Abstract
Antenatal vaginal progesterone (VP) reduces the risk of preterm birth (PTB) in women with shortened cervical length, and we hypothesize that it may also prevent PTB in women with HIV as their primary risk factor. We conducted a pilot feasibility study in Lusaka, Zambia to investigate uptake, adherence, and retention in preparation for a future efficacy trial. This was a double-masked, placebo-controlled, randomized trial of 200mg daily self-administered VP suppository or placebo. Pregnant women with HIV who were initiating or continuing antiretroviral therapy were eligible for participation. Potential participants underwent ultrasound to assess eligibility; we excluded those ≥24 gestational weeks, with non-viable, multiple gestation, or extrauterine pregnancies, with short cervix (<2.0cm), or with prior spontaneous PTB. Participants initiated study product between 20–24 weeks of gestation and continued to 37 weeks (or delivery, if sooner). The primary outcome was adherence (proportion achieving ≥80% study product use), assessed by dye stain assay of returned single-use vaginal applicators. Secondary outcomes with pre-defined feasibility targets were: uptake (≥50% eligible participants enrolled) and retention (≥90% ascertainment of delivery outcomes). We also evaluated preliminary efficacy by comparing the risk of spontaneous PTB <37 weeks between groups. From July 2017 to June 2018, 208 HIV-infected pregnant women were eligible for screening and 140 (uptake = 67%) were randomly allocated to VP (n = 70) or placebo (n = 70). Mean adherence was 94% (SD±9.4); 91% (n = 125/137) achieved overall adherence ≥80%. Delivery outcomes were ascertained from 134 (96%) participants. Spontaneous PTB occurred in 10 participants (15%) receiving placebo and 8 (12%) receiving progesterone (RR 0.82; 95%CI:0.34–1.97). Spontaneous PTB < 34 weeks occurred in 6 (9%) receiving placebo and 4 (6%) receiving progesterone (RR 0.67; 95%CI:0.20–2.67). In contrast to findings from vaginal microbicide studies in HIV-uninfected, non-pregnant women, our trial participants were highly adherent to daily self-administered vaginal progesterone. The study’s a priori criteria for uptake, adherence, and retention were met, indicating that a phase III efficacy trial would be feasible.
Highlights
Preterm birth (PTB) is the most common cause of neonatal death worldwide.[1]
We described the performance of dose diary estimates of adherence compared to dye stain assay (DSA) estimates by calculating sensitivity, specificity, positive predictive value, and negative predictive value with corresponding 95% exact binomial confidence intervals (CI)
Because initial accrual was slow (i.e., 18 participants randomized over 3 months), we expanded recruitment in November 2017 to the nearby Chawama First-Level Hospital and achieved a monthly accrual average of 16 participants per month for the remainder of the study
Summary
Preterm birth (PTB) is the most common cause of neonatal death worldwide.[1]. The majority of this disease burden is borne by poor countries in South Asia and sub-Saharan Africa, where access to life-saving neonatal care is often limited.[2]. Antenatal progesterone—an anti-inflammatory hormone administered intramuscularly or vaginally—reduces the risk of PTB in women with prior spontaneous PTB[4] or shortened cervix,[5,6,7] and is used widely for these indications. HIV infection leads to immune activation and inflammation, both systemically and in the lower genital tract.[8, 9] While antenatal progesterone has been studied in women with a range of other PTB risk factors,[10] its efficacy in pregnancies complicated by HIV alone is unknown. We conducted a pilot randomized, double-masked, placebo-controlled trial of VP to prevent PTB among HIV-infected pregnant women in Zambia. Our overall goal was to gather feasibility data that might inform the design and implementation of a phase III efficacy trial
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