Optimal tuberculosis screening and tuberculosis preventive therapy delivery strategies to improve maternal and birth outcomes among pregnant women with HIV in Uganda: a randomized trial

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

PROJECT SUMMARY Pregnancy and the early postpartum period are times when women, especially women with HIV, are at highest risk for tuberculosis (TB). To reduce TB burden among all people with HIV, WHO recommends 1) intensified case finding (“ICF,” systematic TB screening followed by confirmatory TB testing for all who screen-positive) at every clinic visit and 2) immediate TB preventive therapy (TPT) for eligible individuals who screen-negative, in- cluding pregnant women with HIV (PWWH). Both ICF and TPT are particularly important during pregnancy to reduce risk of poor maternal and fetal outcomes. However, there are two main problems with the current approach to ICF and TPT for PWWH. First, symptom screening – the most widely used screening tool for TB – has unacceptably poor sensitivity among PWWH, missing up to 70% of all PWWH with TB, and performs worse with repeated rounds of screening. Second, the optimal timing of TPT is unclear because studies of PWWH receiving TPT have reported conflicting results, leading to inconsistent international guidelines on the use of TPT in pregnant women. New options for TB screening (CRP, C-reactive protein) and TPT (rifapentine-based short-course regimens) are now recommended by WHO and data among a general population of people with HIV suggest better accuracy and tolerability, respectively, relative to traditional tools. Definitive evidence is now urgently needed to determine whether CRP and/or short-course TPT can improve pregnancy outcomes at antenatal clinics in Africa, where TB remains a leading cause of non-obstetric maternal death. As such, we propose a highly efficient and innovative study using a sequential, multiple assignment, randomized trial (SMART) design to conduct a two-stage randomized trial to determine the optimal TB screening strategy and optimal timing of TPT initiation for PWWH. For the TB screening trial (Aim 1), we will randomize 1,500 PWWH presenting for routine antenatal care in Uganda to either CRP or symptom-based TB screening for the duration of their pregnancy and up to 6 months postpartum. The primary outcome for Aim 1 will be the proportion of all TB cases detected. For the TPT delivery trial (Aim 2), we will further randomize screen-negative PWWH enrolled in Aim 1 to either immediate (antenatal) TPT or deferred TPT. We will compare composite safety outcomes (primary outcome of spontaneous abortion, stillbirth, preterm birth, low birthweight, neonatal death) and composite effectiveness outcomes (co-primary outcome of maternal 2-year TB incidence and all-cause mortality) of immediate and deferred TPT. For Aim 3, we will use data collected from Aim 2 and IGRA results to construct a third TPT arm (targeted TPT) where immediate TPT is targeted to IGRA+ (high TB risk) PWWH and deferred for IGRA- (low TB risk) PWWH. We will compare safety and effectiveness outcomes of targeted TPT to the two untargeted (immediate and deferred) TPT strategies. This work will generate important data that will be critical to the future development of pregnancy-specific TB control activities, thus changing standard practice to improve the health of 1.3 million PWWH who give birth each year.