Changes in glomerular kidney function among HIV-1-uninfected men and women receiving emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial

Abstract

Importance: Tenofovir disoproxil fumarate (TDF) use has been associated with declines in the estimated glomerular filtration rate (eGFR) when used as part of antiretroviral treatment by persons with human immunodeficiency virus (HIV) type 1, but limited data are available for risk when used as preexposure prophylaxis (PrEP) for HIV-1 prevention.

Objective: To determine whether TDF-based PrEP causes eGFR decline in HIV-1-uninfected adults.

Design, setting, and participants: A per-protocol safety analysis of changes in eGFR in the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among heterosexual HIV-1-uninfected members of serodiscordant couples in Kenya and Uganda. The trial was conducted from 2008 to 2012.

Main outcomes and measures: Predefined outcomes of this analysis were mean eGFR change and a 25% or greater eGFR decline from baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

Results: Of 4640 participants in the once-daily TDF (n = 1548), FTC-TDF (n = 1545), or placebo (n = 1547) groups, 63% were men. At enrollment, median age was 35 years (range, 18-64 years), and mean eGFR was 130 mL/min/1.73 m². During a median follow-up of 18 months (interquartile range 12-27 months), mean within-group eGFR change from baseline was +0.14 mL/min/1.73 m² for TDF, -0.22 mL/min/1.73 m² for FTC-TDF, and +1.37 mL/min/1.73 m² for placebo, translating into average declines in eGFR attributable to PrEP vs placebo of -1.23 mL/min/1.73 m² (95% CI, -2.06 to -0.40; P = .004) for TDF and -1.59 mL/min/1.73 m² (95% CI, -2.44 to -0.74; P < .001) for FTC-TDF. The difference in mean eGFR between PrEP and placebo appeared by 1 month after randomization, was stable through 12 months, and then appeared to wane thereafter. The respective proportions of persons who developed a confirmed 25% or greater eGFR decline from baseline by 12 and 24 months was 1.3% and 1.8% for TDF and 1.2% and 2.5% for FTC-TDF, and these frequencies were not statistically different from the confirmed decline in the placebo group (0.9% and 1.3% by 12 and 24 months, respectively).

Conclusions and relevance: In this large randomized, placebo-controlled trial among heterosexual persons, with median follow-up of 18 months and maximum follow-up of 36 months, daily oral TDF-based PrEP resulted in a small but nonprogressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (≥25%) eGFR decline.

Trial registration: clinicaltrials.gov Identifier: NCT00557245.

Conflict of interest statement

Conflict of Interest Disclosures: All authors declare no conflict of interest and no financial interests.

Figures

Figure 1. Study Participants

Overall, 4640 (98%) HIV-1 uninfected persons contributed to the primary per-protocol safety analysis. 107 participants were not included in the primary analysis: 51 because they did not have any post-randomization creatinine measurement to permit estimation of glomerular filtration rate and 56 because were >4 consecutive weeks off study medication by the time of their first post-randomization creatinine measurement mostly due to missed visits and drug refusal. The intention-to-treat analysis included all randomized participants with at least one post-randomization serum creatinine measurement regardless of time off study medication (n=4696). FTC denotes emtricitabine and TDF denotes tenofovir disoproxil fumarate.

Figure 2. Variation over time in crude means eGFR change from baseline, according to treatment group

Plot 2A represents all data collected through July 2011, when the trial’s placebo arm was discontinued; because of truncation of follow-up time in July 2011, few participants had achieved >30 months of follow-up. Plot 2B represents crude mean eGFR changes from baseline that includes additional follow-up of the TDF and FTC-TDF arms beyond July 2011. The placebo group contributed person-time only up to July 2011. Whiskers represent 95% confidence intervals. FTC denotes emtricitabine and TDF denotes tenofovir disoproxil fumarate.

Figure 3. Cumulative probability of a ≥25% estimated glomerular filtration rate decline from baseline, according to study treatment

Plot 3A represents estimates for the primary per-protocol safety analysis including data accrued up to July 2011 when the placebo arm was discontinued by the DSMB. The proportion of persons who developed a ≥25% eGFR decline from baseline was 1.3% for TDF, 1.2% for FTC-TDF, and 0.9% for placebo by 12 months; 1.8% for TDF, 2.5% for FTC-TDF, and 1.3% for placebo by 24 months; and 1.8% for TDF, 2.5% for FTC-TDF, and 2.2% for placebo by 36 months. Plot 3B represents estimates for the sensitivity analysis that included additional follow-up of the TDF-and FTC-TDF arms beyond July 2011 with placebo arm data truncated at July 10, 2011. The proportion of persons who developed a ≥25% eGFR decline from baseline was 1.3% for TDF, 1.3% for FTC-TDF, and 0.9% for placebo by 12 months; 1.9% for TDF, 2.3% for FTC-TDF, and 1.3% for placebo by 24 months; and 2.3% for TDF, 2.8% for FTC-TDF, and 2.2% for placebo by 36 months. Failure function was calculated over full data and evaluated at indicated times; it is not calculated from aggregates of number of persons shown on the x-axis plots. FTC denotes emtricitabine and TDF denotes tenofovir disoproxil fumarate.