Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial

Abstract

BackgroundIn Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV-positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy.Methods/designIn order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation.DiscussionGiven the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies.Trial registrationClinicalTrials.gov, NCT02400021

Pregnancy favors circulating IL‐21–secreting TFH‐like cell recovery in ARV‐treated HIV‐1–infected women

“…43 diol. [45][46][47] In conclusion, our results suggest that pregnancy, probably by elevating circulating levels of estrogen, favors a better functional circulating T FH -cell recovery in HIV-1-infected women after ARV introduction. Some studies report effects on the reduction in serum estradiol through the administration of protease inhibitors and non-nucleoside reverse transcriptase inhibitors during the treatment of HIV-1-infected women with oral contraceptives.…”

“…Some studies report effects on the reduction in serum estradiol through the administration of protease inhibitors and non-nucleoside reverse transcriptase inhibitors during the treatment of HIV-1-infected women with oral contraceptives. [45][46][47] In conclusion, our results suggest that pregnancy, probably by elevating circulating levels of estrogen, favors a better functional circulating T FH -cell recovery in HIV-1-infected women after ARV introduction. This phenomenon could help virus-infected mothers to protect their newborns from infectious diseases by transferring IgG cross the placenta.…”

Protease inhibitors and preterm delivery

“…We excluded women on unboosted PIs from our analysis, as the small number precluded statistical comparison with other groups; the PTD rate in this group was 5•2%. PIs are associated with reduced levels of progesterone [9], possibly by reducing prolactin levels and increasing placental expression of the prolactin-regulated, progesterone-inactivating enzyme 20-αhydroxysteroid dehydrogenase (20α-HSD) [27] and a study of topical cervical progesterone in HIV has been proposed to explore whether this improves perinatal outcomes [11], but it is clear that more research is needed, including to understand the effect of PI exposure throughout pregnancy on progesterone levels. The PROMISE study Copyright © 2017 Wolters Kluwer Health, Inc.…”

“…Limited data on mechanisms suggest that PIs may reduce progesterone levels in pregnancy [9], leading to fetal growth restriction. Progesterone may also play an important role in PTD [10,11].…”

Perceived acceptability of progesterone to prevent preterm births and low birth weight among HIV-infected and HIV-uninfected Zambian pregnant women

“…A pilot study of progesterone supplementation in HIV-infected pregnant women is currently underway in Canada. 19 At a health systems level, there is a need for cost-benefit analysis of progesterone supplementation in preventing PTL and LBW, and cost-effectiveness analysis of modes of administration.…”