PROMISE: 2 Strategies to Prevent Perinatal HIV Transmission

“The goals of IMPAACT PROMISE are to maximize prevention of mother-to-child HIV transmission (PMTCT), while also optimizing maternal and child health and survival,” stated Mary Glenn Fowler, MD, MPH, Johns Hopkins University School of Medicine, Baltimore, MD during her presentation at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI).

PROMISE involved a protocol to assess the safety and efficacy of a triple antiretroviral regimen in 3 randomizations in the breastfeeding (BF) version: the antepartum period, post-partum period, and maternal health component after BF cessation. The antepartum period completed enrollment of 3,529 women in October 2014. During a November 2014 meeting, the Data and Safety Monitoring Board (DSMB) indicated that pre-specified efficacy boundaries for the antepartum component had been crossed — additionally there were found to be safety differences between the study arms.

Fowler and her team assessed the relative safety and efficacy of triple ARVs compared to other proven regimens among healthy HIV-infected women with higher CD4 counts. They conducted the PROMISE study in the context of the standard of local care (SOC) for adult HIV treatment and infant feeding — in breastfeeding (BF) and formula feeding (FF) resource-limited settings.

The women who participated in this trial were predominantly from Africa, with a median age of 26 and gestational age of 26 weeks at enrollment.

Fowler explained that the eligibility criteria for PROMISE included currently pregnant women with:a gestational age greater or equal to 14 weeks, documented HIV infection, and no previous receipt of triple ARVS in the current pregnancy, as well as no acceptance of country guidelines for ART treatment.

Furthermore, their required CD4 counts had to be at least equal to or greater than 350 or the country threshold if it was recorded as higher. The Antepartum component included 2 versions of the protocol. Under version 2, only Hepatitis B+ women could be randomized to Arm C (FTC-TDF + LPV-RTV). However, under version 3, all women could be randomized.

The efficacy results were based on HIV transmission through 14 days, which were all reported to be less than 2% for both strategies. Adverse pregnancy outcomes were defined as composite outcomes including stillbirths, fetal loss, as well as congenital anomalies, low birthrate (less than 2,500 grams), and preterm delivery (less than 37 weeks).

Fowler remarked, “We noticed that for the triple regimens there is an increased risk of having moderate, but not severe, pregnancy outcomes, for any outcome. And then when we looked at severe outcomes; however, we found no difference between Arms A and B. We did; however, they did find that the zidovudine 2TC did have the lowest risk of severe outcomes compared to the tenofovir FTC arm.”

According to study results, there were seemingly no significant differences in infant signs and symptoms or lab adverse events by study arms for all infants as well as those only in version 3. There were 60 early infant deaths in all versions by the 14-day period.

The randomized trial results presented do, in fact, support the 2013 WHO recommendations for using triple maternal ARVs in pregnancy to attain the lowest risk of transmission.

Fowler concluded, “However, the antepartum triple regimens were associated with higher risk of moderate, but not severe, adverse maternal and pregnancy outcomes including preterm birth and low birth weight, which will require follow up at 12-month to look at infant mortality and HIV-free survival.”

The difference in risk of early infant deaths in the FTC tenofovir arm compared to the 3TC zidovudine triple arm was unanticipated, thus spurring further investigation.