In May 2018, many medical authorities raised red flags about newly available data showing an alarming number of babies born with neural tube defects to women with HIV in Botswana who started a regimen with dolutegravir (Tivicay, DTG) and then later got pregnant. New information was presented at the 2018 International AIDS Conference in Amsterdam about these women, and about World Health Organization recommendations for the use of dolutegravir in people who want to get pregnant.
TheBodyPRO spoke with Lynn Mofenson, M.D., who is a researcher with the Elizabeth Glaser Pediatric AIDS Foundation. At AIDS 2018, Mofenson gave a presentation on these issues, entitled Overview on HIV Treatment and Pregnancy, Including Genetics, Drugs and Pregnancy.
Terri Wilder, M.S.W.: I felt like you did a great orientation to neural tube defects. And I just always assumed they were kind of just one thing. But you described it as there being two types. So, I wonder if we could just start with the basics: How does that happen? When does it happen in the development of the fetus, etc.?
Lynn Mofenson, M.D.: The neural tube develops very early in the stages of development, and it actually is completed by day 28 post-fertilization. That is so early that most women don't even know they're pregnant at the time the neural tube forms. So, you have what's called a neural plate that then begins to fold up over itself. That's where the spinal cord and the brain will be.
As it folds up, it folds in; it kind of zippers. And it zippers in several directions: it zippers up, and it zippers down. So, you have one area of the tube that's folding together, going towards the head, and the other area of the tube that's folding together, going towards the feet.
And so, you have what's called the cranial nerve neuropore, which is in the head, and a caudal neuropore, which is in the bottom. And you can have disruption at any of these levels. Depending on where that disruption occurs, you get a different phenotype.
So, for example, if the disruption is at the cranial neuropore -- that's where it doesn't close -- you get anencephaly. You have problems with the brain. Or you get what's called iniencephaly, where the head is like pulled all the way back. But if the area of closure problem is down at the bottom, what you get is spina bifida, or myelomeningocele, which is back in the spine. And then you can have a defect that's the whole thing; that's the worst. It's called cranioschisis.
All of this is happening in the first, between week 2 and week 4 after fertilization. So, it's very early. As I said at the meeting, the real danger with drugs is not giving the drug during pregnancy. It's women who are on the drug, get pregnant, and don't know that they're pregnant, and therefore, they're exposing the fetus during this very early period. Which is one of the issues. When we introduce a new drug into a population of adults that includes women of childbearing potential, you need to be able to look for these rare but serious problems. You just don't put a drug into the population and say everything is going to be fine; you put a drug into a population and then you monitor for whether there are any problems.
TW: Great. The Elizabeth Glaser Foundation released a media statement about dolutegravir, which is used in treatment for people with HIV, but it's also a drug that's used in prevention of HIV [from mother to child]. That media release talked about that it's a preferred regimen for many women, and it demonstrates efficacy and tolerability, and a high genetic barrier to drug resistance. But because of recent data from a National Institutes of Health-funded birth outcomes surveillance observational study in Botswana, it's raised some questions around safety for infants or women taking dolutegravir therapy at the time of conception.
Can you talk about what that study showed, what raised the alarm for this particular drug?
LM: So, it's very interesting. This is a very well done birth surveillance study that covers 45% of the population in Botswana. It's located at the largest maternity centers. In Botswana, most women deliver in hospitals, and most HIV-positive women are on treatment.
The study was actually set up five years ago to rule out neural tube defects with a drug called efavirenz [Sustiva, Stocrin]. Now, efavirenz had animal studies that raised a concern about neural tube defects. And so the study was set up to basically do birth surveillance, surface birth surveillance, on every child born in these eight hospitals: HIV-uninfected women, HIV-positive women on different regimens. The goal was to evaluate whether efavirenz was causing neural tube defects. It was due to be looked at in August.
Because the WHO, the World Health Organization, was developing its guidelines on what should be the preferred first regimen -- and one of the things that was going to be the preferred first regimen was dolutegravir -- they were asked to provide their data a little bit earlier. And their data showed that starting the drug during pregnancy was safe and, basically, the same as any other regimen in terms of pregnancy outcome.
When they provided me with that data, I asked them whether they had any data on preconception use. And, of course, since they were studying that for efavirenz, they said, yes; they hadn't looked at it yet. When they evaluated that data they found an elevated incidence of neural tube defects with dolutegravir, not with efavirenz.
So, the rate of neural tube defects: It was four neural tube defects out of 426 preconception exposures to dolutegravir, which is a .94% incidence. The usual incidence is .1%, so that's almost a tenfold increase. In contrast with efavirenz preconception, the rate was .05%.
So, we definitively excluded efavirenz from causing these problems. But with dolutegravir, we saw a problem. And they looked at 11,000, over 11,000, women who received other antiretroviral regimens preconception, and the rate was .12%. They looked at over 66,000 uninfected women, and the rate of neural tube defects there was .09%.
This provided an early signal that there's a potential problem. It is not definitive proof. You can always run into cases where, you know, you have a cluster that isn't verified, but it is certainly something of concern. And so, that was shared with the World Health Organization, and it left the guidelines group with the question of: Well, how do we deal with this? Do we recommend dolutegravir for anyone, anyway? Do we say that women can't get dolutegravir, but men can get dolutegravir? What should we do?
What the World Health Organization did recommend actually makes a lot of sense, which is, dolutegravir may be a preferred regimen for everyone. The evidence for that varies, depending on the population. For women of childbearing age the evidence is pretty low right now. And for women who want to get pregnant, using a regimen like efavirenz is, we do know that it's safe; we know it's effective; it prevents mother-to-child transmission. It would make sense to use an alternative regimen.
For women who don't want to get pregnant or can't get pregnant, they can use dolutegravir. And the issue for a woman who is of childbearing potential is that they should be able to get contraception, so that they can use contraception, use dolutegravir. And then if they want to get pregnant, they can change.
We will have a much more definitive answer about whether this is real or not within, I would say, a year. Because they're continuing to collect data on women who were already pregnant. They have another thousand or so women.
So, if this turns out to be real, then I think what it doesn't do: It doesn't say that women can't get dolutegravir. What it says is that women who want to use dolutegravir should have access to contraception so that they can plan when their pregnancy is going to be.
TW: I've noticed that communications have come out from lots of different health departments [that] are starting to send out information about this. And I've noticed that a lot of the information keeps referring to women of childbearing potential, versus people. Because, you know, there have been some conversations about trans men should be included in this conversation, as well.
LM: Mm-hmm. Yeah. Well, the issue is whether or not you can get pregnant, right? So, if you don't get pregnant -- if you are sterile or you've had surgery or you're a trans man -- you can use dolutegravir without a problem. As a matter of fact, if you're pregnant you can still use dolutegravir.
The only issue is this risk period, during the area, the time that the neural tube closes. That's the risk period.
TW: Great. Thanks so much for being with us today. Obviously, your session was full of people, since people, particularly medical providers, have been pretty concerned about this and needing some direction on which way to go. So, we'll be sure to keep up with this story as it unfolds.
This transcript has been lightly edited for clarity.