Oby: From the campus of Harvard Medical School, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan: And I'm Brendan. And we are your hosts. ThinkResearch is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

Oby: And by NCATS, the National Center for Advancing Translational Sciences.

Brendan: The epidemiology of infectious disease is closely tied to public health efforts, resources, and access to care. The HIV epidemic forced countries in sub-Saharan Africa to build public health infrastructure that could prevent and treat the disease. Now that people with HIV are living longer, how can these same systems prevent and treat other chronic diseases. And how does HIV complicate treatment?

In South Africa, Mark Siedner and his team are working with local health departments and health care providers to understand the best ways to treat hypertension and other chronic diseases in people living with HIV. Dr. Mark Siedner is an infectious disease clinician at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School.

Dr. Siedner, thank you very much for joining us and welcome to ThinkResearch.

Mark Siedner: Thank you, my pleasure.

Brendan: So you're a clinical epidemiologist by training and you have a research program in Uganda and South Africa that aims to improve health for people living with HIV. When did you become interested in HIV?

Mark Siedner: I think, like many people in my field, it was really a personal experience, which I think first got me interested in the field in general. As a youngster, I had a cousin who was infected with HIV who was actually also a magician. So he was my favorite cousin no offense to all the rest of my cousins. But he was infected with the disease at a time when treatments weren't yet available. He did unfortunately succumb to the disease.

And actually, I think other than losing a family member and friend, I think I was young at the time but striking was the fact that people didn't really talk about his death in my family. It wasn't a secret, but it wasn't discussed. And I remember some conversations with my mother about why that might be and not really understanding it. But as I, of course, grew and expanded my ability to really conceptualize those things, it became increasingly of interest to me not just as a medical disease but as a stigmatizing disease, and one that affected people on multiple levels. And slowly pursued a path through my education to see if I could learn more about it.

And I actually took me on a trip after college as part of a research fellowship. You have to spend a year, largely in sub-Saharan Africa, doing independent study. And I chose to study the effect of the epidemic on various social and behavioral responses in countries in sub-Saharan Africa and India. And after that it was pretty much clenched that I want to spend the rest of my life and learn more about it and being able to come back at a point in my life when I had the skill set to finally have a greater impact.

Brendan: That's such an interesting story that your family experience and the death of your cousin really propelled you into medicine and your career. Your life's work, I guess.

Mark Siedner: Yeah. I think many of us in medicine and science I think will have a personal experience at some point that really triggers our curiosity, our dedication, to try to be able to return and make a contribution. And for me, I think that was really the first of those experiences. And then many others throughout my life, especially when I got a chance, I think, to spend some time globally and see how the HIV epidemic had really just destroyed a generation of people. I was pretty much convinced at that point that I wanted to learn skills that would allow me to somehow come back and make a contribution and respond. So it was the first of many experiences I think that certainly led me on that path.

Brendan: And so you said that your interest in sub-Saharan Africa started with a trip after college. And you were fortunate to be able to come back and continue and work there. Maybe you could tell us a little bit about the research program that you have now and what some of the goals are.

Mark Siedner: I think one of the greatest privileges of being a physician scientist is that you're offered an opportunity not just to care for people as a clinician, but really to learn from the greatest challenges that people face both as patients and as humans. And I had the opportunity through my work at Massachusetts General Hospital to spend time living in Uganda and then later in South Africa and learn by practicing medicine what were the greatest challenges to patients' lives and the delivery of health care.

And I'd like to say that most of my research and most of our research questions are not ones that I think I really developed myself, but ones that my patients ask me, or our colleagues in the clinics asked me, and we didn't have an answer to. And so to give an example our work is largely revolves around answering questions that say, how can we do better by our patients? How can we allow people with HIV, which is a chronic disease, to live healthier, longer lives?

And so for example in Uganda, two of our current projects involve studying how HIV affects the heart. And that's because we increasingly have seen over the last 20 years, which in some ways a very good thing, that people are no longer dying of AIDS at such high numbers. That they're living with the disease, which is a chronic disease, but suffering consequences of its treatment or suffering consequences of a chronic infection that's actually well controlled with the medicines we have. And so, the priorities are shifting in our patients from dying of AIDS to after delivery of treatment, living with AIDS. And so we're trying to understand how do people live long, healthy lives with HIV, with a chronic disease, whether that pertains to their heart health or other factors things like their priorities as they age. What determines their social life, what determines whether they're able to accomplish their activities of daily living. And those are the primary focuses that we've shifted to over the last 5 to 10 years.

Mark Siedner: And you mentioned the challenges of health care delivery in these countries. What are some of those challenges? I know that sometimes there are long distances people have to travel, but what specifically about HIV and heart health. What are some challenges that you face?

Mark Siedner: So I think first and foremost, the health care systems and health care delivery models in low income countries differ greatly from for many high income countries. And we won't spend time talking about the challenges of health care delivered in the United States but I think it's quite unique.

But in many of these countries, public spending on health care is just a few of GDP, a fraction of what it is here in the United States. And so the actual public health infrastructure, the way health care is delivered, is incredibly different there in terms of what facilities have to offer, what patients can expect to receive at the hospital in terms of care. What they have to pay for themselves, what they can afford to pay for.

