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TDF/FTC and TDF Alone Slash HIV Risk in Partners PrEP HIV-Discordant Couples
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini (contribution by Jules Levin)
Daily tenofovir/emtricitabine (TDF/FTC) or TDF alone as pre-exposure prophylaxis (PrEP) dramatically cut the risk of HIV infection in HIV-negative partners of 4758 African couples with one positive and one negative partner, according to final results of the placebo-controlled Partners PrEP trial [1]. Both PrEP strategies worked in women and men.
Partners PrEP is one of three placebo-controlled trials demonstrating that oral TDF/FTC lowers the risk of HIV acquisition: TDF2 also involved heterosexual women and men [2], while iPrEx studied men who have sex with men and transgender women who have sex with men [3]. The FEM-PrEP trial in African women at high risk of HIV infection did not demonstrate protection with daily TDF/FTC, probably because of poor adherence [4] (see separate NATAP report at link below). Another PrEP trial, VOICE, stopped its TDF-only arm because this approach was not protecting women from HIV [5]. Reasons for this failure remain to be determined.
Partners PrEP enrolled 4758 HIV-discordant couples in Kenya and Uganda and randomized the HIV-positive partner to daily TDF, TDF/FTC (in a single pill), or placebo. Everyone received HIV treatment and prevention services, individual and couples risk-reduction counseling, and condoms. Monthly follow-up extended as long as 36 months. Most HIV-negative partners, 62%, were men. Monthly pill count of unused product figured a 97% rate of dispensed doses taken; study retention was 98% at 6 months and 100% at 36 months. The average age of the seronegative partner was 33 and the average duration of the partnership was 7 years (3-14). But on average they knew their HIV- serodiscordance a half a year. The average CD4 of the HIV- serpositive partner was 497. The median follow-up was 23 months. At an interim review of 10 July 2011, the studyÕs independent Data and Safety Monitoring Board (DSMB) recommended public report of results and discontinuation of placebo arm, due to definitive HIV-1 protection. The study is ongoing with placebo randomized to TDF or TDF/FTC and the study is expected to end at the end of 2012.
During follow-up, 82 partners became infected with HIV--17 in the TDF-only arm, 13 in the TDF/FTC arm, and 52 in the placebo arm. There were 96 HIV-1 acquisition events observed, ITT analysis, 14 retrospectively found to be HIV-1 infected at enrollment (seronegative acute infection: subsequent testing of enrollment samples after HIV-1 seroconversion by HIV-1 RNA PCR demonstrated HIV-1 infection). Those numbers translated into a 67% lower HIV acquisition risk with TDF than with placebo (95% confidence interval [CI] 44% to 81%, P < 0.0001) and a 75% lower HIV risk with TDF/FTC (95% CI 55% to 87%, P < 0.0001). Protection from HIV did not differ significantly between the TDF group and the TDF/FTC group, and both strategies protected both women and men:
-- TDF alone in women: Efficacy 71% (95% CI 37% to 87%), P = 0.002
-- TDF alone in men: Efficacy 63% (95% CI 20% to 83%), P = 0.01
-- TDF/FTC in women: Efficacy 66% (95% CI 28% to 84%), P = 0.005
-- TDF/FTC in men: Efficacy 84% (95% CI 54% to 94%), P < 0.001
Serious medical problems arose 7% in all three study arms, and fewer than 1% in any arm died. Grade 2 or worse creatinine elevations occurred in fewer than 1% of any study group (n=6). Confirmed phosphorus decreases affected 9% in each study arm. During the first month of the study about 10% of patients receiving TDF or TDF/FTC reported mild fatigue but 7% in the placebo arm reported mild fatigue, After the first month over the remainder of the study about 3.5% of participants in all 3 study arms reported mild fatigue. During the first month of the study about 6% of those receiving TDF or TDF/FTC reported mild nausea which compared to 4.5% in the placebo arm, and during the remainder of the study 1.5% across all 3 study arms reported mild nausea.
Among 8 people infected with HIV at the time of randomization, resistance mutations evolved in 2--1 with the TDF-related K65R mutation and 1 with the FTC-related M184V. No one who got infected after randomization (n=27) had evidence of emergent K65R or M184V. After enrollment investigators detected the nonnucleoside mutation K103N or V106A in 2 people assigned to TDF, 1 assigned to TDF/FTC, and 1 assigned to placebo--all probably the result of transmitted resistance.
About one quarter of couples reported unprotected sex at enrollment, and that rate dropped steadily through 30 months of follow-up.
Another Partners PrEP analysis (reviewed separately by NATAP) found that having detectable blood levels of tenofovir dramatically improved chances of protection from HIV among people taking TDF or TDF/FTC [6]. Reviewing data from all PrEP trials in a symposium lecture, Partners PrEP investigator Jared Baeten proposed that adherence may explain efficacy differences across PrEP studies, "but perhaps not completely" [7]. Other factors that may be involved include marginal vaginal concentrations of tenofovir, inflammation, and high viral loads in some infecting partners--all of which would make PrEP "more sensitive to less-than-perfect adherence."
References
1. 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.
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. 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. http://www.natap.org/2012/CROI/croi_19.htm.
5. 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.
6. Donnell D, Baeten J, C 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. http://www.natap.org/2012/CROI/croi_10.htm.
7. Baeten J. What can the twisted tale of PrEP results teach us? 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Invited lecture 67.
Complete slides for CROI presentations are online at http://retroconference.org/static/webcasts/2012/. Click on Tuesday, then go to Oral Abstract: HIV Prevention: PrEP, Microbicides, and Circumcision. For the Baeten lecture [7] go to Symposium: Next Steps in Using ARV for Prevention.
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