Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment.
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ABSTRACT: 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.
SUBMITTER: Swindells S
PROVIDER: S-EPMC8711605 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionCARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries.MethodsPSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted.ResultsOverall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations.ConclusionsPSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.
| S-EPMC11367594 | biostudies-literature
Project description:ObjectiveEfficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc.Design and methodsData from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination.ResultsOverall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated (P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35).ConclusionCVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.
| S-EPMC8270504 | biostudies-literature
Project description:Purpose of reviewCabotegravir (CAB) and rilpivirine (RPV) is the first long-acting injectable antiretroviral therapy (ART) option approved for virologically suppressed adults with HIV-1. In addition, long-acting CAB is a promising agent for HIV preexposure prophylaxis (PrEP). This review focuses on phase 3 clinical trial results and implementation considerations for these long-acting ART and PrEP strategies.Recent findingsLong-acting CAB and RPV administered every 4 weeks demonstrated noninferiority to oral ART through week 96 in both the ATLAS and FLAIR studies, whereas ATLAS-2M found similar efficacy through 96 weeks when the long-acting injectable ART was administered every 8 weeks instead of every 4 weeks. For prevention, two phase 3 trials were stopped early due to fewer incident HIV infections in participants receiving long-acting CAB every 8 weeks compared with daily oral tenofovir disoproxil fumarate-emtricitabine for PrEP. The long-acting therapies were well tolerated across all clinical trials.SummaryClinical trial results support the use of long-acting CAB for HIV PrEP and long-acting CAB and RPV as a switch strategy for adults with HIV-1 who are first virologically suppressed with oral ART. Implementation challenges persist, and data are urgently needed in populations who may benefit most from long-acting therapy, including adolescents, pregnant individuals, and those with barriers to medication adherence.
| S-EPMC8694245 | biostudies-literature
Project description:BackgroundAdvances in HIV-1 therapeutics have led to the development of a range of daily oral treatment regimens, which share similar high efficacy rates. Consequently, more emphasis is being placed upon the individual's experience of treatment and impact on quality of life. The first long-acting injectable antiretroviral therapy for HIV-1 (long-acting cabotegravir + rilpivirine [CAB + RPV LA]) may address challenges associated with oral treatment for HIV-1, such as stigma, pill burden/fatigue, drug-food interactions, and adherence. Patient-reported outcomes (PROs) collected in an HIV-1 clinical trial (ATLAS-2M; NCT03299049) comparing participants' experience with two dosing regimens (every 4 weeks [Q4W] vs. every 8 weeks [Q8W]) of CAB + RPV LA are presented herein.MethodsPRO endpoints evaluated through 48 weeks of therapy included treatment satisfaction (HIV Treatment Satisfaction Questionnaire [HIVTSQ]), treatment acceptance ("General Acceptance" domain of the Chronic Treatment Acceptance [ACCEPT®] questionnaire), acceptability of injections (Perception of Injection [PIN] questionnaire), treatment preference (questionnaire), and reasons for switching to/continuing long-acting therapy (exploratory endpoint; questionnaire). Participants were randomized 1:1 to receive CAB + RPV LA Q8W or Q4W. Results were stratified by prior CAB + RPV exposure in either preplanned or post hoc analyses.ResultsOverall, 1045 participants were randomized to the Q8W (n = 522) and Q4W (n = 523) regimens; 37% (n = 391/1045) had previously received CAB + RPV in ATLAS. For participants without prior CAB + RPV exposure, large increases from baseline were reported in treatment satisfaction in both long-acting arms (HIVTSQ status version), with Q8W dosing statistically significantly favored at Weeks 24 (p = 0.036) and 48 (p = 0.004). Additionally, improvements from baseline were also observed in the "General Acceptance" domain of the ACCEPT questionnaire in both long-acting arms for participants without prior CAB + RPV exposure; however, no statistically significant difference was observed between arms at either timepoint (Week 24, p = 0.379; Week 48, p = 0.525). Significant improvements (p < 0.001) in the "Acceptance of Injection Site Reactions" domain of the PIN questionnaire were observed from Week 8 to Weeks 24 and 48 in both arms for participants without prior CAB + RPV exposure. Participants with prior CAB + RPV exposure reported high treatment satisfaction (mean [HIVTSQ status version]: Q8W 62.2/66.0; Q4W 62.0/66.0), treatment acceptance (mean: Q8W 89.3/100; Q4W 91.2/100), and acceptance of injection site reactions (mean [5 = not at all acceptable; 1 = totally acceptable]: Q8W 1.72; Q4W 1.59) at baseline/Week 8 that were maintained over time. Participants without prior CAB + RPV exposure who received Q8W dosing preferred this regimen over oral CAB + RPV (98%, n = 300/306). Among those with prior Q4W exposure, 94% (n = 179/191) preferred Q8W dosing versus Q4W dosing (3%, n = 6/191) or oral CAB + RPV (2%, n = 4/191).ConclusionsBoth long-acting regimens provided high treatment satisfaction and acceptance, irrespective of prior CAB + RPV exposure, with most participants preferring Q8W dosing over both the Q4W regimen and their previous daily oral regimen. The PRO data collected at Week 48 support the therapeutic potential of CAB + RPV LA.FundingViiV Healthcare and Janssen.Trial registrationATLAS-2M: ClinicalTrials.gov NCT03299049, registered October 2, 2017.
