Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention: prospective studies in HIV-uninfected men and women

Antiretroviral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) alone or when co-formulated with emtricitabine (FTC), the same medication used for treatment of HIV infection, is a recommended and highly effective strategy to reduce the risk of sexual acquisition of HIV. The central objective of the studies described in this dissertation was to quantify the risk of potential off-target safety signals associated with TDF-based PrEP use in HIV-uninfected men and women with the overarching goal of providing the evidence base for clinical practice guidelines to accelerate population level delivery of PrEP to fight the global HIV epidemic. The specific aims include to: 1) determine whether TDF-based PrEP causes clinically significant decline in glomerular filtration rate (eGFR), a commonly used-measure of overall kidney function, in HIV-uninfected men and women; 2) determine whether TDF-based PrEP causes proximal tubular dysfunction when used as PrEP and whether proximal tubular dysfunction is associated with clinically relevant decline eGFR; 3) quantify infant exposure to tenofovir and emtricitabine via maternal breast milk when used as PrEP by lactating HIV-uninfected women; 4) determine whether open-label PrEP use for HIV prevention is associated with reduction in safer sex practices (i.e., sexual risk compensation); and 5) review and summarize the totality of empirical literature on the TDF-induced off-target effects when use as PrEP. Findings: Effect of TDF-based PrEP on eGFR: In a large randomized, placebo-controlled trial of daily oral TDF and FTC-TDF PrEP among 4640 heterosexual persons, with median per-protocol follow-up of 18 months and maximum follow-up of 36 months, PrEP resulted in a small but non-progressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (≥25%) eGFR decline. The decline quickly resolves within weeks after TDF discontinuation. Effect of FTC-TDF PrEP on proximal tubular dysfunction: In a randomized, placebo-controlled comparison among >1500 HIV-uninfected men and women, FTC-TDF PrEP was not associated with increased risk for proximal tubular dysfunction up to 24 months nor was proximal tubular dysfunction associated with clinically relevant decline in eGFR. Infant exposure to PrEP via breastfeeding: Among lactating women using FTC-TDF PrEP during early postpartum, the estimated infant doses received from breastfeeding and the resultant infant plasma concentrations for both tenofovir and emtricitabine are 12500- and >200-fold below the respective proposed pediatric doses used for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection and tenofovir was unquantifiable in a majority of infant plasma samples, suggesting that PrEP can be safely used during breastfeeding with minimal infant drug exposure. Sexual risk compensation: The transition from a double-blinded, placebo-controlled phase to one in which all participants were aware that they were receiving active, effective PrEP in the Partners PrEP Study, provided a natural experiment to assess behavioral risk compensation. PrEP given as part of a comprehensive HIV prevention package, did not result in substantial changes in risk-taking sexual behavior by heterosexual couples. Summary of current empirical literature: TDF-based PrEP is generally safe and well tolerated in HIV-uninfected men and women, and infant exposure via breastfeeding is minimal. The risk of the small, non-progressive, and reversible decline in eGFR and bone mineral density as well as the potential for selection of drug resistant viral mutation associated with PrEP are outweighed, at the population level and broadly for individuals, by PrEP’s substantial reduction in the risk of HIV infection. These data support the safety of TDF-based PrEP for prevention HIV combination with safer sex practices.