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Lower HIV Rate With F/TAF Than F/TDF in Double-Blind Noninferiority Trial
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10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City
Mark Mascolini
Chances of getting infected with HIV were 53% lower with emtricitabine/tenofovir alafenamide (F/TAF) than with emtricitabine/tenofovir disoproxil fumarate (F/TDF) in the 96-week randomized DISCOVER trial [1]. Although that protection rate did not reach statistical significance, F/TAF proved noninferior to F/TDF in preventing HIV infection.
Single-tablet T/TDF has long held center stage in clinical use of preexposure prophylaxis (PrEP) to prevent HIV infection. But several inherent properties of TAF suggest that F/TAF could emerge as a stronger and safer PrEP pill.
DISCOVER is a double-blind noninferiority trial that randomized 5387 adult men who have sex with men or transgender women to F/TAF or F/TDF. Participants had to be negative for HIV and HBV and had to report sexual behaviors or infections that indicated high risk of picking up HIV (recent condomless anal sex with 2 or more partners or recent rectal gonorrhea, chlamydia, or syphilis).
Through 8756 person-years of follow-up, researchers recorded 7 HIV infections in the F/TAF group and 15 in the F/TDF group. The incidence rate ratio (IRR) comparing HIV risk with F/TAF versus F/TDF was 0.47, meaning the F/TAF group had 53% lower HIV risk than the F/TDF group. Although that difference lacked statistical significance (the 95% confidence interval [CI] 0.19 to 1.15 crossed 1.0), the results did establish that F/TAF is noninferior to F/TDF in preventing HIV infection.
Researchers suspected that 1 person randomized to F/TAF and 4 randomized to F/TDF already had HIV infection when entering the trial. If they eliminated those 5 people from the analysis, F/TAF remained noninferior to F/TDF (IRR 0.55, 95% CI 0.20 to 1.48).
DISCOVER investigators figured rates of several HIV risk factors in trial participants to see if they could uncover reasons why fewer people taking F/TAF than F/TDF picked up HIV infection during the trial. Through 96 weeks of follow-up, the two groups differed hardly at all in number of sex partners with whom they had condom-free receptive anal sex or in new cases of rectal gonorrhea or chlamydia. So more sex or riskier sex in people taking F/TDF apparently did not explain the fewer new HIV cases with F/TAF.
F/TAF takers did not differ from F/TDF takers in self-reported adherence to their PrEP pill schedule or adherence determined by pill counts or tenofovir-diphosphate (TFV-DP) levels in dried blood spots. So pill-taking habits did not seem to explain the higher HIV rate with F/TDF. But poor pill-taking adherence strongly predicted HIV infection in both study arms.
Although TAF is dosed at 25 mg daily and TDF at 300 mg daily, in previous research TAF delivered 4- to 7-fold higher levels of TFV-DP (the active form of tenofovir) to blood cells than TDF. In a prior PrEP study of F/TDF, TFV-DP in peripheral blood mononuclear cells (PBMCs) correlated with HIV risk reduction--the higher the tenofovir level in cells, the lower the HIV risk [2]. In DISCOVER, steady-state TFV-DP levels in PBMCs were 6.3-fold higher with F/TAF than with F/TDF.
F/TAF also yields effective tenofovir-diphosphate levels in PBMCs faster than F/TDF. In previous research, TFV-DP concentrations with F/TAF always climbed above the 90% effective concentration (EC90) within 4 hours, while people had to take 3 daily doses of F/TDF to reach that level. Other work shows that effective TFV-DP levels in PBMCs last longer after a person stops taking F/TAF than F/TDF--about 16 days versus 10 days. All these drug-level findings favor F/TAF and explain why it may ward off HIV infection better than F/TDF.
Combining all these findings, DISCOVER investigators proposed that F/TAF is a "potentially more efficacious option than F/TDF for prevention of HIV."
References
1. Spinner CD, Brunetta J, Shalit P, et al. DISCOVER study for HIV pre-exposure prophylaxis (PrEP): F/TAF has a more rapid onset and longer sustained duration of HIV protection compared with F/TDF. 10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City. Abstract TUAC0403LB.
2. Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4:151ra125.
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