Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium study.
Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium study.
复制标题
DOI：
10.1097/qai.0b013e31823e7884
复制
发表时间：
2012-04-15
期刊：
影响因子：
--
通讯作者：
Dittmer DP
中科院分区：
文献类型：
--
作者：
Krown SE;Roy D;Lee JY;Dezube BJ;Reid EG;Venkataramanan R;Han K;Cesarman E;Dittmer DP
哺乳动物雷帕霉素靶点 (mTOR) 在卡波西肉瘤 (KS) 中被激活，其抑制剂雷帕霉素可诱导移植相关 KS 中的 KS 消退。本研究旨在评估雷帕霉素在接受抗逆转录病毒治疗（ART）的 KS HIV 感染者中的安全性和毒性，研究雷帕霉素与含蛋白酶抑制剂（PI）和非核苷逆转录酶抑制剂（NNRTI）的 ART 方案的相互作用，并评估临床和生物学终点，包括 KS 反应和 mTOR 依赖性信号传导。七名参与者（其中 4 名接受基于 PI 的 ART 治疗，3 名接受基于 NNRTI 的 ART 治疗）滴定了雷帕霉素，以达到 5-10 ng/mL 的谷浓度。监测患者的安全性和 KS 反应。评估 KS 活检中磷酸核糖体 S6 蛋白 (pRPS6) 和磷酸 Akt 表达的变化。监测白介素6和血管内皮生长因子水平、HIV和KS相关疱疹病毒载量以及CD4计数。尽管药代动力学相互作用导致接受含 PI 和含 NNRTI 方案的参与者每周累计雷帕霉素剂量存在 200 倍以上的差异，但治疗耐受性良好。病毒载量或细胞因子水平没有显着变化；一些患者的 CD4 计数最初出现适度下降。三名参与者均采用含 PI 的方案且雷帕霉素暴露量较高，显示出部分 KS 反应。在第 50 天以上进行活检的四名受试者中，有三名显示 pRPS6 染色减少。雷帕霉素对于患有 KS 的 HIV 感染者似乎是安全的，并且在某些情况下可以诱导肿瘤消退并影响其分子靶标。显着的药代动力学相互作用需要仔细滴定以达到目标药物谷浓度，但可以用来实现治疗效果。
The mammalian target of rapamycin (mTOR) is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mTOR-dependent signaling. Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phospho-Ribosomal S6 protein (pRPS6), and phospho-Akt expression. Interleukin-6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored. Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of four subjects whose biopsies were studied at ≥day 50 showed decreased pRPS6 staining. Rapamycin appears safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations, but may be exploited to achieve therapeutic benefit.