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Poor Adherence May Explain FEM-PrEP
Failure to Find Protection From HIV With Truvada
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
FEM-PrEP, a placebo-controlled trial of oral Truvada (tenofovir/emtricitabine) in African women at high risk of HIV infection, found that taking the two-in-one pill once daily did not protect these women from HIV [1].
Poor adherence appears to explain that result, which runs counter to findings of Partners PrEP [2] and TDF2 [3]. Those trials determined that daily Truvada or tenofovir alone (in Partners PrEP) protected HIV-negative women and men from getting infected [4]. FEM-PrEP results are also at odds with findings in iPrEx, a placebo-controlled trial of daily Truvada in men who have sex with men and transgender women who have sex with men [5].
Preliminary FEM-PrEP results were released in 2011, when the trial was stopped because it became clear that Truvada would not ward off HIV infection. Researchers detailed their findings at the 19th Conference on Retroviruses.
FEM-PrEP enrolled more than 2000 women in Kenya, South Africa, and Tanzania and randomized them equally to daily Truvada or placebo. All enrollees were HIV-negative, were between the ages of 18 and 35, and had at least one vaginal sex act in the last 2 weeks or more than one sex partner in the last month. Only 12% of study participants said they exchanged sex for money or gifts, but these women were having lots of sex--an average of 3.7 vaginal sex acts in the week before enrollment [6].
When FEM-PrEP stopped at a planned interim analysis, 2056 women had contributed follow-up data. Among women randomized to Truvada, 33 became infected with HIV, compared with 35 in the placebo group. HIV incidence was virtually identical in the Truvada group (4.7 cases per 100 person-years) and the placebo group (5.0 cases per 100 person-years). Compared with women randomized to placebo, those randomized to Truvada had a similar risk of HIV infection (hazard ratio 0.94, 95% confidence interval 0.59 to 1.52, P = 0.81). A sensitivity analysis that included women only up to the last date they would have used Truvada or placebo also found no HIV risk difference between the two groups (hazard ratio 0.84, P = 0.44).
Three other placebo-controlled trials found daily Truvada protective in heterosexual women and men or in MSM. Partners PrEP enrolled 4758 HIV-discordant couples in Kenya and Uganda and found that both tenofovir and Truvada lowered the risk of HIV acquisition in HIV-negative women and men with an HIV-positive partner (reviewed separately by NATAP) [2]. TDF2, a placebo-controlled trial of Truvada in 1219 high-risk men and women in Botswana, also found that daily Truvada lowers HIV acquisition risk [3], as did iPrEx, an international placebo-controlled trial of daily Truvada in 2499 men who have sex with men [5]. But the international VOICE trial released early results indicating that tenofovir alone does not prevent HIV acquisition by women [7], as it did in Partners PrEP.
FEM-PrEP differed from Partners PrEP in at least two important ways. First, HIV-negative women in Partners PrEP knew their partners had HIV and so may have had more motivation to take the study drug than FEM-PrEP women [2], who would never know which partners had HIV and which did not. In fact, almost three quarters of FEM-PrEP participants did not believe they ran a risk of becoming infected with HIV. Self-reported adherence to Truvada or placebo in FEM-PrEP was 95% when study products were available. Pill counts indicated an 86% adherence rate. But drug-level monitoring made those high rates questionable: Plasma drug levels at or above 10 ng/mL could be detected in fewer than half of infected women or uninfected controls matched to cases by time of infection.
The FEM-PrEP team suggested that, "despite substantial counseling efforts, inadequate adherence may have undermined the trial's ability to assess the efficacy of [Truvada]" for PrEP.
In Partners PrEP adherence measured by monthly pill count of unused product was 97%. And a study of drug levels in Partners PrEP presented at this meeting (and reported separately by NATAP) found a strong correlation between detectable tenofovir and protection from HIV infection [8].
FEM-PrEP also differed from Partners PrEP in that two thirds of FEM-PrEP participants were taking injectable hormonal contraceptives and one third were taking oral contraceptives. Hormonal contraceptives, particularly the injected kind, may alter HIV acquisition risk [9] [from jules: may increase HIV transmission risk]. In contrast, only 26% of Partners PrEP participants were taking injectable hormonal contraceptives, and only 8% were taking hormonal oral contraceptives.
In FEM-PrEP more women randomized to Truvada than to placebo got pregnant (11.2% versus 7.5%). Family Health International, which ran the trial, noted in an earlier statement that this result was unexpected "and inconsistent with known drug interactions involving tenofovir and contraceptive hormones, and with known metabolic effects of emtricitabine" [6]. The statement suggests that different adherence rates between the FEM-PrEP Truvada and placebo arms, undefined drug-drug interactions, and/or other factors could contribute to the unexpectedly high pregnancy rate in the Truvada group.
References
1. Van Damme L, Corneli A, Ahmed K, et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 32LB.
2. Baeten J, Donnell D, Ndase P, et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 29.
3. 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.
4. Mascolini M for NATAP. Two more randomized trials show that daily TDF/FTC protects from HIV. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. http://www.natap.org/2011/IAS/IAS_10.htm.
5. 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.
6. Family Health International. FEM-PrEP fact sheet. Key findings. http://www.fhi360.org//NR/rdonlyres/exo44wsp2ibf7d2ssrny7wzxhlb6xbhy6at5rgjwwt37bhy6kjwqjfjmkmxtqb7tw5xno4psfseugk/FEMPrEPFactSheetKeyFindings1.pdf.
7. Microbicide Trials Network. MTN statement on decision to discontinue use of oral tenofovir tablets in VOICE, a major HIV prevention study in women. September 28, 2011. http://www.mtnstopshiv.org/node/3619.
8. Donnell D, Baeten J, Hendrix C, et al. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 30.
9. Heffron R, Donnell D, Rees H, et al; Partners in Prevention HSV/HIV Transmission Study Team. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect Dis. 2011;12:19-26.
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