Week 96 Extension Results of a Phase 3 Study Evaluating Long-Acting Cabotegravir with Rilpivirine for HIV-1 Treatment

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

Evaluation of Inflammation and Atherogenesis Biomarkers Through 148 Weeks Postswitch to Dolutegravir and Rilpivirine in SWORD-1/SWORD-2

Background: Switching to the 2-drug regimen dolutegravir + rilpivirine demonstrated noninferiority vs continuing a 3-drug or 4-drug current antiretroviral regimen (CAR) at week 48 and maintained high levels of virologic suppression to week 148 in the SWORD studies. We report inflammation and atherogenesis biomarkers postswitch to dolutegravir + rilpivirine. Setting: SWORD-1: 65 centers, 13 countries; SWORD-2: 60 centers, 11 countries. Methods: Virologically suppressed adults were randomized to switch to dolutegravir + rilpivirine (early-switch group; n = 513) or continue CAR (n = 511). Participants continuing CAR switched to dolutegravir + rilpivirine at week 52 (late-switch group; n = 477). Biomarkers were evaluated from Baseline to week 48 for dolutegravir + rilpivirine and CAR and noncomparatively for dolutegravir + rilpivirine postswitch through 148 weeks (early-switch) and 96 weeks (late-switch). Results: Through week 48, changes in biomarkers did not significantly differ between dolutegravir + rilpivirine and CAR groups, except for increases in soluble CD14 and decreases in fatty acid–binding protein-2, which favored dolutegravir + rilpivirine. For inflammation biomarkers through week 148, there was no marked change in C-reactive protein, inconsistent changes in soluble CD14 and interleukin-6, and increases in soluble CD163. For atherogenesis biomarkers through week 148, fatty acid–binding protein-2 and soluble vascular cell adhesion molecule-1 showed sustained reductions; D-dimer showed inconsistent increases between early-switch vs late-switch groups. Conclusions: No consistent pattern of change in biomarkers postswitch to dolutegravir + rilpivirine was observed through weeks 48 and 148 in SWORD-1/SWORD-2, suggesting no association of increased inflammation or atherogenesis with the 2-drug regimen while maintaining virologic suppression

Brief Report: Evaluation of Inflammation and Atherogenesis Biomarkers Through 148 Weeks Postswitch to Dolutegravir and Rilpivirine in SWORD-1/SWORD-2.

Switching to the 2-drug regimen dolutegravir + rilpivirine demonstrated noninferiority vs continuing a 3-drug or 4-drug current antiretroviral regimen (CAR) at week 48 and maintained high levels of virologic suppression to week 148 in the SWORD studies. We report inflammation and atherogenesis biomarkers postswitch to dolutegravir + rilpivirine. SWORD-1: 65 centers, 13 countries; SWORD-2: 60 centers, 11 countries. Virologically suppressed adults were randomized to switch to dolutegravir + rilpivirine (early-switch group; n = 513) or continue CAR (n = 511). Participants continuing CAR switched to dolutegravir + rilpivirine at week 52 (late-switch group; n = 477). Biomarkers were evaluated from Baseline to week 48 for dolutegravir + rilpivirine and CAR and noncomparatively for dolutegravir + rilpivirine postswitch through 148 weeks (early-switch) and 96 weeks (late-switch). Through week 48, changes in biomarkers did not significantly differ between dolutegravir + rilpivirine and CAR groups, except for increases in soluble CD14 and decreases in fatty acid-binding protein-2, which favored dolutegravir + rilpivirine. For inflammation biomarkers through week 148, there was no marked change in C-reactive protein, inconsistent changes in soluble CD14 and interleukin-6, and increases in soluble CD163. For atherogenesis biomarkers through week 148, fatty acid-binding protein-2 and soluble vascular cell adhesion molecule-1 showed sustained reductions; D-dimer showed inconsistent increases between early-switch vs late-switch groups. No consistent pattern of change in biomarkers postswitch to dolutegravir + rilpivirine was observed through weeks 48 and 148 in SWORD-1/SWORD-2, suggesting no association of increased inflammation or atherogenesis with the 2-drug regimen while maintaining virologic suppression

Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC(24h), C(max), and C(min) of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC12

Efficacy, Safety, and Tolerability of Dolutegravir-Rilpivirine for the Maintenance of Virological Suppression in Adults with HIV-1: Phase 3, Randomised, Non-Inferiority SWORD-1 and SWORD-2 Studies

International audienc

Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With HIV-1 Infection: ~5-Year Results From the LATTE-2 Study

Background. In the Long-Acting Antiretroviral Treatment Enabling Trial 2 (LATTE-2) phase 2b study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or every 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with human immunodeficiency virus type 1 (HIV-1). Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over approximately 5 years. Methods. After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA 1 participant. Conclusions. Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection