Option B+: ART Safety and Durability during First and Subsequent Pregnancies

描述（由申请人提供）：该提案由位于马拉维利隆韦的北卡罗莱纳大学项目提出，旨在表征在马拉维接受以依非韦伦为基础的预防母婴传播（PMTCT）和艾滋病毒治疗的B+方案的母亲和婴儿的安全性、持久性、抗逆转录病毒药物耐药性和临床结果。B+方案是马拉维首创的一项创新战略，为孕妇和哺乳期妇女提供普遍的终身抗逆转录病毒治疗（替诺福韦/拉米夫定/依非韦伦：TDF/3TC/EFV）。重要的是，B+方案的采用主要是基于程序性需求，尚未在临床试验中直接研究。妊娠期间使用TDF/3TC/EFV方案的安全性尚未得到系统评价。值得注意的是，TDF/3TC/EFV具有较低的耐药屏障，因此妇女和婴儿在未达到最佳保留或依从性的情况下可能特别容易产生耐药性。因此，随着时间的推移，该方案的持久性可能不是最佳的，并且可能需要对后续妊娠进行二线治疗。现在，在马拉维的选项B+项目中进行了2年多的随访，我们处于一个独特的位置来探索这些与治疗失败有关的问题，除了阿扎那韦/利托那韦二线治疗在项目中出现的后续怀孕妇女中的有效性和安全性。拟议的研究将在马拉维利隆圭的四个高容量产前地点进行，UNC项目和Baylor Tingathe方案（将合作进行这项研究）已经建立了基础设施。采用前瞻性队列研究设计，我们将在首次产前检查时招募新发现的艾滋病毒感染妇女，并跟踪分娩后3年的母婴结局。在该项目的后续妊娠妇女中，我们将测量病毒学失败的患病率，并评估二线治疗的必要性。如果失败，我们将评估阿扎那韦/利托那韦在妊娠期间的安全性。在该计划的违约者中，在恢复一线治疗后，我们将评估早期治疗失败并确定与该人群相关的耐药概况。对于所有队列，关键结局将包括艾滋病3级或4级事件、不良妊娠和分娩结局、HIVRNA抑制、母婴耐药和婴儿神经发育。我们的研究计划经过精心制定，以补充现有的项目和研究活动，并预测下一个关键问题，这些问题只能通过更成熟的选项B+项目来回答。因此，我们现在回答这些问题的能力将为其他项目提供信息，因为他们开始了B+选项项目。

DESCRIPTION (provided by applicant): This proposal by the University of North Carolina Project based in Lilongwe, Malawi aims to characterize safety, durability, ART resistance, and clinical outcomes for mothers and infants exposed to the efavirenz-based Option B+ regimen for Prevention of Mother to Child Transmission (PMTCT) and HIV treatment in Malawi. Option B+ is an innovative strategy pioneered within Malawi that provides universal life-long ART (tenofovir/lamivudine/efavirenz: TDF/3TC/EFV) for pregnant and breastfeeding women. Importantly, Option B+ was adopted largely based on programmatic need and has not been directly studied in clinical trials. The safety of a TDF/3TC/EFV based regimen used during pregnancy has not been systematically evaluated. Notably, TDF/3TC/EFV has a low barrier to resistance such that women and infants may be particularly susceptible to resistance in the event of sub- optimal retention or adherence. Hence, the durability of the regimen may be sub- optimal over time and second line therapy may be required for subsequent pregnancies. Now, with over 2 years of follow-up time in the Option B+ program in Malawi, we are in a unique position to explore these questions related to treatment failure, in addition to the effectiveness and safety of second line therapy with Atazanavir/ritonavir among women presenting with subsequent pregnancies in the program. The proposed study will take place at four high volume antenatal sites within Lilongwe, Malawi where UNC project and the Baylor Tingathe Program (who will be collaborating on this study) have established infrastructure. Using a prospective cohort study design, we will enroll newly identified HIV infected women at the first antenatal visi and follow maternal and infant outcomes through year 3 post-delivery. Among women with subsequent pregnancies in the program, we will measure the prevalence of virologic failure and assess the need for second line therapy. In the event of failure, we will evaluate the safety of Atazanavir/ritonavir during pregnancy. Among defaulters of the program with subsequent pregnancies, after resumption of first line therapy, we will evaluate for early treatment failure and determine resistance profiles associated with this population. For all cohorts, key outcomes will include DAIDS grade 3 or 4 events, adverse pregnancy and birth outcomes, HIVRNA suppression, maternal and infant drug resistance, and infant neurologic development. Our research plan has been carefully developed to be complementary to existing program and research activities and anticipates the next critical questions that can only be answered with a more mature Option B+ program. Hence, our ability to answer these questions now will inform other programs as they embark on an Option B+ program.