title: Association between antiretroviral exposure and renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study.
abstract: BACKGROUND
  Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)-positive persons with initially normal renal function is unknown.
  
  
  METHODS
  D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥ 90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤ 70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤ 60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥ 3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.
  
  
  RESULTS
  Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤ 70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35-5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10-1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7-6.1 years). A current eGFR of 60-70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38-2.14]) but not other ARVs compared with a current eGFR of ≥ 90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12-1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09-1.32]) were independent predictors of a confirmed eGFR of ≤ 70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05-1.17] and 1.22/year [95% CI, 1.16-1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs.
  
  
  CONCLUSIONS
  Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.
authors: Copenhagen HIV Program, Faculty of Health and Medical Sciences, University of Copenhagen, N Denmark. lrn@cphiv.dk
authors: Lene
authors: L
authors: Ryom
authors: Amanda
authors: A
authors: Mocroft
authors: Ole
authors: O
authors: Kirk
authors: Signe W
authors: SW
authors: Worm
authors: David A
authors: DA
authors: Kamara
authors: Peter
authors: P
authors: Reiss
authors: Michael
authors: M
authors: Ross
authors: Christoph A
authors: CA
authors: Fux
authors: Philippe
authors: P
authors: Morlat
authors: Olivier
authors: O
authors: Moranne
authors: Colette
authors: C
authors: Smith
authors: Jens D
authors: JD
authors: Lundgren
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000453:epidemiology*; D028761:Withholding Treatment
chemical_list: D044966:Anti-Retroviral Agents
references: Clin J Am Soc Nephrol. 2010 Dec;5(12):2269-75
references: 20876679
references: Lab Invest. 2011 Jun;91(6):852-8
references: 21403643
references: Nephrol Dial Transplant. 2005 Apr;20(4):743-6
references: 15741212
references: J Infect Dis. 2011 Oct 15;204(8):1191-201
references: 21917892
references: Clin Infect Dis. 2003 Dec 15;37(12):e174-6
references: 14689363
references: Clin J Am Soc Nephrol. 2011 Jul;6(7):1700-7
references: 21566114
references: JAMA. 2004 Jul 14;292(2):191-201
references: 15249568
references: HIV Med. 2009 Jul;10(6):343-50
references: 19490182
references: Clin Infect Dis. 2003 Apr 15;36(8):1070-3
references: 12684922
references: Expert Opin Drug Saf. 2006 Mar;5(2):275-87
references: 16503748
references: Am J Kidney Dis. 2012 May;59(5):628-35
references: 22206742
references: AIDS. 2012 Apr 24;26(7):867-75
references: 22313955
references: J Acquir Immune Defic Syndr. 2008 Jan 1;47(1):74-8
references: 17971715
references: Am J Kidney Dis. 2012 Oct;60(4):539-47
references: 22521282
references: N Engl J Med. 2008 Feb 7;358(6):568-79
references: 18256392
references: N Engl J Med. 2006 Nov 16;355(20):2158-9
references: 17108352
references: AIDS. 2012 Mar 13;26(5):567-75
references: 22398568
references: J Acquir Immune Defic Syndr. 2012 Jan 1;59(1):18-30
references: 21992924
references: J Postgrad Med. 2006 Oct-Dec;52(4):296-7
references: 17102551
references: AIDS. 2012 Sep 24;26(15):1917-26
references: 22781222
references: AIDS. 2004 Mar 5;18(4):705-6
references: 15090783
references: Virchows Arch. 2007 Jun;450(6):665-70
references: 17464512
references: Clin Infect Dis. 2012 Nov;55(9):1262-9
references: 22820542
references: Ann Intern Med. 2003 Sep 2;139(5 Pt 1):313-20
references: 12965939
references: Nephrol Dial Transplant. 2010 Mar;25(3):801-7
references: 19889870
references: Clin Infect Dis. 2006 Jan 15;42(2):283-90
references: 16355343
references: J Infect Dis. 2008 Jan 1;197(1):102-8
references: 18171292
references: AIDS. 2003 Nov 21;17(17):2543-4
references: 14600530
references: Ann Intern Med. 2003 Jul 15;139(2):137-47
references: 12859163
references: Nephron. 1976;16(1):31-41
references: 1244564
references: Clin Infect Dis. 2005 Apr 15;40(8):1194-8
references: 15791522
references: AIDS Patient Care STDS. 2010 Jun;24(6):353-60
references: 20515419
references: AIDS. 2010 Jul 17;24(11):1667-78
references: 20523203
references: N Engl J Med. 2003 Nov 20;349(21):1993-2003
references: 14627784
references: Clin Nephrol. 2012 Apr;77(4):311-20
references: 22445475
references: N Engl J Med. 1987 Oct 22;317(17):1098
references: 3657876
references: Antimicrob Agents Chemother. 2004 May;48(5):1469-87
references: 15105094
references: Kidney Int. 2006 Jan;69(2):375-82
references: 16408129
references: J Acquir Immune Defic Syndr. 2009 Jul 1;51(3):258-63
references: 19582894
references: AIDS. 2007 Nov 12;21(17):2357-8
references: 18090291
references: Am J Kidney Dis. 2004 Nov;44(5):e81-4
references: 15492941
references: HIV Med. 2010 May;11(5):308-17
references: 20002500
references: AIDS. 2011 Aug 24;25(13):1671-3
references: 21716074
references: Clin Infect Dis. 2010 Sep 1;51(5):496-505
references: 20673002
references: PLoS One. 2011;6(10):e26042
references: 22022501
references: Kidney Int. 2011 Aug;80(3):302-9
references: 21544066