Jyoti Mathad, MD, MS, on Tuberculosis in Pregnant Women Living with HIV


In this podcast, Jyoti Mathad, MD, MS, talks about her session "Pregnancy, HIV, and Tuberculosis: Current Practices and Research Opportunities" at the Conference on Retroviruses and Opportunistic Infections 2021, including progress on TB prevention therapies in pregnancy, and the large gaps that exist in the studies.

Additional Resource:

Jyoti Mathad, MD, MS, is an assistant professor at the Center for Global Health at Weill Cornell Medical College in New York City.  



Jessica Bard:  Hello everyone and welcome to another installment of Podcast 360. Your go-to resource for medical news and clinical updates. I'm your moderator Jessica Bard with Consultant360 Specialty Network.

Tuberculosis is a leading cause of maternal mortality, particularly among women living with HIV. Researchers are making progress on TB prevention therapies in pregnancy, but there are still large gaps in the studies.

We have Dr Jyoti Mathad, here to speak with us about that today. Dr Mathad is a faculty member at the Center for Global Health at Weill Cornell Medical College in New York City.

Thank you for joining us today Dr Mathad, you're presenting your research: Pregnancy, HIV and Tuberculosis, Current Practices, and Research Opportunities at CROI 2021. Can you give us an overview of your session?

Dr Jyoti Mathad: TB is a leading cause of maternal mortality, but pregnant women are often excluded from TB clinical trials. For example, we don't even know how many pregnant women get TB every year, regardless of HIV status.

During the talk, what I hope to do is to highlight the progress we've made on TB prevention therapies in pregnancy, and discuss a lot of detail on those trials, and then also point out some of the gaps we have in areas that I hope we can focus research on in the coming years.

Jessica: Well, let's dive into your study. What is the impact of pregnancy and HIV on the immune response to mycobacterium tuberculosis?

Dr. Mathad:  Here's what we know, as pregnancy progresses, there are estrogen and progesterone levels that increase, and as those hormone levels increase, they modulate the way the woman's immune system functions.

We don't exactly understand the details of how, but we do know that the body is trying to find a balance between keeping the woman safe from infections, but also simultaneously not rejecting the fetus. It's a very well-orchestrated system normally.

The changes that happen during pregnancy in terms of immune modulation are not the same as if you had chemotherapy or if you have uncontrolled HIV infection where we know your immune system is completely suppressed, it's much milder than that, but we do know that it affects the immune system enough that it can impact the way infectious diseases are handled.

For example, there are some infections where pregnant women are much more likely to get the infection, so listeria for example, every time we have a listeria outbreak, we always look for the disease in pregnant women because we know they're more likely to get it.

There are other infections that you're not necessarily more likely to get during pregnancy, but if you get it while you're pregnant, you're more likely to have a more severe form of it. The most common example we use is influenza. You're not more likely to get influenza when you're pregnant, but if you get influenza, when you're pregnant, you're more likely to need an ICU, you're more likely to die from it, we think COVID‑19 is probably in the same category.

When it comes to these immune changes and interacting with TB, again, there's less known about this because there are less pregnant women included in some of these trials.

Some of the research that our team has done in India suggests that pregnancy does suppress some of the key cell populations that are important in the immune response to TB, including CD4 cells, CD8 cells, and the chemicals, the cytokines that they produce.

What we think happens is this occurs during pregnancy, and especially if you have latent TB infection, it may allow TB to start to replicate in your body when you're pregnant.

Because of the immune suppression that happens during pregnancy, you may not see the symptoms during pregnancy, but rather after pregnancy when you're postpartum, your immune system is trying to go back to normal and now all of a sudden we see the symptoms.

Epidemiologically, we know that the highest risk time for pregnant women to get TB is in that immediate postpartum period, and we think that this is some of the immunology that contributes to that happening. With HIV, because you asked about both HIV and pregnancy. HIV, of course, we know depressed and CD4 accounts. We know CD4 T-cells are important for TB immunology.

What's interesting though, is that we would expect that if we treat the HIV and your CD4 accounts go up, then the increased risk of TB would go completely away.

We continue to see an increased risk of TB and people even when they're living with well controlled HIV, it's a little unclear as to what's going on there. Is it a functional issue, like their CD, four cells go up, but maybe they're not behaving in the same way as it would happen in someone who doesn't have HIV, or is it something that we don't fully understand.

The studies that we've been conducting largely in India has been in pregnant women with and without HIV, and so we're able to compare the immune response to TB in both those populations.

Again, most of the women in our study on antiretroviral therapy virally suppressed, but we do notice that women with HIV have a lower expression of interferon gamma, which is one of these chemicals, it's really important for the immune response to TB. It lends more support to this concept that even having well controlled HIV may still impact the way your body handles TB.

