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.

Virological Failure After Switch to Long-Acting Cabotegravir and Rilpivirine Injectable Therapy: An In-depth Analysis.

BACKGROUND: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for human immunodeficiency virus type 1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merit further evaluation. METHODS: We performed an in-depth clinical, virological, and pharmacokinetic analysis on the reasons behind and the impact of VF during LA CAB/RPV therapy in 5 cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF, and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cutoff (≤Q1) were considered to be low. RESULTS: Five cases who were eligible for LA CAB/RPV experienced VF despite a low predicted risk at baseline. Genotypic resistance testing revealed extensive selection of nonnucleoside reverse transcriptase inhibitor-associated mutations in all cases, and integrase strand transfer inhibitor mutations in 4 cases. All cases displayed low drug levels of either CAB, RPV, or both during the treatment course, likely contributing to the occurrence of VF. In 3 cases, we were able to identify the potential mechanisms behind these low drug levels. CONCLUSIONS: This is the first in-depth multiple case analysis of VF on LA CAB/RPV therapy in a real-world setting. Our observations stress the need to be aware for (evolving) risk factors and the yield of a comprehensive clinical, virological, and pharmacokinetic approach in case of failure.

Effect of Obesity on the Exposure of Long-acting Cabotegravir and Rilpivirine: A Modeling Study.

BACKGROUND: Obesity is increasingly prevalent among people with human immunodeficiency virus (HIV, PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in silico trials using physiologically based pharmacokinetic (PBPK) modeling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections. METHODS: Our PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/ overweight (body mass index [BMI] <30 kg/m2) and in obese (BMI >30 kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60 kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (area under the curve [AUC]) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25 kg/m2). RESULTS: Obesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35 kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40 kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration, but this was less frequent with the monthly administration. CONCLUSIONS: Morbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment.

A HIV Superinfection Diagnosed in a Patient on Intramuscular Long-acting Combination of Cabotegravir and Rilpivirine.

A case of a male with human immunodeficiency virus with plasma genotyping detecting no resistance and a CRF02_AG subtype had a controlled HIV RNA on antiretroviral therapy since 2010. We introduced intramuscular therapy with cabotegravir and rilpivirine. One month later, his HIV RNA was 1500 copies/mL; genotyping found a subtype B with many mutations.

Cabotegravir and rilpivirine long acting injectables in a pregnant woman living with HIV.

This case report describes bimonthly LAI CAB/RPV prior to and throughout pregnancy. CAB concentration was comparable to non-pregnant individuals, RPV was 70-75% lower. No virologic failure orvertical transmission occurred. Despite placental transfer, no congenital malformations were noted. Bimonthly CAB/RPV LAI may not be suitable for pregnant women and monitoring of exposed infants is warranted.

Global HIV Incidence Analysis and Implications for Affordability Using Long-Acting Cabotegravir Versus Continuous and Event-Driven Oral Preexposure Prophylaxis.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 083/084 trials showed up to 88% increased efficacy of long-acting cabotegravir (CAB-LA) versus continuous oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). However, CAB-LA's high price limits the number of people who can be treated within fixed prevention budgets. Global human immunodeficiency virus (HIV) prevention budgets are highly limited, with TDF/FTC widely available as a low-cost generic. In randomized clinical trials, event-driven TDF/FTC has shown similar preventive efficacy to continuous TDF/FTC. METHODS: A systematic review of global HIV incidence studies was conducted. Weighted incidence was calculated in each at-risk population. HIV infection rates were evaluated for 5 prevention strategies, with additional HIV testing, education, and service access costs assumed for each ($18 per person per year). Assumed efficacies were 90% (continuous CAB-LA), 60% (continuous TDF/FTC), and 60% (event-driven TDF/FTC). Using weighted incidence and an assumed 100 000 target population, annual HIV infection rates by population were calculated for each prevention strategy. RESULTS: Ninety-eight studies in 5 230 189 individuals were included. Incidence per 100 person-years ranged from 0.03 (blood donors) to 3.82 (people who inject drugs). Using the number needed to treat to benefit for each strategy, a mean incidence of 2.6 per 100 person-years in at-risk populations, and a 100 000 target population, current-price continuous CAB-LA cost $949 487 per HIV infection successfully prevented, followed by target-price CAB-LA ($11 453), continuous TDF/FTC ($4231), and event-driven TDF/FTC ($1923). CONCLUSIONS: High prices of CAB-LA limit numbers treatable within fixed budgets. Low-cost event-driven TDF/FTC consistently prevents the most HIV infections within fixed budgets.

