Switch to INSTI + NNRTI

In the field of HIV treatment, switching to integrase strand transfer inhibitors (INSTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) has been studied extensively. The SWORD Study examined the switch to dolutegravir (DTG) plus rilpivirine (RPV) while the LATTE-2 Study focused on the switch to cabotegravir (CAB) long-acting injection with RPV long-acting injection. Both studies evaluated virologic outcomes and safety in HIV patients. The FLAIR Study investigated the use of cabotegravir and rilpivirine for maintenance therapy in ARV-naive patients older than 18 years, providing insights into efficacy, safety, and patient preferences.

• HIV treatment
• SWORD Study
• LATTE-2 Study
• FLAIR Study
• ARV therapy

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Uploaded on Feb 20, 2025 | 0 Views

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1. Switch to INSTI + NNRTI Switch to DTG + RPV SWORD Study Switch to CAB LA + RPV LA IM LATTE-2 Study FLAIR ATLAS

2. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Design Randomisation 1:1 Induction Maintenance Extension ARV naive > 18 years DTG/ABC/3TC (N = 283) CAB LA + RPV LA IM Q4W DTG/ABC/3TC HIV RNA > 1 000 c/mL Any CD4 HBs Ag negative No NNRTI RAMs (K103N allowed) (N = 629) Oral CAB + RPV (N = 283) CAB LA 400 mg + RPV LA 600 mg * IM every 4 weeks (N = 278) W-20 W-4 D1 W4 W32 W48 W96 Confirm * Loading dose at W4: CAB 600 mg + RPV 900 mg HIV RNA < 50 c/mL If HLA-B*5701 positive: 2 alternative non-ABC NRTI allowed Objective Primary: % HIV RNA 50 c/mL at W48 of maintenance phase with monthly IM CAB LA + RPV LA (ITT, snapshot algorithm) ; non-inferiority if upper margin of a two-sided 95% CI for the difference = 6% Secondary: HIV RNA < 50 c/mL at W48, safety, resistance emergence, PRO, participant s preference of the LA regimen, W96 efficacy and safety FLAIR Orkin C. CROI 2019, Abs. 140LB

3. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Baseline characteristics (ITT-maintenance exposed) and patient disposition DTG/ABC/3TC N = 283 CAB LA + RPV LA N = 283 W-20 characteristics Median age, years 34 34 Female, % 23 22 White / Black or African American, % 71 / 20 76 / 17 80 / 20 80 / 20 HIV RNA, copies/mL: < 100 000 / 100 000, % CD4 cell count/mm3 median < 200/mm3, % 452 8 437 6 HCV co-infection, % 3 7 D1: CD4 cell count/mm3, median 625 624 Discontinuation D1-W48, N (%) For adverse event For other reasons 12 (4.2) 2 10 12 (4.2) 8 2 Orkin C. CROI 2019, Abs. 140LB FLAIR

4. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Virologic outcome at W48 (snapshot analysis, ITT-E) Difference * (95% CI) CAB LA + RPV LA (N = 283) Primary endpoint: HIV RNA 50 c/mL DTG/ABC/3TC (N = 283) CAB LA + RPV LA DTG/ABC/3TC % 100 93.6 93.3 -0.4 - 2.8 2.1 80 + 6% 10% 0 60 Secondary endpoint HIV RNA < 50 c/mL DTG/ABC/3TC CAB LA + RPV LA 40 0.4 20 - 3.7 4.5 4.2 4.2 2.1 2.5 + 10% 10% 0 0 * Adjusted for gender and baseline HIV RNA (< vs 100 000 c/mL) HIV RNA 50 c/mL Virologic success HIV RNA < 50 c/mL No virologic data Non inferiority achieved for primary and secondary endpoints Orkin C. CROI 2019, Abs. 140LB FLAIR

5. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Confirmed virologic failures (CVF) Defined as 2 consecutive HIV RNA 200 c/mL DTG/ABC/3TC, N = 3 (W8, W12, W16): no emergence of resistance CAB LA + RPV LA, N = 3 Confirmed virologic failures, CAB LA + RPV LA arm (N = 3) Baseline plasma genotype RAMs Plasma genotype RAMs at SVF Sex, Country, HIV subtype, Baseline HIV RNA (c/mL) Suspected VF (SVF) HIV RNA (c/mL) SVF / CVF Fold change in sensitivity at SVF NNRTI NNRTI INSTI INSTI RPV 7.1 CAB 5.2 DTG 1.0 RPV 2.6 CAB 6.7 DTG 1.0 RPV 1.0 CAB 9.4 DTG 1.1 L74I, Q148R F, Russia, A1, 54 000 373 / 456 E138E/A/K/T None L74I W20 L74I, G140R M, Russia, A1, 23 000 287 / 299 K101E None L74I W28 L74I, Q148R F, Russia, A1, 20 000 488 / 440 E138K None L74I W48 Plasma CAB and RPV concentrations at the time of failure were below the population means Orkin C. CROI 2019, Abs. 140LB FLAIR

