Tenofovir alafenamide (TAF) is a novel oral prodrug of tenofovir (TFV) that at low doses achieves ~90% lower plasma TFV exposure and increased intracellular TFV-diphosphate (TFV-DP) levels compared with 300 mg of tenofovir disoproxil fumarate (TDF). An investigational fixed dose combination of emtricitabine (FTC) and TAF (200/25 mg) (FTC/TAF) is currently under regulatory review for HIV treatment. If FTC/TAF will be as effective as FTC/TDF for HIV pre-exposure prophylaxis (PrEP) is not known. We investigated in macaques the efficacy of FTC/TAF in preventing rectal SHIV infection to determine the potential use for PrEP.
The prophylactic efficacy of FTC/TAF was investigated using a repeat low virus dose macaque model that predicted efficacy of oral FTC/TDF in humans. Rhesus macaques (n = 12) were exposed rectally once a week to low (10 TCID50) doses of SHIV162p3 for up to 19 weeks. Animals were exposed to a first stock of SHIV162p3 for up to 5 weeks and to a second stock of the same virus isolate for up to 14 additional weeks. Six animals received FTC/TAF (20/1.5 mg/kg) orally 24h before each virus exposure and 2h thereafter and 6 received saline as a placebo. Infection was monitored by serology and RT-PCR. Intracellular TFV-DP and FTC-triphosphate (FTC-TP) concentrations in PBMCs were measured in FTC/TAF-treated animals at first dose and 7 and 14 weeks later to evaluate drug accumulation.
All 6 macaques that received FTC/TAF remained seronegative and viral RNA negative during the 19 virus challenges and a follow up period of 10 weeks. In contrast, all 6 placebo controls were SHIV RNA positive after a median of 8 (range = 1-15) exposures. The median (IQR) intracellular TFV-DP and FTC-TP concentrations in PBMCs at first dose were 554 (310, 870) fmols/106 cells and 1065 (912, 2459) fmols/106 cells, respectively. Levels accumulated approximately to 2-fold after 7 to 14 weeks of dosing (median 1365 (976, 1689) and 1626 (1311, 3252) fmols/106 cells of TFV-DP and FTC-TP, respectively).
We show that FTC/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with FTC/TDF but with a substantially reduced dose. As expected, low TAF doses result in high intracellular TFV-DP concentrations in PBMCs with levels that exceed those previously seen with oral TDF. Our results in macaques suggest that FTC/TAF may be a feasible alternative to FTC/TDF for PrEP against rectal HIV infection.