Jessica: What research gaps for pregnancy, HIV and tuberculosis exist in the United States, and how can these gaps be filled? I know you had mentioned before, we don't know how many pregnant women even get TB each year. What do you think about all of that?

Dr Mathad: There are gaps everywhere you look when it comes to TB and pregnancy. As you mentioned, there's gaps in the epidemiology. There's gaps in how we prevent TB, there's gaps in how we treat TB during pregnancy, lots of gaps.

If we want to start with some good news, I'm very proud that the US CDC has recently started collecting data on whether or not a woman is pregnant when she's diagnosed with active TB, which was a huge advocacy and scientific effort to get those forms changed. It seems something simple, but it's a huge system.

It's hard to get things Incorporated, but we're very excited that the CDC has decided to do that. We should soon have some data on the epidemiology of TB in pregnant women in the US, at least. Then we hope that that will provide a model for other countries to be able to incorporate that into their systematic data collection on TB.

What we don't have data on is whether some of the newer TB prevention regimens are safe in pregnancy. That's especially important in people with HIV, not only because of the increased risks that we mentioned, but because people with HIV are taking medications that treat HIV, and we need to know how those medications interact.

Especially like as we're rolling out, dolutegravir not only in the United States, but in other countries, that's going to be an important issue to address.

As I mentioned before, in terms of the treatment of active TB, we actually have slightly different recommendations for how we treat active TB in pregnancy in women who don't have HIV in this country versus women who do have HIV. The reason why there's a discrepancy in what we recommend, and what the rest of the world recommends, is largely because we don't have the safety data in pregnancy.

I think that's an important gap that needs to be filled not only for the United States, but for the whole world to know that we're all on the same page, and we provide the same treatment regardless of where you are.

One of the problems is that pregnant women are not included in a lot of the treatment shortening trials. For example, with active TB, they generally are not included in any of the treatment trials for drug resistant TB, and so we have no recommendations about exactly what to do when you have a pregnant woman with drug resistant TB.

I think those are major gaps that need to start being filled sooner rather than later.

Jessica: What behavioral and immunological risk factors can predict which women are at highest risk for developing active TB postpartum?

Dr Mathad:  This is an area of very active research. As I mentioned, we have very little data on pregnancy. It's harder to say, what are the specific risk factors to pregnancy. We know that risk factors we know of are the ones that are not exclusive to pregnancy.

We know that women with HIV have a higher risk of postpartum TB, or if they have non‑nutrition, they're more risk, just like we know in non-pregnant populations. Immunologically, what puts them at risk is what we're still trying to figure out. As I mentioned, we're conducting a study that's looking at this in India to try to answer some of these questions more globally.

We have some data that our team has generated on certain genes that seem to be turned on in women who go on to develop postpartum TB compared to matched women who don't develop postpartum TB. Those types of findings are exciting.

They kind of provide a lot of insight hopefully into TB pathophysiology, but need to be done on a much larger scale before we can say for sure that these are the exact immunologic mechanisms that are happening in pregnancy.

Jessica: What are the overall take‑home messages from your session?

Dr Mathad: Pregnancy is a high-risk time for women to develop active TB. That's especially true if they have HIV. The highest this time for women to develop active TB is within those first 90 days after they have a baby. When pregnant women have TB, bad things happen, they're more likely to die, their children are more likely to have problems. It's an important thing for us to try to prevent.

Best practices for TB prevention and pregnancy are unknown. The current regimens that we have, we've either proven have increased risk of adverse effects during pregnancy, or we don't have safety data on it at all. That's an area that needs to be addressed. Treatment of active TB, also it varies based on whether you're in a high burden or a low burden setting.

That's largely again, because we have lack of safety data on any of these medications in pregnancy. One of my big take‑home points is that we need to start including pregnant and lactating women in clinical TB trials to make sure that everyone is able to reap the benefits of the incredible research that's going on in the area of TB.

Jessica: What is next for research in this topic?

Dr Mathad:  There's been a lot of progress in this area. Again, scientists and advocacy coming together to bring this issue about TB and pregnancy on a larger platform. We have high hopes for getting more of the epidemiology data. As I mentioned, the CDC has already agreed to collect that data. We're hopeful that the WHO will consider doing the same thing, including that in their global TB report every year.

There's also a lot of interest in conducting some of these safety trials, at least in the TB prevention regimens, specifically with the new regimens like 3HP and 1HP, and whether or not they interact with dolutegravir in pregnancy. I'm hopeful that those studies are actually going to happen in the near future.

I would love to see more clinical trials of TB shortening regimens or drug resistant regimens in pregnancy. I know there's a lot of regulatory challenges with these trials in general, and then you add pregnancy. Obviously, that makes it more complicated.

