title: Tenofovir plasma concentrations related to estimated glomerular filtration rate changes in first-line regimens in African HIV-infected patients: ANRS 12115 DAYANA substudy.
abstract: OBJECTIVE
  An open-label randomized trial (DAYANA) was conducted in sub-Saharan settings to evaluate four different regimens containing tenofovir disoproxil fumarate as first-line treatment for HIV infection. The objectives of the present substudy were to assess the relationship between trough concentrations of tenofovir in plasma collected after 24 h (C24) and estimated glomerular filtration rates (eGFR) calculated by the different formulae that are available.
  
  
  METHODS
  The criteria for eligibility were those of the DAYANA trial, recruiting naive patients. The four tenofovir regimens were: Group 1, tenofovir/emtricitabine/nevirapine; Group 2, tenofovir/lopinavir/ritonavir; Group 3, tenofovir/emtricitabine/zidovudine; and Group 4, tenofovir/emtricitabine/efavirenz. The C24 of tenofovir was determined using LC-MS/MS. The eGFR was calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae.
  
  
  RESULTS
  The median C24 of tenofovir was 42 ng/mL. The C24 of tenofovir was higher with lopinavir/ritonavir than with the other three regimens: at Week 4, 84 ng/mL versus 25 ng/mL; and at Week 48, 81 ng/mL versus 52 ng/mL. The baseline merged eGFR was 98.2 mL/min/1.73 m(2) with the CKD-EPI equation. Only the mean changes in eGFR in Group 2 differed from the absolute value of zero (-8.2 mL/min/1.73 m(2)) with the CKD-EPI equation between baseline and Week 48. The Cockcroft-Gault formula is inappropriate for these African patients because it underestimated the baseline eGFR and overestimated the changes in eGFR between baseline and Week 48.
  
  
  CONCLUSIONS
  In this population of mostly female HIV-1-infected African patients, tenofovir plasma overexposure was associated with PI/ritonavir and a time-dependent decrease in eGFR, probably via an inhibition of MRP2/MRP4 efflux transporters. The close monitoring over time of the eGFR using MDRD or CKD-EPI calculations and by using other biomarkers of renal disorder should be proposed as an alternative to therapeutic drug monitoring in resource-limited countries.
authors.affiliation: APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Paris, France minh.le@bch.aphp.fr.
authors.forename: Minh Patrick
authors.initials: MP
authors.lastname: Lê
authors.affiliation: Institut de Médecine et d'Epidémiologie Appliquée, Paris, France APHP, Bichat-Claude Bernard Hospital, Tropical and Infectious Disease Department, Paris, France IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Landman
authors.affiliation: Central Hospital, Yaoundé, Cameroon.
authors.forename: Sinata
authors.initials: S
authors.lastname: Koulla-Shiro
authors.affiliation: IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France APHP, Bichat-Claude Bernard Hospital, Virology Department, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.affiliation: Fann University Hospital, Dakar, Senegal.
authors.forename: Papa-Salif
authors.initials: PS
authors.lastname: Sow
authors.affiliation: Fann University Hospital, Dakar, Senegal.
authors.forename: Mamadou-Baila
authors.initials: MB
authors.lastname: Diallo
authors.affiliation: Fann University Hospital, Dakar, Senegal.
authors.forename: Ndèye Fatou
authors.initials: NF
authors.lastname: Ngom Gueye
authors.affiliation: Central Hospital, Yaoundé, Cameroon.
authors.forename: Maguy
authors.initials: M
authors.lastname: Ngolle
authors.affiliation: Department of Infectious Diseases, CHU Montpellier, Montpellier, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Le Moing
authors.affiliation: UMI 233, Institut de Recherche pour le Développement-Université Montpellier 1, Montpellier, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Eymard-Duvernay
authors.affiliation: Institut de Médecine et d'Epidémiologie Appliquée, Paris, France.
authors.forename: Aïda
authors.initials: A
authors.lastname: Benalycherif
authors.affiliation: Department of Infectious Diseases, CHU Montpellier, Montpellier, France UMI 233, Institut de Recherche pour le Développement-Université Montpellier 1, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Delaporte
authors.affiliation: Institut de Médecine et d'Epidémiologie Appliquée, Paris, France APHP, Saint-Antoine Hospital, Department of Infectious Diseases, Pierre et Marie Curie University, Paris, France.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Girard
authors.affiliation: APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Paris, France IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D002853:Chromatography, Liquid; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir
keywords: ART; antiretroviral therapy; drug monitoring