6. 103 FLAIR Study: LA cabotegravir + rilpivirine for maintenance Plasma CAB and RPV trough concentrations (median, 5thand 95thpercentiles) RPV (ng/mL), N = 278 CAB ( g/mL), N = 278 10 100 1 PA-IC90 (12 ng/mL) 10 PA-IC90 (0.166 g/mL) 0,1 4 8 12 16 20 24 28 32 36 40 44 Week 48 4 8 12 16 20 24 28 32 36 40 44 48 Week Orkin C. CROI 2019, Abs. 140LB FLAIR

7. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Adverse events by W48 DTG/ABC/3TC N = 283 CAB LA + RPV LA N = 283 Adverse event in 10% of participants, % Nasopharyngitis Headache Upper respiratory tract infection Diarrhea Drug-related adverse event in 3% of participants, % Any Headache Pyrexia Adverse event leading to discontinuation, % 17 7 10 9 20 14 13 11 10 1 0 1 28 5 5 3 (2 due to ISR pain) Day 1- W72 : ISR events, % of injections NA 28.6 Day 1- W72 : Nature of ISR events, % Pain (grade 3) Nodule Induration Swelling Warmth Over time, incidence of ISR decreased (from 71% at W4 to 20% at W48) 99% of ISR were grade 1-2 and most (88%) resolved within 7 days (median : 3 days) 85.3 (0.6) 3.9 3.7 1.7 1.7 NA Orkin C. CROI 2019, Abs. 140LB FLAIR

8. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Patient reported outcomes Change in satisfaction with current treatment vs induction phase treatment (HIVTSQc at W48), mean total score LA CAB + RPV: 29.6/33 DTG/ABC/3TC: 25.5/33 (p < 0.001) Participant preference at W48 Preferred LA: 91% Preferred daily oral therapy: 1% Orkin C. CROI 2019, Abs. 140LB FLAIR

9. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Treatment satisfaction (HIVTSQc Questionnaire) Overall treatment acceptance (ACCEPT Questionnaire) CAB + RPV LA DTG/ABC/3TC Adjusted mean change (SD) from baseline Adjusted mean change (SD) from baseline % 0 Improvement 33 (max) 100 86.0 88.5 89.1 85.4 87.9 83.8 85.6 83.4 80 N = 263 29.6 Difference (95% CI): 4.1 (2.8-5.5) ; p < 0.001 60 N = 266 40 25.5 20 N = 258 267 272 269 280 278 280 280 NB: HIVTSQs at randomization = 59/66 0 D1 maintenance W8 W24 W48 Murray M, IAS 2019, Abs. MOPEB258 FLAIR

10. 50 FLAIR Study: LA cabotegravir + rilpivirine for maintenance Acceptability of injection site reaction and pain % 3 5 < 1 1 1 1 Totally acceptable 100 2 11 3 12 3 11 6 4 14 11 Very acceptable 16 80 29 24 Moderately acceptable 31 35 35 29 60 A little acceptable 28 Not at all acceptable 40 57 55 49 47 45 20 33 0 ISR Pain ISR Pain ISR Pain W5 W41 W48 Participants with ISR % 100 80 71 60 43 38 34 33 40 32 31 29 27 27 24 20 20 0 4 8 12 16 20 24 28 32 36 40 44 48 Loading dose Weeks Murray M, IAS 2019, Abs. MOPEB258 FLAIR

11. FLAIR Study: LA cabotegravir + rilpivirine for maintenance Conclusion IM injections of CAB LA + RPV LA every 4 weeks was non inferior to daily oral DTG/ABC/3TC at W48 For proportion of virologic rebound: HIV RNA 50 c/mL in 2.1% vs 2.5% For proportion maintaining HIV-1 suppression Three participants in each arm experienced confirmed virologic failure No emergence of resistance in DTG/ABC/3TC arm Emergence of both NNRTI and INSTI resistance-associated mutations in 3/3 in LA arm, all had HIV-1 subtype A1 Injection site reactions in the LA arm were common but mainly grade 1 or 2, with few associated discontinuations Highly positive treatment satisfaction and preference outcomes with LA regimen Orkin C. CROI 2019, Abs. 140LB FLAIR