Novel mechanisms contributing to failure of dolutegravir-containing cART in clinical practice

导致含多替拉韦的 cART 在临床实践中失败的新机制

• 批准号: 10863066
• 负责人: David van de Vijver
• 金额: $ 1.34万
• 依托单位: ERASMUS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10863066
• 关键词: Adherence; Affect; Algorithms; Anti-Retroviral Agents; Brazil; CD4 Lymphocyte Count; Caring; Clinical Trials; Combined Modality Therapy; Country; Data; Development; Drug resistance; Event; Failure; Future; Generations; Genes; Goals; Guidelines; HIV; HIV-1; Health system; In Vitro; Income; Individual; Infection; Integrase; Integrase Inhibitors; Lamivudine; Life; Mediating; Minority; Modeling; Molecular; Mutation; Nucleosides; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Prediction of Response to Therapy; Predisposition; Public Health; Recombinants; Recommendation; Regimen; Resistance; Resistance development; Reverse Transcriptase Inhibitors; Risk; South American; Tenofovir; Testing; Treatment Failure; Variant; Viral; Virus; World Health Organization; acquired drug resistance; clinical practice; comparative; detection assay; diagnostic value; experimental study; improved; in vivo; inhibitor; innovation; insight; low and middle-income countries; next generation sequencing; novel; novel diagnostics; pharmacologic; public health priorities; resistance mechanism; resistance mutation; transmission process; treatment guidelines; viral fitness

Millions of people living with HIV (PLWH) will soon receive the integrase strand-transfer inhibitor (INSTI) dolutegravir (DTG), as the World Health Organization (WHO) now recommends DTG combined with two nucleoside reverse transcriptase inhibitors (NRTIs) as first- and second-line therapy. This combination therapy demonstrated very high efficacy in clinical trials and acquired drug resistance was absent (first-line treatment) or very rare (second-line treatment). It remains to be determined whether this high efficacy and lack of resistance development can be extrapolated to treatment of non-B subtype viruses in low- and middle-income countries where most PLWH live. Our long-term goal is to provide a scientific basis for optimal large-scale and long-term treatment of PLWH with DTG. Our central hypothesis is that novel viral mutations in and outside the integrase gene (with an emphasis on 3’-polypurine tract changes) contribute to virologic failure with DTG in clinical practice. This hypothesis will be tested by identifying PLWH failing DTG containing regimens in Brazil which is a model country for large-scale DTG implementation where various HIV subtypes co-circulate. Subsequently we will perform in-depth in vitro characterizations of novel viral mutations in and outside integrase gene in an HIV subtype comparative manner. The specific aims of this proposal are: 1) To characterize the pattern of INSTI resistance mutations that emerge during failure of DTG-containing cART in individuals infected with subtypes C, F, and BF recombinant forms in Brazil. These are the most prevalent non-B subtypes on the South-American continent. 2) To determine which changes in the 3’-PPT are observed in viruses from DTG failing individuals. Results of this study will show if this novel resistance pathway contributes to acquired drug resistance in clinical practice. 3) To determine the phenotypic consequences of mutations identified in specific aims 1 and 2. These studies assess and compare the effect of novel viral mutations on INSTI susceptibility and viral fitness in HIV subtypes A, B, C, and F in vitro (representing 70% of all infections worldwide), and the molecular mechanism of 3’-PPT mediated INSTI resistance will be determined. The insights generated with these studies will contribute to a more effective use of second generation INSTIs in the future.

数以百万计的艾滋病毒（PLWH）将很快收到综合酶链转移抑制剂（Insti）Dolutegravir （DTG），正如世界卫生组织（WHO）现在建议DTG与两个核苷反面相反 转录酶抑制剂（NRTIS）作为一线和二线治疗。这种组合疗法表现很高 没有（一线治疗）或非常罕见的临床试验和获得的耐药性（二线）的功效 治疗）。是否可以确定这种高效率和缺乏抵抗力发展是否可以是 推断在大多数PLWH居住的低收入和中等收入国家中的非B亚型病毒治疗。我们的 长期目标是为使用DTG对PLWH的最佳大规模和长期治疗提供科学基础。我们的 中心假设是整合酶基因内外的新型病毒突变（重点是3'-二嘌呤 区域变化）在临床实践中导致DTG的病毒学衰竭。该假设将通过识别 PLWH失败的DTG含有巴西的DTG，这是一个大规模DTG实施的模型国家 各种HIV亚型共同循环。随后，我们将在新的病毒中进行深入的体外特征 HIV亚型比较方式中的突变和外部整合酶基因内外的突变。该提案的具体目的是： 1）表征在含DTG的手推车失败期间出现的Insti抗性突变的模式 在巴西感染了亚型C，F和BF重组形式的个体。这些是最普遍的非B 南美洲大陆的亚型。 2）确定在病毒中观察到3'-PPT的哪些变化 DTG失败的人。这项研究的结果将表明这种新型的抗性途径是否有助于获得的药物 临床实践中的抵抗力。 3）确定特定目的中鉴定出的突变的表型后果1 和2。这些研究评估和比较了新型病毒突变对Insti易感性和HIV病毒适应性的影响 体外亚型A，B，C和F（占全球所有感染的70％），以及3'-PPT的分子机制 将确定介导的Insti阻力。这些研究产生的见解将有助于更多 将来有效使用第二代学院。

项目成果

HIV-1 resistance against dolutegravir fluctuates rapidly alongside erratic treatment adherence: a case report.

• DOI: 10.1016/j.jgar.2022.11.001
• 发表时间: 2022-12
• 期刊: JOURNAL OF GLOBAL ANTIMICROBIAL RESISTANCE
• 影响因子: 4.6
• 作者: van Kampen, Jeroen J. A.;Pham, Hanh Thi;Yoo, Sunbin;Overmars, Ronald J.;Lungu, Cynthia;Mahmud, Rizwan;Schurink, Carolina A. M.;van Boheemen, Sander;Gruters, Rob A.;Fraaij, Pieter L. A.;Burger, David M.;Voermans, Jolanda J. C.;Rokx, Casper;van de Vijver, David A. M. C.;Mesplede, Thibault
• 通讯作者: Mesplede, Thibault