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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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Efficacy 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 Methods: Data 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., Results: Overall, 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)., Conclusion: CVF 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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: In the week 48 primary analysis of ECHO and THRIVE, rilpivirine demonstrated noninferior efficacy and more favourable tolerability versus efavirenz in treatment-naive, HIV-1-infected adults. Pooled 96-week results are presented., Methods: Patients (N = 1368) received rilpivirine 25 mg once-daily (q.d.) or efavirenz 600 mg q.d., with two background nucleoside/nucleotide reverse transcriptase inhibitors, in two randomized, double-blind, double-dummy Phase III trials., Results: At week 96, response rate (% confirmed viral load <50 copies/ml; intent-to-treat, time-to-loss-of-virologic response) was 78% in both groups. Responses were similar for both treatments by background regimen, sex, race, and in patients with more than 95% adherence (M-MASRI) or baseline viral load 100,000 copies/ml or less. Responses were lower and virologic failure higher for rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load more than 100,000 copies/ml. Beyond week 48, the incidence of virologic failure was comparable (3 versus 2%) between treatment groups, rilpivirine resistance-associated mutations were consistent with those observed in year 1, there were few adverse events in both groups and no new safety concerns. Over 96 weeks, discontinuations due to adverse events (4 versus 9%), treatment-related grade 2-4 adverse events (17 versus 33%), rash (4 versus 15%), dizziness (8 versus 27%) and abnormal dreams/nightmares (8 versus 13%), and grade 2-4 lipid abnormalities were lower with rilpivirine than efavirenz. Only 2 and 4% of patients in the rilpivirine and efavirenz treatment groups, respectively, reported at least possibly treatment-related grade 2-4 adverse events during the second year of treatment., Conclusions: Rilpivirine 25 mg q.d. and efavirenz 600 mg q.d. had comparable responses at week 96. Rilpivirine had more virologic failures but improved tolerability versus efavirenz. The majority of virologic failures occurred in the first 48 weeks.

Purpose of Review: Long-acting formulations of antiretrovirals have the potential to reshape the treatment paradigm for HIV infection. Emerging evidence demonstrates efficacy and safety of two drug regimens for the treatment of HIV infection. This review focuses on recent advances with long-acting cabotegravir and rilpivirine administered intramuscularly every 4 weeks for the treatment of HIV infection in virologically suppressed patients., Recent Findings: Despite the development of complete, orally administered single tablet regimens with improved efficacy, side effects, tolerability, with an improved drug interaction potential, patients still have challenges adhering to daily oral therapy. Psychological factors including HIV stigma contribute to patient's ability to adhere to treatment. Newer nonoral treatment regimens may improve adherence, patient satisfaction and limit HIV stigma., Summary: A two-drug intramuscular regimen of cabotegravir and rilpivirine has advanced through phase 3 clinical development. Results from studies assessing safety, virologic, pharmacologic, and drug interactions have been completed. Larger efficacy studies have demonstrated noninferiority of switching virologically suppressed patients from a three drug daily oral regimen to a two-drug intramuscular regimen administered Q4W with long-term data to 160 weeks demonstrating durability of treatment response.