The 10th International Workshop on HIV and Women was held this past March in Boston. Although COVID-19 prevented some participants and presenters from attending, 116 people gathered together to share knowledge and life experiences. It was the only event affiliated with the Conference on Retroviruses and Opportunistic Infections (CROI) that went ahead.
On the first day of the workshop, Lynne Mofenson, M.D., gave a presentation titled, “Success and Challenges Over the Last Decade in Research on Prevention of Mother-to-Child HIV Transmission.” Mofenson is a board-certified pediatric infectious disease specialist. After 26 years directing research on the prevention and treatment of pediatric and maternal HIV infection in the United States and globally at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, she retired from the National Institutes of Health (NIH) in 2014. She currently serves as senior HIV technical advisor for the Elizabeth Glaser Pediatric AIDS Foundation, where she’s involved in research evaluating the implementation of many of the interventions she studied while at the NIH.
Terri Wilder recently spoke with Mofenson to learn more about her work and what we’ve learned over the past decade regarding the prevention of mother-to-child HIV transmission.
Terri Wilder: Dr. Mofenson, thanks for joining me. Before we talk about the information you presented at the 10th edition of the International Workshop on HIV and Women, I’d love to hear more about your background and how you got interested in the prevention of mother-to-child HIV transmission.
Lynne Mofenson: Thank you for having me. I’ve been involved in HIV since the very early days of HIV and, actually, probably before. When I was a resident in Massachusetts, in Boston, I think I took care of one of the first HIV-infected children that was in the state, who, unfortunately, died. And as a pediatric infectious disease doctor, I was, of course, interested in the children who have HIV, as opposed to the adults who have HIV. So, I’ve been doing this since the early 1980s.
TW: Great. In your presentation, you kind of divided up what was happening in the world of mother-to-child transmission—the good, the bad, the ugly—to give us the scope of what was working and what wasn’t working so well. But one of the things that you talked about was our success, in terms of decline in new child HIV infections. Can you talk about our successes?
LM: Sure. Over the past decade, we’ve learned a great deal about how to prevent mother-to-child transmission. And these successes have led us to the aspiration that we could potentially eliminate new pediatric infections. We’ve done some clinical trials that have shown that maternal antiretroviral treatment during pregnancy and breastfeeding can reduce transmission to near 1%.
We’ve also learned that being on treatment earlier is more effective. And for women who are on treatment at the time they get pregnant and they’re [virally] suppressed, the transmission rate is almost zero.
We’ve had a remarkable increase in women who are receiving treatment during pregnancy globally. It’s increased from 44% in 2010 to 82% in 2018. And accompanying this, there’s been a 63% decline in new child infections since 2000. So, in 2000, there were 450,000 new infections in just that year; but in 2018, it’s decreased down to 160,000. And in countries like the U.S. and in Europe, transmission is currently under 1%. We have under 100 children born with HIV each year in the U.S., and it’s decreasing.
Even in countries where there is breastfeeding, we’ve seen a decline in transmission from early 2008, from 17% to 20%, down to under 5% now. So, those are tremendous successes.
TW: While we’re doing really well, in terms of decline, it seems like the decline has slowed down. Can you talk about why this is happening, and what really needs to happen to correct it?
LM: Most of the decline that we just talked about occurred between 2004 and 2012. Since 2015, there’s been a slowing of this decline. And part of this is getting those pregnant women on treatment. While 82% globally are receiving treatment, this varies tremendously by region and is lowest, for example, in West and Central Africa. So, different coverage and the lack of getting universal coverage has been important.
Secondly is that pregnancy and the peripartum period is a time that there’s an increasing risk of HIV acquisition for women. This high increased risk of transmission per sex act for women who are pregnant or early postpartum translates into high rates of incidence with sex during pregnancy and postpartum. So, these periods constitute periods of substantial risk for HIV acquisition by women. And incident HIV infection during pregnancy and breastfeeding is associated with high viral loads and an increased risk of mother-to-child transmission. In this case, since the mother is just becoming infected, she’s not on treatment, so there’s a very high risk of infection [for the infant].
And so, globally, eliminating new pediatric infections is really not going to be possible without eliminating incident infection, new infections, in pregnant and postpartum women.
And the other issue is that a substantial proportion of women on treatment experience viral rebound postpartum. In some studies, this is as high as 30%. They’re on treatment; they’re doing well; they’re suppressed. But postpartum, the viral load goes up, and, of course, that then increases the risk of transmission to the infant.
TW: Two questions related to what you just talked about: I don’t think I can quite understand why there’s a significant increase in acquired HIV in the second and third trimester and early postpartum period, compared to non-pregnant, non-postpartum period. Why does this happen?
LM: Yeah. I think the reason is not completely known. But a woman’s body changes significantly during pregnancy. The quality of her vaginal lining, the hormonal milieu that she’s in—there are very big changes in hormones during pregnancy. This takes a couple of weeks to months to revert after pregnancy. So it may be just the kind of milieu, the hormonal milieu that women have during that period, that’s sort of an excess risk.
