Short communication Impact of tenofovir dose adjustment on both estimated glomerular filtration rate and tenofovir trough concentration

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1 Antiviral Therapy 2017; 22: (doi: /IMP3137) Short communication Impact of tenofovir dose adjustment on both estimated glomerular filtration rate and tenofovir trough concentration Sylvie Bregigeon 1, Caroline Solas 2, Olivia Faucher 1, Véronique Obry-Roguet 1, Catherine Tamalet 3, Isabelle Poizot-Martin 1,4 * 1 Aix-Marseille University, APHM Sainte-Marguerite, Service d Immuno-hématologie clinique, Marseille, France 2 Aix-Marseille University, APHM La Timone, Pharmacocinétique et Toxicologie, INSERM S_911 CRO2-SMARTc, Marseille, France 3 IHU Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène- Virologie, APHM Timone, Marseille, France 4 INSERM U912 (SESSTIM), Marseille, France *Corresponding author isabelle.poizot@ap-hm.fr Background: Tenofovir disoproxil fumarate (TDF)-based regimen is a treatment option for HIV-infected patients. TDF dose adjustment is recommended in patients with impaired renal function. We assessed the impact of TDF dose adjustment on renal function and tenofovir trough concentration. Methods: Fourteen HIV patients for whom TDF dose was adjusted (1 tablet/48 h) because of estimated glomerular filtration rate (egfr) <60 ml/min/1.73 m 2, and/or due to a tenofovir trough concentration >90 ng/ml between 2006 and 2013 were selected. The egfr was measured at baseline and 3, 6 and 12 months after TDF dose adjustment. Results: A 50% TDF dose reduction resulted in a significant increase of the egfr 3 months after dose adjustment (61.1 versus 72.8 ml/min/1.73 m 2 ; P=0.003). Concomitantly, tenofovir trough concentration decreased from 175 to 66 ng/ml (P=0.009). Antiviral efficacy was maintained in all patients. Conclusions: TDF dose adjustment combined with therapeutic drug monitoring may be useful especially in patients at risk of kidney dysfunction. Introduction Tenofovir disoproxil fumarate (TDF), a nucleoside reverse transcriptase inhibitor (NRTI), is one of the most widely used antiretroviral agents worldwide, and represents a treatment option in first-line combination antiretroviral therapy (cart) [1,2]. Although TDF is usually well tolerated, renal tubular dysfunction remains the key potential toxicity of TDF and was already well described [3]. This can vary from low to moderate decline of the estimated glomerular filtration rate (egfr) to significant renal tubular dysfunction and most rarely to Fanconi s syndrome [4]. Adverse effects of medications are often correlated with systemic exposure of drugs and previous studies showed that tenofovir (TFV) plasma concentrations and cumulative exposition of TDF were associated with an increased risk of kidney disease [5 7]. Moreover, a large interindividual variability of TFV pharmacokinetics has been reported [8] and high TFV exposure was significantly associated with lower body weight, lower egfr or comedications such as ritonavir or cobicistat through P-glycoprotein inhibition [8 10]. In France, TDF therapeutic drug monitoring (TDM) is therefore recommended particularly for all patients with impaired renal function [6,11,12]. Other factors such as age and female gender were shown to be independently associated with renal impairment in HIV-patients receiving a TDF-containing regimen [11]. During Phase I and II studies, a daily dose of 300 mg of TDF was determined for adults with normal renal function [13] and a dose reduction is currently recommended when creatinine clearance (CrCl) calculated with the Cockcroft and Gault (CG) formula [14] is <50 ml/min. However, in clinical practice, high TFV concentrations are frequently observed in patients before egfr falls below 50 ml/ min/1.73 m 2. Thus, in the present study, we assessed the impact of TDF dose reduction on glomerular function and TFV plasma trough concentration International Medical Press (print) (online) 529

