OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) 
injections fully protected macaques from vaginal simian HIV (SHIV) infection. 
Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone 
acetate and multiple sexually transmitted infections (STIs) that are known to 
increase HIV susceptibility in women.
DESIGN: Two macaque models of increasing vaginal STI severity were used for 
efficacy assessment.
METHODS: The first study (n = 11) used a double STI model that had repeated 
exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis. 
Six animals were CAB-LA treated and five were controls. The second study (n = 9) 
included a triple STI model with repeated exposures to C. trachomatis, T. 
vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate 
(DMPA). Six animals were CAB-LA treated and three were controls. All animals 
received up to 14 vaginal SHIV challenges. A survival analysis was performed to 
compare the number of SHIV challenges to infection in the drug-treated group 
compared with untreated controls over time.
RESULTS: All six CAB-LA treated animals in both models, the double STI or the 
triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, 
while the untreated animals became SHIV-infected after a median of two 
challenges (log-rank P < 0.001) or one challenge (log-rank P = 0.002), 
respectively. Both models recapitulated human STI disease, with vaginal 
discharge, ulcers, and seroconversion.
CONCLUSION: In these high and sustained susceptibility models spanning more than 
3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the 
CAB-LA dose used in clinical trials, and suggesting its insensitivity to 
multiple STIs and DMPA.