Antiretroviral therapy (ART) is essential for preventing transmission of HIV during pregnancy and for maintaining the mother’s health.

However, there is a lack of information on the risks of perinatal exposure – the period of time during pregnancy and soon after birth – to this type of medication.

Recent pre-clinical studies conducted at UHN’s Toronto General Hospital Research Institute (TGHRI) indicate that ART exposure during pregnancy can cause long-term effects on brain development, as well as on cognitive and motor skills.

“There is no doubt that the benefits of ART outweigh the risks, and ART has significantly lowered the number of children born with HIV,” says Dr. Lena Serghides, Senior Scientist at TGHRI. “Consequently, the population of children who have been exposed to HIV but are uninfected has increased.

“While most of these children are healthy, they are more likely to be born premature or small for gestational age, and may be at a higher risk for developmental, cognitive and behavioural delays,” adds Dr. Serghides, who is a Tier 1 Canada Research Chair in Maternal-Child Health and HIV, and an associate professor in the Department of Immunology at the University of Toronto.

ART medications often include protease inhibitors, which are drugs that block a specific enzyme called a protease that viruses need to replicate. They are usually administered with two nucleoside reverse transcriptase inhibitors (NRTIs) that work by blocking the virus from copying its genetic material.

Perinatal exposure to these drugs has been linked to language and hearing delays, premature birth, placental dysfunction and neurodevelopmental impairments, among other issues.

Dr. Serghides’ lab has shown connections between protease inhibitor-based ART and delays in reaching early developmental milestones in experimental models.

“Unfortunately, the mechanisms underlying these outcomes remain poorly understood,” says Dr. Serghides says. “There are a limited number of studies that correlate neurodevelopmental outcomes to specific ART regimens and there is a need to learn about long-term effects of exposure.”

To study the effects of ART, researchers used pre-clinical models to assess changes in brain structure, behaviour, cognition and genes involved in neural circuitry. Researchers tested two ART regimens: a protease inhibitor mix – ritonavir and atazanavir – combined with either one of two groups of NRTIs.

“We found that these ART medications were associated with long-term negative effects on brain development and that the results varied depending on the drug combination,” says Dr. Shreya Dhume, a postdoctoral researcher in Dr. Serghides’ lab. “We saw that exposure to both drug regimens led to impairments in working memory and sociability compared to controls.”

The team also found that both ART regimens altered gene expression in the hippocampus – a part of the brain that is responsible for memory and learning – affecting proteins involved in how the brain adapts and learns.

“Interestingly, exposure to one regimen reduced brain volume and caused memory problems, while the other regimen led to changes in behaviour like exploration,” says Dr. Kayode Balogun, a former postdoctoral fellow at TGHRI.

“The goal of Serghides’ lab is to optimize the antiretroviral regimens during pregnancy to have the best possible outcome for the mother and child,” says Dr. Dhume. “These findings help us understand how exposure to specific antiretroviral drugs during pregnancy impacts cognitive and behavioural development.

“We hope that this will guide the selection of the safest antiretroviral medication to use in pregnancy to ensure the best maternal and child health outcomes.”

By UHN Research Communications

This study was supported by generous donors to UHN Foundation.