TW: My second question is: I think you were referring to the UK study about a significant portion of women on ART [antiretroviral therapy] experience viral rebound, postpartum. I also don’t understand why that happens, as well. Can you talk about that a little bit more?
LM: Yeah. It’s not just in the UK; I think it’s been found in both developed and developing countries. And I think part of it is—probably a large part of it is—related to adherence. A woman gives birth to a baby. She’s home. She’s got to take care of the baby. It’s very distracting.
And I think that adherence becomes very hard for people immediately postpartum, when they’re dealing with all of the issues with the new infant—and their other children, if they have other children. Yeah. I think that that’s really mixed with the other. The issue is that many women are taking the antiretrovirals because they don’t want their infant to be infected. And they’re less concerned about their own health than they are about their infant’s health. And so, taking those drugs every day becomes less of a priority.
So, I think most of this relates to adherence and the ability to maintain taking a drug every day for the rest of your life. And that’s hard.
TW: With the success of prevention of mother-to-child transmission, there’s an increasing number of children who will be exposed to HIV and ART but are HIV negative. But they may have excess morbidity and mortality. Why is that something that folks are seeing?
LM: So, now that we’ve got such a great success—since, you know, in 2018, we have about 50 million children who’ve been born who have been exposed to HIV and antiretrovirals; but they’re HIV negative. In some countries where there’s a high prevalence of HIV among pregnant women, such as Botswana or South Africa, 20% to 30% of all children in that country have been exposed to HIV and antiretrovirals, because there’s such a high percentage of women who are infected.
The reasons for the excess morbidity and mortality are not known. There’s a number of different hypotheses. And one has to do with the exposure to HIV that could relate to changing the immunologic status of the child; exposure to antiretroviral drugs. You know, we’ve had experience for only, I don’t know, 20 years or so, with primarily AZT, now a lot of other drugs. But it’s not known whether there might be effects of in utero exposure to antiretroviral drugs.
And then there may be some behavioral issues—which is that perhaps women in developing countries who are breastfeeding are concerned that they might be transmitting to their babies in breast milk, even though they’re on treatment; and they stop breastfeeding early. And we know that in developing countries, breastfeeding is extremely important for the child’s survival. So there are a number of different reasons.
And there are a number of different people who are doing research in this area and looking at immunologic function in these children, and other things, as well.
TW: I’d like to talk a little bit more about adverse pregnancy outcomes, and how they differ between ART regimens. Can you talk about that? I know you had a very detailed slide about that.
LM: Right. So, there’s been a number of studies. Probably the best one comes from Botswana. And it’s shown two things. One is that there’s a difference in the rate of adverse pregnancy outcome—and by that, I mean preterm delivery, or small for gestational age, stillbirth, neonatal death—between the regimens. So, dolutegravir and efavirenz look pretty much the same; but nevirapine has higher rates; and lopinavir/ritonavir, in particular, has higher rates. If you look at the drugs, in general, there does appear to be somewhat more preterm delivery with protease inhibitors than with other drugs.
We really need to be able to study this to be able to determine not just to get the woman on treatment and get her virally suppressed, but determine what’s the best treatment for her, and her child, and her fetus.
The other thing is that, even with treatment, even with very highly effective treatment—like efavirenz, dolutegravir—the rate of adverse outcomes are higher than in women who are uninfected. And that’s another [area] of research. Why is this? If we have a woman who’s HIV positive, she’s on good treatment and she’s suppressed, why is her rate of adverse pregnancy outcome not the same as an uninfected woman? And we don’t; we don’t know this. And so, that’s another area of important research.
TW: In 2018, you and I talked about the newly available data showing an alarming number of babies born with neural tube defects to women with HIV in Botswana, who started the regimen with dolutegravir and then later got pregnant. We also talked about the new information that was presented at the 2018 International AIDS Conference in Amsterdam about these women and about the World Health Organization [WHO] recommendations for these of dolutegravir in people who want to get pregnant. Do we have any new data or updates about this issue?
LM: Yes. In March 2019, the Botswana group published in the New England Journal an analysis that included four times the number of patients than they had in their original report. And the rate of neural tube defects has gone down. In May of 2018, they had about 420-something dolutegravir-exposed women. And the rate of neural tube defects was near 1%—.94%. They now have over 1,600 women. And the neural tube defect rate has gone down to .3%. So, that’s a significant decline.
But if you compare that to non–dolutegravir-received preconception efavirenz, preconception HIV-uninfected women; it’s still higher than in all of those other types of treatment. And there has been some additional data that—there’s additional data from Botswana, from the Ministry of Health, that did an evaluation outside of the Tsepamo Study sites. They found one neural tube defect in 152 infants; that was .6%. And there’s been a case reported in the Antiretroviral Pregnancy Registry—one out of 313 exposures; so that’s about .3%.
