Switch to INSTI and NNRTI in LATTE-2 Study
The LATTE-2 Study explores switching to INSTI and NNRTI therapies for HIV treatment. The study evaluates the efficacy and safety of Cabotegravir and Rilpivirine injections versus oral regimens, focusing on maintaining HIV RNA levels below 50 c/mL. Key findings include high virologic success rates and non-inferiority of the intramuscular regimens compared to oral Cabotegravir. The study aims to confirm dosing schedules for Phase III trials and ensure patient safety.
Download Presentation
Please find below an Image/Link to download the presentation.
The content on the website is provided AS IS for your information and personal use only. It may not be sold, licensed, or shared on other websites without obtaining consent from the author. If you encounter any issues during the download, it is possible that the publisher has removed the file from their server.
You are allowed to download the files provided on this website for personal or commercial use, subject to the condition that they are used lawfully. All files are the property of their respective owners.
The content on the website is provided AS IS for your information and personal use only. It may not be sold, licensed, or shared on other websites without obtaining consent from the author.
E N D
Presentation Transcript
Switch to INSTI + NNRTI Switch to DTG + RPV SWORD Study Switch to CAB LA + RPV LA IM LATTE-2 Study
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Design Randomisation 2 : 2 : 1 Maintenance Induction (oral) (if HIV RNA < 50 c/mL at W-4 and Day 1) ARV naive > 18 years CAB 600 mg IM + RPV 900 mg IM Q8W * (N = 115) HIV RNA > 1 000 c/mL CD4 > 200/mm3 HBs Ag negative ALT < 5 UNL Creatinine clearance > 50 mL/min CAB 30 mg QD + ABC/3TC CAB 400 mg IM + RPV 600 mg IM Q4W ** (N = 115) (N = 309) CAB 30 mg QD + ABC/3TC QD (oral) (N = 56) W-20 W-4 D1 W32 W48 W96 addition of RPV 25 mg QD oral * CAB IM, loading dose 800 mg at D1 and 600 mg at W4 ** CAB IM, loading dose 800 mg at D1 Q8W: injection every 8 weeks ; Q4W: injection every 4 weeks Induction phase: HIV RNA < 50 c/mL (ITT-E) after 20 weeks = 91.3 % ; discontinuation in 18/309 patients, including 6 for adverse event and 2 for lack of efficacy Objective Primary: % HIV RNA < 50 c/mL at W32 of maintenance phase: selection of dosing schedule for phase III studies (confirmation of dose on W48 analysis) ; safety Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Baseline characteristics (ITT-maintenance exposed) and patient disposition Q8W IM N = 115 Q4W IM N = 115 Oral CAB N = 56 Median age, years 35 36 35 Female, % 7 5 18 White / African American, % 81 / 15 82 / 10 70 / 27 CDC Class C, % < 1 2 0 HIV RNA, log10c/mL, median CD4 cell count (/mm3), median Discontinuation by W48, N (%) For lack of efficacy, N For adverse event, N Withdrew consent / other Discontinuation between W48 and W96, N For adverse event, N Withdrew consent, N 4.42 4.46 4.29 449 499 518 4 (3.5%) 1 1 1 / 1 1 0 1 11 (9.6%) 0 7 1 / 3 3 1 2 6 (10.7%) 1 1 2 / 2 3 0 3 Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Primary endpoint: HIV RNA < 50 c/mL at W32 (snapshot analysis, ITT-ME) % 95 94 91 100 Q8W IM (N = 115) Q4W IM (N = 115) CAB oral (N = 56) Difference (95% CI) Oral Intramuscular 80 Q8W 60 3.7 - 4.8 12.2 40 + 10% 10% 20 Q4W 5 5 4 4 < 1 < 1 2.8 0 Virologic success Virologic Non response No virologic data 11.5 - 5.8 0 + 10% 10% Non inferiority of the 2 IM regimens vs oral CAB Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM HIV RNA < 50 c/mL at W48 and W96 (snapshot analysis, ITT-ME) W48 W96 Q8W IM (N = 115) Q4W IM (N = 115) Oral (N = 56) Difference, % (95% CI) % Oral Intramuscular 94 92 100 91 89 8784 Q8W 2.9 W48 12.6 80 10 - 6.6 W96 - 0.6 20.5 60 10 % + 10 % Q4W 40 13 14 2.0 W48 11.6 - 7.6 9 8 20 7 3.0 14.4 W96 4 2 2 - 8.4 2 < 1 < 1 0 0 10 % + 10 % Virologic success Virologic non response No virologic data 0 Non inferiority of the 2 IM regimens vs oral CAB, at W48 and W96 Lower performance of Q4W (vs Q8W) at W96 due to more discontinuations for AE (9 vs 1) Protocol-defined virologic failure: 1 in oral arm (no resistance), 2 in Q8W arm (emergence of resistance at failure: K103N, E138G, K238T (NNRTI) and Q148R (INSTI) in 1, R269R/G in 1 Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Virologic non response and no data in window (snapshot analysis at W96) Q8W IM, N = 115 2 Q4W IM, N = 115 Oral, N = 56 HIV RNA in window not < 50 c/mL 1 patient with HIV RNA 87 c/mL at W96; 1 patient with