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

描述(由申请人提供)：这项由设在马拉维利隆圭的北卡罗来纳大学项目提出的建议旨在描述暴露于马拉维预防母婴传播(PMTCT)和艾滋病毒治疗的基于efavirenz的Option B+方案的母亲和婴儿的安全性、耐受性、抗逆转录病毒治疗和临床结果。备选方案B+是马拉维首创的一项创新战略，为孕妇和哺乳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/法韦伦：TDF/3TC/EFV)。重要的是，方案B+在很大程度上是基于规划需要而采用的，并没有在临床试验中直接进行研究。妊娠期间使用的基于TDF/3TC/EFV的方案的安全性尚未得到系统评估。值得注意的是，TDF/3TC/EFV具有较低的耐药屏障，因此在保留或粘连不佳的情况下，妇女和婴儿可能特别容易受到耐药性的影响。因此，随着时间的推移，该方案的耐受性可能是次优的，后续怀孕可能需要二线治疗。现在，在马拉维的Option B+计划中有超过2年的随访时间，我们处于独特的地位来探索这些与治疗失败相关的问题，以及在该计划中再次怀孕的女性中使用阿扎那韦/利托那韦的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地点进行，联合国儿童基金会项目和贝勒·廷加计划(将在这项研究上进行合作)已经建立了基础设施。采用前瞻性队列研究设计，我们将在第一次产前检查时招募新发现的艾滋病毒感染妇女，并跟踪母亲和婴儿的结局，直到产后第三年。在该计划中再次怀孕的女性中，我们将测量病毒学失败的流行率，并评估二线治疗的必要性。如果失败，我们将评估阿扎那韦/利托那韦在妊娠期的安全性。在计划的违约者中，在恢复一线治疗后，我们将评估早期治疗失败的情况，并确定与这一群体相关的耐药性特征。对于所有队列，关键结果将包括DAIDS 3级或4级事件、不良妊娠和分娩结果、HIVRNA抑制、母婴抗药性以及婴儿神经发育。我们的研究计划经过精心制定，以补充现有的计划和研究活动，并预计下一个关键问题，只有更成熟的选项B+计划才能回答。因此，我们现在回答这些问题的能力将在其他计划开始实施Option B+计划时提供信息。

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.