Safety, adherence and acceptability of intermittent tenofovir/emtricitabine as HIV pre-exposure prophylaxis (PrEP) among HIV-uninfected Ugandan volunteers living in HIV-serodiscordant relationships: a randomized, clinical trial

Freddie M Kibengo, Eugene Ruzagira, David Katende, Agnes N Bwanika, Ubaldo Bahemuka, Jessica E Haberer, David R Bangsberg, Burc Barin, James F Rooney, David Mark, Paramesh Chetty, Patricia Fast, Anatoli Kamali, Frances H Priddy, Freddie M Kibengo, Eugene Ruzagira, David Katende, Agnes N Bwanika, Ubaldo Bahemuka, Jessica E Haberer, David R Bangsberg, Burc Barin, James F Rooney, David Mark, Paramesh Chetty, Patricia Fast, Anatoli Kamali, Frances H Priddy

Abstract

Background: Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens.

Design: Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment.

Methods: Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT.

Results: Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen.

Conclusions: Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing.

Registration: Clinicaltrials.gov number NCT00931346.

Conflict of interest statement

Competing Interests: Gilead Sciences provided the study drug and placebo tablets at no cost. Co-author James Rooney is employed by Gilead Sciences. Gilead Sciences developed and is marketing the study drug, Truvada, for treatment of HIV infection. Co-author Burc Barin is employed by the EMMES Corporation, and does not have any relevant declarations relating to consultancy, patents, products in development or marketed products. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

