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HIV Prevention Fails in All Three VOICE Arms, as Daily Truvada PrEP Falls
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20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Daily Truvada (tenofovir/emtricitabine) failed to protect African women from HIV infection in VOICE, the second placebo-controlled trial to find Truvada ineffective as daily preexposure prophylaxis (PrEP) in young, mostly single African women [1].
In 2012, VOICE researchers stopped studying oral tenofovir alone and 1% tenofovir vaginal gel when early results made it clear that neither of these interventions was shielding women from HIV. VOICE results contrast with findings in three other placebo-controlled PrEP trials (Partners PrEP [2], TDF2 [3], and iPrEx[4]) and one placebo-controlled vaginal gel trial (CAPRISA 004) [5]. Partners PrEP studied Truvada and tenofovir alone in HIV-discordant committed African couples, TDF2 studied heterosexual African women and men, iPrEx studied gay and bisexual men on four continents, and CAPRISA 004 studied South African women.
Poor adherence appears to be the prime reason for failure of all three VOICE arms, as it was in FEM-PrEP, a study in young African women [6]. The successful trials [2-5] all found that better adherence increases efficacy of oral Truvada, oral tenofovir, or vaginal tenofovir.
VOICE is a double-blind, placebo-controlled trial that enrolled 5029 HIV-negative women at 15 sites in Uganda, South Africa, and Zimbabwe between September 2009 and June 2011. The researchers completed follow-up for all participants by August 2012. Women used tenofovir vaginal gel daily in VOICE, whereas in CAPRISA 004 [5] they applied the gel before and after sex. VOICE Participants had normal liver and kidney function and reported vaginal intercourse in the past 3 months. Women got tested for HIV monthly, and plasma tenofovir levels were measured quarterly. Monthly visits included adherence counseling.
Most women (62%) were from Durban, while another 14% were from Johannesburg. Age averaged 25.3 years, 79% of women were unmarried, 22% had more than 2 male sex partners in the past 3 months, 17% had anal sex in the past 3 months, and 85% reporting using a condom during their last vaginal sex. Through 5511 person-years of follow-up, 91% of women remained in the study.
Among the 334 women who became infected with HIV, 22 entered the trial with acute HIV infection. If those 22 women are excluded, HIV incidence was 5.7 per 100 person-years, meaning about 6 of 100 women got infected every 12 months. HIV incidence rates per 100 person-years were 6.3 and 4.2 for oral tenofovir versus placebo, 4.7 and 4.6 for Truvada versus placebo, and 5.9 and 6.8 for tenofovir gel versus placebo.
None of the three strategies worked. Hazard ratios (and 95% confidence intervals [CI]) indicating HIV protection efficacy versus placebo were:
-- Oral tenofovir: HR 1.49 (95% CI 0.97 to 2.29, P = 0.07)
-- Oral Truvada: HR 1.04 (95% CI 0.73 to 1.49)
-- Tenofovir gel: HR 0.85 (95% CI 0.6 to 1.2)
In every treatment arm, women reported taking 90% or 91% of doses in the past week. Product-return data suggested similarly high levels of adherence. But tenofovir levels in plasma told a different story: 30% or fewer women in all three treatment arms had detectable tenofovir in plasma--30% taking oral tenofovir, 29% taking oral Truvada, and 25% using tenofovir gel. In the three treatment arms, 50% or more women never had detectable blood in any plasma sample. Three factors predicted detectable tenofovir in plasma--being married (univariate odds ratio [OR] 1.66), being older than 25 (OR 2.62), and reporting a primary male partner older than 28 (OR 1.49).
The VOICE investigators proposed that their results and those in the similar FEM-PrEP study group "suggest that products that are long acting and require minimal daily adherence may be more suitable for this population." But iPrEx, TDF2, and CAPRISA 004 all found that young, sexually active, single people can be motivated to take oral Truvada or tenofovir gel regularly enough to protect themselves from HIV.
In the United States the FDA licensed Truvada for PrEP in high-risk men and women. The World Health Organization has issued guidance on PrEP for HIV-discordant couples and men who have sex with men, but not for single women or single heterosexual men.
References
1. Marrazzo J, Ramjee G, Nair G, et al. Pre--exposure prophylaxis for HIV in Women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 26LB.
2. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399-410. http://www.nejm.org/doi/full/10.1056/NEJMoa1108524
3. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-434. http://www.nejm.org/doi/full/10.1056/NEJMoa1110711
4. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599. http://www.nejm.org/doi/full/10.1056/NEJMoa1011205
5. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329:1168-1174. http://www.sciencemag.org/content/329/5996/1168.long
6. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411-422. http://www.nejm.org/doi/full/10.1056/NEJMoa1202614
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