Tenofovir plasma exposures and Creatinine Clearance changes in 1st line Regimen of African patients in Cameroon and Senegal: ANRS12115 DAYANA study

Transcription

1 Abstract O_03 Tenofovir plasma exposures and Creatinine Clearance changes in 1st line Regimen of African patients in Cameroon and Senegal: ANRS12115 DAYANA study M.P. Lê Pharmacy Resident Clinical Pharmacology Department Bichat Claude Bernard Hospital Univ Paris Diderot, Paris, France 15 May 2013

2 Background Biological monitoring in resource-limited settings: challenge in managing HIV infection, in particular therapeutic drug monitoring Scarcity of pharmacokinetic and pharmacodynamic data in African populations Several available formulae for determination estimated glomerular filtration rate (egfr) DAYANA ANRS study: DAkar YAoundé New Antiretroviral treatment 96-week, pilot, multicenter, open-label, noncomparative, randomized trial Evaluation of 4 regimens with tenofovir disoproxil fumarate (TDF)

3 Objectives To assess adherence and safety of the tested antiretroviral (ARV) regimens at W4 and W48 To assess the relationship between tenofovir (TFV) trough plasma concentrations and egfr calculated by the different available formulae

4 Material and Methods TFV trough plasma concentrations: Collected 24 hrs (C 24h ) after the last drug intake Determined with LC-MS/MS at W4-48 (LOQ <10 ng/ml) TFV C 24h interpretation: Adequate C 24h (North Countries): 50 ng/ml (35-77) Predictive cut-off for tubulopathy: 80 ng/ml egfr: Cockroft-Gault (adjusted /BSA), MDRD, CKD-EPI Treatment adherence Data are presented as median (IQR25-75%) Statistical analysis: Spearman and t-tests

5 DAYANA study design D0 INCLUSION AND RANDOMIZATION Group 1 TDF/FTC (Truvada ) + NVP (generic tablets) Group 2 TDF (Viread ) + LPV/r (Aluvia ) Group 3 TDF/FTC (Truvada ) + ZDV (generic tablet) Group 4 TDF/FTC/EFV (Atripla ) (300/200mg QD + 200mg BID) (300 mg QD + 400/100 mg BID) (300/200 mg QD mg BID) (300/200/600 mg QD) Follow-up: W16: Treatment modification if plasma HIV-1 RNA > 800 copies/ml W24: Treatment modification if plasma HIV-1 RNA > 100 copies/ml W96: End of Trial Eligibility criteria: age 18 years in Senegal or 21 years in Cameroon ARV-naïve CD4+ cell count>50/mm 3 Exclusion criteria: Opportunistic infections, severe pathology, treatment containing rifampin, Severe renal or liver impairments Clearance of creatinine 50 ml/min (Cockroft-Gault) Hemoglobin < 8 g/dl, Neutrophils < 500/mm 3 Pregnancy

6 Patient Baseline Characteristics Characteristics, median (IQR25-75%) Group 1 TDF/FTC/NVP (n=31) Group 2 TDF+LPV/r (n=29) Group 3 TDF/FTC/ZDV (n=29) Group 4 TDF/FTC/EFV (n=30) Female, n (%) 17 (55) 20 (69) 20 (69) 22 (73) Age (years) 37 (22-56) 42 (25-62) 39 (23-55) 40 (26-56) Plasma HIV-1 RNA, log 10 copies/ml 5.4 ( ) 5.4 ( ) 5.1 ( ) 5.6 ( ) CD4 (cells/mm 3 ) 191 (53-345) 208 (63-336) 203 (77-358) 201 (55-308) Hemoglobin (g/dl) 11.8 ( ) 11.3 ( ) 11.4 ( ) 11.5 ( ) Neutrophils, cells/mm ( ) 1970 ( ) 1650 ( ) 1830 ( ) egfr (ml/min/1.73m 2 ), Cockroft-Gault 80.7 ( ) 76.9 ( ) 86.2 ( ) 79.9 ( ) MDRD 87.6 ( ) 84.3 ( ) 95.4 ( ) 91.4 ( ) CKD-EPI 93.9 ( ) 90.5 ( ) ( ) 99.2 ( ) African population have a higher GFR than Caucasians at the same level of serum creatinine. This is due to higher average muscle mass and creatinine generation rate in the African population