Preferential Initiation of Long-Acting Injectable Versus Oral HIV Pre-Exposure Prophylaxis Among Women Who Inject Drugs.

Fifty-five of 62 women who inject drugs (WWID) selected long-acting cabotegravir (CAB-LA) over oral PrEP, and 51/55 received a first injection. More recent injection drug use and number of sexual partners were associated with selecting CAB-LA (P < .05). Findings provide preliminary evidence of a strong preference for longer-acting products among WWID.

48-week viral suppression rates in people with HIV starting long-acting CAB/RPV with initial viremia.

BACKGROUND: We previously demonstrated at the Ward 86 HIV clinic in San Francisco that long-acting cabotegravir/rilpivirine (LA-CAB/RPV) can rapidly lead to viral suppression (VS) in people with HIV (PWH) with viremia due to adherence challenges. We now evaluate VS durability in this population. METHODS: We conducted a retrospective cohort study of PWH who started LA-CAB/RPV with viremia (HIV RNA viral load [VL]≥50 copies/mL) before December 2022. Our primary outcome was VS (VL<50 copies/mL) with LA-CAB/RPV persistence (not discontinued or late by >14 days) at 48 weeks, using the closest VL to 48+/-8 weeks. We also describe viral failure (VF), defined as <2-log VL decline at 4 weeks or VL≥200 copies/mL after initial VS with emergent CAB- or RPV-associated resistance mutations; and overall 48-week VS including those switched to alternative ART. RESULTS: Fifty nine PWH initiated LA-CAB/RPV with viremia and were included in analysis; 49% had CD4<200 cells/µL and median baseline VL was 42,900 copies/mL (Q1-Q3 5,272-139,038). At 48 weeks, 47 met the primary outcome of VS with LA-CAB/RPV persistence (80%; 95%CI 67-89%). Five had VF with resistance (three with RPV-associated mutations, two with CAB and RPV-associated mutations) and one was lost-to-follow-up. At week 48, two of those with VF were suppressed on alternative regimens (lenacapavir+BIC/TAF/FTC and CAB+lenacapavir). Overall week 48 VS on either LA-CAB/RPV or alternative ART was 92% (54/59). CONCLUSIONS: In PWH initiating LA-CAB/RPV with initial viremia, 48-week VS (<50 copies/mL) was 92%. Long-acting ART can be an important tool for improving VS among patients who face adherence challenges to oral ART.

Comparison of At-Home Versus In-Clinic Receipt of Long-Acting Injectable Cabotegravir/Rilpivirine.

