and relaxing the gluteus muscle before injecting (53%) were ranked as effective preinjection/injection procedure practices for minimizing pain. Most injectors (60%) indicated that a prone position provided optimal patient comfort, and 41% had no preference on injection medication order. Conclusions: Taken together, the data demonstrate favorable tolerability with CAB + RPV LA injections over the long term and simple techniques routinely used by injectors to help optimize the administration of CAB + RPV LA injections.

Safety and Effectiveness From the Cabotegravir and Rilpivirine Implementation Study in European Locations Study: Phase 3b Hybrid Type III Implementation Study Integrating Cabotegravir + Rilpivirine Long-Acting Into European Clinical Settings.

BACKGROUND: Cabotegravir + rilpivirine long-acting (CAB + RPV LA) dosed every 2 months (Q2M) is a complete regimen for the maintenance of HIV-1 virologic suppression. In this study, we report month 12 clinical outcomes in patient study participants (PSPs) in the CAB and RPV Implementation Study in European Locations (CARISEL) study. SETTING: CARISEL is a phase 3b implementation-effectiveness study. METHODS: CARISEL was designed as a 2-arm, unblinded study with centers randomized to either enhanced or standard implementation arms. For PSPs, this study is single arm, unblinded, and interventional; all PSPs switched from daily oral therapy to CAB + RPV LA dosed Q2M. The primary objective was to evaluate the perceived acceptability, appropriateness, and feasibility of CAB + RPV LA implementation for staff participants (presented separately). Clinical secondary endpoints assessed through month 12 included the proportion of PSPs with plasma HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive plasma HIV-1 RNA levels ≥200 copies/mL), adherence to injection visit windows, and safety and tolerability. RESULTS: Four hundred thirty PSPs were enrolled and treated; the mean age was 44 years (30% ≥50 years), 25% were women (sex at birth), and 22% were persons of color. At month 12, 87% (n = 373/430) of PSPs maintained HIV-1 RNA <50 copies/mL, with 0.7% (n = 3/430) having HIV-1 RNA ≥50 copies/mL. One PSP had CVF. The safety profile was consistent with previous findings. Overall, the results were similar between implementation arms. CONCLUSION: CAB + RPV LA Q2M was well tolerated and highly effective in maintaining virologic suppression with a low rate of virologic failure.

Implementation of long-acting cabotegravir and rilpivirine: primary results from the perspective of staff study participants in the Cabotegravir And Rilpivirine Implementation Study in European Locations.

INTRODUCTION: Cabotegravir plus rilpivirine (CAB + RPV) is the first complete long-acting (LA) regimen recommended for maintaining HIV-1 virological suppression. Cabotegravir And Rilpivirine Implementation Study in European Locations (CARISEL) is an implementation-effectiveness study examining the implementation of CAB+RPV LA administered every 2 months (Q2M) in European HIV centres. We present staff study participant (SSP) perspectives on the administration of CAB+RPV LA over 12 months. METHODS: Eighteen clinics were randomized to one of two implementation support packages: standard arm (Arm-S) or enhanced arm (Arm-E). Arm-S included video injection training and provider/patient toolkits. Additionally, Arm-E included skilled wrap-around team meetings, face-to-face injection training and continuous quality improvement (CQI) calls. SSPs completed surveys on the acceptability, appropriateness and feasibility of CAB+RPV LA as an intervention and its implementation into their clinics, as well as barriers and facilitators to implementation. All surveys were completed at Month (M)1 (baseline), M5 and M12; data collection was completed by February 2022. Qualitative data were obtained from semi-structured interviews at M1, M5 and M12. The primary objective was assessed via formal statistical comparisons between study arms of the Acceptability of Implementation Measure, Implementation Appropriateness Measure and Feasibility of Implementation Measure surveys (1-5 Likert scale ranging from 1 = "completely disagree" to 5 = "completely agree"). Equivalent measures anchored to CAB+RPV LA as a therapy were also assessed. RESULTS: Seventy SSPs completed surveys and interviews at M1, 68 at M5 and 62 at M12. Mean acceptability/appropriateness/feasibility scores were ≥3.8 (out of 5) at M12 for implementation- and intervention-based measures. An analysis of covariance showed no significant differences between study arms for these outcomes. Although barriers were noted, most SSPs were not overly concerned that these would impact implementation; concern about these anticipated barriers also decreased over time. At M12, 90.3% (n = 56/62) of SSPs held a positive opinion about CAB+RPV LA implementation. Qualitative interviews and CQI calls highlighted three top practices that supported implementation: implementation planning; education about CAB+RPV LA clinical efficacy; and education around administering injections and managing pain/discomfort after injections. CONCLUSIONS: CARISEL demonstrated that CAB+RPV LA dosed Q2M was successfully implemented across a range of European locations, with SSPs finding implementation highly acceptable, appropriate and feasible. GOV NUMBER: NCT04399551.

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.