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In many developing countries, low-cost antiretroviral drugs have helped extend the lives of people living with human immunodeficiency virus (HIV), as well as prevent transmission of the virus from pregnant women to babies.

These treatments may not be free of risk. A few years ago, a high-profile paper alerted the international community that babies in Botswana that were exposed to the anti-HIV drug dolutegravir in utero had an increased risk of birth defects.

While  amid concerns that pausing use of the drug could have consequences for HIV transmission in low-resource countries, researchers at U of T and its partner hospitals are continuing to investigate.

“The administration of the drugs to the mother prevents the transmission of infection to the newborn, and there’s no question that this treatment is extremely effective in eradicating the infection in newborns, so there is a great benefit,” says Reina Bendayan, professor at the University of Toronto’s Leslie Dan Faculty of Pharmacy whose research has long focused on HIV antiretroviral treatments – specifically examining how specialized proteins called transporters move these drugs from blood into tissues.

“However, a number of problems have been reported in the clinic in some of the children that have been exposed to the anti-HIV drugs.”

With the support of the Canadian Institutes of Health Research, Bendayan and co-principal investigator Lena Serghides, senior scientist at the Toronto General Hospital Research Institute at the University Health Network and associate professor in the department of immunology at the Temerty Faculty of Medicine, will study membrane transport proteins, including folate transporters, that regulate the distribution and delivery of anti-HIV drugs to the fetus – not just dolutegravir but also newer drugs of the same class.

In recent years, Bendayan’s lab has looked at transport proteins that move the nutrient folate into the placenta and fetus during pregnancy and how interactions with these transport proteins could contribute to folate deficiency, which can result in neurodevelopmental defects in children.

So when her team saw the research about a potential link between dolutegravir and birth defects, they immediately wondered whether these drugs might be interacting with the folate transporters and inhibiting folate uptake in the placenta. Their initial studies identified a potential interaction.

The team is now looking to investigate the potential interaction of first-line anti-HIV drugs during pregnancy and further examine folate levels in the fetus. “We are looking at biodistribution of these drugs, but at the same time we are investigating potential fetal toxicities that may result from these drugs,” Bendayan says.

Using human cells, placenta tissue and research models, the researchers are examining how expression and location of transport proteins in the placenta change through gestation, the impact this has on how much of the drug crosses into the placenta and whether this results in any neurodevelopmental defects.

They’re also examining whether male and female fetuses differ in their membrane transport expression, drug concentrations and toxicity levels.

“By improving our basic understanding of how these transporters change throughout pregnancy, our findings could have broader implications, providing insights about safety and fetal development of a wide spectrum of medications used in pregnancy,” says Serghides.

Teresa Bennett, a master’s student in the department of pharmaceutical sciences at the Leslie Dan Faculty of Pharmacy and recipient of a Canada Graduate Scholarship, is running experiments and collecting data for the research as part of her thesis project, which she says combines her two academic interests – newborn and fetal health and HIV care.

“Before a drug is approved for use, it has to go through rigorous testing, but oftentimes there isn’t as much research done on the pregnant population and how it will impact them and their baby,” says Bennett, who began working in Bendayan’s lab in 2022 after conducting undergraduate research on HIV-related stigma. “I’m hoping this research will further inform guidelines so that we can keep the pregnant population in a controlled HIV status throughout their pregnancy, but also keep the baby healthy.”

Bendayan agrees that the study will provide important information on the impact of these critical drugs on fetuses, which will help guide treatment decisions for pregnant people with HIV.

“We really want to clarify whether the newer drugs in this class would potentially be a better choice. These haven’t been in the clinic very long, so we don’t know yet, and we hope our studies can shed some light on that,” says Bendayan.

“We hope that this research will provide a greater understanding of the potential toxicity implications of these specific antiretroviral drugs so that we have better guidance on which antiretroviral drugs physicians should recommend to their patients.”