1. Tenofovir disoprovil fumarate (TDF) based preexposure prophylaxis (PrEP) causes a small but statistically significant decrease in kidney function, as measured by estimated glomerular filtration rate (eGFR), in HIV-1 uninfected individuals.
2. TDF therapy did not result in a clinically significant decrease in eGFR as compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Previous studies have shown the efficacy of tenofovir disoprovil fumarate (TDF) in decreasing viral load in patients with HIV-1. However, the literature also shows that TDF administration is associated with a decline in estimated glomerular filtration rate (eGFR) in HIV infected patients. It is unclear whether this decrease in eGFR also occurs in healthy patients using TDF for preexposure prophylaxis (PrEP). This randomized controlled trial (RCT) aimed to study the impact of daily TDF-based PrEP on eGFR in HIV-1 non-infected individuals as compared to placebo.
Both TDF-based PrEP regimens were associated with a small but statistically significant decline in eGFR. There was a 0.9% and 1.2% decline in eGFR associated with TDF and emtricitabine with TDF (FTC-TDF), respectively. This decrease occurred within 4 weeks of TDF PrEP administration, remained stable through 12 months and diminished thereafter, and were constant through all age and sex subgroup and sensitivity analyses.
Strengths of this study include it being a large RCT using appropriately chosen per-protocol analysis to determine TDF drug safety. Also, usage of the validated Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equation provides higher accuracy in normal range eGFR values and African patient populations. However, these GFR estimating equations may still be inaccurate in those with low muscle mass, reduced meat intake or muscle wasting. Additionally, this study was conducted in healthy individuals, thus generalization to populations with comorbidities or are on nephrotoxic medications may not be possible.
In-Depth [randomized controlled trial]: This randomized controlled trial took place between 2008 and 2012 and randomized 4,640 HIV-1 uninfected Kenyan and Ugandan men and women to one of the three study groups: placebo, TDF, and FTC-TDF. TDF-based groups were given standard HIV-treatment doses of the drugs. Serum creatinine levels were measured at baseline, at month 1 and then quarterly subsequently. The validated CKD-EPI equation was used to calculate the eGFR. Predetermined study outcomes include mean eGFR change and a 25% or greater eGFR decline from baseline. Outcomes were analyzed through a per-protocol safety analysis, standard regression methods and were adjusted for site, sex and age.
Study participants were majority male (63%), had a mean age of 35 years, and were followed for a median of 18 months to a maximum of 36 months. Overall mean baseline eGFR for participants was 130 mL/min/1.73 m2. Average decline in eGFR in TDF PrEP vs. placebo was -1.23 mL/min/1.73 m2 (95%CI -2.06 to -0.40, P<0.001) for TDF and -1.59 mL/min/1.73 m2 (95%CI -2.44 to -0.74, P<0.001) for FTC-TDF. Incidence rate differences of a 25% or greater decline in eGFR were 0.25/100 person-years (95%CI -0.33 to 0.83) for TDF and 0.41/100 person-years (95%CI -0.19 to 1.01) for FTC-TDF.
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