HIV-1 subtype, specific drug resistance in patients failing Dolutegravir-based 1st, 2nd or 3rd line regimens: the International epidemiological Databases to Evaluate AIDS (IeDEA)

HIV-1 亚型，基于多替拉韦的第一、第二或第三线治疗方案失败的患者的特异性耐药性：评估艾滋病的国际流行病学数据库 (IeDEA)

• 批准号: 10680506
• 负责人: Matthias Egger
• 金额: $ 6.12万
• 依托单位: UNIVERSITAT BERN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680506
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adolescent; Adult; Affect; Africa; Age; American; Anti-Retroviral Agents; Asia; Biological; Biological Assay; Biological Sciences; Canada; Caribbean region; Central America; Clinical; Clinical Data; Collaborations; Country; Data; Databases; Development; Drug resistance; Early Diagnosis; Epidemic; Epidemiology; European; Exposure to; Failure; France; Frequencies; Funding; Genes; Genetic; Genotype; Geographic Locations; Germany; Goals; Guidelines; HIV; HIV Infections; HIV drug resistance; HIV-1; Health system; Individual; Integrase; International; Modeling; Monitor; Mutation; Netherlands; Pathway interactions; Patient Recruitments; Patients; Pattern; Persons; Pharmaceutical Preparations; Phase; Phenotype; Predisposition; Prevalence; Recommendation; Recording of previous events; Recycling; Regimen; Resistance; Rifampin; Risk Factors; Role; Sampling; Site; South Africa; South America; Spain; Specimen; Standardization; Switzerland; System; Testing; Time; United States National Institutes of Health; Viral Genome; Viral Load result; Virus; World Health Organization; advanced disease; antiretroviral therapy; clinical research site; cohort; data harmonization; detection platform; experience; genome sequencing; inhibitor; inhibitor therapy; male; nef Genes; next generation sequencing; novel; pre-exposure prophylaxis; prospective; public health intervention; resistance mutation; response; sequencing platform; sex; treatment program; whole genome

ABSTRACT Antiretroviral therapy (ART) of HIV infection has been one of the most successful public health interventions in history, but the emergence of HIV drug resistance is a threat to ending the HIV epidemic. The next phase of the global HIV response will rely on integrase strand transfer inhibitors (InSTIs), particularly dolutegravir (DTG), a potent antiretroviral with a high genetic barrier to resistance. DTG is recommended for all lines of treatment (1st, 2nd- and 3rd-line) by the World Health Organization, and drugs from the same class are developed for pre- exposure prophylaxis. There is limited understanding of the spectrum of DTG-selected mutations and their effects on phenotypic susceptibility, particularly in non-B subtype viruses, and of the importance of mutations outside of the integrase gene. It is critical to establish robust systems for early detection of InSTI resistance in HIV treatment programs, and develop an understanding of where and how resistance to DTG occurs in real world cohorts. We propose to do this in the NIH-funded International epidemiology Databases to Evaluate AIDS (IeDEA) and the Antiretroviral Therapy Cohort Collaboration (ART-CC). Specifically, we aim i) to determine the patterns and spectrum of InSTI drug resistance mutations in adults and adolescents with virologic failure on DTG-based ART by regimen and HIV-1 subtype; ii) to identify risk factors for virologic failure and resistance in adolescents and adults on DTG-based ART; and iii) to investigate correlations between novel resistance genotypes and phenotypic InSTI resistance across HIV-1 subtypes. In total, 46 IeDEA sites and 7 ART-CC cohorts from 32 countries will participate in this study. Ten sites and cohorts will contribute existing data (Sanger sequences and clinical data), rather than prospectively recruiting patients; 19 sites and cohorts will contribute pairs of samples or sequences at switch and failure, and 32 will contribute data on adolescents. We will include adults (≥18 years) and adolescents (10-17 years) with virologic failure (viral load ≥1000 copies/mL) on any DTG- based ART. Analyses will be based on about 4600 patients failing DTG-based ART and about 490 patients with DTG drug resistance mutations. We will perform whole genome sequencing using the Illumina MiSeq next- generation sequencing platform to detect integrase mutations and mutations outside integrase (e.g. in the 3' polypurine tract region of the nef gene). We will combine the data with existing sequence data from North American and European cohorts. We will compare the prevalence of InSTI DRMs at different frequency thresholds (20%, 5%, and 2%) by ART regimen and HIV-1 subtype. We will identify predictors of virologic failure and drug resistance, and characterize the phenotypic effect of novel resistance genotypes by performing phenotypic testing on selected specimens across the range of HIV-1 subtypes. Our proposal has three key strengths: i) the pooling of clinical and sequence data across a vast global network to explore the determinants of DTG resistance in people on 1st, 2nd-, and 3rd-line ART; ii) inclusion of multiple HIV-1 subtypes across geographic areas and iii) combining expertise from clinical, epidemiological, biological, and computational fields.

