Tenofovir plasma concentration is a strong predictor of albuminuria in HIV-1-infected women Mwila Mulubwa1, Malie Rheeders1, Carla Fourie 2, I.M. Kruger 3, Linzie Du Plessis 4, Anne Grobler 4, Michelle Viljoen1 1Centre
of Excellence for Pharmaceutical Sciences (Pharmacen), Division of Pharmacology, 2Hypertension in Africa Research Team (HART), School for Physiology, Nutrition and Consumer Science,3Africa Unit for Transdisciplinary Health Research (AUTHUeR), 4DST/NWU Preclinical Drug Development Platform (PCDDP), North-West University, Potchefstroom campus, South Africa.
[email protected]
Introduction Treatment with tenofovir disoproxil fumarate (TDF) has been linked to increased biomarkers of bone turnover, reduced estimated glomerular filtration rate (eGFR)1 and decreased bone mineral density2. Elevated tenofovir (TFV) trough concentration is associated with increased risk of renal impairment and bone mineral loss3,4. However, no correlation was found between plasma TFV and creatinine clearance5. We investigated the relationship between mid-dose plasma TFV and markers of renal function and bone resorption in HIV-1-infected women and compared these markers with HIV-negative controls.
Fig. 1: Regression plot of plasma TFV concentration and albuminuria n=25, r=0.606, p=0.001
Methods Study design & ethics This was a pilot cross-sectional sub-study within Prospective Urban and Rural Epidemiology-South Africa (PURE-SA). It is a large epidemiological study taking place in low-, middle-, and high-income countries around the world whose overarching aim is to examine the relationship of societal influences on human lifestyle behaviours, cardiovascular risk factors, and incidence of chronic non communicable diseases6.The sub-study was approved by the Human Research Ethics Committee (HREC) of the North-West University, Potchefstroom (NWU00016-10-A1) and North West Department of Health, Mmabatho. Participants Sixty women participated; 30 HIV-1-infected on 300 mg daily TDF antiretroviral regimen were matched with 30 HIV-1-uninfected for age and body mass index (BMI) via propensity score matching. Plasma TFV was assayed using a validated HPLC/MS/MS method. Plasma and urine samples were analysed on Elecsys 2010 and Cobas Intergra 400 for the following markers: parathyroid hormone (PTH), C-terminal telopeptide (CTx), alkaline phosphatase (ALP), albuminuria, creatinine clearance (CrCl) and maximal renal tubular phosphate reabsorption (TmPO4/GFR). Blood samples were collected in the morning by registered nurses for all PURE-SA related investigations including TFV analysis (12-18 hours post TDF dose). Medication history was recorded by qualified pharmacists and assistants on a structured questionnaire.
Fig.2: Box and whisker plot of ALP and albuminuria
Statistical analysis Stepwise regression was used to determine relationship between plasma TFV and the markers. Mann-Whitney U test was used to compare markers between groups and then box and whisker plots were used to display significant markers.
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Results Plasma TFV calibration curves were linear (r2, 0.9942-0.9970) over concentration range of 12.5-600 ng/mL. Mean recovery was 91.5%. Accuracy, inter and intra precision were in the range of ≤15% relative standard error. Table 1: Participant’s comparative results HIV-1-infected (n=30) HIV-1-uninfected (n=30) P value Age , years (median) BMI, Kg/m2 (median) ALP, mean rank Albuminuria, mean rank
52 (IQR: 49-59) 20.5 (IQR: 18-28.9) 40.1 35.0
57 (IQR: 53-63) 24.4 (IQR: 19-33.5) 20.9 25.2
.011 .249 .000 .028
Median tenofovir concentration was 113 ng/mL (IQR: 74-139). No plasma TFV was found in 5 (16.7%) participants. TDF exposure ranged from 2-30 months. Plasma TFV correlated statistically significantly with albuminuria (r= 0.606, p= 0.001, see Fig.1) while PTH, CTx, CrCl and TmPO4/GFR were not significant. Albuminuria and ALP was significantly higher in HIV-1-infected than uninfected women (p