BACKGROUND: The need for frequent travel to a clinic could impair access to injectable antiretroviral therapy for persons living with human immunodeficiency virus type 1 (HIV-1) infection. We hypothesized that allowing persons receiving treatment with long-acting injectable cabotegravir plus rilpivirine (LA CAB/RPV) to receive and store the medication in their own refrigerator prior to in-home administration by a healthcare provider would be as safe and effective as receiving treatment in a clinic. METHODS: Persons prescribed LA CAB/RPV in the Infectious Diseases clinic at the Medical University of South Carolina were offered enrollment in this non-randomized, observational study between August 2021 and December 2022. After in-clinic receipt of the initial LA CAB/RPV injection, participants chose to receive each subsequent injection over the following 12-months either in clinic or at home. RESULTS: The 33 enrolled participants were primarily Black (64%), male (73%), and had a median age of 46. Three participants stopped LA CAB/RPV and transitioned to oral antiretroviral therapy due to allergy (n = 1), loss of virologic suppression (n = 1), and visit adherence (n = 1) concerns. A comparable number of participants received treatment primarily in clinic (n = 18) relative to at home (n = 15). Injection site pain/soreness was common (52% of injections) but did not differ between groups. There were no differences in safety or efficacy between groups and both groups reported high treatment satisfaction. All participants were virologically suppressed and retained in care at the end of the study. CONCLUSIONS: At-home administration of LA CAB/RPV by a healthcare provider was comparably safe, effective, and associated with high participant satisfaction relative to in-clinic administration.

Challenges for novel antiretroviral development in an era of widespread TLD availability.

Over 80% of people living with HIV in low-and-middle-income countries (LMICs) take first-line TDF/XTC/DTG (TLD). Due to hard-fought activism, in >100 LMICs TLD now costs under $45pppy under Voluntary License. With final DTG patents expiring by 2029, generic TLD will soon be available globally. We identify seven critical benchmarks underpinning TLDs success which novel ART should now meet, and an eighth for which novel ART should aim. These are superior efficacy; a high genetic barrier to resistance; safety in hepatitis B coinfection; favourable drug-drug interaction profiles including with antimycobacterials; efficacy in HIV-2; safety in pregnancy, long-acting formulation availability and affordable pricing from the outset. We illustrate when generic TLD will become available worldwide and compare this with trial programmes and approval timelines for two case-study novel ART combinations: islatravir/doravirine and cabotegravir/rilpivirine. We demonstrate that currently these regimens and trial programmes will not meet key benchmarks required to compete with TLD.

Interest in and Preference for Long-acting Injectable Antiretroviral Therapy in the Era of Approved Cabotegravir/Rilpivirine among Reproductive-aged Women in the U.S. South.

Among 103 reproductive-aged women with HIV in the U.S. South surveyed post-approval of long-acting injectable (LAI) cabotegravir/rilpivirine, nearly two-thirds reported willingness to try LAI antiretroviral therapy (ART). Most expressed preference for LAI over daily oral ART and had minimal concerns over potential LAI-ART use impacting reproductive health.

Virological History Predicts Non-sustained Viral Suppression with Long-Acting Cabotegravir and Rilpivirine Therapy, independent of Pharmacokinetic Parameters.

BACKGROUND: This study aimed to investigate factors contributing to non-sustained viral suppression, including intermittent viremia and persistent low-level viremia, during cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) injectable therapy, with a focus on pharmacokinetics (PK). METHODS: A prospective cohort study was conducted on people with HIV (PWH) transitioning from stable oral antiretroviral therapy (ART) to bimonthly CAB+RPV LA. Standardized follow-up included close monitoring through blood sampling for plasma HIV-1 viral load (VL) and multiple plasma drug concentrations measurements to analyze the connection between PK parameters and virologic outcomes. RESULTS: Among 173 patients with a median (IQR) follow-up of 11.1(7.1-13.2) months and 789 pre-dose measurements, 38.7% experienced VL≥20 copies/mL, and 16.2% had levels ≥50 copies/mL. Intermittent viremia occurred in 34.7% of patients, and persistent low-level viremia in 4%. Virological failure developed in two cases. Predictors of non-sustained viral suppression included VL at HIV diagnosis [AHR: 1.49 per log10 VL, 95% CI: 1.04-2.12, P =.027], detectable viremia on oral ART [AHR: 2.45, 95% CI: 1.29-4.65, P =.006], and the level of viral suppression at transition [AHR: 0.38, 95% CI: 0.19-0.75, P =.004]. We found a significant association between low trough concentrations of CAB and RPV and episodes of detectable viremia exceeding 50 copies/mL. However, none of the assessed PK covariates predicted non-sustained viral suppression in multivariable models. CONCLUSION: Non-sustained viral suppression in PWH transitioning from stable oral ART to CAB+RPV LA was linked to pre-existing factors before transition. Higher VL pre-ART and incomplete suppression on oral therapy increased the risk, independent of PK parameters.

