Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance
Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance
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DOI：
10.1097/qad.0b013e3282170ab1
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发表时间：
2007-07-11
期刊：
影响因子：
3.8
通讯作者：
Gazzard, Brian
中科院分区：
文献类型：
--
作者：
Boffito, Marta;Winston, Alan;Gazzard, Brian
背景：累积抗逆转录病毒暴露可导致多类HIV耐药。实验性抗逆转录病毒药物提供有限的治疗益处，因为它们作为唯一的新药物引入后迅速产生耐药性。目的：评估两种新型研究性抗逆转录病毒药物在合并多药耐药病毒的HIV-1感染受试者中联合使用时的药代动力学特征、安全性和病毒学应答。方法：HIV-1感染的受试者，目前在稳定的抗逆转录病毒治疗方案中病毒学失败，没有可行的治疗选择，被分配到一个方案，该方案包括两种新的研究药物，依曲韦林，一种新型的非核苷类逆转录酶抑制剂，和一种新型的蛋白酶抑制剂地瑞那韦，加核苷类逆转录酶抑制剂（在选定的患者中加恩夫韦肽）治疗24周。收集病毒学、免疫学和安全性参数。第7天和第28天分别测定地瑞那韦和依曲韦林的药代动力学参数。结果：10/12例患者随访24周。HIV RNA的中位减少为2.7 log（10）拷贝/ml（范围，2.3-3.9），CD 4淋巴细胞的增加为113个细胞/μ l（范围，41-268）。9例HIV RNA <40拷贝/ml。未记录严重不良事件。地瑞那韦的血浆暴露量与历史对照数据相似，依曲韦林的暴露量与依曲韦林与蛋白酶抑制剂联合给药时的历史数据相似。这是第一项评估依曲韦林和达芦那韦在HIV-1中的使用的研究-无治疗选择的感染受试者在24周的治疗中显示出高度有效的病毒学和免疫学应答，没有新的安全性问题或意外的药代动力学交互. (c)2007年利平科特威廉姆斯&威尔金斯。
Background: Cumulative antiretroviral exposure can result in multiclass HIV drug resistance. Experimental antiretroviral agents offer limited therapeutic benefit as resistance quickly develops after their introduction as a sole new agent.Objective: To assess the pharmacokinetic profile, safety and virological response of two novel investigational antiretroviral agents when used in combination in HIV-1 -infected subjects with multidrug-resistant virus.Methods: HIV-1-infected subjects, with current virological failure on a stable antiretroviral regimen with no viable treatment options were assigned to a regimen comprising two new investigational agents, etravirine, a novel nonnucleoside reverse transcriptase inhibitor, and darunavir, a novel protease inhibitor, plus nucleoside reverse transcriptase inhibitors (and enfuvirtide in selected patients) for 24 weeks. Virological, immunological and safety parameters were collected. Detailed pharmacokinetic assessments of darunavir and etravirine were determined on days 7 and 28.Results: Follow up of 24 weeks was achieved by 10/12 patients. Median reduction in HIV RNA was 2.7 log(10)copies/ml (range, 2.3-3.9) and increase in CD4 lymphocytes was 113cells/mu l (range, 41-268). HIV RNA was < 40copies/ml in nine. No serious adverse events were recorded. Plasma exposure to darunavir was similar to historic control data and exposure to etravirine similar to historic data when etravirine was administered with a boosted protease inhibitor.Conclusion: This first study to assess the use of etravirine and darunavir in HIV-1-infected subjects with no treatment options showed highly effective virological and immunological responses over 24 weeks of therapy with no new safety concerns or unexpected pharmacokinetic interactions. (c) 2007 Lippincott Williams & Wilkins.