HIV-1 uninfected individuals within HIV-1 discordant partnerships are at high-risk for HIV acquisition. The majority of HIV-1 transmissions to adults in Africa occur within stable, HIV-1  discordant couples. Novel strategies to prevent HIV-1 transmission within discordant couples, especially interventions that might allow pregnancy to occur safely, are urgently needed. Pre-exposure chemoprophylaxis, in which an HIV-1 uninfected individual at high risk for contracting HIV-1  takes antiretroviral medications to maintain blood and genital drug levels sufficient to prevent HIV-1 acquisition, has been proposed as a potential  HIV-1 prevention strategy. A randomized , blinded, placebo controlled trial is required to demonstrate if PrEP  decreases HIV-1 acquisition and has an acceptable safety profile when given to HIV-1 uninfected individuals within HIV-1 discordant partnerships.

Both Tenofovir disoproxil fumarate (TDF) and co-formulated Emtricitabine/Tenofovir disoproxil fumarate (FTC/TDF) have been proposed as possible safe and effective medications to serve as pre-exposure chemoprophylaxis. The potential for differential safety, cost, and efficacy for these two medications justifies evaluating both, against placebo, in single clinical trial. This trial will directly answer  whether PrEP decreases HIV-1 acquisition among HIV-1 uninfected individuals within HIV-1 discordant couples, a very high-risk heterosexual population who could benefit from this type of intervention, if found to be safe and efficacious.

Primary Objectives:

1. To determine if once-daily, oral PrEP with TDF or FTC/TDF provides additional protective benefit in preventing HIV-1  acquisition among HIV-1 uninfected persons within heterosexual HIV-1 discordant couples who are also receiving standard prevention interventions.
2. To assess the safety of daily PrEP using TDF or TDF/FTC by comparing rates of adverse events (AEs) among HIV-1 uninfected individuals randomized to  TDF or FTC/TDF PrEP to those randomized to placebo.

Secondary Objectives: 

1. Factors influencing efficacy

• To evaluate the efficacy of PrEP by the level of HIV-1 exposure for HIV-1 uninfected partners within HIV-1 discordant couples, defined by the frequency of sexual activity and the HIV-1 viral load in the HIV-1 infected partner.
• To assess efficacy of PrEP by gender of the HIV-1 uninfected partner.
• To measure the effect  on efficacy of other factors, including CD4 count of the HIV-1  infected partner and, for both partners, herpes simplex virus type 2 (HSV-2) serostatus, sexually transmitted infections (STIs), and male circumcision.

       2.  Adherence:

• To assess adherence  to once daily TDF or FTC/TDF PrEP among HIV-1 uninfected persons within HIV-1 discordant couples, and the effect of adherence on efficacy of PrEP to prevent HIV-1 acquisition.
• To evaluate the frequency of PrEP  drug sharing between the HIV-1 uninfected and HIV-1 infected partners within HIV-1  discordant couples, as measured by drug assays in HIV-1  infected and uninfected partners.

       3.   Risk Compensation:

• To characterize the association of once daily TDF or FTC/TDF PrEP  with sexual bahaviour change of HIV-1 uninfected individuals within HIV-1 discordant partnerships.
• To compare risk bahaviors among HIV-1  discordant couples previously enrolled in the Partners in Prevention trial(which evaluated the efficacy of HSV-2  suppressive therapy when given to the HIV-1 infected partner for preventing HIV-1 transmission), by examining changes in sexual behaviors when the HIV-1 infected versus HIV-1 uninfected partner is receiving a study drug.

        4.  Safety

• To assess the effect of TDF and FTC/TDF chemoprophylaxis on the rate of congenital abnormalities and growth among infants born to HIV-1 uninfected female participants who become pregnant during the study (and in whom study drug is stopped at the time pregnancy is detected, using monthly pregnancy testing).

        5. Effect of PrEP on early HIV-1 disease

Among those initially HIV-1 uninfected individuals in the trial who seroconvert to HIV-1, to assess the effect of PrEP on:

• Plasma HIV-1 viral load and CD4 cell counts during at least 12 months after HIV-1 seroconversion.
• Frequency of genotypic and phenotypic antiretroviral drug resistance .
• Other clinical, immunologic, and virologic parameters of HIV-1 disease.

Tertiary Objectives:

To utilize stored samples for evaluation of immunogenetic and virologic determinants of HIV-1 transmission between transmitting and non-transmitting HIV-1 discordant couples, including viral phenotype and genotype, HIV-1 co- receptor usage, innate immune function polymorphisms, human leukocyte