Minh Patrick Lê1, Roland Landman2, Sinata Koulla-Shiro3, Charlotte Charpentier4, Papa-Salif Sow5, Mamadou-Baila Diallo5, Ndèye Fatou Ngom Gueye5, Maguy Ngolle3, Vincent Le Moing6, Sabrina Eymard-Duvernay7, Aïda Benalycherif8, Eric Delaporte9, Pierre-Marie Girard10, Gilles Peytavin11. 1. APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Paris, France minh.le@bch.aphp.fr. 2. 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. 3. Central Hospital, Yaoundé, Cameroon. 4. IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France APHP, Bichat-Claude Bernard Hospital, Virology Department, Paris, France. 5. Fann University Hospital, Dakar, Senegal. 6. Department of Infectious Diseases, CHU Montpellier, Montpellier, France. 7. UMI 233, Institut de Recherche pour le Développement-Université Montpellier 1, Montpellier, France. 8. Institut de Médecine et d'Epidémiologie Appliquée, Paris, France. 9. Department of Infectious Diseases, CHU Montpellier, Montpellier, France UMI 233, Institut de Recherche pour le Développement-Université Montpellier 1, Montpellier, France. 10. Institut de Médecine et d'Epidémiologie Appliquée, Paris, France APHP, Saint-Antoine Hospital, Department of Infectious Diseases, Pierre et Marie Curie University, Paris, France. 11. APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Paris, France IAME, UMR 1137, Univ Paris Diderot, Sorbonne Paris Cité, and INSERM, Paris, France.
Abstract
OBJECTIVES: 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.
RCT Entities:
OBJECTIVES: 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.
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