Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study.
ABSTRACT To investigate the association between tenofovir disoproxil fumarate (TDF) use and renal abnormality in a large cohort of HIV-1-infected children on antiretroviral therapy (ART).
Nested case-control study.
Patients were from the Collaborative HIV Paediatric Study, a cohort of approximately 95% of HIV-1-infected children in the UK/Ireland. Serum (but not urine) biochemistry results for 2002-2008 were obtained for 456 ART-exposed children (2-18 years) seen at seven hospitals. Cases had either confirmed hypophosphataemia DAIDS grade at least 2 or estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m; three controls per case were matched by hospital. Conditional logistic regression identified risk factors for renal abnormality.
Twenty of 456 (4.4%) had hypophosphataemia, and one had eGFR less than 60 ml/min per 1.73 m. Ten of 20 (50%) cases versus 11 of 60 (18%) controls had taken TDF-containing ART for a median [interquartile range (IQR)] of 18 [17-20] months, as part of second-line or salvage therapy. The hypophosphataemia incidence rate was 4.3/100 person-years in the TDF group versus 0.9/100 person-years in those not exposed to TDF. In multivariable analysis, only TDF exposure in the previous 6 months was associated with hypophosphataemia [odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.45-16.0, P = 0.01]. In six of 10 children with hypophosphataemia and at least four subsequent phosphate measurements, phosphate values returned to normal when TDF was stopped; in four with three measures or less, values rose but remained subnormal.
Hypophosphataemia was uncommon (4%), but was associated with prolonged TDF use, and was generally reversible following TDF withdrawal. Findings highlight the importance of continuing to monitor longer-term renal function, in particular tubular function, especially in those taking TDF. Further studies assessing urine biochemistry measures which more accurately indicate renal tubular damage are required.
SourceAvailable from: Jorge Lujan-Zilbermann[Show abstract] [Hide abstract]
ABSTRACT: Background:Tenofovir disoproxil fumarate (TDF) causes bone, endocrine and renal changes, by unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects.Methods:Using baseline data from a multicenter study in HIV-infected youth on stable treatment with regimens containing TDF (N=118) or no TDF (N=85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 (FGF23)), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF.Results:Mean age was 20.9 (SD 2.0) years; 63% were male; and 52% African American. Compared to the noTDF group, the TDF group showed lower mean estimated glomerular filtration rate and tubular reabsorption of phosphate; and higher parathyroid hormone and 1,25-dihydroxy vitamin D (1,25-OH(2)D). The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH (2)D, higher 25-OH vitamin D and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23.Conclusion:Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH (2)D, suggesting a functional vitamin D deficiency possibly explaining TDF-associated increased parathyroid hormone. The finding of lower FGF-23 accompanying higher intracellular tenofovir diphosphate suggests different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance, and tenofovir diphosphate with hypophosphatemia and FGF23 regulation.The clinical trials registration number for this study is NCT00490412, available online at http://clinicaltrials.gov/ct2/show/NCT00490412.Antimicrobial Agents and Chemotherapy 09/2013; DOI:10.1128/AAC.01096-13 · 4.45 Impact Factor
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ABSTRACT: Formulae used to estimate glomerular filtration rate (GFR) underestimate higher GFRs and have not been well-studied in HIV-infected (HIV(+)) people; we evaluated the relationships of HIV infection and known or potential risk factors for kidney disease with directly measured GFR and the presence of chronic kidney disease (CKD). Cross-sectional measurement of iohexol-based GFR (iGFR) in HIV(+) men (n = 455) receiving antiretroviral therapy, and HIV-uninfected (HIV(-)) men (n = 258) in the Multicenter AIDS Cohort Study. iGFR was calculated from disappearance of infused iohexol from plasma. Determinants of GFR and the presence of CKD were compared using iGFR and GFR estimated by the CKD-Epi equation (eGFR). Median iGFR was higher among HIV(+) than HIV(-) men (109 vs. 106 ml/min/1.73 m(2), respectively, p = .046), and was 7 ml/min higher than median eGFR. Mean iGFR was lower in men who were older, had chronic hepatitis C virus (HCV) infection, or had a history of AIDS. Low iGFR (≤90 ml/min/1.73 m(2)) was associated with these factors and with black race. Other than age, factors associated with low iGFR were not observed with low eGFR. CKD was more common in HIV(+) than HIV(-) men; predictors of CKD were similar using iGFR and eGFR. iGFR was higher than eGFR in this population of HIV-infected and -uninfected men who have sex with men. Presence of CKD was predicted equally well by iGFR and eGFR, but associations of chronic HCV infection and history of clinically-defined AIDS with mildly decreased GFR were seen only with iGFR.PLoS ONE 02/2014; 9(2):e86311. DOI:10.1371/journal.pone.0086311 · 3.53 Impact Factor
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