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: 10483175
• 负责人: Holly Elizabeth Rawizza
• 金额: $ 19.82万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483175
• 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

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.

项目概要 HIV 耐药性 (HIVDR) 的积累可能会削弱全球 HIV 治疗成果。 因此，世界卫生组织 (WHO) 的《艾滋病毒防治全球行动计划》呼吁加大力度 值得注意的是，2019 年世界卫生组织耐药性报告包含了令人震惊的增长数据。 治疗前成人和婴儿的 HIV 耐药性 (PDR) 以及获得性药物的数据 然而，儿童 ADR 的数据却很明显。 缺席的。 随着各国开始实施 2019 年世卫组织指南，用多替拉韦 (DTG) 取代洛匹那韦/利托那韦 - 基于儿童的二线 ART，ADR 的数据更加相关，而 DTG 则很有效。 鉴于其效力和高屏障，有望改善艾滋病毒结果并减少耐药性 耐药性，其在已有核苷逆转录酶患者中用于二线 ART 的用途 DTG 单一疗法的失败研究提供了警示信息。 NRTI 主链对于病毒学抑制和预防整合酶耐药性仍然很重要。 一项全国调查显示，尼日利亚感染艾滋病毒的儿童数量比世界上任何其他国家都多。 在 ≤ 18 个月大的未接受过 ART 的婴儿中，观察到高耐药率，包括对 儿童中最广泛使用的 NRTI 骨干（阿巴卡韦和拉米夫定）然而，ADR 发生率仅次于该药物。 自 2004 年以来，APIN 公共卫生倡议提供了艾滋病毒治疗，一线治疗失败率预计更高。 为尼日利亚超过 20,000 名儿童提供护理和治疗，因此在提供关键药物方面具有得天独厚的优势 我们建议评估尼日利亚多个儿科场所/地区的耐药性数据。 尼日利亚 400 名儿童一线 ART 失败，将利用这些数据得出临床预测规则 (CPR) 以确定最有可能从针对性 HIVDR 检测中受益的人群并避免功能性 DTG 此外，需要快速床旁 (POC) HIVDR 检测来解决单一疗法的可行性障碍。 因此，我们将评估 OLA-Simple POC HIVDR 检测，该检测具有同等效果。 对标准测序方法的敏感性，但尚未在独特的 HIV-1 亚型中得到验证 这些研究的结合弥补了 ADR 方面的知识空白。 在一线抗逆转录病毒治疗失败的儿童中，将为未来在二线治疗前进行针对性 HIVDR 检测的研究提供信息 转换，并将评估这种情况下的快速 POC HIVDR 检测，这有可能产生影响。 关于针对这一弱势儿童群体的二线 DTG 使用和 HIVDR 检测的国际指南。