Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy.
ABSTRACT Tenofovir disoproxil fumarate (TDF) may induce renal proximal tubulopathy (rPT). There are no data on pharmacogenomic predictors of rPT in the genes encoding the multidrug-resistance protein (MRP) 2 and MRP4 transporters.
Mutational screening of the genes for MRP2 (ABCC2) and MRP4 (ABCC4) was performed using genomic DNA from 13 human immunodeficiency virus type 1 (HIV-1)-infected patients (group 1) presenting with TDF-induced rPT. Concomitantly, 17 unrelated HIV-1-infected patients who had received TDF therapy and who did not have rPT (group 2) were included in a case-control analysis, to assess the influence of single-nucleotide polymorphisms (SNPs) identified in ABCC2 and ABCC4.
Six SNPs were identified in ABCC2. A significant allelic association between the 1249 G-->A SNP and TDF-induced rPT was observed (odds ratio, 6.11 [95% confidence interval, 1.19-31.15]; P<.02). ABCC2 haplotypes were significantly associated with the onset of TDF-induced rPT--CATC appeared to be a predisposing haplotype, as it was found in 40.9% of the group 1 case patients and in 13.7% of the group 2 control subjects (P<.01), whereas CGAC appeared to be a protective haplotype, as it was not observed in the group 1 case patients but was present in 20.2% of the group 2 control subjects (P<.01). No association was observed between ABCC4 polymorphism and TDF-induced rPT in the present study.
ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.
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ABSTRACT: Tenofovir disoproxil fumarate, the prodrug of nucleotide reverse transcriptase inhibitor tenofovir, shows high efficacy and relatively low toxicity in HIV patients. However, long-term kidney toxicity is now acknowledged as a modest but significant risk for tenofovir-containing regimens, and continuous use of tenofovir in HIV therapy is currently under question by practitioners and researchers. Co-morbidities (hepatitis C, diabetes), low body weight, older age, concomitant administration of potentially nephrotoxic drugs, low CD4 count, and duration of therapy are all risk factors associated with tenofovir-associated tubular dysfunction. Tenofovir is predominantly eliminated via the proximal tubules of the kidney, therefore drug transporters expressed in renal proximal tubule cells are believed to influence tenofovir plasma concentration and toxicity in the kidney. We review here the current evidence that the actions, pharmacogenetics, and drug interactions of drug transporters are relevant factors for tenofovir-associated tubular dysfunction. The use of creatinine and novel biomarkers for kidney damage, and the role that drug transporters play in biomarker disposition, are discussed. The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilized for future drug development and clinical management programs.Frontiers in Pharmacology 11/2014; 5:248.
- AIDS 03/2015; 29(5):645-647. · 6.56 Impact Factor
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ABSTRACT: Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present.Journal of Clinical Virology 10/2014; · 3.47 Impact Factor