title: Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study.
abstract: BACKGROUND
  Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR).
  
  
  METHODS
  In this prospective international cohort study, HIV-positive adult participants (aged ≥16 years) from the D:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1·73 m(2) were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6 months (whichever occurred first). Chronic kidney disease was defined as confirmed (>3 months apart) eGFR lower than 60 mL/min per 1·73 m(2). The primary outcome was the occurrence of chronic kidney disease. Poisson regression was used to estimate the incidence rate of chronic kidney disease associated with cumulative exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, other ritonavir-boosted protease inhibitors, or abacavir.
  
  
  RESULTS
  Between Jan 1, 2004, and July 26, 2013, 23,905 eligible individuals from the D:A:D study were included. Participants had a median baseline eGFR of 110 mL/min per 1·73 m(2) (IQR 100-125), a median age of 39 years (33-45), and median CD4 cell count of 441 cells per mm(3) (294-628). During a median follow-up of 7·2 years (IQR 5·1-8·9), 285 (1%) of 23,905 people developed chronic kidney disease (incidence 1·76 per 1000 person-years of follow-up [95% CI 1·56-1·97]). After adjustment, we recorded a significant increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate (adjusted incidence rate ratio 1·14 [95% CI 1·10-1·19], p<0·0001), ritonavir-boosted atazanavir (1·20 [1·13-1·26], p<0·0001), and ritonavir-boosted lopinavir (1·11 [1·06-1·16], p<0·0001), but not other ritonavir-boosted protease inhibitors or abacavir.
  
  
  CONCLUSIONS
  In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored.
  
  
  BACKGROUND
  The Highly Active Antiretroviral Therapy Oversight Committee.
authors.affiliation: Department of Infection and Population Health, University College London, London, UK. Electronic address: a.mocroft@ucl.ac.uk.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mocroft
authors.affiliation: CHIP, Department of Infectious Diseases, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
authors.affiliation: Division of Nephrology, Icahn School of Medicine at Mount Sinai School, New York, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ross
authors.affiliation: Clinic for Infectious Diseases and Hospital Hygiene, Kantonsspital Aarau, Aarau, Switzerland.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Fux
authors.affiliation: Academic Medical Center, Division of Infectious Diseases and Department of Global Health, University of Amsterdam, Amsterdam, Netherlands; Stichting HIV Monitoring, Amsterdam, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Reiss
authors.affiliation: Nephrology Unit, Caremeau University Hospital, Nimes, France; Biostatistics, Epidemiology and Public Health, Institut Universitaire de Recherche Clinique, University of Montpellier, Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Moranne
authors.affiliation: Université de Bordeaux, INSERM U 897, CHU de Bordeaux, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Morlat
authors.affiliation: Clinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Antonella d'Arminio
authors.initials: Ad
authors.lastname: Monforte
authors.affiliation: CHIP, Department of Infectious Diseases, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Kirk
authors.affiliation: CHIP, Department of Infectious Diseases, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Ryom
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000069446:Atazanavir Sulfate / Q000009:adverse effects / Q000627:therapeutic use; D001315:Australia; D005060:Europe; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000503:physiopathology; D000068698:Tenofovir / Q000009:adverse effects / Q000627:therapeutic use; D014481:United States; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D000068698:Tenofovir