title: Higher tenofovir exposure is associated with longitudinal declines in kidney function in women living with HIV.
abstract: 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.
  
  
  METHODS
  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 m, 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 m, P = 0.0047) and year 7 (-23 ml/min per 1.73 m, P = 0.0002).
  
  
  CONCLUSIONS
  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.
authors.affiliation: aDepartment of Medicine, University of California, San Francisco bSchool of Public Health, University of California, Berkeley cGeneral Internal Medicine Division, San Francisco Veterans Affairs Medical Center dDepartment of Clinical Pharmacy eDepartment of Epidemiology and Biostatistics, University of California, San Francisco, California fDivision of Infectious Diseases, State University of New York, Downstate Medical Center, Brooklyn, New York gDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York hCORE Center/Division of Infectious Diseases, John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois iDepartment of Medicine, Georgetown University Medical Center, Washington DC jDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Sanjiv M
authors.initials: SM
authors.lastname: Baxi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Scherzer
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Greenblatt
authors.forename: Howard
authors.initials: H
authors.lastname: Minkoff
authors.forename: Anjali
authors.initials: A
authors.lastname: Sharma
authors.forename: Mardge
authors.initials: M
authors.lastname: Cohen
authors.forename: Mary A
authors.initials: MA
authors.lastname: Young
authors.forename: Alison G
authors.initials: AG
authors.lastname: Abraham
authors.forename: Michael G
authors.initials: MG
authors.lastname: Shlipak
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D003404:Creatinine / Q000097:blood; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008875:Middle Aged; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000139:chemically induced*; D000068698:Tenofovir / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; D003404:Creatinine