A5288: Management Using the Latest Technologies in Resource-Limited Settings to Optimize Combination Therapy after Viral Failure - Lancet HIV 2019 publication

Background: Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure. Methods: A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367. Findings: From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60-68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]). Interpretation: Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance.

背景：在资源有限地区的患者接受三线抗逆转录病毒治疗（antiretroviral therapy, ART）时，由于病毒耐药模式复杂——部分原因是病毒载量监测可及性下降——其抗病毒治疗管理极具挑战性。本研究旨在评估新型抗逆转录病毒药物的应用及现代管理策略，包括基于群体的测序技术，以在出现二线治疗病毒学失败的患者中筛选合适的抗逆转录病毒药物、开展血浆病毒载量监测，并实施提高治疗依从性的干预措施。方法：A5288是一项4期三线抗逆转录病毒治疗策略研究，在10个国家的19个城市临床中心开展，纳入了经证实接受基于蛋白酶抑制剂的二线抗逆转录病毒治疗超过24周后，血浆HIV-1 RNA（病毒载量）≥1000拷贝/mL的成年受试者。本研究的主要终点为，通过应用抗逆转录病毒药物（雷特格韦、依曲韦林及利托那韦增效达芦那韦）及病毒载量检测、基因分型、依从性支持等诊断监测技术，使65%及以上的受试者实现病毒载量抑制（定义为≤200拷贝/mL）。研究通过受试者的抗逆转录病毒治疗史及实时药物耐药基因型，将其分为四个队列：队列A（无洛匹那韦耐药）继续接受二线抗逆转录病毒治疗；队列B、C、D则根据耐药水平递增划分，接受包括新型抗逆转录病毒药物在内的个体化治疗方案。其中队列B细分为：B1组为最优可用核苷类反转录酶抑制剂（nucleoside reverse transcriptase inhibitors, NRTIs）联合利托那韦增效达芦那韦及雷特格韦；B2组为利托那韦增效达芦那韦联合雷特格韦及依曲韦林；B3组为利托那韦增效达芦那韦、雷特格韦，联合替诺福韦+恩曲他滨或替诺福韦+拉米夫定。队列C为利托那韦增效达芦那韦联合雷特格韦，联合替诺福韦-恩曲他滨或替诺福韦+拉米夫定。队列D为最优可用NRTIs联合利托那韦增效达芦那韦及雷特格韦。队列B中未检出乙型肝炎表面抗原的受试者通过区组随机化分为B1和B2组，检出乙型肝炎表面抗原的受试者则被分配至B3组。本试验在ClinicalTrials.gov注册，注册号为NCT01641367。结果：2013年1月10日至2015年9月10日，本研究共纳入545名受试者。其中287例（53%）被分配至队列A，74例（14%）至B1组，72例（13%）至B2组，8例（1%）至B3组，70例（13%）至队列C，34例（6%）至队列D。整体而言，349例（64%，95%置信区间60~68）受试者在第48周时实现病毒载量抑制，各队列抑制率从队列A的125/287（44%）至B1组的65/74（88%）、B2组的63/72（88%）、B3组的8/8（100%）、队列C的63/70（90%）以及队列D的25/34（74%）不等。队列A受试者继续接受二线蛋白酶抑制剂治疗，其发生3级及以上不良事件的受试者比例最高，达147例（51%）。解读：针对实时基因分型以筛选三线抗逆转录病毒治疗方案，可将成本更高的抗逆转录病毒药物合理分配给HIV耐药水平更高的患者。