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Clinical Impact of Virological Failure and Resistance Analysis Definitions used in Pivotal Clinical Trials of Initial Antiretroviral Treatment: A Systematic Review
AIDS Reviews ( IF 2.2 ) Pub Date : 2018-9-29 , DOI: 10.24875/aidsrev.18000006
Josep M Llibre 1 , Hortensia Álvarez 2 , Miguel Yzusqui 3
Affiliation  

There are no standardized criteria to characterize confirmed protocol-defined virological failure (PDVF) nor the inclusion criteria for the resistance analysis population (RAP) in Phase III randomized clinical trials (RCTs) of initial antiretroviral therapy (ART). We assessed the clinical impact of mismatching between virological non-response (HIV-1 RNA ≥50 copies/mL), confirmed PDVF (48 weeks), and RAP definition in studies with the newest first-line ART. A systematic review of all Phase III RCTs was performed, including preferred once-daily ART (EACS European AIDS guidelines) or recently approved by the US Food and Drug Administration. We identified 16 treatment arms (14 RCTs) with 6175 participants treated with dolutegravir, bictegravir, elvitegravir/cobicistat, raltegravir, darunavir/cobicistat, rilpivirine, or doravirine. Plasma HIV-1 RNA thresholds for PDVF or RAP ranged from 40 to 50, 200, 400, and 500 copies/mL. This led to discrepancies between trials regarding the participants defined as virological non-responders, PDVF, or included in RAP. Overall, 85/296 (29%) patients with PDVF were not genotyped. There was a linear correlation between the threshold of HIV RNA chosen to perform genotyping and rates of participants with PDVF but not genotyped. Only eight treatment arms genotyped all participants with PDVF. Most of the remaining eight arms genotyped roughly < 50% of those with PDVF. In summary, the absence of standardized definitions of VF and criteria for resistance testing in pivotal Phase III RCTs of the first-line ART leads to the possibility of underreporting of resistance mutations when genotypes are only performed at higher viral load cutoffs. Stringent homogeneous criteria should be defined to ensure that all participants with PDVF (e.g., confirmed HIV RNA ≥ 50 copies/mL and the second > 200 copies/mL) undergo genotyping.

中文翻译:

初始抗逆转录病毒治疗的关键临床试验中使用的病毒学失败和耐药性分析定义的临床影响:系统评价

在初始抗逆转录病毒治疗 (ART) 的 III 期随机临床试验 (RCT) 中,没有标准化的标准来表征已确认的协议定义的病毒学失败 (PDVF),也没有针对耐药性分析人群 (RAP) 的纳入标准。我们在最新的一线 ART 研究中评估了病毒学无应答(HIV-1 RNA ≥50 拷贝/mL)、确认的 PDVF(48 周)和 RAP 定义之间不匹配的临床影响。对所有 III 期 RCT 进行了系统评价,包括首选的每日一次 ART(EACS 欧洲艾滋病指南)或最近获得美国食品和药物管理局批准的 ART。我们确定了 16 个治疗组(14 个随机对照试验),其中 6175 名参与者接受了 dolutegravir、bictegravir、elvitegravir/cobicistat、raltegravir、darunavir/cobicistat、利匹韦林或多拉韦林治疗。PDVF 或 RAP 的血浆 HIV-1 RNA 阈值范围为 40 到 50、200、400 和 500 拷贝/mL。这导致了关于被定义为病毒学无反应者、PDVF 或包含在 RAP 中的参与者的试验之间的差异。总体而言,85/296 (29%) 名 PDVF 患者未进行基因分型。选择进行基因分型的 HIV RNA 阈值与患有 PDVF 但未进行基因分型的参与者的比率之间存在线性相关性。只有 8 个治疗组对所有参与者进行了 PDVF 基因分型。其余 8 个组中的大多数对 PDVF 的基因分型大约 < 50%。总而言之,一线 ART 的关键 III 期 RCT 中缺乏 VF 的标准化定义和耐药性测试标准,导致当基因型仅在较高病毒载量截断值下进行时,耐药突变有可能漏报。
更新日期:2020-08-21
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