| S-EPMC8563641 | biostudies-literature
Project description:Abstract Background Switching to cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) administered every month (Q1M) has demonstrated non-inferiority in viral suppression versus a range of standard of care (SoC) antiretroviral regimens, including tenofovir alafenamide based regimens, in two pivotal phase 3 clinical trials (ATLAS [NCT02951052] and FLAIR [NCT02938520]). Furthermore, CAB LA + RPV LA every 2 months (Q2M) has demonstrated non-inferiority in maintaining viral suppression compared with CAB LA + RPV LA Q1M in a phase 3b study (ATLAS-2M [NCT03299049]). As bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was not widely used at study initiation, the regimen was not present in the SoC arms of ATLAS and FLAIR. The objective was to compare efficacy and safety of CAB LA + RPV LA Q2M to BIC/FTC/TAF using indirect treatment comparison. Methods Two switch studies appropriate for facilitating indirect comparison to BIC/FTC/TAF were identified via systematic literature review (Molina et al. 2018 [NCT02603120] and Sax et al. 2020 [NCT03110380]). Indirect comparison using a generalisation of Bucher’s methodology to calculate relative risk, odds ratio, and risk differences in efficacy (Week 48 HIV RNA < 50 c/mL and ≥50 c/mL per FDA Snapshot approach and CD4+ cell change from baseline) and safety (discontinuation due to adverse events [AEs] and overall and serious AEs excluding injection site reactions [ISRs]) was conducted. Results for CAB LA + RPV LA Q2M in ATLAS-2M participants with prior integrase inhibitor (INI) exposure, but without prior CAB exposure, were indirectly compared to those with prior INI use in ATLAS and FLAIR via the common CAB LA + RPV LA Q1M comparator and were then indirectly compared to BIC/FTC/TAF via the INI comparator (Figure 1). Results No statistically significant differences in virologic failure, virologic suppression, CD4+ cell change, discontinuations due to AEs, and non-ISR serious/non-serious AEs were found between CAB LA + RPV LA Q2M and BIC/FTC/TAF (Table 1). Conclusion Indirect treatment comparison indicated efficacy and safety of CAB LA + RPV LA Q2M is not different from BIC/FTC/TAF. These regimens will be further compared in a randomized head-to-head non-inferiority trial (SOLAR, NCT04542070). Disclosures Sonya J. Snedecor, PhD, ViiV Healthcare (Other Financial or Material Support, Author’s employer, OPEN Health received funding to execute this study) Melanie Schroeder, MSc, ViiV Healthcare (Employee) Nicolas Van de Velde, PhD, ViiV Healthcare (Employee)
| S-EPMC8644599 | biostudies-literature
Project description:BackgroundLong-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.ObjectivesTo 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).MethodsEighteen 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.ResultsMedian 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.ConclusionsA dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.
| S-EPMC7021098 | biostudies-literature
Project description:The retrovirus HIV-1 is the etiological agent of the decades-long AIDS pandemic. Although vaccination is the most common preexposure route to prevent acquisition of viral disease, scalable efficacious vaccination strategies have yet to be developed for HIV-1. By contrast, small molecule inhibitors of the HIV-1 enzymes reverse transcriptase, integrase, and protease have been developed that effectively block virus replication. Three different drug compounds are commonly prescribed for people living with HIV as once-daily oral tablets. Once-daily pills composed of two different reverse transcriptase inhibitors are moreover approved as preexposure prophylaxis (PrEP) treatment for virus naïve individuals who may partake in behaviors associated with increased risk of HIV-1 acquisition such as unprotected sex or injection drug use. Long-acting (LA) injectable HIV-1 enzyme inhibitors are at the same time being developed to sidestep adherence noncompliance issues that can arise from self-administered once-daily oral dosing regimens. Cabotegravir (CAB)-LA, which inhibits integrase strand transfer activity, has in recent clinical trials been shown to prevent HIV-1 acquisition more effectively than once-daily oral dosed reverse transcriptase inhibitors. In this Perspective, we examine bench to bedside aspects of CAB-LA treatment and development, starting from the biochemical basis of HIV-1 integration and pharmacological inhibition of integrase catalysis. We also review the results of recent clinical trials that evaluated CAB-LA, as well as the promises and challenges that surround its use for HIV/AIDS PrEP.
| S-EPMC8515172 | biostudies-literature
Project description:BackgroundThe use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction.MethodsWe used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective.FindingsIn our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of $120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced.InterpretationOur modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives.FundingBill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655).
| S-EPMC8050198 | biostudies-literature
Project description:ObjectivesLong-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).DesignA Phase 2b, multicenter, open-label, rollover study.MethodsLATTE 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.ResultsOf 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.ConclusionCAB+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.
| S-EPMC8711606 | biostudies-literature
Project description:BACKGROUND AND OBJECTIVES:Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling. METHODS:Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. RESULTS:Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. CONCLUSIONS:The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.
| S-EPMC5701864 | biostudies-literature