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Two More Randomized Trials Show that Daily TDF/FTC Protects From HIV
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Two randomized trials in Africa found that pre-exposure prophylaxis (PrEP) with daily tenofovir (TDF) or tenofovir/emtricitabine (TDF/FTC) lowered the risk that an HIV-negative partner in a heterosexual couple would pick up HIV from an HIV-positive partner [1,2]. The results of Partners PrEP [1] and TDF2 [2] confirm results of the iPrEx trial, which found that daily TDF/FTC cuts the risk of HIV acquisition about 45% in sexually active gay and bisexual men [3]. A fourth placebo-controlled PrEP trial that enrolled highly sexually active HIV-negative African women, FEM-PrEP, found no protection from HIV infection with TDF/FTC [4]. Why FEM-PrEP results differ from those of the other three studies remains unclear.
Partners PrEP, the largest PrEP trial so far, randomized sexually active HIV-negative partners in 4758 heterosexual couples to daily TDF, daily TDF/FTC, or daily placebo. The trial took place in urban and rural Kenya and Uganda and was double-blinded, meaning neither study participants nor researchers knew whether a participant was taking TDF, TDF/FTC, or placebo. Study participants averaged 33 years in age, and 98% were married.
An independent monitoring panel recommended stopping the trial when they saw results heavily favoring daily TDF or TDF/FTC over placebo. At that point 78 people had picked up HIV, 18 in the TDF group, 13 in the TDF/FTC group, and 47 in the placebo group. Those rates meant TDF alone lowered HIV risk 62% compared with placebo (95% confidence interval [CI] 34% to 78%, P = 0.0003), while TDF/FTC cut the risk 73% (95% CI 49% to 85%, P < 0.0001). The difference between the two active PrEP arms was not statistically significant. The protective effect of TDF and TDF/FTC did not differ between women and men.
Rates of serious medical complications were similar in the three Partners PrEP groups, though more people in the TDF and TDF/FTC groups had nausea or diarrhea. No evidence suggested that TDF or TDF/FTC complicated pregnancies in the 10% of women who became pregnant yearly. Women stopped taking study medications if they became pregnant.
Adherence to daily PrEP was high, as study participants took more than 97% of dispensed doses, and 98% of pill bottles were returned. More than 95% of study participants remained in the trial to the latest follow-up point.
Partners PrEP is the first PrEP trial to show that TDF alone protects from HIV as well as TDF/FTC. Researchers are eager to examine that finding more closely because using only TDF for PrEP would cost less and could have advantages in tolerability and risk of antiretroviral resistance if a person using PrEP does become infected.
In Botswana, TDF2 investigators enrolled 1219 HIV-negative heterosexual men and women who had an HIV-positive partner and randomized them to take daily TDF/FTC or placebo. The primary analysis involved 1200 people, 55% of them men. About 90% of study participants were between 21 and 29 years old, and 73% had secondary-school education.
Nine of 601 people assigned to TDF/FTC (1.5%) became infected, compared with 24 of 559 assigned to placebo (4%). Those rates meant TDF/FTC cut the risk of HIV acquisition by 62.6% (95% CI 21.5 to 83.4, P = 0.0133). A second analysis eliminating people who became infected more than 30 days after they last reported taking TDF/FTC or placebo determined that TDF/FTC sliced HIV risk by 77.9% (95% CI 41.2 to 93.6, P = 0.0053).
TDF2 was not large enough to prove that TDF/FTC prevented HIV transmission in men as well as it did in women. But the results suggest that is so, just as in Partners PrEP. In TDF2, 3 women using TDF/FTC PrEP and 13 women in the placebo group became infected to yield a protective efficacy of 75.5%, which was statistically significant (95% CI 23.8 to 94.4, P = 0.021). One man using TDF/FTC PrEP became infected compared with 6 men taking placebo to yield a protective efficacy of 82.4%, but that finding fell short of statistical significance (95% CI -2.8 to 99.1, P = 0.065).
Nobody in either study group had a serious medical problem during TDF2, but people randomized to TDF/FTC reported nausea, vomiting, and dizziness more than those randomized to placebo.
Participants in both Partners PrEP and TDF2 got intensive risk-reduction counseling, free condoms, and regular checkups and care for sexually transmitted infections.
FEM-PrEP enrolled 1951 women in Kenya, South Africa, and Tanzania who averaged more than 3.5 vaginal sex acts weekly before and during the study [4]. Investigators randomized them to daily TDF/FTC or placebo. The trial stopped when an interim review disclosed that 28 women in the TDF/FTC group and 28 in the placebo group had picked up HIV. FEM-PrEP investigators are conducting several analyses to see if they can figure why TDF/FTC PrEP did not ward off HIV infection in these women. Possibilities include poor adherence and unreported interactions between TDF or FTC and hormonal contraceptives these women were taking. And of course the study population differed from the populations in Partners PrEP and TDF2.
References
1. Baeten J. Antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrEP study. HIV-1-infected adults. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAX0106.
2. Thigpen MC, Kebaabetswe PM, Smith DK, et al. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study. HIV-1-infected adults. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract WELBC01.
3. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2011;363:2587-2599. http://www.nejm.org/doi/full/10.1056/NEJMoa1011205.
4. Family Health International. FHI statement on the FEM-PrEP HIV prevention study. April 18, 2011. http://www.fhi.org/en/AboutFHI/Media/Releases/FEM-PrEP_statement041811.htm.
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