As we often say, there are sick people that get pregnant, there are pregnant people who get sick, holding our breath and hoping that the next 9 or 10 months go well for a woman is not a viable solution. Oftentimes, especially both in the US, but also abroad, pregnancy is one of those times where most women will interact with healthcare at some point during their pregnancy to make sure that their baby is safe, to make sure that they're doing OK.

It's an important entry point for women into health care. If we can identify all the different things that we can do to help keep women safe, help keep their babies safe, this is such a crucial time to do it. I think that being able to include pregnant women in these trials would help move that needle forward.

Jessica: Thank you so much for talking with us. This is such a fascinating topic, and so important. Is there anything else that you'd like to add at all that we missed?

Dr Mathad: A lot of people assume that maybe pregnant women would not want to be part of trials, and it's very natural to be very nervous when you're pregnant. I luckily had a very straightforward pregnancy, but you're nervous about everything you do, like, what do I eat? What do I drink? Where do I go?

These things are all part of your mind. All the studies that we've done in pregnancy, the important thing when you're doing research is that informed consent. We do informed consent not as a formality, we're informing them of the risks and the benefits that we think they will personally and on a larger level glean from this research.

The purpose of doing that is, like I said, not a formality, it's so that they can understand it, and they can make the decision themselves. One of the frustrating things at times can be, there are times when we exclude people from research. A lot of times we get nervous about including children because we know children can't make decisions for themselves.

We are cautious about including prisoners, or including people with mental health issues, and then also pregnant women. It's like one of these things is not like the other. There are people who can make decisions on their own. They make a lot of decisions every day [laughs] on their own about what they're going to do.

Then all of a sudden, with research, we're like, "No, no, we'll make this decision for you. You're not going to be included in these studies, because we're worried on your behalf for your baby." There's something a bit not right with that. When we talk with pregnant women that are in our studies, especially with HIV trials, there were times when we didn't want to include them.

They were like, "Please include us. We want to be part of these trials because we want to use these newer medications." The thing that is important to remember as a researcher is, when you choose to exclude people from your study, you have made a choice in and of itself. It's not necessarily always the safer choice.

With HIV in pregnancy, for example, pregnant women, in the beginning, we did a great job of including them in trials, because we wanted to prevent mother to child transmission, so they were included in a lot of those trials. Then we stopped. Once we figured out we knew how to do that we stopped doing it. Then they got stuck on this old regimen for antiretroviral therapy that included AZT, which we know causes anemia, and most pregnant women get anemia.

It was like we paused in time and then everyone else was getting to one day one pill. All this stuff, and pregnant women were left with these complicated regimens that had a lot more adverse effects. At some point, people were like, "Hey, wait a minute, why are we still giving them these archaic medications?"

The same kind of revolution is hopefully happening with TB also. Most of our first line medications were developed in the 1950s and we've been on that regimen ever since. Now there's these newer medications and they have less side effects. You can shorten your regimen. That's something that pregnant women are also interested in doing.

Allowing them to participate in the conversation, and allowing them to have a say in what they think is safe and not safe is so important. That's why informed consent is so important. You provide them the information, and if they say no, great, then they said no. But, if they want to, then that's a choice that they should get to make, it's an opportunity they should be able to have.

A lot of the studies that I've conducted have been observational. Observational studies make it a lot easier, because there's not an intervention. There are some clinical trials that I've been part of, and we've always been pleasantly surprised at how willing pregnant women are to be in some of these studies, even for a preventive regimen for TB.

If you live in a TB endemic country, and you see people around you dying of TB all the time, you want to be part of that preventive trial. You want to be able to make sure that you and your baby are going to stay safe. That's even more why I feel so strongly about including pregnant women in a lot of trials, because they weigh these things. No one cares more about their fetus than they do. So, give them that opportunity to make that choice.

The final point I'll make is, when you include pregnant women in research you're actually watching them so much more closely than you do in standard care. If anything is going to happen, you're going to know because you're seeing them every two weeks. You're checking their bloodwork, and you're keeping track of them so closely.

If we don't do the research, then what happens is, providers, wherever, who see the patient who is pregnant and has TB, or drug resistant TB, and we haven't given them research‑based guidelines to follow, they have to guess at what's the right thing to do.

They treat them, and they're probably not following them every two weeks. They may not have the capacity to do that. Something goes wrong, they might not necessarily have the same infrastructure to build into catch that. When we don't include them, we're basically putting the onus on someone else who may not have the ability to check the safety as quickly and as systematically as we do in a study.

Jessica: Well, thank you again, Dr Mathad.

Dr Mathad: Thank you for giving me the opportunity to talk about the work that we're doing, to highlight this major issue. I want to thank your listeners for listening into this, and hopefully, trying to think every time you do a study, and you check that box that you're going to exclude pregnant women to think about it twice.

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