The 10th edition of the International workshop on HIV and women was held this past March in Boston, Massachusetts. Although COVID-19 prevented some participants and presenters from attending, 116 people gathered together to share knowledge and life experiences. It was the only CROI affiliated event that went ahead.
Shahin Lockman, M.D., gave a presentation titled Better Earlier Pregnancy and Lactation Data For New HIV Drugs: How Do We Get There? Lockman is an infectious disease trained clinician and has conducted clinical trials, epidemiologic and implementation science investigations related to HIV-1 in Botswana since 1996. One of her research focus areas is the safety and efficacy of antiviral drugs used for HIV treatment and prevention among pregnant and postpartum women. She currently serves as co-chair for the IMPAACT 2010 trial, which is evaluating the safety and efficacy of dolutegravir versus efavirenz based antiretroviral treatment regimens in pregnant and postpartum women. Lockman mentors many early stage investigators on a range of clinical research projects in Botswana. She is principal investigator of the Botswana clinical trials unit at the Botswana Harvard AIDS Institute Partnership, conducting ACTG, IMPAACT and HPTN network trials.
Terri Wilder recently spoke with Dr. Lockman to learn more about her work and the growing momentum to make sure pregnant women have access to high quality evidence and forming the Use of drugs and pregnancy.
Terri Wilder: So Dr. Lockman before we talk about the information you presented at the International Workshop on HIV and Women, I'd love to hear more about your background, and how you got interested in researching the safety and efficacy of HIV medication among pregnant and postpartum women.
Shahin Lockman: Hi, Terri, thank you so much for highlighting this topic, which I think is actually incredibly important and salient in the midst of this COVID pandemic as well. And I'll get back to that in a moment, too. So I really appreciate the opportunity to talk to you today. I was always interested in women's health and women's health, specifically in resource constrained settings. And while working in Botswana, as well as seeing patients on the inpatient ID consult services in Boston, it became glaringly apparent that women are often if pregnant or breastfeeding, offered antiquated treatments
for which there are minimal, high quality data about their safety and efficacy in pregnancy, really, because they have been used before and not because there's any good evidence to support their use. And at the same time, they're often denied newer, more effective, potentially safer drugs specifically for HIV treatments as a good example, but even other drugs, antibiotics, antidepressants, etc. Because there is an absence of data on the pharmacokinetics of pregnancy and more, even more on their effectiveness and safety and pregnancy. And so it just really became clear that we needed to do a much better job trying to protect women through research as opposed to from research during pregnancy, to avoid them either being treated with older, less effective drugs, or having their drug stopped altogether, and suffering the harms of not being able to be offered the best treatment purely
because of a lack of data. So that's really what was the impetus for me.
And I think I think it's important to note that of course, women are not defined because they bear children or are pregnant or will become pregnant. But it is a truth that globally, the majority of women living with HIV will have at least one pregnancy during the course of living with their HIV and that has affected the regimens that they are offered or asked to switch to. And it's also impeded, moving globally to perhaps better treatment because of this consideration. So it just became clear that we needed to try to be part of the solution of this problem, as many other people felt as well.
TW: So at the beginning of your workshop presentation, you talked about the fact that between 1920 and 2010, more than 90% of FDA for drugs had no data on safety and efficacy in pregnancy and that over 80% of women take a drug in pregnancy with minimal safety, efficacy data. That was a little shocking for me to hear.
SL: It’s appalling. It’s terrible. Even though our track record HIV is not great, we have done a better job trying to get some data on the pharmacokinetics and safety of ARVs in pregnancy. But, you know, for most other classes of drugs, there's just not much interest. And so women are often in pregnancy forced with the decision of taking a drug for which there aren't that isn't just isn't that much information about the safety or effectiveness, or often sometimes choosing to stop the drug which can have devastating consequences, for example, stopping antidepressants in pregnancy.
You know, that that exposes women to potential harm, again, of either being undertreated or treated with suboptimal medications. So it's really shocking and this is, you know, as true here in the US as it is anywhere else in the world.
TW: So in terms of HIV, drug safety and efficacy among pregnancy and postpartum women, I feel like ACT UP and other active activist groups started yelling about this in the late 1980s, early 1990s. So I guess my question is, why have we made so little progress?
