Background:  The efficacy of daily oral pre-exposure prophylaxis (PrEP) with Truvada for the prevention of HIV transmission is currently being evaluated in human clinical trials. There is increasing interest in intermittent PrEP (iPrEP) because of potential cost-effectiveness and lower risks of drug toxicity. We used a repeat-exposure macaque model to investigate if iPrEP given around the time of virus exposure is protective. We also explored the efficacy of intermittent post-exposure prophylaxis (PEP) initiated shortly after virus exposure.

Methods:  We evaluated 3 modalities of a 2-dose iPrEP regimen with Truvada in 6 male rhesus macaques by using an established rectal transmission model consisting of 14 weekly virus (simian HIV [SHIV]_162p3,10 TCID₅₀) exposures. Truvada at human equivalent dosing was delivered by oral gavage. Drug doses were given at different intervals relative to virus exposure:  2 groups of macaques received the 2 doses of Truvada over a 24-hour period, either 2 hours before and 22 hours after virus exposure (group I) or 22 hours before and 2 hours after exposure (group II). Group III received the first dose of Truvada 3 days before exposure and a second dose 2 hours after exposure. A fourth group of 6 macaques received 2 PEP doses 2 hours and 26 hours after exposure. Infection was monitored by serology and polymerase chain reaction (PCR) amplification of SHIV sequences from plasma and peripheral blood mononuclear cells (PBMC). The Cox proportional hazards model was used to estimate the risk of infection in treated animals relative to 27 untreated controls (6 real-time and 21 historical controls).

Results:  Of the 27 untreated macaques, 26 became infected after a median of 2 rectal exposures (range, 1 to 12). Of the 12 macaques that received the 2 Truvada doses over a 24-hour period, 3 of 6 from group I and 5 of 6 from group II were protected; the risk of infection was reduced by 3.9- (p = 0.029) and 15.9-fold (p = 0.007), respectively. Despite early administration of Truvada in group III animals, 5 of 6 macaques remained protected after 14 challenges with a reduction in the risk of infection of 14.5-fold (p = 0.01). The risk of infection was also significantly lower (3.8-fold) in group IV macaques that received a 2-dose PEP regimen (p = 0.033); 3 of the 6 animals remained protected after 14 challenges.

Conclusions:  Our results in a repeat-exposure macaque model suggest that effective PrEP with Truvada does not require daily dosing, define several highly protective iPrEP modalities, and support iPrEP efficacy trials in humans.