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

项目总结 艾滋病毒抗药性(HIVDR)的积累有可能侵蚀全球艾滋病毒治疗方面的成果。作为一名 结果，世界卫生组织(WHO)关于艾滋病毒/艾滋病的全球行动计划呼吁增加 监视系统。值得注意的是，2019年世卫组织耐药性报告包括了关于 成人和婴儿的艾滋病毒耐药性(PDR)以及获得性药物的数据 成人对一线抗逆转录病毒治疗失败的抵抗力。然而，有关儿童ADR的数据令人震惊 缺席。 随着各国开始实施2019年世卫组织指南，以多洛替格韦(DTG)取代洛比那韦/利托那韦- 基于儿童中的二线艺术，有关ADR的数据甚至更有针对性。虽然DTG持有很好的 鉴于艾滋病毒的效力和高门槛，承诺改善艾滋病毒结果和减少抗药性 核苷逆转录酶患者的耐药性及其在二线抗逆转录病毒治疗中的应用 抑制剂(NRTI)的耐药性尚不清楚。DTG单一疗法的失败研究提供了一个警示信息 NRTI主干对于病毒学抑制和防止整合酶耐药仍然重要。 尼日利亚是世界上感染艾滋病毒儿童最多的国家。在一项全国性的调查中 在18个月大的幼稚婴儿≤中，观察到高耐药率，包括对 在儿童中使用最广泛的NRTI主干(阿巴卡韦和拉米夫定)。然而，治疗后的ADR比率 一线失败率预计会更高。自2004年以来，APIN公共卫生倡议提供了艾滋病毒 为尼日利亚2万多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 来自尼日利亚多个儿科站点/地区的耐药性数据。我们建议在以下几个方面评估ADR 尼日利亚400名未能通过第一线抗逆转录病毒治疗的儿童，并将利用这些数据来得出临床预测规则 (CPR)确定那些最有可能从目标HIVDR测试中受益的人，并避免功能性DTG 单一疗法。此外，需要快速进行护理点(POC)HIVDR测试，以解决以下问题的可行性障碍 低收入环境。因此，我们将评估OLA-Simple POC HIVDR检测，它具有同等的 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 流行于尼日利亚。这项研究的结合解决了有关ADR知识的一个关键差距 在未通过一线抗逆转录病毒治疗的儿童中，将在二线之前通知未来有针对性的HIVDR检测研究 Switch，并将在此设置下评估快速POC HIVDR检测。这有可能影响到 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。

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.