Lynne Mofenson, MD, on Antiretroviral Drugs and Birth Defects

A dominating theme at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019) was the safety of antiretroviral therapy (ART) in pregnancy and whether the drugs pose a birth defect risk.

Lynne Mofenson, MD, HIV technical advisor with the Elizabeth Glaser Pediatric AIDS Foundation, delivered a symposium on ART and birth defects and spoke to Contagion® in an exclusive interview to explain what the current data suggest and what hurdles still exist for women of reproductive potential.

Interview transcript (modified slightly for readability):

Contagion®: What does the current data tell us about antiretrovirals and birth defects? What regimens are safe for women of reproductive potential?

Dr. Mofenson: The question of birth defects and antiretroviral drugs is a difficult one to give a simple answer to, and the reason is is that there is such limited data about the use of these drugs in pregnancy. The effect of a drug, in terms of causing a birth defect, depends on timing and so it's not necessarily starting a drug during pregnancy that puts a woman at risk; it's being on the drug when she gets pregnant, at conception, that puts a woman at risk.

The limited data suggest most of the drugs are relatively safe. There was a report from Botswana that provided a potential signal of development of the neural tube defect birth defect with the use of pre-conception dolutegravir. There were 4 cases out of 426 pre-conception exposures, a rate of 0.94%, and this was significantly above the rates seen with other regimens started pre-conception or other regimens started during pregnancy or in uninfected women where the rates were about .09 to 0.1%.

Where we are right now is in the time of uncertainty. We still need to collect more data to be able to refute or confirm this signal. At the present time, the drug label recommends that you not start this drug in the first trimester. It's probably a little conservative. The neural tube closes by 8 weeks gestation, and so probably use after that time is safe. And it’s a good drug. Hopefully by the end of this year we’ll have sufficient data to be able to conclude this real or it's not real.

Contagion®: How do we shorten the delay that exists between the time of FDA approvals and the point at which we receive pregnancy safety data?

Dr. Mofenson: There has been a significant delay in terms of getting any information on drugs in pregnancy after the drug is approved. There's a mean of 6 years’ delay from the time a drug is approved and used in the general population [to when] we even have data about whether that dose is appropriate in pregnancy. One way to get that information earlier is to do the pharmacokinetic studies looking at what's the appropriate dose in pregnancy and preliminary safety in pregnancy before the drug is approved rather than waiting until after the drug is approved.

There was a recent large group that gave the government recommendations about studying drugs in pregnancy called the PRGLAC group and they sent recommendations to the Department of Health and Human Services recommending that studies in pregnancy be conducted earlier rather than waiting until the drug is approved and then saying, “well maybe we should study this in pregnancy.”

Contagion®: In your CROI symposia, “Update on Antiretroviral Drugs and Birth Defect,” you emphasized how critically important it is we continue to collect prospective, non-biased data on new drugs. What do you mean by “non-biased”?

Dr. Mofenson: What is non-biased data? One of the problems with looking at reports of birth defects is that oftentimes you get case reports or you get a report after the birth occurs and there’s a defect and that goes to, say, the [US Food and Drug Administration] or the drug company. You have no denominator there; all you have is “we have a birth defect.” We don’t know how many women were exposed, so it could be we have 1 birth defect out of 50 exposures, 1 birth defect out of 1000 exposures. And you really need to be able to know both the denominator and the numerator here. Even in a pregnancy in an HIV-uninfected woman who's taking no drugs, there is a 3% risk of birth defects so there is not no risk; there's always a risk when there's a pregnancy whether or not you're HIV infected or not. In order to gather data about whether an antiretroviral drug increases the risk, you need to be able to have information that’s collected prospectively that is reported before the woman delivers and then you follow the woman to find out what's her outcome afterwards so that you're not biasing the reports to the rare case reports that could occur with or without the drug