GH12-008, NIGERIA, RESEARCH: HIV Drug Resistance: Implications for Optimizing Antiretroviral Therapy

摘要 抗逆转录病毒疗法(ART)在全球范围内的推广降低了艾滋病毒死亡率和 改善了资源受限环境(RLS)的临床结果，然而，20%-30%的患者 ART通常在12个月后出现可检测到的病毒血症[1，2]。作为不完全的镇压 已知是发生耐药突变(DRM)的风险因素[3]， 抗药性的发展可能侵蚀全球在提供抗逆转录病毒药物方面取得的成果[4-7]。在大多数RLS中， 利用公共卫生方法选择一线(1L)和二线(2L)抗逆转录病毒治疗[8]。为 包含特定NRTI主干的1L方案失败的患者，2L NRTI主干是 预计有保存下来的活动。然而，在故障检测延迟的设置中， DRM的积累可能导致2L NRTI主干的损害。 除了对2L方案的NRTI易感性的担忧外，问题仍然存在 关于将患者从1L转为2L抗逆转录病毒治疗的最佳时间；对于失败的患者 1L，但具有次优的粘附性，已表明在附加粘附性的情况下 干预后，患者重新抑制，实际上很少或没有耐药突变[14]。的确有 需要更好地了解不同原因导致的DRM的阈值和后果 不遵守规则的模式。最后，关于累积的DRM对 随后的2L结果。 在这项研究中，我们建议在1L ART失败的患者中评估DRM，检查 与DRM发展相关的坚持模式，并评估这种联系 在DRMS和随后对2L ART的反应之间。通过对DRM的分析，我们希望能够 获得可以为1L方案建议提供信息的洞察力，并增加我们对 与后续2L结果的次优坚持相关的风险。建议进行的研究 将利用尼日利亚研究所接受抗逆转录病毒治疗的患者的数据和样本 医学研究(NIMR)、乔斯大学教学医院(JUTH)和大学学院 尼日利亚伊巴丹(UCH)医院。通过PEPFAR的资助，所有3个治疗中心都 为超过8年的21,138名病人提供全面的爱滋病护理和治疗服务 目前正在进行艺术创作。哈佛大学已经建立了在这三个地方进行DRM基因分型的能力 中心，并将提供技术援助和支持。

ABSTRACT The worldwide scale-up of antiretroviral therapy (ART) has decreased HIV mortality and improved clinical outcomes in resource-limited settings (RLS), however, 20-30% of patients on ART typically experience detectable viremia after 12 months [1, 2]. As incomplete suppression is known to be a risk factor for developing drug resistance mutations (DRMs) [3], the development of resistance may erode global gains in the provision of ART [4-7]. In most RLS, a public health approach to choosing first-line (1L) and second-line (2L) ART is utilized [8]. For patients who fail a 1L regimen containing a specific NRTI backbone, the 2L NRTI backbone is expected to have preserved activity. However, in settings where detection of failure is delayed, the accumulation of DRMs may result in compromise of the 2L NRTI backbone. In addition to the concerns regarding NRTI susceptibility for 2L regimens, questions remain regarding the optimal time to switch a patient from 1L to 2L ART; for patients who are failing 1L, but have suboptimal adherence, it has been shown that with additional adherence interventions, patients re-suppress and actually had few or no resistance mutations [14]. There is a need to better understand the threshold and consequences of DRMs resulting from different patterns of non-adherence. Finally, little is known about the impact of accumulated DRMs on subsequent 2L outcomes. For this study, we propose to evaluate the DRMs among patients failing 1L ART, examine the patterns of adherence associated with the development of DRMs, and assess the association between DRMs and subsequent response to 2L ART. Through the analysis of DRM we hope to gain insight that can inform 1L regimen recommendations and increase our understanding of the risks associated with sub-optimal adherence on subsequent 2L outcomes. The proposed study will utilize data and samples from patients that have received ART at the Nigerian Institute of Medical Research (NIMR), Jos University Teaching Hospital (JUTH), and University College Hospital in Ibadan (UCH) in Nigeria. Through PEPFAR funding, all 3 treatment centers have been providing comprehensive HIV care and treatment services for over 8 years 21,138 patients currently on ART. Harvard has established the capacity for DRM genotyping at all three of these centers and will provide technical assistance and support.