抽象的 HIV 感染的抗逆转录病毒治疗 (ART) 是最成功的公共卫生干预措施之一 历史，但艾滋病毒耐药性的出现对结束艾滋病毒流行的下一阶段构成威胁。 全球艾滋病毒应对措施将依赖于整合酶链转移抑制剂（InSTI），特别是多替拉韦（DTG），一种 建议将具有高遗传耐药性的强效抗逆转录病毒药物 DTG 用于所有治疗方案（第一， 世界卫生组织规定的第二线和第三线），并且同一类别的药物是为预治疗而开发的 对 DTG 选择的突变谱及其影响的了解有限。 对表型易感性的影响，特别是在非 B 亚型病毒中，以及突变的重要性 建立强大的系统以早期检测 InSTI 耐药性至关重要。 HIV 治疗计划，并了解 DTG 耐药性在现实中发生的地点和方式 我们建议在 NIH 资助的国际流行病学数据库中进行艾滋病评估。 (IeDEA) 和抗逆转录病毒治疗队列协作 (ART-CC) 具体而言，我们的目标是 i) 确定 病毒学失败的成人和青少年 InSTI 耐药突变的模式和谱 按治疗方案和 HIV-1 亚型进行基于 DTG 的 ART；ii) 确定病毒学失败和耐药的危险因素 青少年和成人接受基于 DTG 的 ART；以及 iii) 研究新型耐药性之间的相关性 HIV-1 亚型的基因型和表型 InSTI 耐药性总共有 46 个 IeDEA 站点和 7 个 ART-CC。 来自 32 个国家的队列将参与这项研究，十个地点和队列将贡献现有数据（桑格）。 19 个站点和群组将做出贡献 转换和失败时的成对样本或序列，32 将提供有关青少年的数据。 任何 DTG 治疗后出现病毒学失败（病毒载量≥1000 拷贝/mL）的成人（≥18 岁）和青少年（10-17 岁） 基于 ART 的分析将基于约 4600 名基于 DTG 的 ART 失败的患者和约 490 名接受过基于 DTG 的 ART 的患者。 接下来我们将使用 Illumina MiSeq 进行 DTG 耐药突变。 一代测序平台，用于检测整合酶突变和整合酶外部的突变（例如，在 3' nef 基因的多嘌呤束区域）我们将把数据与来自 North 的现有序列数据结合起来。 我们将比较不同频率下 InSTI DRM 的流行率。 我们将根据 ART 方案和 HIV-1 亚型确定病毒学失败的预测因子（20%、5% 和 2%）。 和耐药性，并通过执行来表征新耐药基因型的表型效应 对一系列 HIV-1 亚型的选定样本进行表型测试 我们的建议包括三个关键内容。 优势： i) 通过庞大的全球网络汇集临床和序列数据以探索决定因素 接受第一、二线和三线 ART 的人群中 DTG 耐药性的影响；ii) 涵盖多种 HIV-1 亚型； 地理区域和 iii) 结合临床、流行病学、生物学和计算领域的专业知识。

项目成果

sHIV-1 drug resistance in people on dolutegravir-based ART: Collaborative analysis of cohort studies.

接受基于多替拉韦的 ART 人群中 sHIV-1 耐药性：队列研究的协作分析。

• 发表时间: 2023-04-05
• 作者: Loosli, Tom;Hossmann, Stefanie;Ingle, Suzanne M;Okhai, Hajra;Kusejko, Katharina;Mouton, Johannes;Bellecave, Pantxika;van Sighem, Ard;Stecher, Melanie;d'Arminio Monforte, Antonella;Gill, M John;Sabin, Caroline A;Maartens, Gary;Günthard, Huldry
• 通讯作者: Günthard, Huldry

Implementation and outcomes of dolutegravir-based first-line antiretroviral therapy for people with HIV in South Africa: a retrospective cohort study.

南非艾滋病毒感染者基于多替拉韦的一线抗逆转录病毒治疗的实施和结果：一项回顾性队列研究。

• 发表时间: 2023-05
• 作者: Dorward, Jienchi;Sookrajh, Yukteshwar;Khubone, Thokozani;van der Molen, Johan;Govender, Riona;Phakathi, Sifiso;Lewis, Lara;Bottomley, Christian;Maraj, Munthra;Lessells, Richard J;Naidoo, Kogieleum;Butler, Christopher C;Van Heerden, Rose;Garre
• 通讯作者: Garre

Clinical outcomes after the introduction of dolutegravir for second-line antiretroviral therapy in South Africa: a retrospective cohort study.

南非引入多替拉韦作为二线抗逆转录病毒治疗后的临床结果：一项回顾性队列研究。

• 发表时间: 2023-07-08
• 作者: Asare, Kwabena;Sookrajh, Yukteshwar;van der Molen, Johan;Khubone, Thokozani;Lewis, Lara;Lessells, Richard J;Naidoo, Kogieleum;Sosibo, Phelelani;van Heerden, Rosemary;Garrett, Nigel;Dorward, Jienchi
• 通讯作者: Dorward, Jienchi

HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis.

接受基于多替拉韦的抗逆转录病毒治疗的人群中 HIV-1 耐药性：一项协作队列分析。

• 发表时间: 2023-11
• 作者: Loosli, Tom;Hossmann, Stefanie;Ingle, Suzanne M;Okhai, Hajra;Kusejko, Katharina;Mouton, Johannes;Bellecave, Pantxika;van Sighem, Ard;Stecher, Melanie;d'Arminio Monforte, Antonella;Gill, M John;Sabin, Caroline A;Maartens, Gary;Günthard, Huldry
• 通讯作者: Günthard, Huldry