And if you put it all together, you have an increased risk of about .3% to .4% in countries without food folate fortification, like Botswana; and in countries with food folate fortification, a prevalence of about .12%.
You have to compare that to the prevalence in the general population. And in the general population in the U.S., the prevalence is .06 percent. So, it does appear that there’s some increase. The increase appears to be less than we thought with the original data on neural tube defects. If we can confirm this over the next year or so, it does appear to be significantly under 1%. There’s been a number of risk-benefit analyses that have shown that there’s substantial benefit of dolutegravir in women of childbearing potential, even accounting for the potential for neural tube defects. And because of that, WHO changed their guidelines and recommends dolutegravir as preferred for all individuals.
TW: Can you talk about what folate food fortification is? What exactly does it do? And why is it important for people to take it?
LM: Folate is important, in terms of the formation of the neural tube, the development of the brain in the infant. It’s actually very important for the development of the embryo. And studies have demonstrated, in women that have a prior infant with neural tube defects, that if they take folate prior to and during their pregnancy, you can significantly reduce this risk, from a 30%-to-60% reduction in risk.
Many countries, many developed countries, have added folate to food—such as wheat flour or rice flour, depending on the country—to be able to provide benefit to the population of women. Because, what people did before was, they waited till they got pregnant; and then they were put on folate and other vitamins. But by the time you know you’re pregnant, the neural tube is already developed. It develops over the first four weeks of the embryo’s life. So, that’s too late.
You need to have adequate folate levels before you get pregnant. And one way to make sure of that is to put it in food that everyone eats every day. And so, the U.S., and Canada, and Brazil all have food folate fortification. And many countries in Africa, like Botswana, do not.
TW: We talked about that progress has slowed in the prevention of mother-to-child transmission. And it feels like what you were saying is it’s primarily due to implementation challenges. Can you talk about what some of the implementation challenges are and, really, what can be done to correct them?
LM: Well, first is to be able to make sure that every woman who gets pregnant knows her HIV status and, better than that, that women know their HIV status before they’re pregnant. While testing has improved considerably, we’re not at 100% yet. And every woman who doesn’t know her HIV status and is really living with HIV, and not on treatment, is putting herself and the infant at risk. So, the issue of identification of women is important.
And then the next piece is being able to prevent new infections in women. Because, as we talked about, incident infection is a significant risk for mother-to-child transmission. And so, enabling women to better protect themselves—and that includes use of PrEP [pre-exposure prophylaxis].
Many countries were reluctant to use PrEP in pregnancy. But the data to date suggests that it is safe, and not associated with any adverse pregnancy outcomes. Having programs scale up to be able to provide those women who test negative, but are in HIV-endemic countries, where they’re at risk of developing infection, or they have an HIV-positive partner that they know about but they’re negative; giving them the ability to protect themselves, enabling them to be able to access PrEP, is an important piece.
And then ensuring that all women are on treatment, as we talked about. While we’ve had great success in getting women on treatment, it’s been very regionally different. And getting those countries that don’t have women that have known HIV infection on treatment is important.
And then, finally, supporting those women who are HIV positive and are on treatment in the postpartum period. Everyone is very concerned during pregnancy. But after the woman gives birth, she kind of falls off people’s attention; falls off the radar; goes back to the regular HIV clinic. And those women may need some additional attention, particularly during those first few months when they’re adjusting to having a new baby, to enable them to stay on treatment and to stay suppressed.
Those are the primary challenges, I think.
TW: While we’re all being impacted by the COVID-19 pandemic, I’m just wondering; in terms of your work, have you had to kind of switch priorities? Or has it brought up new challenges, in terms of mother-to-child transmission?
LM: I think there are two issues. One is the issue of COVID-19 and transmission, in general, which is very interesting to me. I’ve been involved in trying to look at that. But I have great concerns that our HIV programs are going to be significantly disrupted by this. And we need to ensure that if countries are putting in place, for example, stay-in-place and don’t-go-out recommendations, that those women who are pregnant are able to access treatment—and that we’re not giving them treatment monthly; that we’re giving them treatment for the entire pregnancy, so that they have it at home and can access it. So, I have a concern that all of the attention and interventions put in for COVID-19 can affect our success with mother-to-child transmission globally.
Then there is another issue, which is the effects of COVID-19 in HIV-infected individuals. So far, most of the infections, most of the information we have about infections, come from countries with very low HIV prevalence—like the U.S., like Europe, like China. They don’t have many HIV-infected individuals. So, we really don’t know whether COVID is going to be worse in HIV-infected individuals—better, the same? And, as COVID-19 moves into Africa, moves into places where HIV is more endemic and high rates, we don’t know what that’s going to do.
So, again, that’s an important thing for us to be able to look at in the future.