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Objective: Tenofovir disoproxil fumarate is a commonly used antiretroviral drug, but risk factors for tenofovir (TFV)-associated kidney disease are not fully understood. We used intensive pharmacokinetic studies in a cohort of HIV-infected women on TFV-based therapy to study the relationship between TFV exposure and subsequent kidney function.

Design: This is a nested study within the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected women. Participants on TFV-based therapy underwent 24-h intensive pharmacokinetic sampling after witnessed dose. Kidney function was measured over the succeeding 7 years by serum creatinine [estimated glomerular filtration rate calculated by serum creatinine (eGFRcr)].

Methods: Multivariable linear mixed models evaluated the relationship of baseline TFV area under the-time concentration curves (AUCs) with subsequent changes in kidney function. Covariates included age, diabetes, hypertension, race, BMI, ritonavir use, duration of TFV exposure, current CD4 cell count, and HIV viral load.

Results: Of the 105 participants, persons within the highest baseline TFV AUC tertile had significantly lower eGFRcr compared with those in the lowest tertile (mean /- standard error: 80 /- 4.3 vs. 104 /- 2.5 ml/min per 1.73 m2, P < 0.0001). By year 7, this difference widened (72 /- 4.9 vs. 105 /- 2.9, P < 0.0001). After multivariable adjustment, TFV AUC in the highest tertile remained associated with lower eGFRcr relative to values in the lowest tertile at both baseline (-15 ml/min per 1.73 m2, P = 0.0047) and year 7 (-23 ml/min per 1.73 m2, P = 0.0002).

Conclusion: Through intensive TFV pharmacokinetic sampling, we found a strong association between greater TFV exposure and subsequent decline in kidney function. Variations in TFV drug exposure may partially account for subsequent nephrotoxicity in persons infected with HIV.

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