2 S Bregigeon et al. Methods This retrospective study was conducted in an HIV outpatient clinical unit following about 1,000 patients annually. Glomerular function was assessed by CrCl calculated with the CG formula and egfr by using MDRD equation [15]. Renal impairment was defined as egfr less than 60 ml/min/1.73 m 2, according to stage 3 of the Chronic Kidney Disease (CKD) classification [16]. egfr and CrCl were measured at baseline and 3, 6 and 12 months after TDF dose adjustment. Patients for whom TDF dose was adjusted (1 tablet/48 h) because of egfr <60 ml/min/1.73 m 2 and/or due to a TFV trough concentration >90 ng/ml between 2006 and 2013 were selected from the local electronic medical record NADIS [13]. Other inclusion criteria included undetectable HIV RNA before dose adjustment, presence of at least one egfr measurement and one assessment of TFV trough concentration before and after dose adjustment. Moreover, TDF treatment had to be maintained for at least 3 months after dose adjustment. All patients had a TDF dose reduction from 245 mg/24 h to 245 mg/48 h. Demographic, epidemiological and immunovirological characteristics were collected. Baseline was considered as the date of TDF dose adjustment. TFV trough concentration was determined using a liquid chromatography-tandem mass spectrometry method (limit of quantification: 10 ng/ml; expected concentration range: ng/ml), according to the lower and upper limits mentioned in the Summary of Product Characteristics of TDF [17]. TFV trough concentration was assessed at the time of dose adjustment and at least once thereafter. The median duration between TDF dose adjustment and the second assessment of TFV trough concentration was 0.9 months. Urinary markers of tubular function (proteinuria and glycosuria on urinary sticks) were also analysed when available. Median values and IQRs were calculated for the description of quantitative variables. The c 2 test (or Fisher exact test when necessary) was used to compare proportions. The Kruskal Wallis and Mann Whitney non-parametric tests were used for group comparison of quantitative variables. A P-value <0.05 was considered as statistically significant. All analyses were performed using SPSS v.19 for Windows (IBM Corp., Armonk, NY, USA). This study was conducted in accordance with French ethics regulations. All patients included in this study gave their written informed consent to allow the use of their personal clinical data. Results Fourteen patients met the selection criteria over the study period: nine had a TFV trough concentration >90 ng/ml (median 178 ng/ml; IQR ), of whom one had concomitant egfr <50 ml/min/1.73 m 2. Five other patients had an egfr below 60 ml/min/1.73 m 2, including four with an egfr <50 ml/min/1.73 m 2. Similar results were obtained if we considered CrCl. Patients characteristics are presented in Table 1. Eleven patients (78.6%) were male and median age was 53 years. At baseline, eight patients (57.1%) had a mild kidney disease (CKD stage 2) whereas six patients (42.9%) had a moderate kidney damage (CKD stage 3). TDF dose adjustment led to a significant improvement of egfr in all patients (Figure 1). The median egfr increased from 61.1 ml/min/1.73 m 2 (IQR ) at baseline to 72.8 ml/min/1.73 m 2 ( ) at 3 months (P=0.003). It further increased to 76.2 ml/min/1.73 m 2 ( ) at 6 months and then stabilized at 12 months (76.6 ml/min/1.73 m 2 [ ]). Similar results were Table 1. Patients characteristics at baseline (n=14) Characteristic Value Age, years 53.0 ( ) Sex, male 11 (78.6) Weight M/F, kg 72.0 ( )/50.0 ( ) BMI M/F, kg/m ( )/20.0 ( ) Duration of HIV, years 19.8 ( ) CDC Stage C 6 (42.9) Nadir CD4 + T-cells/mm (52 268) Duration of exposure to 15.3 ( ) ART-regimen, years Overall duration of exposure 66.6 ( ) to TDF, months Duration of exposure to the 36.4 ( ) last ART regimen, months Type of ongoing cart 2 NRTI + 1 bpi 8 (57.1) 2 NRTI + 1 NNRTI 2 (14.3) 2 NRTI + 1 II 2 (14.3) 2 NRTI + 1 PI 1 (4.1) 2 NRTI + 1 bpi + 1 II 1 (7.1) HBsAg (+) 1 (7.1) HCV PCR (+) 3 (21.4) egfr (MDRD) 61.1 ( ) CKD classification Stage 1 (egfr 90 ml/min/1.73 m 2 ) 0 Stage 2 (egfr 60 89) 8 (57.1) Stage 3 (egfr 30 59) 6 (42.9) Stage 4 (egfr 15 29) 0 Creatinine clearance 59.9 ( ) (Cockcroft Gault), ml/min Data are median (IQR) or n (%). ART, antiretroviral therapy; BMI, body mass index; bpi, boosted protease inhibitor; CKD, chronic kidney disease; egfr, estimated glomerular filtration rate; F, female; HBsAg, hepatitis B surface antigen; II, integrase inhibitor; M, male; MDRD, Modification of Diet in Renal Disease; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; TDF, tenofovir disoproxil fumarate International Medical Press

