HIV Drug Resistance: Implications for Optimizing Antiretroviral Therapy

摘要 全球范围内抗逆转录病毒疗法的推广降低了艾滋病毒死亡率， 在资源有限的环境（RLS）中改善临床结局，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]。作为不完全抑制 已知是产生耐药突变（DRM）的风险因素[3]， 耐药性的发展可能会侵蚀全球在提供抗逆转录病毒疗法方面取得的进展[4-7]。在大多数RLS中， 利用公共卫生方法选择一线（1 L）和二线（2L）ART [8]。为 对于含有特定NRTI骨架的1 L方案失败的患者， 预计将保留活动。然而，在故障检测延迟的情况下， DRM的积累可能导致2LNRTI主干的损害。 除了对2L方案的NRTI敏感性的担忧外， 关于患者从1 L ART转换为2L ART的最佳时间;对于失败的患者 1 L，但具有次优的粘附性，已经表明， 然而，在干预措施中，患者重新抑制，实际上很少或没有耐药突变[14]。有 需要更好地理解不同的灾害风险管理的门槛和后果， 不遵守的模式。最后，人们对累积的DRM的影响知之甚少， 后续2L结果。 在这项研究中，我们建议在1 L ART失败的患者中评估DRM， 与DRM发展相关的依从性模式，并评估 通过对数字版权管理的分析，我们希望能对数字版权管理与2L ART的后续反应之间的关系进行研究， 获得洞察力，可以告知1 L方案的建议，并增加我们对 与后续2L结局的次优依从性相关的风险。拟定研究 将利用在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 位于尼日利亚伊巴丹（UCH）的医院。通过PEPFAR资金，所有3个治疗中心都 为21，138名患者提供全面的艾滋病毒护理和治疗服务超过8年 哈佛大学已经建立了在所有这三个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.