repeated blips then failure (HIV RNA: 90-151 c/mL between W72-W96) 0 0 Discontinuation for lack of efficacy 1 (rebound > 400 c/mL at W4) 0 1 2 Discontinuation for other reason, while HIV RNA not < 50 c/ml 56 c/mL at W4 with injection intolerance ; HIV RNA > 400 c/mL at W48, physician decision 1 0 0 Discontinuation for AE Discontinuation for other reason 9 *, (7/9 before W48) 2 ** (at W36) 1 5 *** 6 **** Missing data during window but on study 1 (HIV RNA < 40 c/mL at all visits) 0 0 * Rash, N = 1, liver stopping criteria, N = 1, QT prolongation, N = 1, mesenteric vein thrombosis, N = 1, Churg-Strauss vasculitis, N = 1, epilepsy leading to death, N = 1, psychosis, N = 1, depression, N = 1, hepatitis C, N = 1 ** Acute hepatitis C, N = 1, liver stopping criteria, N = 1 *** Withdrawal by subject, N = 3 ; protocol deviation, N = 2 **** Withdrawal by subject, N = 5 ; lost to follow-up, N = 1 Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Adverse events and laboratory abnormalities (ITT, maintenance period D0-W96), % Q8W IM (N = 115) Q4W IM (N = 115) Oral (N = 56) Drug-related adverse events, excluding ISRs Pyrexia Headache Influenza-like illness Fatigue 3 3 3 2 6 3 3 3 0 4 0 2 Grade 3-4 adverse event, excluding ISRs Drug-related 11 2 * 16 4 ** 7 2 Serious adverse event (none drug-related) 10 10 13 Adverse event leading to withdrawal 2 7 2 Grade 3 and 4 laboratory abnormalities 19 29 21 Injection site reactions (ISR) *** D1 W8 W48 W96 85 48 37 31 88 40 30 28 - * Influenza-like illness, N = 1, chills and pain, N = 1 ** Influenza-like illness, N = 1, rash, N = 1, depression, N = 1, QT prolongation, N = 1 *** ISR = pain (66%), nodules (8%), swelling( 6%), pruritus (6%), resolved < 7 days: 89% Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Overall injection site reaction incidence, by visit Day 1-Day 96 (% patients with ISR) 100 8488 Q8W IM Q4W IM 80 57 60 50 46 4640 45 3842 38 37 40 35 2933 35 32 31 31 3128 31 30 30 29 29 28 20 0 Day 1 W4 W8 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W64 W72 W96 Subjects at visit 115 115 114 113 112 112 111 111 110 109 109 Q8W IM 115 115 115 114 112 111 109 109 107 107 105 105 104 102 103 101 Q4W IM 99% of ISRs were mild (84%) or moderate (15%) Median duration was 3.0 days in both groups, and 89% resolved within 7 days Most common ISR events : pain (66%), nodules (8%), swelling (6%) and pruritus (6%) The number of subjects reporting ISRs decreased over time, from 86% (D1) to 35% (W48) and 30% (W96) 2/230 subjects (< 1%) withdrew as a result of injection reactions (both in Q8W group) Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Pharmacokinetics (mean + SD plasma concentration ( g/mL) 100 1 000 CAB RPV PA-IC90 25 mg PO C Q4W Q8W Q4W Q8W 10 100 1 PA-IC90 10 mg PO C 30 mg PO C Q8W: 7/9 patients with virological non-response at W48 had RPV C in the lowest 25th quartile 0,1 10 0 1 4 8 12 16 20 24 28 32 36 40 44 48 0 1 4 8 12 16 20 24 28 32 36 40 44 48 Week Week Q8W Q4W Oral Q8W Q4W Mean (95% CI) C at W48 Mean (95% CI) C at W48 2.58 1.46 94.64 64.48 4.47 (3.9 - 5.2) (2.4 - 2.8) 16 (1.3 - 1.6) 19 (86.6 - 103.4) 8 (60.0 - 69.3) 5 27 x times PA-IC90 x times PA-IC90 C , trough concentration ; PA-IC90, protein binding-adjusted 90% inhibitory concentration Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Patient reported-outcomes (HIV Treatment satisfaction questionnaire, status version) % % 2 2 100 100 < 1 1 < 1 3 2 4 10 14 4 7 15 9 21 80 80 11 60 60 35 40 40 20 20 76 85 76 88 89 43 0 0 Q4W (N = 100) Q8W (N = 108) Q4W (N = 100) Q8W (N = 108) Oral CAB + ABC/3TC (N = 46) Oral CAB + ABC/3TC (N = 46) IM CAB LA + RPV LA IM CAB LA + RPV LA 6 5 4 3 2 1 0 Very satisfied Very dissatisfied Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM Conclusion LATTE-2 results successfully demonstrate ability to maintain HIV-1 RNA < 50 c/mL with IM CAB + RPV LA, dosed every 4 or 8 weeks Three subjects met PDVF criteria during maintenance Q8W (N = 2), oral CAB (N = 1) ; one Q8W subject with emergent RPV and CAB resistance, and one Q8W subject with minor INSTI mutation emergence Injection tolerability Majority of ISRs were grade 1 to 2 pain, with a median duration of 3 days Few subjects had an ISR that led to discontinuation, with higher rate in Q4W group High overall reported satisfaction Dose selection Q4W dosing resulted in lower rates of virologic non-response with similar safety to Q8W Q4W dosing was selected for pivotal phase III studies Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510. LATTE-2
