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

Amanda Mocroft, Jens D. Lundgren, Michael G. Ross, Christoph A. Fux, Peter Reiss, Olivier Moranne, Philippe Morlat, Antonella d'Arminio Monforte, Ole Kirk, Lene Ryom, Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) Study, Mauro Zaccarelli, Andrea Antinori, Rosa Antonietta Acinapura, Gianpiero D'Offizi

Research output: Contribution to journalArticle

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.

FINDINGS: 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.

INTERPRETATION: 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.

FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee.

Original languageEnglish
Pages (from-to)e23-32
JournalThe Lancet HIV
Volume3
Issue number1
DOIs
Publication statusPublished - Jan 2016

Fingerprint

Glomerular Filtration Rate
Chronic Renal Insufficiency
Ritonavir
Cohort Studies
HIV
Tenofovir
Lopinavir
Incidence
Protease Inhibitors
Kidney
Highly Active Antiretroviral Therapy
CD4 Lymphocyte Count
HIV Infections

Keywords

  • Adolescent
  • Adult
  • Anti-HIV Agents
  • Atazanavir Sulfate
  • Australia
  • Europe
  • Female
  • Glomerular Filtration Rate
  • HIV Infections
  • Humans
  • Male
  • Middle Aged
  • Prospective Studies
  • Renal Insufficiency, Chronic
  • Tenofovir
  • United States
  • Young Adult
  • Clinical Trial
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

Cite this

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. / Mocroft, Amanda; Lundgren, Jens D.; Ross, Michael G.; Fux, Christoph A.; Reiss, Peter; Moranne, Olivier; Morlat, Philippe; Monforte, Antonella d'Arminio; Kirk, Ole; Ryom, Lene; Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) Study ; Zaccarelli, Mauro; Antinori, Andrea; Acinapura, Rosa Antonietta; D'Offizi, Gianpiero.

In: The Lancet HIV, Vol. 3, No. 1, 01.2016, p. e23-32.

Research output: Contribution to journalArticle

Mocroft, Amanda ; Lundgren, Jens D. ; Ross, Michael G. ; Fux, Christoph A. ; Reiss, Peter ; Moranne, Olivier ; Morlat, Philippe ; Monforte, Antonella d'Arminio ; Kirk, Ole ; Ryom, Lene ; Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) Study ; Zaccarelli, Mauro ; Antinori, Andrea ; Acinapura, Rosa Antonietta ; D'Offizi, Gianpiero. / 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. In: The Lancet HIV. 2016 ; Vol. 3, No. 1. pp. e23-32.
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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.FINDINGS: 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.INTERPRETATION: 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.FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee.",
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author = "Amanda Mocroft and Lundgren, {Jens D.} and Ross, {Michael G.} and Fux, {Christoph A.} and Peter Reiss and Olivier Moranne and Philippe Morlat and Monforte, {Antonella d'Arminio} and Ole Kirk and Lene Ryom and {Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) Study} and Mauro Zaccarelli and Andrea Antinori and Acinapura, {Rosa Antonietta} and Gianpiero D'Offizi",
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year = "2016",
month = "1",
doi = "10.1016/S2352-3018(15)00211-8",
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volume = "3",
pages = "e23--32",
journal = "The Lancet HIV",
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TY - JOUR

T1 - 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

T2 - a prospective international cohort study

AU - Mocroft, Amanda

AU - Lundgren, Jens D.

AU - Ross, Michael G.

AU - Fux, Christoph A.

AU - Reiss, Peter

AU - Moranne, Olivier

AU - Morlat, Philippe

AU - Monforte, Antonella d'Arminio

AU - Kirk, Ole

AU - Ryom, Lene

AU - Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) Study

AU - Zaccarelli, Mauro

AU - Antinori, Andrea

AU - Acinapura, Rosa Antonietta

AU - D'Offizi, Gianpiero

N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.

PY - 2016/1

Y1 - 2016/1

N2 - 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.FINDINGS: 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.INTERPRETATION: 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.FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee.

AB - 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.FINDINGS: 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.INTERPRETATION: 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.FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee.

KW - Adolescent

KW - Adult

KW - Anti-HIV Agents

KW - Atazanavir Sulfate

KW - Australia

KW - Europe

KW - Female

KW - Glomerular Filtration Rate

KW - HIV Infections

KW - Humans

KW - Male

KW - Middle Aged

KW - Prospective Studies

KW - Renal Insufficiency, Chronic

KW - Tenofovir

KW - United States

KW - Young Adult

KW - Clinical Trial

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, P.H.S.

U2 - 10.1016/S2352-3018(15)00211-8

DO - 10.1016/S2352-3018(15)00211-8

M3 - Article

VL - 3

SP - e23-32

JO - The Lancet HIV

JF - The Lancet HIV

SN - 2352-3018

IS - 1

ER -