Progesterone Supplementation for HIV-positive Pregnant Women on Anti-Retrovirals (ProSPAR)

In pregnancy, cART is considered optimal for maternal health and for preventing the emergence of resistance that could compromise further care. In Canada, the majority of HIV-positive pregnant women receive a PI-based cART regimen. In the past, therapy was generally deferred until after the first trimester (if not required for maternal health) to minimize any unknown risk of teratogenicity. However, as treatment is now started earlier in HIV infection and as perinatal transmission rates are lowest in those with prolonged suppression of viral load during pregnancy, women are increasingly commencing cART either before conception or earlier in pregnancy. Multiple reports and cohort studies provided data suggesting an association between PI-based cART use and preterm birth, low birth weight, and small for gestational age (SGA) babies, although conflicting data exist. In the general population progesterone supplementation is widely used, is well tolerated, is considered safe, and is beneficial to prevent recurrent pre-term birth and increase birth weight. The investigators experimental findings suggest that PI use during pregnancy is associated with declines in progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve PI-induced fetal growth restriction. The investigators preliminary findings in HIV+ pregnant women suggest that PI-use is associated with declines in progesterone levels, which correlate with birth weight percentile. Since HIV-positive women have higher rates of pre-term delivery and low birth weight that may be magnified by the use of PIs, then progesterone supplementation could be of benefit to neonatal health in the context of HIV-positive pregnancy.

Qualitative information on the reasons to decline participation will be collected and summarized. Reasons for non-enrolling questionnaire will be used.

The number of Grade 3 or 4 AE in the ITT vs. comparator group. The number of Grade 1 or 2 AE in the ITT vs. comparator group. AE questionnaire.

Assessed in the ITT group. Acceptability based on experience with medication questionnaire. Screening questionnaire (acceptability of being recruited to no treatment arm)

Distribution of birth weight, birth weight percentile, and gestational age at birth, compared by treatment group.

Relationship between progesterone levels (serum or urine) at GW25-28 or GW33-36 and birth weight, birth weight percentile, and gestation age at birth.

levels of sex steroids, angiogenic, vasoactive, and inflammatory factors, factors associated with placentation, placenta dysfunction, pre-term delivery and fetal growth restriction between treatment groups

trough PI drug levels in plasma collected from women in both tx groups at baseline and each study visit. changes in drug levels over time will be evaluated.

Inclusion Criteria: Documented HIV-1 infection On (stable) or initiating a cART regimen containing either ritonavir-boosted lopinavir (LPV/r), atazanavir (ATZ/r) or darunavir (DRV/r) Pregnant up to 24 weeks gestational age Singleton pregnancy 18 years or older Ability to give informed consent Exclusion Criteria: Hypersensitivity or allergy to soya or peanut (non-active ingredient supplement in Prometrium) Contraindications to intravaginal progesterone use including: documented hypersensitivity to Prometrium active or history of breast cancer, active or history of arterial thromboembolitic disease (e.g. stroke, myocardial infarction, coronary heart disease) active or history of venous thromboembolism (e.g. deep venous thrombosis or pulmonary embolism) or active thrombophlebitis any prior neoplasia, except for skin abnormal vaginal bleeding Known lethal fetal anomaly Any contraindication to continuation of pregnancy Inability to communicate in English Prior participation in this trial

Siou K, Walmsley SL, Murphy KE, Raboud J, Loutfy M, Yudin MH, Silverman M, Ladhani NN, Serghides L. 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. Pilot Feasibility Stud. 2016 Aug 12;2:49. doi: 10.1186/s40814-016-0087-6. eCollection 2016. Erratum In: Pilot Feasibility Stud. 2017 Apr 28;3:21.