Renal Impairment in Patients Receiving a Tenofovir-cART Regimen

Poizot‐Martin, Isabelle; Solas, Caroline; Allemand, Jean-François; Obry-Roguet, Véronique; Pradel, Vincent; Brégigeon, Sylvie; Faucher, Olivia; Lacarelle, Bruno

doi:10.1097/qai.0b013e31827ce4ee

Cited by 63 publications

(38 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is evidence of an association between tenofovir plasma concentrations and renal toxicity (4,6,7,14). A study by Rodríguez-Nóvoa et al has shown that patients with a tenofovir plasma concentration of more than 160 ng/ml at middose (10 to 14 h after the last dose) were at a 4.8 times higher risk of experiencing KTD than patients with a tenofovir plasma concentration below this cutoff value (6).…”

Section: Discussionmentioning

confidence: 99%

“…The cutoff values of the middose (12-h) tenofovir concentration (C 12 ) and the trough (minimum) concentration (C min ) (Ͼ160 ng/ml and Ͼ90 ng/ml, respectively) were proposed to discriminate a risk of kidney tubular dysfunction (KTD) (6,7). These results suggest that genetic variation in tenofovir transporter genes may lead to overexposure to tenofovir, resulting in kidney tubular cell damage.…”

mentioning

confidence: 94%

“…Previous studies have shown that the polymorphisms of ABCC2 and ABCC4 are associated with higher tenofovir concentrations (4,5) and a higher tenofovir plasma concentration is associated with renal impairment (6,7). The cutoff values of the middose (12-h) tenofovir concentration (C 12 ) and the trough (minimum) concentration (C min ) (Ͼ160 ng/ml and Ͼ90 ng/ml, respectively) were proposed to discriminate a risk of kidney tubular dysfunction (KTD) (6,7).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Rungtivasuwan

Avihingsanon

Thammajaruk

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

f Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged >18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ؎ 7.2 years. The mean tenofovir plasma concentration was 100.3 ؎ 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T ¡ G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.) T enofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir (TFV), is widely used for the treatment of human immunodeficiency virus (HIV) infection because of its high potency, good safety profile, limited drug interaction, and convenient once-daily dosing (1, 2). After absorption, TDF is rapidly converted to tenofovir. Tenofovir is then phosphorylated intracellularly to tenofovir diphosphate, an active analog, which inhibits HIV reverse transcriptase, resulting in a termination DNA chain elongation (1, 2).Tenofovir is eliminated by renal excretion through glomerular filtration and active tubular secretion. It is transported into kidney tubular cells by organic anion transporter 1 (OAT1) and OAT3, encoded by the SLC22A6 and SLC22A8 genes, respectively, at the basolateral membrane. Subsequently, tenofovir is secreted to the tubular lumen by multidrug-resistant protein 2 (MRP2) and MRP4, encoded by the ABCC2 and ABCC4 genes, respectively, at the apical membrane (3). Therefore, genetic polymorphisms of these transporter genes may affect the transport of tenofovir at ...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

See 1 more Smart Citation

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Rungtivasuwan

Avihingsanon

Thammajaruk

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…While in clinical reports, the impact of TDF on renal function is mostly described in terms of decrease of estimated glomerular filtration rate (GFR), TDF appears unlikely to directly harm any glomerular structure and its effect on GFR estimation depends upon the decreased creatinine secretion that is secondary to tubular dysfunction (3). In four independent clinical studies, TDF pharmacokinetic (PK) exposure was found to be associated with alterations in a series of renal function markers, both glomerular and tubular (4)(5)(6)(7). According to drug-drug interaction studies of healthy volunteers, the PK exposure of tenofovir seems to be rather sensitive to the choice of companion drugs, which suggests that, depending on the specific HAART regimen, its impact on tubular function may also vary.…”

mentioning

confidence: 99%

Tenofovir Plasma Concentrations According to Companion Drugs: a Cross-Sectional Study of HIV-Positive Patients with Normal Renal Function

