Zhao Ying, Keene Claire, Griesel Rulan, Sayed Kaneez, Gcwabe Zimasa, Jackson Amanda, Ngwenya Olina, Schutz Charlotte, Goliath Rene, Cassidy Tali, Goemaere Eric, Hill Andrew, Maartens Gary, Meintjes Graeme
Department of Medicine, University of Cape Town, Cape Town, South Africa.
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Wellcome Open Res. 2021 Feb 17;6:33. doi: 10.12688/wellcomeopenres.16597.1. eCollection 2021.
Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE). We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load <50 copies/mL at week 24 using a modified intention-to-treat analysis and the U.S. Food and Drug Administration snapshot algorithm. Secondary endpoints include virologic suppression at weeks 12 and 48, time to suppression, emergence of dolutegravir and new NRTI resistance mutations, safety, and tolerability. Impaired viral fitness due to NRTI resistance mutations and dolutegravir's high barrier to resistance provide rationale for switching patients from a failing TEE regimen to TLD; however, clinical evidence regarding virologic efficacy is lacking. This study provides estimates of such a strategy's early virologic efficacy with and without a supplementary dolutegravir dosing. ClinicalTrials.gov NCT03991013 (19/06/2019).
在基于一线非核苷类逆转录酶抑制剂的治疗方案失败后的二线抗逆转录病毒治疗中，当多替拉韦与至少一种完全有效的核苷类逆转录酶抑制剂（NRTI）联用时，其疗效和耐受性优于洛匹那韦 - 利托那韦。由于成本和实验室能力有限，在低收入和中等收入国家进行NRTIs耐药性检测以选择药物并不可行。有证据表明，将替诺福韦加拉米夫定或恩曲他滨的药物组合与多替拉韦联合使用可提供有效的二线治疗方案。本研究旨在确定在一线替诺福韦 - 恩曲他滨 - 依非韦伦（TEE）治疗方案失败的患者中，使用和不使用导入补充剂量多替拉韦（以抵消依非韦伦的诱导作用）的替诺福韦 - 拉米夫定 - 多替拉韦（TLD）的病毒学疗效。我们将进行一项平行组、随机（1:1）、双盲、安慰剂对照的II期试验，比较一线TEE治疗方案失败的患者每日服用TLD固定剂量组合与先服用50mg多替拉韦补充剂量，12小时后服用匹配安慰剂，共14天的疗效。该试验将在南非开普敦一个大型城郊非正式定居点凯伊利沙的两家初级保健诊所进行。我们将招募130名参与者，随访48周。主要终点是使用改良意向性分析和美国食品药品监督管理局快照算法，在第24周时病毒载量<50拷贝/mL的患者比例。次要终点包括第12周和第48周时的病毒学抑制、达到抑制的时间、多替拉韦和新的NRTI耐药突变的出现、安全性和耐受性。由于NRTI耐药突变导致的病毒适应性受损以及多替拉韦的高耐药屏障为将患者从失败的TEE治疗方案转换为TLD提供了理论依据；然而，缺乏关于病毒学疗效的临床证据。本研究提供了这种策略在使用和不使用补充多替拉韦剂量情况下早期病毒学疗效的评估。ClinicalTrials.gov NCT03991013（2019年6月19日）
