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Changes in Glomerular Kidney Function Among HIV-1–Uninfected Men and Women Receiving Emtricitabine–Tenofovir Disoproxil Fumarate Preexposure Prophylaxis -A Randomized Clinical Trial
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JAMA Intern Med. 2015
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.
In this safety analysis from a large randomized placebo-controlled trial, daily oral TDF-based PrEP resulted in a small but statistically significant decrease in eGFR-specifically, a change of less than 1.5% from baseline that was nonprogressive for 36 months and not accompanied by a significant increase in the likelihood of a clinically relevant change in eGFR (ie, ≥25%). The observed results were consistent in different subgroups and in multiple statistical approaches to evaluate the treatment causal effects. To our knowledge, this is the largest randomized trial to quantify the magnitude of subclinical eGFR decline in the presence of high adherence to PrEP in HIV-1–uninfected men and women and across a broad range of ages.
Mean eGFR decline appeared to be nonprogressive to a period of 36 months, as assessed with the additional follow-up of the 2 active PrEP arms beyond July 2011. The majority of creatinine elevations observed were self-limited and were not confirmed on subsequent measurement, and the occurrence of clinically relevant decline in eGFR (ie, ≥25% eGFR decline from baseline) was low. In the 2 subjects who developed eGFR of less than 60 mL/min/1.73 m2, eGFR rebounded to greater than 60 mL/min/1.73 m2 within 4 weeks after drug treatment discontinuation. There was no evidence of substantial increase in clinically relevant eGFR decline related to PrEP compared with placebo, although given the 95% CIs, an increase in absolute rate of a greater than 25% eGFR decline as high as 1% per year attributable to PrEP cannot be ruled out.
Second, long-term treatment effects beyond the study period cannot be ascertained. However, it is reassuring that in a large observational study with long-term follow-up (median, 7.9 years) of HIV-1–infected individuals undergoing TDF-containing combination antiretroviral therapy, most of the observed eGFR loss occurred during the first year of TDF exposure and stabilized after 2 years.7 In our study, mean eGFR decline appeared to stabilize after the first year of observation and then waned over time.
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