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

项目摘要 艾滋病毒耐药性的积累有可能侵蚀全球艾滋病毒治疗的成果。作为 因此，世界卫生组织（世卫组织）《艾滋病毒/艾滋病全球行动计划》呼吁增加 监视值得注意的是，2019年世卫组织耐药性报告包括了关于 成人和婴儿治疗前的艾滋病毒耐药性（PDR），以及获得性药物耐药性数据 然而，关于儿童ADR的数据令人担忧， 无托叶 随着各国开始实施2019年世卫组织指南，用度鲁特韦（DTG）取代洛匹那韦/利托那韦- 在儿童中使用二线抗逆转录病毒疗法的情况下，关于药品不良反应的数据甚至更为相关。虽然DTG拥有强大的 鉴于其效力和高屏障， 耐药，在已有核苷逆转录酶的患者中用于二线ART 抑制剂（NRTI）耐药性未知。DTG单药治疗失败的研究提供了警示信息 NRTI骨架对于病毒学抑制和防止整合酶抗性仍然重要。 尼日利亚的艾滋病毒感染儿童比世界上任何其他国家都多。在一项全国性的调查中， 在年龄≤18个月的ART初治婴儿中，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，ADR发生率在 一线故障预计将更高。自2004年以来，APIN公共卫生倡议提供了艾滋病毒 为尼日利亚的20，000多名儿童提供护理和治疗，因此具有提供关键药物的独特地位。 来自尼日利亚多个儿科研究中心/地区的耐药数据。我们建议评估ADR， 尼日利亚一线抗逆转录病毒治疗失败的400名儿童，并将利用这些数据得出临床预测规则 (CPR)确定那些最有可能受益于有针对性的艾滋病病毒检测和避免功能性DTG 单一疗法。此外，需要快速护理点（POC）HIVDR检测来解决 低收入环境。因此，我们将评估OLA-Simple POC HIVDR检测试剂盒，该试剂盒具有等效性 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。这些研究的结合解决了关于ADR知识的关键差距 在一线抗逆转录病毒治疗失败的儿童中，将为未来的研究提供信息， 开关，并将评估快速POC艾滋病病毒检测在这种情况下。这有可能影响到 国际指导，二线DTG使用和艾滋病病毒检测，为这一脆弱的儿童群体。

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.