Abstract 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.
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
Cabotegravir (CAB) + rilpivirine (RPV) dosed intramuscularly monthly or every 2 months is a complete, long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. ...Here, we report the antiretroviral therapy as long acting suppression (ATLAS)-2M study week 152 results.
Methods
ATLAS-2M is a phase 3b, randomized, multicenter study assessing the efficacy and safety of CAB+RPV LA every 8 weeks (Q8W) versus every 4 weeks (Q4W). Virologically suppressed (HIV-1 RNA <50 copies/mL) individuals were randomized to receive CAB+RPV LA Q8W or Q4W. Endpoints included the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL and <50 copies/mL, incidence of confirmed virologic failure (CVF; 2 consecutive measurements ≥200 copies/mL), safety, and tolerability.
Results
A total of 1045 participants received CAB+RPV LA (Q8W, n = 522; Q4W, n = 523). CAB+RPV LA Q8W demonstrated noninferior efficacy versus Q4W dosing, with 2.7% (n = 14) and 1.0% (n = 5) of participants having HIV-1 RNA ≥50 copies/mL, respectively, with adjusted treatment difference being 1.7% (95% CI: 0.1–3.3%), meeting the 4% noninferiority threshold. At week 152, 87% of participants maintained HIV-1 RNA <50 copies/mL (Q8W, 87% n = 456; Q4W, 86% n = 449). Overall, 12 (2.3%) participants in the Q8W arm and 2 (0.4%) in the Q4W arm had CVF. Eight and 10 participants with CVF had treatment-emergent, resistance-associated mutations to RPV and integrase inhibitors, respectively. Safety profiles were comparable, with no new safety signals observed since week 48.
Conclusions
These data demonstrate virologic suppression durability with CAB+RPV LA Q8W or Q4W for ∼3 years and confirm long-term efficacy, safety, and tolerability of CAB+RPV LA as a complete regimen to maintain HIV-1 virologic suppression.
Cabotegravir+rilpivirine long-acting dosed every 8 weeks continued to be noninferior to every-4-week dosing over 152 weeks, with comparable safety profiles and no new safety signals since week 96. These data demonstrate durability of virologic suppression with cabotegravir+rilpivirine long-acting for nearly 3 years.
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.
Plain language summary
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.
Abstract
Background
Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for ...maintenance of virological suppression.
Objectives
To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352).
Methods
Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM every 4 weeks (Q4W), n = 3 or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM every 8 weeks (Q8W), n = 15 with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays.
Results
Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF.
Conclusions
A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.
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.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were ...expanded to include data beyond week 48, additional covariates, and additional participants.
Methods
Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population—baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination).
Results
Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses.
Conclusions
The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.
Confirmed virologic failure occurred in 1.4% of long-acting cabotegravir + rilpivirine participants up to 3 years on study. Having ≥2 baseline factors (rilpivirine resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and/or body mass index ≥30 kg/m2) was associated with increased failure risk, consistent with prior analyses.
Cabotegravir (CAB) is an integrase strand transfer inhibitor in development as a long-acting injectable formulation, with an oral formulation used during a safety lead-in period. Tuberculosis ...(TB)-HIV coinfection is common, often requiring simultaneous treatment. Rifabutin (RBT) is an alternative antimycobacterial agent for TB and a moderate inducer of cytochrome P450 and UDP-glucuronosyltransferase isoenzymes. This study evaluated the impact of RBT on the pharmacokinetics (PK) of oral CAB.
In this Phase I, single-centre, open-label, two-period, fixed-sequence, drug interaction study, subjects received oral CAB 30 mg once daily for 14 days in period 1, and oral CAB plus RBT 300 mg once daily for 14 days in period 2. Serial PK sampling was performed on days 14 and 28. Geometric least squares (GLS) mean ratios with associated 90% CIs were calculated to compare CAB noncompartmental PK parameters following CAB+RBT versus CAB alone. Safety was also assessed.
A total of 15 male subjects were enrolled and 12 completed all treatments. Comparing CAB+RBT with CAB alone, the GLS mean ratios (90% CIs) for CAB area under the concentration-time curve from time zero to the end of the dosing interval (AUC
), maximum observed plasma concentration (C
) and concentration at the end of the dosing interval (C
) were 0.79 (0.74, 0.83), 0.83 (0.76, 0.90) and 0.74 (0.70, 0.78), respectively. 11 subjects reported 24 adverse events (AEs); 22 were reported with CAB+RBT (3 drug-related) and 2 with CAB alone (not drug-related). All AEs resolved by study end.
RBT had a modest impact on plasma CAB exposure following oral coadministration, resulting in overall plasma CAB trough exposures above the 10 mg oral dose shown to maintain viral suppression in HIV-1-infected subjects. Oral CAB can be coadministered with RBT without dosage adjustment.
Objective
Whether concomitant HIV antiretroviral therapy (ART) affects the safety and efficacy of interferon‐free HCV therapies or whether HCV treatment may negatively affect HIV control is unclear. ...We assessed the 3 direct‐acting antiviral (3D) regimen of ombitasvir, ABT‐450 (identified by AbbVie and Enanta; co‐dosed with ritonavir) and dasabuvir with ribavirin (RBV) in HCV/HIV‐1 co‐infected patients with and without cirrhosis, including HCV treatment‐experienced, receiving atazanavir (ATV)‐ or raltegravir (RAL)‐based ART therapy.
Methods
HCV genotype 1‐positive treatment‐naïve or pegIFN/RBV‐experienced patients, with or without Child‐Pugh A cirrhosis, CD4+ count ≥200 cells/mm3 or CD4 + % ≥14%, and plasma HIV‐1 RNA suppressed on stable ART received open‐label 3D + RBV for 12 or 24 weeks. Rates of HCV‐sustained virologic response at post‐treatment weeks 4 and 12 (SVR4 and SVR12, respectively) and bilirubin‐related adverse events (AEs) are reported from post‐hoc analyses for subgroups defined by treatment duration and ART regimen.
Results
The SVR12 rate for patients receiving 12 weeks of 3D + RBV was 93.5% with comparable rates in patients receiving either ATV (93.8%) or RAL therapy (93.3%) (Table 1). The SVR4 rate for the 24‐week arm was 96.9% with a single virologic breakthrough at treatment week 16 in a patient receiving RAL therapy. Patients receiving concomitant ATV had more AEs related to indirect hyperbilirubinemia including ocular icterus, jaundice and grade 3 or 4 elevations in total bilirubin (predominantly indirect). No patient discontinued the study due to AEs, and no serious AEs were reported during or after treatment. No patient had a confirmed plasma HIV‐1 RNA value ≥200 copies/mL during the treatment period.
Conclusions
In this first study to evaluate an IFN‐free regimen in HCV genotype 1‐positive treatment‐naïve and experienced patients with HIV‐1 co‐infection, including those with cirrhosis, high rates of SVR were comparable to those with HCV monoinfection. Indirect hyperbilirubinemia was consistent with the known ABT‐450 inhibition of the OATP1B1 bilirubin transporter, RBV‐related haemolytic anaemia and inhibitory effect of ATV on bilirubin conjugation. The laboratory abnormalities and AEs observed did not negatively affect treatment response or lead to treatment discontinuation.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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