Background: Cabotegravir (CAB, GSK744) is an HIV INSTI under development as both an oral and long-acting (LA) injectable. LATTE was designed to select an oral dose of CAB and to evaluate a two-drug ART regimen with rilpivirine (RPV), as suppressive maintenance therapy.
Methods: Phase 2b, multicentre, partially-blinded, dose-ranging study in ART-naïve HIV infected adults, randomized 1:1:1:1 to the induction regimen of once daily oral CAB 10 mg, 30 mg, 60 mg or efavirenz (EFV) 600 mg with TDF/FTC or ABC/3TC through Week (W) 24, followed by a two-drug oral maintenance regimen of CAB (blinded dose) + RPV 25 mg through W96. CAB patients (pts) with a VL <50 c/mL immediately prior to W24 discontinued NRTIs and began RPV 25 mg; no change was made for EFV + NRTIs pts (ITT-Maintenance Exposed (ME)).
Results: 243 pts were randomized and treated (ITT-E): 96% male, 38% non-white, 14%>100,000 c/mL HIV-1 RNA, 61% TDF/FTC. Amongst pts who began CAB + RPV at W24, 86% had HIV-1 RNA <50 c/mL by snapshot at W96 overall, relative to 83% of pts continuing EFV (ITT-ME). Five protocol-defined virologic failures occurred during 72 weeks of Maintenance (CAB 10 mg [2], CAB 30 mg [1], EFV [2] including two on CAB + RPV with treatment emergent resistance [INI + NNRTI, NNRTI]). Drug-related AEs ≥ Grade 2 were reported by 14% and 19% of CAB and EFV pts, respectively with 4% and 4% occurring during the 72W Maintenance phase. SAEs occurred in 10% of CAB pts (none drug related); and 6% EFV pts (one drug-related – suicide attempt). Fewer CAB pts withdrew due to AEs (3%), than EFV pts (15%), mostly prior to the Maintenance phase. Treatment-emergent lab abnormalities ≥ Grade 3 occurred in 26% of CAB and 37% of EFV pts through W96, most commonly elevated creatine kinase. Rates of any graded ALT elevations were 20% with CAB and 21% with EFV.
Conclusions: When used as two-drug maintenance therapy in virologically suppressed pts, CAB + RPV provided similar antiviral activity to EFV+2 NRTIs through W96. CAB + RPV was well tolerated overall, with no SAEs considered drug related and few AEs leading to withdrawal. Considering all safety and efficacy data, oral CAB 30mg once-daily was selected for further development. Results support the selected dose regimens for the ongoing Ph2 LATTE-2 study with CAB LA + RPV LA as injectable two-drug maintenance therapy.
Snapshot Study Outcomes | CAB ⇥⇥⇥10 mg ⇥⇥⇥(n=60) |
CAB ⇥⇥⇥30 mg ⇥⇥⇥(n=60) |
CAB ⇥⇥⇥60 mg ⇥⇥⇥(n=61) |
CAB ⇥⇥⇥Subtotal ⇥⇥⇥(n=181) |
EFV ⇥⇥⇥Control ⇥⇥⇥(n=62) |
%<50c/mL at W96 Snapshot (ITT-E) (95%CI)++ | 41 (68%) ⇥⇥⇥(57%,80%) |
45 (75%) ⇥⇥⇥(64%,86%) |
51 (84%) ⇥⇥⇥(74%,93%) |
137 (76%) ⇥⇥⇥(69%,82%) |
39 (63%) ⇥⇥⇥(51%,75%) |
Protocol-defined Virologic Failure | 3 (5%) | 2 (3%) | 1 (2%) | 6 (3%) | 6 (10%) |
Failure due to Adverse Event | 1 (2%) | 1 (2%) | 4 (7%) | 6 (3%) | 9 (15%) |
Failure due to HIV-1 RNA ≥50 c/mLÂ¥ | 5 (8%) | 1 (2%) | 2 (3%) | 8 (4%) | 2 (3%) |
Failure due to Other Reasons While Not Suppressed+ | 2 (3%) | 2 (3%) | 1 (2%) | 5 (3%) | 3 (5%) |
Failure due to Other Reasons While Suppressed+ | 8 (13%) | 9 (15%) | 2 (3%) | 19 (10%) | 3 (5%) |
Other Results | |||||
<50 c/mL at W96 Snapshot (ITT-ME) | 41/52 ⇥⇥⇥(79%) |
45/53 ⇥⇥⇥(85%) |
51/55 ⇥⇥⇥(93%) |
137/160 ⇥⇥⇥(86%) |
39/47* ⇥⇥⇥(83%) |
Grade 2-4 Drug Related AEs | 5 (8%) | 8 (13%) | 13 (21%) | 26 (14%) | 12 (19%) |
Median Baseline CD4+ cells/mm3 (Change from Baseline at W96) | 415.0 ⇥⇥⇥(236.5) |
404.0 ⇥⇥⇥(249.5) |
420.0 ⇥⇥⇥(271.5) |
412.0 ⇥⇥⇥(259.5) |
416.5 ⇥⇥⇥(289.0) |
Â¥ HIV-1 RNA ≥50 c/mL reasons include HIV-1 RNA ≥50c/mL at Week 96 or discontinued while not suppressed (≥50 c/mL) for Lack of Efficacy ⇥⇥⇥+ Other reasons include missing data; protocol deviation, non-compliance, lost to follow-up, withdrawn consent, investigator discretion, ART change, and ineligible for Maintenance phase ⇥⇥⇥++W96 represents a 24 Week Induction phase followed by a 72 Week Maintenance phase ⇥⇥⇥*EFV pts with a W24 visit (n=47) ⇥⇥⇥Intent to Treat-Exposed (ITT-E) and Intent to Treat- Maintenance Exposed (ITT-ME) |