References

    1. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C et al. (2000) Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 342: 921-929. doi:. PubMed: .
    1. Ministry of Health Republic of Uganda, ORC Macro (2006); HIV Uganda /AIDS Sero-behavioural Survey 2004-2005. Available: . Accessed October 31, 2012.
    1. Malamba SS, Mermin JH, Bunnell R, Mubangizi J, Kalule J et al. (2005) Couples at Risk: HIV-1 Concordance and Discordance among sexual partners receiving voluntary counseling and testing in Uganda. J Acquir Immune Defic Syndr 39: 576-580. PubMed: .
    1. Ruzagira E, Wandiembe S, Abaasa A, Bwanika AN, Bahemuka U et al. (2011) HIV incidence and Risk factors for Acquisition in HIV discordant couples in Masaka, Uganda: An HIV vaccine Preparedness study. PLOS ONE 6: e24037. doi:. PubMed: .
    1. Commission Uganda AIDS (2007) Towards universal access to HIV/AIDS prevention, treatment, care and support in Uganda by 2012: Synopsis of the epidemic, the response and priorities for future action. Available: . Accessed October 31, 2012.
    1. Government of Uganda (2010) UNGASS Progress Report, Uganda: January 2008 -December 2009 Available: . Accessed October 31, 2012.
    1. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY et al. (2010) Preexposure chemoprophylaxis for HIV Prevention in men who have sex with men. N Engl J Med 363: 2587-2599. doi:. PubMed: .
    1. Anderson P, Liu A, Buchbinder S, Lama J, Guanira J et al. (2012) Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th Conference on Retroviruses and Opportunistic Infections. Washington: Seattle.
    1. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE et al. (2012) Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana. N Engl J Med 367: 423-434. doi:. PubMed: .
    1. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD et al. (2012) Antiretroviral Prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 367: 399-410. doi:. PubMed: .
    1. Donnell D, Baeten J, Hendrix C, Bumpus N, Bangsberg D et al. (2012) 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. Washington: Seattle.
    1. FHI 360 (2011) FHI Statement on the FEM-PrEP HIV Prevention Study: FHI to Initiate Orderly Closure of FEM-PrEP. Available: Accessed October 31, 2012.
    1. Microbicide Trials Network (2011) Microbicide Trials Network Statement on Decision to Discontinue Use of Oral Tenofovir Tablets in VOICE, a Major HIV Prevention Study in Women. Available: . Accessed October 31, 2012.
    1. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J et al. (2012) Preexposure prophylaxis for HIV infection among African women. N Engl J Med 367: 411-422. doi:. PubMed: .
    1. Steinbrook R (2012) Preexposure prophylaxis for HIV infection. JAMA, 308: 865-866. doi:. PubMed: .
    1. Wang LH, Begley J, St Claire RL 3rd, Harris J, Wakeford C et al. (2004) Pharmacokinetic and pharmacodynamic characteristics of Emtricitabine support its once daily dosing for treatment of HIV infection. AIDS Res Hum Retroviruses 20: 1173-1182. doi:. PubMed: .
    1. Kearney BP, Flaherty JF, Shah J (2004) Tenofovir Disoproxil Fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 43: 595-612. doi:. PubMed: .
    1. García-Lerma JG, Otten RA, Qari SH, Jackson E, Cong ME et al. (2008) Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLOS Med 5: e28. doi:. PubMed: .
    1. Mutua G, Sanders E, Mugo P, Anzala O, Haberer JE, et al. (2012) Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PLOS ONE 7: e33103. doi:. PubMed: . . doi: PubMed:
    1. Sobell LC, Sobell MB (1996) Timeline Followback: User’s Guide - A calendar method for assessing alcohol and drug use. Toronto: Addiction Research Foundation.
    1. Weinhardt LS, Carey MP, Maisto SA, Carey KB, Cohen MM et al. (1998) Reliability of the timeline followback sexual behavior interview. Ann Behav Med 20: 25-30. doi:. PubMed: .
    1. Carey MP, Carey KB, Maisto SA, Gordon CM, Weinhardt LS (2001) Assessing sexual risk behaviour with the Timeline Followback (TLFB) approach: continued development and psychometric evaluation with psychiatric outpatients. Int J STD AIDS 12: 365-375. doi:. PubMed: .
    1. Stiles T, Grant V (2011) Good Clinical Laboratory Practice: GCLP Version Two. Ipswich: BARQA.
    1. Karita E, Ketter N, Price MA, Kayitenkore K, Kaleebu P et al. (2009) CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa. PLOS ONE 4: e4401. doi:. PubMed: .
    1. Grohskopf L, Gvetadze R, Pathak S, O’Hara B, Mayer K et al. (2010) Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among U.S. men who have sex with men (MSM). XVIII International AIDS Conference Vienna, Austria.
    1. Peterson L, Taylor D, Roddy R, Belai G, Phillips P et al. (2007) Tenofovir disoproxil fumarate for prevention of HIV infection in women: A phase 2, double-blind, randomized, placebo-controlled trial. PLoS. Clin Trials 2: e27. doi:.
    1. Haberer J, Baeten J, Celum C, Katabira E, Ronald A et al. (2012) High adherence among HIV—1 serodiscordant couples in the Partners PrEP ancillary adherence study. 7th International Conference on HIV Treatment and Adherence. Beach, FL: Miami.
    1. Van der Elst EM, Mbogua J, Operario D, Mutua G, Kuo C, et al (2012) High acceptability of HIV pre-exposure prophylaxis but challenges in adherence and use: qualitative insights from a phase I trial of intermittent and daily PrEP in at-risk populations in Kenya. AIDS Behav, 17: 2012 Oct 19. [Epub ahead of print] PubMed: .
    1. Ware NC, Wyatt MA, Haberer JE, Baeten JM, Kintu A et al. (2012) What’s love got to do with it? Explaining adherence to oral antiretroviral pre-exposure prophylaxis for HIV-serodiscordant couples. J Acqui Immune Defic Syndr 59: 463-468. doi:.
    1. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C et al. (2010) Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science 329: 1168-1174. doi:. PubMed: .
    1. Hugen PW, Langebeek N, Burger DM, Zomer B, van Leusen R et al. (2002) Assessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring. J Acquir Immune Defic Syndr 30: 324-334. doi:. PubMed: .
    1. Simoni JM, Kurth AE, Pearson CR, Pantalone DW, Merrill JO et al. (2006) Self-report measures of antiretroviral therapy adherence: a review of the recommendations for HIV research and clinical management. AIDS Behav 10: 227-245. doi:. PubMed: .
    1. Arnsten JH, Demas PA, Farzadegan H, Grant RW, Gourevitch MN et al. (2001) Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis 33: 1417-1423. doi:. PubMed: .
    1. Skoler-Karpoff S, Ramjee G, Ahmed K, Altini L, Plagianos MG et al. (2008) Efficacy of carraguard for prevention of HIV infection in women in South Africa: a randomized, double-blind, placebo-controlled trial. Lancet 372: 1977-1987. doi:. PubMed: .
    1. van der Straten A, Van Damme L, Haberer JE, Bangsberg DR (2012). Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention. 26: F13-F19.
    1. Amico R, Liu A, McMahan V, Anderson P, Lama J et al. (2011) Adherence indicators and PrEP drug levels in the iPrEx study. Abstract 95LB. 1 8th Conference on Retroviruses and Opportunistic Infections, Boston
    1. Anderson PL, Glidden DV, Liu A, Buchbinder S, Lama JR et al. (2012) Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med 4: 151 PubMed: .
    1. Guest G, Shattuck D, Johnson L, Akumatey B, Clarke EE et al. (2010) Acceptability of PrEP for HIV Prevention Among Women at High Risk for HIV. J Womens Health 19: 791-798. doi:. PubMed: .
    1. Guest G, Shattuck D, Johnson L, Akumatey B, Clarke EE et al. (2008) Changes in Sexual Risk Behaviour Among Participants in a PrEP Prevention Trial. Sex Transm Dis 35: 1002-1008. PubMed: .

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