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  Conference on Retroviruses
and Opportunistic Infections (CROI)
Boston, Massachusetts
March 4-7, 2018
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Oral TAF/FTC PrEP Prevents Vaginal SHIV Infection in Monkeys
25th Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2018, Boston
Mark Mascolini
Oral tenofovir alafenamide/emtricitabine (TAF/FTC) given before and after 16 once-weekly vaginal simian HIV (SHIV) challenges protected 5 of 6 animals from SHIV infection [1]. The 1 animal that became infected did not have detectable tenofovir-diphosphate (TFV-DP) peripheral blood mononuclear cells (PBMCs).
Oral tenofovir disoproxil fumarate (TDF)/FTC remains the only licensed regimen for preexposure prophylaxis (PrEP) against HIV. If TAF/FTC proves as effective in preventing infection, it could pose a lower toxicity threat. In humans a 25-mg dose of TAF yields 4- to 7-fold higher concentrations of TFV-DP in PBMCs than 300 mg of TDF. (TFV-DP is the active form of TAF and TDF.)
Centers for Disease Control and Prevention (CDC) researchers who conducted the vaginal exposure trial previously reported that TAF/FTC PrEP protected macaques from repeated rectal exposure to SHIV [2], and a TAF/FTC PrEP trial (DISCOVER) has begun in men who have sex with men. The new study had two phases: (1) a single-dose pharmacokinetic (PK) study to identify a clinically relevant TAF dose for macaques, and (2) a challenge study to assess whether TAF/FTC prevents SHIV infection in macaques after vaginal exposure.
The PK study involved 5 female macaques that received a single weight-adjusted oral-gavage dose selected to mimic a therapeutic dose in humans (1.5 mg/kg TAF, 20 mg/kg FTC). Researchers measured drug concentration in PBMCs, plasma, and tissue 24 hours after dosing. Compared with a 25-mg TAF dose in humans, 1.5 mg/kg in macaques yielded tenofovir area under the concentration-time curve (AUC) in plasma higher in macaques than humans (150 vs 57.7 ng*h/mL) Levels of TFV-DP were similar in macaques and humans in PBMCs (2001 and 2094 ng*h/mL) and vaginal tissue (9 vs 9.6 fmol/mg). TFV exposure proved lower in vaginal fluids than in rectal fluids, but the difference was not statistically significant (P = 0.38). Median TFV-DP half-life stood at 38 hours in macaque PBMCs, compared with 54 hours in humans.
The SHIV challenge study involved 6 macaques orally dosed at 1.5/20 mg/kg TAF/FTC 24 hours before and 2 hours after 16 once-weekly vaginal challenges with 50 TCID50 of SHIV162p3. Five macaques received placebo before and after challenge. All 5 placebo recipients became infected after a median of 5 exposures. Five of 6 animals that received TAF/FTC remained protected through 16 challenges (P = 0.0422, hazard ratio 5.6, efficacy 82%).
Protected TAF/FTC recipients attained a median TFV-DP concentration of 237.5 fmol/million PBMCs, while the unprotected treated macaque had undetectable TFV-DP in PBMCs. FTC-triphosphate levels were similar in the infected macaque (1499 fmol/million PBMCs, interquartile range 1092 to 1760) and in the 5 protected monkeys (median 1837 fmol/million PBMCs, interquartile range 1255 to 2653).
The CDC team concluded that TAF/FTC administered at this dose before and after SHIV challenge protects from vaginal SHIV to a degree similar to that seen with TDF/FTC. They believe their findings support study of TAF/FTC PrEP against vaginal infection in humans.
1. Massud I, Cong M, Ruone S, et al. Oral FTC/TAF combination prevents vaginal SHIV infection in pigtail macaques. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 85. 2. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis With oral emtricitabine and tenofovir alafenamide combination protects macaques from rectal simian/human immunodeficiency virus infection. J Infect Dis. 2016;214:1058-1062.
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