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Oral TAF alone offers modest protection
against vaginal SHIV in monkeys
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Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2019, Seattle
Mark Mascolini
Single-agent oral tenofovir alafenamide (TAF) protected 4 of 7 macaque monkeys from vaginal exposure to simian HIV (SHIV) in a CDC study [1]. Tenofovir levels in peripheral blood mononuclear cells (PBMCs) were similar in protected and unprotected animals.
TAF is replacing tenofovir disoproxil fumarate (TDF) in treating HIV infection. Coformulated oral TDF/emtricitabine (FTC) remains the standard agent for preexposure prophylaxis (PrEP) against HIV. But many other PrEP drugs and delivery methods are under study, including long-acting single-agent TAF delivered by implant. This new study assessed the protective efficacy of oral single-agent TAF in preventing vaginal SHIV infection in monkeys. Compared with TDF, TAF has less toxicity and delivers more tenofovir diphosphate (TFV-DP), the active form of the drug, to PBMCs.
Previous research found that a low 0.1-mg dose of oral TAF did not protect newborn macaques orally exposed to simian immunodeficiency virus [2]. And a high 13.7-mg/kg dose of oral TAF did not protect monkeys from rectal SHIV [3]. But human-equivalent doses of TAF/FTC protected monkeys from vaginal and rectal SHIV [4].
The new study began with 9 female macaques with regular menstrual cycles. Because 2 monkeys had dosing difficulties, the analysis focused on the remaining 7. Researchers gave a human-equivalent dose (1.5 mg/kg) by oral gavage 24 hours before and 2 hours after each vaginal SHIV challenge. They exposed the animals to low-dose SHIV once a week for 15 weeks. The investigators used serology and PCR amplification of SHIV RNA and DNA to test for infection. They compared infection outcomes to results in 21 untreated animals, including 6 real-time controls and 15 historical controls exposed to the same SHIV.
Through 15 weeks of SHIV challenge, 4 of the 7 TAF-treated macaques remained protected, while nearly all untreated animals became infected. The researchers calculated overall 73% efficacy with single-agent TAF compared with 21 control animals (95% confidence interval 10.6 to 91.6, P = 0.036). Drug-level analyses showed that TFV-DP levels and TFV-DP/dATP ratios in PBMCs were similar in protected and unprotected macaques.
The CDC team believes the findings "point to an important contribution of FTC in the protection [from SHIV] seen with FTC/TAF" [4]. They underscored the importance of pinpointing TFV-DP levels in PBMCs associated with complete vaginal protection with single-agent TAF.
References
1. Massud I, Cong M, Ruone S, et al. Moderate efficacy of oral single-agent TAF against vaginal SHIV infection in macaques. Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2019. Seattle. Abstract 102.
2. Van Rompay KK, Kearney BP, Sexton JJ, et al. Evaluation of oral tenofovir disoproxil fumarate and topical tenofovir GS-7340 to protect infant macaques against repeated oral challenges with virulent simian immunodeficiency virus. J Acquir Immune Defic Syndr. 2006;43:6-14.
3. Garcia-Lerma JG, Aung W, Cong ME, et al. Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol. 2011;85:6610-6617.
4. 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.
CROI: THE PHASE 3 DISCOVER STUDY: DAILY F/TAF OR F/TDF FOR HIV PREEXPOSURE PROPHYLAXIS - (03/06/19)
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