Acquired HIV drug resistance among Nigerian children failing first-line ART: Implications for second-line dolutegravir use

一线抗逆转录病毒疗法失败的尼日利亚儿童获得了艾滋病毒耐药性：对二线多替拉韦使用的影响

• 批准号: 10326999
• 负责人: Holly Elizabeth Rawizza
• 金额: $ 18.03万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326999
• 关键词: 15 year old; Address; Adult; Advisory Committees; Africa; Age-Months; Biological Assay; Caring; Categories; Child; Childhood; Clinical; Country; Data; Databases; Dose; Drug resistance; Drug usage; Essential Drugs; Evaluation; Failure; Future; Genotype; Goals; Guidelines; HIV; HIV drug resistance; HIV-1; Home; Infant; Integrase; International; Knowledge; Lamivudine; Logistic Regressions; Lopinavir/Ritonavir; Low income; Methods; Modeling; Nigeria; Nigerian; Nucleosides; Outcome; Patients; Population; Positioning Attribute; Protease Inhibitor; Public Health; Regimen; Reporting; Resistance; Reverse Transcriptase Inhibitors; Risk; Sampling; Sensitivity and Specificity; Site; Surveys; Testing; Time; Vertebral column; Viral load measurement; Vulnerable Populations; World Health Organization; abacavir; acquired drug resistance; antiretroviral therapy; base; design; detection test; high risk; improved; improved outcome; next generation; non-nucleoside reverse transcriptase inhibitors; novel; point of care; point of care testing; prevent; resistance mutation; scale up; success; virology

PROJECT SUMMARY The accumulation of HIV drug resistance (HIVDR) threatens to erode gains in HIV treatment globally. As a result, the World Health Organization (WHO) Global Action Plan on HIVDR has called for increased surveillance. Notably, the 2019 WHO Drug Resistance report included data on the alarming increase in pretreatment HIV drug resistance (PDR) among adults and infants, as well as data on acquired drug resistance (ADR) among adults failing first-line ART. However, data on ADR among children is glaringly absent. As countries begin to implement 2019 WHO guidance to replace lopinavir/ritonavir- with dolutegravir (DTG)- based second-line ART among children, data on ADR is even more pertinent. While DTG holds great promise for improving HIV outcomes and reducing drug resistance given its potency and high barrier to resistance, its use for second-line ART among patients with pre-existing nucleoside reverse transcriptase inhibitor (NRTI) resistance is unknown. Failed studies of DTG monotherapy provide a cautionary message that the NRTI backbone remains important for virologic suppression and preventing integrase resistance. Nigeria is home to more children living with HIV than any other country in the world. In a national survey of PDR among ART-naïve infants ≤18 months of age, high rates of resistance were observed, including to the most widely used NRTI backbone among children (abacavir and lamivudine). However, rates of ADR after first-line failure are expected to be even higher. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 20,000 children in Nigeria, and thus is uniquely positioned to provide critical drug resistance data from multiple pediatric sites/regions across Nigeria. We propose to evaluate ADR among 400 children in Nigeria failing first-line ART, and will utilize these data to derive a clinical prediction rule (CPR) to identify those most likely to benefit from targeted HIVDR testing and avoid functional DTG monotherapy. Further, rapid point-of-care (POC) HIVDR testing is needed to address feasibility barriers in low income settings. We will therefore evaluate the OLA-Simple POC HIVDR assay, which has equivalent sensitivity to standard sequencing methods, but has not been validated among the unique HIV-1 subtypes prevalent in Nigeria. This combination of studies addresses a critical gap in knowledge regarding ADR among children failing first-line ART, will inform future studies of targeted HIVDR testing prior to second-line switch, and will evaluate a rapid POC HIVDR assay in this setting. This has the potential to impact international guidance on second-line DTG use and HIVDR testing for this vulnerable population of children.

项目摘要 HIV耐药性（HIVDR）的积累有可能在全球HIV治疗中侵蚀增益。作为 结果，世界卫生组织（WHO）HIVDR的全球行动计划要求增加 监视。值得注意的是，2019年WHO抗药性报告包括有关令人震惊的增加的数据 成人和婴儿的预处理HIV耐药性（PDR）以及获得药物的数据 一线艺术失败的成年人中的抵抗（ADR）。但是，关于儿童ADR的数据非常明显 缺席的。 随着各国开始实施2019年WHO指导，用Dolutegravir（DTG）取代Lopinavir/Ritonavir-- 基于儿童的二线艺术，有关ADR的数据更加相关。虽然DTG很棒 鉴于其效力和高障碍，可以改善艾滋病毒结局并降低耐药性 耐药性，其用于二线ART的二线ART在患有核苷逆转录酶的患者中 抑制剂（NRTI）抗性尚不清楚。 DTG单一疗法的研究失败提供了警示信息 NRTI主链对于病毒学抑制和防止整合酶抗性仍然很重要。 尼日利亚是艾滋病毒携带的儿童的所在地，而不是世界上任何其他国家。在全国调查中 在未经艺术的婴儿中，PDR≤18个月大，观察到较高的抵抗发生率，包括 儿童中使用最广泛的NRTI主链（阿巴卡维尔和拉米夫丁）。但是，ADR的比率 一线故障预计会更高。自2004年以来，APIN公共卫生倡议提供了艾滋病毒 尼日利亚超过20,000名儿童的护理和治疗 来自尼日利亚多个儿科地点/地区的电阻数据。我们建议评估ADR 尼日利亚的400名儿童失败了一线艺术，并将利用这些数据来得出临床预测规则 （CPR）确定最有可能受益于靶向HIVDR测试的人并避免功能性DTG 单一疗法。此外，需要快速护理（POC）HIVDR测试以解决可行性障碍 低收入环境。因此，我们将评估具有等效性的Ola-simple POC HIVDR分析 对标准测序方法的敏感性，但尚未在唯一的HIV-1亚型中验证 在尼日利亚流行。这项研究的组合解决了有关ADR知识的关键差距 在失败的一线艺术的儿童中，将在二线之前对有针对性的HIVDR测试的未来研究告知 切换，并将在这种情况下评估快速的POC HIVDR分析。这有可能影响 对这一脆弱儿童人群的二线DTG使用和HIVDR测试的国际指南。