SL: I think that activism has played a key role in the HIV response in the U.S. and globally. And that is why it is through activism that we have globally made so much progress. I think that part of the issue may be that, especially in places where activists have had greater voice in the U.S., pregnancy is maybe not the biggest or most pressing issue. And 15 to 20% of clinical trial participants in HIV trials in the U.S. are female. Globally, more than half of people living with HIV are women. So I think part of it is just the way that activism has evolved over time. But I also think that there are many systematic barriers to doing research in pregnancy where you know, the tide is I think, just beginning to start to turn and I think there have been regulatory barriers up until recently, international research ethics standards classify pregnant woman as vulnerable. A vulnerable class in terms of taking part in research. IRB s felt that we had to protect pregnant woman from research as opposed to saying it's important that the ethical imperative is to actually try to get pregnancy data. And then industry, I think, has had truly only
disincentives to take part in research in pregnant women.
If something goes wrong, it can really jeopardize their drug development and there's no mandate for them to study drugs in pregnancy as there is for studying drugs in pediatrics. So it's more costly and it only exposes them to risk of bad potential outcome or bad bad news as well As extra time to get these studies done. So there are multiple forces that have worked against studying drugs and pregnancy, but I think that is starting to change.
TW: I'd like to deconstruct this a little bit more like, I think this is about gender, the way that women are treated, the way that many times the fetus is prioritized over the woman's body. I mean, I remember researching kind of the history of women and HIV and came across that at one point, clinical trials said things like, no pregnant women, and no non pregnant women allowed in this study, which means the women!
SL: [laughing] Yeah, I know. I think you're absolutely right. And, you know I think less than a clinical setting where I think clinicians treat the patients, treat the woman, well pregnant woman there are two patients but really the patient in front of you is the woman who is making her own choices about her own health. And I think clinicians recognize that and are often frustrated by the lack of good information that they can give to women to help enable women to make choices. They're the best choice for themselves in terms of treatments in pregnancy.
But I do think that very paternalistic approaches have been taken to allowing women to make choices about taking part in research again, is because of this risk aversion. And even in the early days of prevention of mother to child transmission, the discussion and dialogue was always around the primary endpoints of studies, you know, what is a mother to child transmission rate, not necessarily maternal outcomes, maternal health outcomes, or even pregnancy outcomes were secondary in those studies. And so it's great and important And of course, to try to protect the fetus, but first and foremost, to protect the mother and take care of the mother and enable her to make choices.
TW: Right? I mean, our world has a long history of policing women's bodies. And, you know, not recognizing that women have agency over the life and like you sat can make decisions on their own. And so, you know, in a way, you know, it feels like some, you know, as I'm hearing you talk and reviewing materials about this issue, you know, it feels like sexism is kind of foundationally here.
SL: Yes, I think it's sexism and also just the deeply entrenched sense that when a woman becomes pregnant, she is really there for purposes of bearing a healthy fetus and, you know, this kind of loss of ability to see the woman as an individual.
And I think that, you know, just bringing together to the themes that you've mentioned, both activism and agency, the Afro Cab [community advisory board] put together a statement that was released at the International AIDS Society meeting in Amsterdam, which was also attended by women activists from Africa who basically presented their view and then in the statement they widely disseminated around dolutegravir neural tube defect finding that, first of all, respectfully, women are not purely around for the purposes of bearing children. And that woman should be able to have a say in and make an informed decision as to whether they would like to take a drug that they may tolerate better and that they be maybe more effective for them even if it is associated with a small increase in the risk of neural tube defects, and that women are absolutely capable of weighing the pros and the cons and making those decisions.
And this was this is where the activism that you know, from the ground up, came in, and really also, I think, released and empowered The World Health Organization to relax some of their language around the use of dolutegravir by women of childbearing potential. And I think the activists played a big role
in making that change happen.
TW: So, you know, when I was looking at your slides from your presentation, it really kind of just hit me in the face. If we don't find out answers via research, and you actually said this, it ends up shifting the risk to the clinical setting. So wouldn't it be better to find out information during a controlled research setting?
SL: Absolutely. Do you know Polly Claydon?
TW: I know who she is. Yes.