Calcagno

Requena

Simiele

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bAs the risk of tenofovir-associated renal toxicity has been found to be proportional to the drug plasma concentration, our aim was to measure the determinants of tenofovir plasma exposure in HIV-positive patients with normal renal function. A crosssectional analysis was conducted in HIV-positive patients chronically receiving tenofovir-containing highly active antiretroviral therapies (HAARTs). Patients on tenofovir-containing antiretroviral regimens, presenting 22 to 26 h after drug intake, having estimated glomerular filtration rates above 60 ml/min, reporting high adherence to antiretroviral medications (above 95% of the doses), and signing a written informed consent were included. Plasma tenofovir concentrations were measured through a validated high-performance liquid chromatography-mass spectrometry (HPLC/LC-MS) method. The tenofovir trough concentrations in 195 patients (median, 50 ng/ml, and interquartile range, 35 to 77 ng/ml) were significantly associated with the estimated glomerular filtration rate, body mass index, and third-drug class (protease-containing versus protease-sparing regimens) (with the highest exposure in unboosted-atazanavir recipients). The results of multivariate analysis showed that the third-drug class and the weight/creatinine ratio were independent predictors of tenofovir trough concentrations. This cross-sectional study shows that tenofovir trough concentrations are predicted by the weight/creatinine ratio and by the coadministered antiretrovirals, with protease inhibitors (whether boosted or unboosted) being associated with the highest plasma exposure. These data, previously available in healthy subjects or for some drugs only, could be useful for designing strategies to manage tenofovir-associated toxicity, since this toxicity has been reported to be dose dependent.

show abstract

“…30,31 Our data showed that the use of tenofovir combined with a protease inhibitor increased the risk of kidney disease (abnormal eGFR and abnormal UPC or UAC ratios), as previously described in large cohorts. 15,22,32 Higher tenofovir plasma concentration was associated with alterations in renal markers (both glomerular and tubular), 33,34 and the highest plasma exposure was associated with the concomitant use of protease inhibitors. 35 However, whether co-administered or not with protease inhibitors, tenofovir was not associated with proteinuria > 300 mg/g in our cohort.…”

Section: Discussionmentioning

confidence: 99%

High Prevalence of Signs of Renal Damage Despite Normal Renal Function in a Cohort of HIV-Infected Patients: Evaluation of Associated Factors

Bonjoch

Juega

Puig

et al. 2014

AIDS Patient Care and STDs

View full text Add to dashboard Cite

Renal disorders are an emerging problem in HIV-infected patients. We performed a cross-sectional study of the first 1000 HIV-infected patients attended at our HIV unit who agreed to participate. We determined the frequency of renal alterations and its related risk factors. Summary statistics and logistic regression were applied. The study sample comprised 970 patients with complete data. Most were white (94%) and men (76%). Median (IQR) age was 48 (42-53) years. Hypertension was diagnosed in 19%, dyslipidemia in 27%, and diabetes mellitus in 3%. According to the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation, 29 patients (3%) had an eGFR < 60 ml/min/1.73 m 2 ; 18 of them (62%) presented altered albumin/creatinine and protein/creatinine (UPC or UAC) ratios. Of the patients with eGFR > 60 mL/min, it was present in 293 (30%), 38 of whom (7.1%) had UPC > 300 mg/g. Increased risk of renal abnormalities was correlated with hypertension (OR, 1.821 [95%CI, 1.292;2.564]; p = 0.001), age (OR, 1.015 [95%CI, 1.001;1.030], per one year; p = 0.040), and use of tenofovir disoproxil fumarate (TDF) plus protease inhibitor (PI), (OR, 1.401 [95%CI, 1.078;1.821]; p = 0.012). Current CD4 cell count was a protective factor (OR, 0.9995 [95%CI, 0.9991;0.9999], per one cell; p = 0.035). A considerable proportion of patients presented altered UPC or UAC ratios, despite having an eGFR > 60 mL/min. CD4 cell count was a protective factor; age, hypertension, and use of TDF plus PIs were risk factors for renal abnormalities. Based on our results, screen of renal abnormalities should be considered in all HIV-infected patients to detect these alterations early.

show abstract

Renal Impairment in Patients Receiving a Tenofovir-cART Regimen

Abstract: The high prevalence of elevated Ctrough-TDF and its correlation with an increased risk of renal impairment support the usefulness of therapeutic drug monitoring for TDF, particularly in women and older patients.

Cited by 63 publications

References 20 publications

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Tenofovir Plasma Concentrations According to Companion Drugs: a Cross-Sectional Study of HIV-Positive Patients with Normal Renal Function

High Prevalence of Signs of Renal Damage Despite Normal Renal Function in a Cohort of HIV-Infected Patients: Evaluation of Associated Factors

Contact Info

Product

Resources

About