Cattaneo Dario, Minisci Davide, Baldelli Sara, Mazzali Cristina, Giacomelli Andrea, Milazzo Laura, Meraviglia Paola, Resnati Chiara, Rizzardini Giuliano, Clementi Emilio, Galli Massimo, Gervasoni Cristina
Unit of Clinical Pharmacology, L. Sacco University Hospital, Milan, Italy.
Department of Infectious Disease, L. Sacco University Hospital, Milan, Italy.
J Acquir Immune Defic Syndr. 2018 Jan 1;77(1):86-92. doi: 10.1097/QAI.0000000000001558.
The dose of tenofovir alafenamide is reduced from 25 to 10 mg daily when given with boosting agents. However, such dose reduction has never been adopted for tenofovir disoproxil fumarate (TDF). In this study, we aim to quantify the effect of cobicistat (COBI) both on tenofovir concentrations and TDF durability in real life setting.
HIV-positive patients receiving TDF-containing antiretroviral therapies with at least 1 assessment of tenofovir plasma trough concentrations were included in the study. Univariate and multivariate regression analyses were performed considering tenofovir concentration as the dependent variable and clinical characteristics as independent covariates. Subsequently, survival and Cox analyses were performed considering as the primary outcome TDF discontinuation for any reasons.
Patients were given TDF with protease inhibitors/ritonavir (n = 212), non-nucleoside reverse transcriptase inhibitors (n = 176), integrase inhibitors (dolutegravir or raltegravir, n = 46), or with elvitegravir/COBI (ELV/COBI) (n = 76). By multivariate analysis, concomitant antiretroviral therapies resulted significantly associated with tenofovir levels, with the highest drug concentrations measured in patients given ELV/COBI. By survival analysis, we found that patients given TDF with ELV/COBI had the lowest rate of drug durability. Overall, these patients had a 2.3-fold increased risk to experience TDF discontinuation.
Coadministration with COBI resulted in significantly higher tenofovir concentrations and higher TDF discontinuation compared with other antiretroviral regimens. Accordingly, the possibility that the lack of proper dose adjustment for TDF when given with COBI might have biased the safety comparisons with tenofovir alafenamide during registrative trials cannot be ruled out.
替诺福韦艾拉酚胺与增效剂联用时，每日剂量从25毫克降至10毫克。然而，富马酸替诺福韦二吡呋酯（TDF）从未采用过这种剂量降低方法。在本研究中，我们旨在量化考比司他（COBI）在实际应用中对替诺福韦浓度和TDF持久性的影响。
本研究纳入了接受含TDF抗逆转录病毒疗法且至少有1次替诺福韦血浆谷浓度评估的HIV阳性患者。以替诺福韦浓度为因变量，临床特征为独立协变量进行单变量和多变量回归分析。随后，以任何原因导致的TDF停药作为主要结局进行生存分析和Cox分析。
患者接受TDF与蛋白酶抑制剂/利托那韦（n = 212）、非核苷类逆转录酶抑制剂（n = 176）、整合酶抑制剂（多替拉韦或拉替拉韦，n = 46）或与埃替拉韦/COBI（ELV/COBI）（n = 76）联用。通过多变量分析，同时使用的抗逆转录病毒疗法与替诺福韦水平显著相关，在接受ELV/COBI治疗的患者中测得的药物浓度最高。通过生存分析，我们发现接受TDF与ELV/COBI治疗的患者药物持久性率最低。总体而言，这些患者经历TDF停药的风险增加了2.3倍。
与其他抗逆转录病毒方案相比，与COBI联用导致替诺福韦浓度显著升高且TDF停药率更高。因此，不能排除在注册试验期间，TDF与COBI联用时缺乏适当剂量调整可能会使与替诺福韦艾拉酚胺的安全性比较产生偏差的可能性。