SL: So she summed it up beautifully. And she is a long-time activist in this arena around women's health and specifically also related to pregnancy. And she said that basically the absence of clinical trial data, or high-quality research data on new newer drugs, ARVs as we're talking about right now, during pregnancy, basically ends up once these drugs are rolled out for use becoming a gigantic, uncontrolled, unmonitored experiment. So women don't have the benefit of being carefully monitored for outcomes or systematically monitored. There's no external data safety monitoring board that really needs to look and see are there higher rates of neurologic failure or adverse outcomes associated with these drugs.
So it basically what it does is, takes the responsibility off of the shoulders of the people who should be gathering these data, whether it's industry or academia or whatever, and shifts it on to onto the shoulders of women who unwittingly become part of this experiment to which they're not really consenting.
TW: So just to put a follow up to the question I just asked, if we don't include pregnant and postpartum women in research, what specific harm could happen to both the woman and the fetus or baby?
SL: What we would be worried about with ARVs specifically, are more in the realm of safety concerns and less in the realm of efficacy concerns for the treatments that we currently have for current ARV, but their effectiveness concerns as well. So, if we don't do good research studies, we may be offering treatments to women that could potentially be associated with greater toxicities in pregnancy or postpartum. So for example, postpartum depression could be exacerbated by some drugs. Liver toxicity could be worse with some drugs in pregnancy than it would be in people who are not pregnant. Adverse birth outcomes, that is something that has been shown to be associated with certain ARVs and not others.
And then in terms of effectiveness, you know, the drug levels change quite a bit in pregnancy with most drugs and to date, only a few of them have been shown to be affected so much that you might need to avoid them in pregnancy. But unless you study that, you won't know it. So an individual may having a negative outcome. But unless you're getting information about a drug, new or old, that hasn't been studied pregnancy, in a larger group and comparing it properly, you'll never know whether that that outcome was because of that drug or just, you know, bad luck for a particular individual.
TW: So, right now, do we know which HIV drugs have been associated with greater harm? And then on the opposite side, are associated with better outcomes?
SL: Thankfully, there are some older drugs which we don't need. We never knew that much about them in pregnancy, and we probably don't need to. We know though that one of those is nevirapine, that one we have pretty good evidence that it is associated with worse pregnancy outcomes. in Botswana, a woman who conceived on nevirapine, 6% of them had a stillbirth, which is an incredibly high number and much higher than with other drugs. And it may be associated with hypertension, which is obviously also dangerous for the mother not only related to the baby's outcome. Ritonavir was also recommended for many years ago too, but in pretty convincing evidence, including some randomized trials. Looks like it's associated with preterm delivery. So and then we do have some information about a few drugs like cobicistat boosted elvitegravir or darunavir. Both of those combinations lead to pregnant woman having lower ARV levels in the third trimester and maybe neurologic failure.
So because of studies we can recommend avoiding those pregnancy. So that's some of the data but not most drugs have not been studied rigorously in pregnancy. And this is one of the reasons we wanted to do the VESTED IMPAACT 2010 trial to get the best kind of data we could for both dolutegravir and tenofovir alafenamide. Those are good drugs that many people in most of the world, you know, many people are using in first line, and there really was very little on their safety in pregnancy.
TW: So during your presentation, you mentioned that there were a few things being done in the us about this issue of, you know, getting better data, or getting data at all, in general to address the lack of pregnancy data for medications. And can you talk about them? I'm particularly interested in hearing about the PRG LAC task force with the CDC and the OHRP.
SL: Sure. So I think there is gathered momentum both in the U.S. and internationally, I'm mostly involved with the World Health Organization initiative on this around, really convening multiple stakeholders including community including industry, academia, etc. to try to move this agenda forward for better data on new ARVs in pregnancy.
But in terms of the US the efforts are not restricted to HIV per se. The PRG LAC is a taskforce on research specific to pregnant and lactating woman. And this really is a group of US government leaders primarily as well as other stakeholders that was convened to try to again move forward an initiative to really make it the norm that pregnant women are no longer routinely excluded, but they're routinely in Included where it's appropriate in clinical research unless there's a compelling reason for excluding pregnant or breastfeeding women. And so they are really trying a multi-pronged approach to try to change kind of the language, the understanding of IRBs around the importance of including rather than excluding women and that it's unethical to exclude pregnant woman from research.