7 TFV C 24h with or without LPV/r at W4 and W48 W4 W48 TFV C 24h (ng/ml) 1000 p < p < ng/ml 84 ng/ml 52 ng/ml 81 ng/ml 10 1 without LPV/r with LPV/r without LPV/r with LPV/r n=78 n=10 n=86 n=10 TFV C 24h was consistent with those reported in North Countries TFV C 24h was statistically higher with LPV/r than without Proportion of TFV C 24h > 80 ng/ml was higher with LPV/r (60%) than without (13%), p<0.05 NB: Treatment adherence by questionnaire was from 93% to 100% at W48

8 egfr according to the different formulae, with or without LPV/r at W4 and W48 egfr (ml/min/1.73m 2 ) W4 p = NS W48 p < 0.05 p = 0.08 p < 0.01 CG MDRD CKD-EPI without LPV/r n=90 with LPV/r without LPV/r n=29 n=90 with LPV/r n=29 egfr decrease between W4 and W48 was modest whatever the association with LPV/r At W48, egfr was lower with LPV/r than without, whatever the formula used TFV C 24h was inversely related to egfr at W48 (p<10-4 ) but not at W4 (p=0.11, p=0.14, p=0.09), for all groups combined, whatever the formula used It confirms the possible cumulative and time-dependant mechanism of renal disease

9 Mean egfr changes between W48 and baseline and its comparison to zero Mean egfr changes (ml/min/1.73m 2 ) 15 12,5 10 7,5 5 2,5 0-2,5-5 -7,5-10 p< p=ns +1.3 p=ns p=ns -6.9 p=ns -8.2 p<0.05 CG MDRD CKD-EPI without LPV/r with LPV/r Mean egfr changes were: significantly different in the regimen with LPV/r with CKD-EPI equation, but modest significantly different in regimens without LPV/r with Cockroft-Gault. However, it should not be considered as adequate in African populations

10 Summary In our population of mostly female adherent HIV-1- infected Africans, these results confirmed that: TFV C 24h was related to a time-dependant decrease of egfr TFV C 24h was increased with LPV/r egfr was decreased with LPV/r at W48 egfr changes with CKD-EPI equation was significant with LPV/r, however it remains a modest decrease (-8.2 ml/min/1.73 m 2 W48-BL)

11 Tenofovir secretion in proximal tubular cells LPV/r Tenofovir Tenofovir Tenofovir hoat1 Tenofovir MP MRP-2 Tenofovir MP hoat3 Tenofovir DP MRP-4 Tenofovir DP Basolateral membrane Blood Luminal membrane Urine

12 Summary In our population of mostly female adherent HIV-1- infected Africans, these results confirmed that: TFV C 24h was related to a time-dependant decrease of egfr 7,8 TFV C 24h was higher with LPV/r 9 egfr was lower with LPV/r at W48 egfr changes with CKD-EPI equation was significant with LPV/r, however it remains a modest decrease (-8.2 ml/min/1.73 m2 W48-BL) Unfortunately, therapeutic drug monitoring is not yet available in resource-limited settings, Close monitoring of egfr by MDRD or CKD-EPI calculation over time and the use of other renal disorders biomarkers are necessary for a better HIVinfection management when TDF is prescribed

13 Acknowledgements S. Koulla-Shiro 2, G. Peytavin 1, P. Salif Sow 3, B. Ndiaye 3, M. B. Koita Fall 3, C. Essomba 2, A. Benalycherif 4, P.M. Girard 4,5, R. Landman 1,4 1 Bichat Claude Bernard Hospital, Univ Paris 7, Univ Denis Diderot, Paris, France 2 Univ of Yaoundé 1 and Central Hospital, Yaoundé, Cameroon 3 Univ Fann Hospital, Dakar, Senegal 4 Institut de Médecine et d Epidémiologie Appliquée, Paris, France 5 Saint-Antoine Hospital, Univ Paris 6, Univ Pierre et Marie Curie, France. Thank you for your attention