Calcagno A, Fiumanò M, Zugna D, Cusato J, Montrucchio C, Marinaro L, Trentini L, Ferrara M, D'Avolio A, Pizzi C, Di Perri G, Bonora S
Unit of Infectious Diseases, University of Torino, Torin, Italy.
Unit of Cancer Epidemiology, Department of Medical Sciences, University of Torino, Torino, Italy.
Pharmacogenomics J. 2019 Feb;19(1):65-71. doi: 10.1038/s41397-018-0064-y. Epub 2018 Nov 8.
Tenofovir disoproxil fumarate (TDF) is a very effective antiviral drug that has been associated with tubular dysfunction. The aim of this study was to analyze the demographic, pharmacokinetic, and pharmacogenetic variables associated with TDF discontinuation for renal outcomes in stable HIV-positive patients using multivariable analyses. Three hundred and four patients were included (73% male, with median age and eCrCl of 45.3 years and 90.9 mL/min, respectively). After a median follow-up of 28.3 months, 27 patients discontinued TDF for renal adverse events [persistent urinary abnormalities (n = 21) or eCrCl < 60 mL/min (n = 6)] providing an incidence of 3.77 events per 100 patient-year. The probability of TDF discontinuation was higher with several features (male gender, older age, not Caucasians ancestry, absence of intravenous drug abuse, protease inhibitors, previous indinavir, HCV-positivity, lower CD4 cell count, detectable HIV-RNA, lower eCrCl, spot-urine proteinuria) and higher tenofovir concentrations but not genetic variants. Tenofovir plasma concentrations were prognostic of TDF discontinuation for renal adverse events suggesting that dose-adjustment may be warranted for long-term safety.
替诺福韦酯（TDF）是一种非常有效的抗病毒药物，但与肾小管功能障碍有关。本研究的目的是使用多变量分析，分析与稳定的HIV阳性患者因肾脏结局而停用TDF相关的人口统计学、药代动力学和药物遗传学变量。共纳入304例患者（73%为男性，年龄中位数和估算肌酐清除率分别为45.3岁和90.9 mL/min）。中位随访28.3个月后，27例患者因肾脏不良事件停用TDF[持续性尿液异常（n = 21）或估算肌酐清除率<60 mL/min（n = 6）]，每100患者年的事件发生率为3.77。具有某些特征（男性、年龄较大、非高加索血统、无静脉药物滥用史、蛋白酶抑制剂、曾使用茚地那韦、丙型肝炎病毒阳性、较低的CD4细胞计数、可检测到的HIV-RNA、较低的估算肌酐清除率、随机尿蛋白尿）以及较高的替诺福韦浓度但非基因变异时，停用TDF的可能性更高。替诺福韦血浆浓度可预测因肾脏不良事件而停用TDF的情况，这表明为了长期安全性可能需要调整剂量。