They're also trying to work with the FDA around harmonizing some of the IRB rules and with the U.S. Department of Health and Human Services to develop guidance around conducting research in pregnant and lactating women, so they're really trying to bring all of those groups together. The CDC is taking more of an observational approach as far as I understand it. They have something called the Treating for Two Safer Medication for Use in Pregnancy Initiative to really try to gather as much data as we can have out there from observational sources. So they're not so much in the business of doing clinical trials or clinical research. They're more trying to gather data. It's kind of with the same end goal of getting a better body of evidence to help women make their treatment decisions in pregnancy.
TW: What's specifically happening to address the lack of data for HIV medications in terms of pregnant women and postpartum women?
SL: So what we're starting to do so there are a couple of things. There is an ongoing observational study done by IMPAACT and other networks in Europe do this as well. And they include women living in resource constrained settings, but most of them are U.S. government or European government funded studies that basically ask women who become pregnant on a regimen to consent to a PK and safety study, so that we at least get some pharmacokinetics data. But that happens late because by definition that is occurring in the context of woman taking drugs that have been approved, and out in use for years. And so eventually, like 5 to 10 years after a drug has been approved and is sold, we may get some data so that's something. But we do have some suggestions as to how we can move the whole research process forward, so that it happens while the drug is still being developed as opposed to after it's been approved.
And there are glimmerings. For example the VESTED trial we were able to get pharma on board. They gave the drugs, they supported the study, they didn't shy away from it. And the network approved it. And it's one of the very few randomized trials done in pregnancy, for the purposes of treating pregnant woman not to see whether it interrupts transmission but for treating pregnant woman and seeing which regimen is safest. So there's things happening, but we're not there yet.
TW: I'm just wondering, are there any additional areas that like researchers, the HIV community, including activists will really need to think about going forward in order to kind of get to a different way of thinking in implementing research?
SL: I think the one of the biggest things is just having this kind of shift in our thinking, and I think if we could collectively get there, people living with HIV, you know, people supporting people living with HIV, academics, industry, and regulators, collectively step back and say that the absence of data and the absence of the opportunity for pregnant woman to take part in these studies is perhaps unethical.
It does not allow women the choice, and so and exposes pregnant woman to potential harm because of the absence of information. So I think if we are conscious of that problem, and become more aware of it and how detrimental it has been for women who end up having delayed or no access to better drugs, I think that is where we need to go. And so I think I would say anything that, you know, people who care about people living with HIV can do to raise awareness about this as a problem as a very real problem that impacts truly millions of women throughout the world. I think it's important.
I think we need to remember though, a couple of things. One is, I would say not every single drug not every single drug necessarily has to be studied in pregnancy. I think we have to prioritize those that are of most critical need to young woman. Number two, I think we have to remember to just be conscious that we can study drugs in the second and third trimester, but to really understand where outcomes
or outcomes that may happen when you're on a drug at conception, you really need good surveillance studies, which is how the neural tube defect signal was found.
I think the third point that that we need to be aware of is that when we start to study these things, we will find some encouraging findings, thankfully, looks like dolutegravir and TAF from our VESTED study are safe and probably safer than Atripla or maybe TDF in pregnancy. But other times we may study a drug and find out that it actually isn't safe in pregnancy and we have to be ready to properly communicate the findings so people understand them and take them on board. And so we don't panic and go back to an era where women don't take any drugs because the last thing we want to do is cause more harm than good.
And the other thing I would say is the one thing that has been somewhat appalling right now is, we're doing clinical trials of different treatments, experimental treatments at our hospital and many places around the world for COVID. People who are admitted with severe COVID. And they exclude women in pregnancy. And they exclude breastfeeding women. And why are we doing that? We even have some data on remdesivir in pregnancy from the Ebola outbreak.
This was kind of a knee-jerk; pregnant women are always excluded. We need to stop the knee-jerk. We need to say “why do we have to exclude women? What is the rationale for excluding pregnant women?”
TW: Yeah. One of the very last things that you talked about in your presentation was at the end of the day, we have to think through all of this stuff, to all come to consensus that pregnant women deserve access to high quality evidence informing the use of drugs and pregnancy.
SL: Yeah, that's it. That's the bottom line.