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圭的北卡罗来纳州大学项目提出，旨在描述马拉维预防母婴传播（PMTCT）和艾滋病毒治疗中暴露于基于依法韦仑的Option B+方案的母亲和婴儿的安全性、持久性、ART耐药性和临床结局。备选方案B+是马拉维国内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/依法韦仑：TDF/3 TC/EFV）。重要的是，方案B+主要是基于方案需要而采用的，尚未在临床试验中直接进行研究。尚未系统评价妊娠期间使用的基于TDF/3 TC/EFV的方案的安全性。值得注意的是，TDF/3 TC/EFV具有低的耐药性屏障，使得妇女和婴儿在次优保留或粘附的情况下可能特别容易受到耐药性的影响。因此，随着时间的推移，该方案的持久性可能是次优的，并且后续妊娠可能需要二线治疗。现在，在马拉维的Option B+项目中，我们有超过2年的随访时间，我们处于一个独特的位置来探讨这些与治疗失败有关的问题，以及在该项目中再次怀孕的妇女中使用阿扎那韦/利托那韦二线治疗的有效性和安全性。拟议的研究将在马拉维利隆圭的四个高容量产前检查点进行，在那里，ESTA项目和Baylor Tinguistics项目（将合作进行本研究）已经建立了基础设施。采用前瞻性队列研究设计，我们将在首次产前访视时招募新发现的HIV感染妇女，并随访母婴结局至分娩后3年。在该项目中随后怀孕的妇女中，我们将测量病毒学失败的患病率，并评估二线治疗的需求。如果失败，我们将评估Atazanavir/利托那韦在妊娠期间的安全性。在后续妊娠的计划违约者中，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特征。对于所有队列，关键结局将包括DAIDS 3级或4级事件、不良妊娠和出生结局、HIVRNA抑制、母婴耐药性和婴儿神经发育。我们的研究计划已经精心制定，以补充现有的程序和研究活动，并预计只能用一个更成熟的选项B+程序回答下一个关键问题。因此，我们现在回答这些问题的能力将告知其他计划，因为他们开始一个选项B+计划。

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.