Institute of Social & Preventive Medicine, University of Bern, Bern, Switzerland
Centre for Infectious Disease Epidemiology and Research, University of Cape Town Faculty of Health Sciences, Cape Town, Western Cape, South Africa.
BMJ Open. 2024 Aug 21;14(8):e085819. doi: 10.1136/bmjopen-2024-085819.
HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the WHO in 2019 for first-line, second-line and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.
Nested within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST is a multicentre study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virological failure on dolutegravir-based ART. At the time of virological failure, whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (1) individuals who experienced virological failure on dolutegravir and (2) those who started or switched to such a regimen and were at risk of virological failure. For population (1), the outcome will be any InSTI drug resistance mutations, and for population (2) virological failure is defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virological failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.
The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in International epidemiology Databases to Evaluate AIDS and have obtained ethics approval from their local ethics committee to collect additional data.
NCT06285110.
HIV 耐药性对联合国终结艾滋病疫情的目标构成挑战。整合酶链转移抑制剂（INSTI）多拉韦林具有更高的耐药屏障，于 2019 年被世界卫生组织（WHO）推荐用于一线、二线和三线抗逆转录病毒治疗（ART）。多拉韦林在 ART 中的多重作用可能会促进多拉韦林耐药性的出现。
嵌套在国际艾滋病流行病学数据库（IeDEA）中的 DTG RESIST 是一项多中心研究，研究对象为撒哈拉以南非洲、亚洲以及南美洲和中美洲的成年和青少年 HIV 感染者，他们在基于多拉韦林的 ART 中出现病毒学失败。在病毒学失败时，将采集全血并进行处理，以制备血浆或干血斑。德班、墨西哥城和曼谷的实验室将进行基因分型。分析将集中在以下两个方面：（1）经历多拉韦林病毒学失败的个体；（2）开始或转换为该方案且有病毒学失败风险的个体。对于人群 1，结果将是任何 INSTI 耐药突变，对于人群 2，病毒学失败定义为病毒载量>1000 拷贝/ml。表型检测将集中于具有主要 INSTI 耐药突变的非 B 亚型病毒。贝叶斯进化模型将探索和预测治疗失败基因型。该研究将具有中等统计效力来检测主要 HIV-1 亚型之间耐药突变流行率的差异；有足够的效力来识别病毒学失败的危险因素，以及分析与个体 INSTI 耐药突变相关因素的有限效力。
该研究方案已获得南非夸祖鲁-纳塔尔大学生物医学伦理委员会和瑞士伯尔尼州伦理委员会的批准。所有参与地点都参与了国际艾滋病流行病学数据库（IeDEA），并已获得其当地伦理委员会的批准，以收集额外的数据。
NCT06285110。
