Objectives: This study evaluated the relationship between intracellular tenofovir diphosphate concentrations in peripheral blood mononuclear cells and prophylactic efficacy in a macaque model for HIV pre-exposure prophylaxis (PrEP).
Methods: Macaques were challenged with simian HIV (SHIV) via rectal inoculation once weekly for up to 14 weeks. A control group (n=34) received no drug, a second group (n=6) received oral tenofovir disoproxil fumarate/emtricitabine 3 days before each virus challenge and a third group (n=6) received the same dosing plus another dose 2 h after virus challenge. PBMCs were collected just before each weekly virus challenge. The relationship between tenofovir diphosphate in PBMCs and prophylactic efficacy was assessed with a Cox proportional hazards model.
Results: The percentages of animals infected in the control, one-dose and two-dose groups were 97, 83 and 17, respectively. The mean (SD) steady-state tenofovir diphosphate concentration (fmol/10(6) cells) was 15.8 (7.6) in the one-dose group and 30.7 (10.1) in the two-dose group. Each 5 fmol tenofovir diphosphate/10(6) cells was associated with a 40% (95% CI 17%-56%) reduction in risk of SHIV acquisition, P=0.002. The tenofovir diphosphate concentration associated with a 90% reduction in risk (EC90) was 22.6 fmol/10(6) cells (95% CI 13.8-60.8).
Conclusions: The prophylactic EC90 for tenofovir diphosphate identified in macaques exposed rectally compares well with the EC90 previously identified in men who have sex with men (MSM; 16 fmol/10(6) cells, 95% CI 3-28). These results highlight the relevance of this model to inform human PrEP studies of oral tenofovir disoproxil fumarate/emtricitabine for MSM.
Keywords: HIV pre-exposure prophylaxis; intracellular pharmacology; non-human primate model; nucleoside analogues; pharmacodynamics.
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