Hepatitis B Virus Reactivation after Switch to Cabotegravir/Rilpivirine in Patient with Low Hepatitis B Surface Antibody.

A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.

Pharmacologic evaluation of delayed long-acting cabotegravir administration among cisgender women in HPTN 084.

HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial. CAB concentrations were evaluated before a delay, at the visit associated with the delay, and the visit after a delayed injection was administered. During the blinded phase of the trial, 194 participants randomized to CAB-LA experienced at least one injection delay. Plasma CAB concentrations were maintained above the 4× protein adjusted 90% inhibitory concentration (4× PA-IC90; protocol-specific threshold) for all loading dose and 98% of Q2M delays when injections were administered up to 6 weeks late. The feasibility of shifting to an every 3-month (Q3M) regimen in females was interrogated via simulation studies using a population pharmacokinetic model. Q3M injections in both CAB-naïve (with a loading dose) and previously CAB-exposed females were predicted to yield higher steady-state exposures than in males on the approved Q2M regimen. Although there is observed forgiveness following an isolated delayed CAB-LA injection and simulations suggest acceptable CAB-LA exposures in women with a 600 mg CAB-LA Q3M regimen, empirical efficacy of this regimen has not been established, and transitioning to this dosing schema is not recommended. Future pharmacokinetic bridging studies are aimed at evaluating higher dose CAB-LA formulations administered less frequently. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03164564.

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.

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.

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.

Therapeutic failure reported with HIV long-acting injectables: An analysis of the FDA Adverse Event Reporting System from 2021 to 2024.

OBJECTIVES: We examined adverse event (AE) reports relating to cabotegravir/rilpivirine (CAB/RPV) in the US FDA Adverse Event Reporting System (FAERS), focusing on therapeutic failure (TF) and non-therapeutic failure (NTF) outcomes. METHODS: FAERS is a database of AE and medication error reports from post-marketing surveillance. The study was granted exempt approval by the Binghamton University Institutional Review Board. We queried reports for CAB/RPV in the FAERS system from 1 January 2021 to 31 March 2024. TFs were defined as involving any of the following terms: viral load increased, virological failure, pathogen resistance, blood HIV RNA increased, treatment failure, drug ineffective, viral mutation identified, viraemia, and therapy non-responder. The top 20 most common AEs were also identified. Means, standard deviations, and percentages were used to characterize the sample. RESULTS: The study cohort consisted of 2605 reports. The reported sex of the study cohort was 50% male (n = 1295), 19% female (n = 505), and 31% unspecified (n = 805), with a mean ± standard deviation (SD) age of 46.9 ± 12.4 years (n = 378). The top three most reported AEs were TFs, product dose omissions, and injection site pain, with 377 (14.5%), 354 (13.6%), and 331 (12.7%) cases, respectively. The mean ± SD weight of people with a report of TF versus NTF was 101.8 ± 33.4 kg and 87.7 ± 26.7 kg, respectively (p = 0.0175). CONCLUSION: Our findings suggest that healthcare professionals should have a heightened awareness of potential challenges with CAB/RPV administration, including TFs and dose omissions in real-world settings.

Multicentre service evaluation of injectable cabotegravir and rilpivirine delivery and outcomes across 12 UK clinics (SHARE LAI-net).

INTRODUCTION: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics. METHODS: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia. RESULTS: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV. CONCLUSION: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure.

Clinical pharmacology considerations and drug-drug interactions with long-acting cabotegravir and rilpivirine relevant to sub-Saharan Africa.

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.