Determinants of Tenofovir Plasma Trough Concentrations: A Cross-sectional Analysis in the Clinical Setting
Andrea Calcagno*1, D Gonzalez de Requena1, M Simiele1, A D’Avolio1, MC Tettoni1, B Salassa1, G Orofino2, V Libanore1, G Di Perri1, and S Bonora1
1Univ of Torino, Italy and 2Ospedale Amedeo di Savoia, Torino, Italy
Background: A link between tenofovir (TDF) plasma concentration and renal toxicity has been previously suggested. Increased incidence of renal toxicity was found to be associated to the use of protease inhibitors (PI) as a third drug of TDF-containing regimens. PI are known to potentially increase TDF plasma concentrations, however, data on its exposure according to different companion drugs are not yet available. Therefore, our aim was to investigate the determinants of TDF plasma exposure in the clinical setting.
Methods: Patients on TDF-containing HAART were consecutively enrolled between September 2010 and January 2011. Inclusion criteria were blood sampling 22 to 26 hours after last TDF intake, self-reported adherence >95%, and no concomitant renal diseases. TDF trough concentrations were measured through a validated HPLC/LC-MS method (limit of detection 2 ng/mL). Estimated glomerular filtration rate (eGFR) was calculated using the Cockroft-Gault formula. Results are expressed as median (interquartile ranges); non-parametric tests were used for all the analysis.
Results: Of the 222 patients considered, 68.9% were male: 46 years old (39 to 53); body mass index, 23.1 kg/m2 (21.1 to 25.4); and plasma creatinine 0.99 mg/dL (0.86 to 1.10). Median time on TDF was 23.5 months (9.3 to 56.5). TDF trough levels (median 51 ng/mL, 36 to 78) were significantly associated to age (r = 0.16, p = 0.02), eGFR (r = 0.24, p <0.01), and body mass index (r = 0.18, p <0.01). TDF concentrations according to third drug class showed that unboosted protease inhibitor (PI) recipients (atazanavir, n = 44,) had higher concentrations (67 ng/ml, 44 to 94) than boosted PI (n = 126, 51 ng/mL, 35 to 76), NNRTI (n = 36, 45 ng/mL, 30 to 59), and raltegravir (RGV) (n = 11, 37 ng/mL, 28 to 79) intakers (Kruskal-Wallis test, p = 0.01) (see the figure). No significant differences of body mass index, eGFR, and time on TDF among these groups emerged. Intra-class exposure differences were not statistically significant. At multivariate analysis third drug class (unboosted/boosted PI vs NNRTI/RGV; p = 0.003, 95%IC 6.7 to 33.5) and weight/creatinine ratio (p = 0.006, 95%IC 0.13 to 0.77) were independently associated with TDF trough levels.
Conclusions: Third drug class was shown to significantly affect TDF plasma exposure, along with body mass index and eGFR. PI recipients showed higher TDF concentrations than other classes and the highest exposure was found in unboosted ATV recipients. These data warrant further investigation to evaluate the clinical impact in terms of risk of tubular toxicity.