3 Tenofovir dose adjustment and renal function Figure 1. Evolution of both the median estimated glomerular filtration rate assessed by the MDRD formula and the creatinine clearance using the Cockcroft and Gault equation, after TDF dose adjustment 90 MDRD, ml/min/1.73 m 2 Cockcroft Gault, ml/min P=0.003 MDRD Cockcroft Gault 30 Baseline M3 M6 M12 Time after TDF dose adjustment Vertical bars indicate the IQR (25th and 75th percentile). M, month; MDRD, Modification of Diet in Renal Disease; TDF, tenofovir disoproxil fumarate. obtained when assessing CrCl (Figure 1). At 3 months, we recorded 3 patients (21.4%) with a CKD stage 1 (egfr 90 ml/min/1.73 m 2 ), 8 (57.1%) with a CKD stage 2, and 3 (21.4%) with a CKD stage 3. These proportions remained stable at 6 and 12 months. In parallel, a significant decrease of TFV median trough concentration from 175 ng/ml ( ) to 66 ng/ml (47 90) was observed after dose adjustment (P=0.009). Among the 10 patients with urinary stick data available, 6 had a proteinuria at baseline. Six months after TDF dose adjustment, only three patients still presented a proteinuria on urinary stick. Elevated glycosuria was positive at baseline for only two patients, of whom one was diabetic. At 6 months, only a mild glycosuria was observed in the diabetic patient. Three months after TDF dose adjustment, one patient had a detectable HIV viral load (278 copies/ml) but viral load became undetectable again at month 6 and 12 (<40 copies/ml). All other patients remained HIV- RNA-negative after TDF dose adjustment. Discussion This study, although retrospective and carried out on a small number of HIV-infected patients, confirms the relevance of a TDF adjustment according to TFV trough concentration and/or egfr decrease below 60 ml/min/1.73 m 2. Indeed, TDF dose adjustment from 245 mg/24 h to 245 mg/48 h considerably improved glomerular renal function in all patients whatever the formulas used. This improvement of renal function was concomitant with a significant decrease in the TFV trough concentration. In a previous study, we showed that high TFV trough concentration (>90 ng/ml) was present in about half of patients receiving TDF-containing cart [11]. We reported a correlation between TFV trough concentration and egfr decrease hereby confirming a concentration-dependent nephrotoxicity of TDF also described on kidney tubular dysfunction [6,7]. Moreover, both older age and female gender were independently associated with impaired renal function [11]. Antiviral Therapy

4 S Bregigeon et al. In the present study we selected patients with impaired renal function (egfr <60 ml/min/1.73 m 2 ) or presenting with elevated TFV trough concentration (>90 ng/ml). The objective was to assess the impact of a TDF dose reduction on both renal function and TFV trough concentration. Our results indicate that such a dose reduction improves renal function significantly both on glomerular and tubular function as shown by the reduction of proteinuria in 3/6 patients. In addition, a significant decrease of 66% in TFV trough concentration was obtained after dose reduction leading to a median exposure within the therapeutic range. Indeed, 9 patients (90%) had a TFV trough concentration >90 ng/ml before TDF dose reduction but only 3 patients (25%) after. According to the CKD classification with MDRD equation, we also observed an improvement of renal function with 3 patients who switched from stage 2 to stage 1, and 4 others from stage 3 to stage 2 after 3 months. It is noteworthy that despite a 50% dose reduction of TDF, treatment efficacy was maintained. All patients remained HIV-RNA-negative within 12 months following the dose adjustment except a possible blip at 3 months in one patient. One major limitation of this study is the small sample size. However, given the significant improvement on renal function observed and as TDF nephrotoxicity is currently well known and related to TFV exposure, our results clearly demonstrate the relevance of implementing TDM for TDF. This would allow detecting high TFV plasma concentration in order to consider a TDF dose adjustment before reaching a CrCl <50 ml/min. However, since TDM is not available in most countries, our data show that TDF dose adjustment can be guided by egfr results only. Although this adjustment leads to TDF withdrawal from Single Tablet Regimen, it may still be used in patients for whom TDF remains active on historical genotyping and in HBV HIV-coinfected patients. Tenofovir alafenamide (TAF), the new prodrug of tenofovir, showed a better tolerance on kidney function, in naive as well in pre-treated patients and seems also to be useful for patients with renal impairment [18 21]. Nevertheless, TAF is so far only available in fixed-dose combinations which could not be proposed to everyone. Furthermore, TDF is going to be available at low generic prices and will therefore remain part of the backbone of choice for a very long time. In conclusion, our results suggest that TDF dose adjustment combined with therapeutic drug monitoring may help to prevent renal toxicity, especially in patients at risk of kidney dysfunction. Disclosure statement The authors have no conflict of interest to disclose. References 1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. (Accessed 4 November 2016.) 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