Background:  Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs is a promising HIV prevention strategy and its efficacy is being evaluated in humans. Acute infection in persons who fail PrEP will inevitably occur under concurrent therapy, thus raising questions regarding the potential impact of PrEP on early viral dynamics and evolution. We investigated acute viremias and virus evolution rates in a macaque PrEP model of rectal simian/human immunodeficiency virus (SHIV) infection.

Methods:  Peak viremias were measured in 35 rhesus macaques infected rectally with SHIV162p3. Of these animals, 6 were infected during daily PrEP with emtricitabine (FTC) or tenofovir/emtricitabine (TNV/FTC), 7 were infected during intermittent PrEP with TNV/FTC, and 22 were untreated controls. env sequence evolution was monitored by single genome amplification in 2 untreated controls and 4 PrEP failures that continued treatment for 13 to 28 weeks after infection. For each animal, a total of 20 to 30 env sequences (V1-V5) were obtained both at peak viremia and during 18 to 29 weeks. None of the specimens had reverse transcriptase drug resistance mutations.

Results:  Peak viremias in daily (median = 4.9 log₁₀ RNA copies/mL; min, max = 3.5, 7.1) or intermittent PrEP failures (median = 5.6; min, max = 3.2, 6.6) were significantly lower than in untreated controls (median = 7.2 log₁₀; min, max = 5.3, 8.9) (p = 0.007 and p = 0.008, respectively). Analysis of env sequences from 4 PrEP failures and 2 untreated controls showed evidence of infection by a single variant in all cases. Mean nucleotide divergence from SHIV162p3 was significantly lower in PrEP failures than in control animals both at peak viremia (0.04 and 0.1 substitutions per site, respectively, p <0.005) and after 18 to 29 weeks (0.27 and 0.77 substitutions per site, respectively, p <0.005). Maximum env diversity in PrEP failures was 0.26% compared to 1.07% in untreated control animals. Overall virus diversity was lower in PrEP failures both at peak viremia (0.025% vs 0.049% in controls, p <0.005) and after 18 to 29 weeks (0.13% vs 0.83% in controls, p <0.005).

Conclusions:  We show in macaques that PrEP with FTC or TNV/FTC significantly limits env sequence evolution during early infection, likely reflecting the antiviral activity of drugs in reducing virus replication. Decreased acute viremia and limited virus evolution may reduce early CD4 depletion and potentially enhance immune control by slowing the selection of escape mutants.