And so the HIV epidemic very interestingly in some ways reinvented that system. Because for the first time, there was a large investment in a public health care system in some of these countries that just really hadn't existed in the past. And so when HIV afforded the health care system do is say now that we have some resources, which were paid for largely through global donations and sometimes through partnerships with these countries, how do we now set up a health care, public health care system? And allow people to have access to chronic care? And that really revolutionized the way treatment was given largely from people coming to clinic only when they felt sick, maybe to get treated for malaria or for childbirth or for other acute problems, to coming into clinic as a way of sustaining health and preventing disease.

The successes, there have been many. Many millions of people's lives have been saved due to HIV, due to tuberculosis, and due to other conditions related to HIV. But what we're left with is a health care system in some ways that is only designed to take care of HIV, because that's how the systems were built. And not so well designed, yet, to take care of hypertension and diabetes and dementia and lung disease and all the things that happen when people live long and healthy lives and don't die of AIDS or other things earlier in life.

And so what we're focused on now is how do we make that shift? From making health care delivery almost purely about things like HIV, tuberculosis, and malaria, which are the primary causes of morbidity and mortality in the last 20 years, to diseases of aging, to chronic health diseases, to non-communicable diseases. And our studies around the heart disease and HIV are really centered at that.

What are the greatest causes of death in the next 20 years in places like sub-Saharan Africa? And how do we help design a health care system to address those.

Brendan: So does the treatment of heart conditions like heart disease and hypertension differ for people with HIV and how so?

Mark Siedner: So the vast majority of the data we have on how HIV affects heart disease has been collected here in the United States and somewhere in Europe. Most of those studies have suggested that having HIV, even if you're treated and your disease is well controlled, increases your risk of having things like heart attacks and strokes. And that's because HIV is a chronic infection and it causes inflammation. And we now know pretty well that inflammation as a major driving force behind many chronic, even non-communicable diseases like heart disease, stroke, and cancer.

We know less about those relationships in sub-Saharan Africa. But I think it's very important that we don't make assumptions that just because the pattern of health and disease is seen here in the United States that it will be replicated in sub-Saharan Africa. I can give you just one example, something we've looked at in this area recently with our group.

About 10 years ago, one of the research institutes I work in KwaZulu-Natal, South Africa called the Africa Health Research Institute conducted a series of tests in people living in rural South Africa where they would measure things like height, weight and blood pressure. And these individuals are followed longitudinally over many years to try to understand what happened to them. And as part of a demographic surveillance every time someone's born, or migrates, or dies, that data is collected. So we were able to take that information and ask the question what did those measurements that were done 10 years ago? How do they predict health? How do they predict whether how long people lived?

And so we did actually a relatively simple study. We took the body mass index of about 10,000 people that had been measured about 10 years ago. And we asked how does body mass index predict whether people are going to live longer or not. As you all in the United States, this data, these same studies have been done over for decades now. And they've typically showed that once your body mass index is above 25, you're considered overweight, And if it's above 30, you're considered obese. And that's because those same kinds of studies show that people with the BMI over 25 or 30 have a higher risk of death than people with a BMI less than 25.

When we repeated that same exact analysis in South Africa, we found that people with a BMI between 30 and 35 actually have the lowest rates of death, much lower than people with a BMI of 18 to 25. But the entire concept of body weight and body mass in rural South Africa, and how it predicted health, is completely different than what we find here.

And so the moral of the story for us is that we can't just collect data the United States and Europe, particularly amongst people like me much of the data comes from Framingham, as you might know not too far from here. That's a population of largely white Caucasian Americans. Those data are not going to apply in many ways to people living in sub-Saharan Africa. And our research program is trying to say let's collect this data locally, regionally, with our partners in country to understand what are the determinants of health locally. And how do you design a health care system in response to those local determinants of health.

Brendan: So let's talk a little bit about the grant that you have looking at blood pressure control. This past year has obviously changed a lot for most people. And clinical and medical research has been disrupted and altered in many ways. Tell us a little bit about this grant and what you're looking at there. And how COVID has kind of changed what you were doing and altered the way you were working this past year.

Mark Siedner: We wrote a grant for Covid-19 that recognize that hypertension care was quite poor in much of sub-Saharan Africa, and certainly in rural South Africa where I worked. We've shown that rates of blood pressure control are 20% to 30% amongst all people with high blood pressure. So the grant we wrote said, let's do something about this. Let's work with the Department of Health. Let's train nurses. Let's figure out ways to make health care delivery for hypertension better. But largely this grant said how can we improve clinic based hypertension care delivery?

And in the middle of us receiving this grant, the Covid-19 epidemic happened and everything went on hold. Most of our research on our health in general, at least for a while. But then when things started to improve, and the epidemic has fortunately improved greatly in South Africa, they're actually just starting to roll up their vaccination program. And we reapproached the Department of Health who is very interested in this problem, and they do consider hypertension one of their greatest health care priorities.

In partnership with them, we decided that we'd been thinking about this wrong all along. That maybe the best way to develop chronic disease care is not by asking people to come to an overburdened clinic and wait in line for four hours and get the blood pressure checked with the meter that they can have at home very easily, but to say what can we learn from this epidemic from depopulating clinics from improving the convenience of health care delivery. And we've basically completely reformulated this project to be almost purely a community health care delivered form of blood pressure care. Where people will either get blood pressure cuffs to measure themselves and a community health worker will come and take those measurements and help transport them to a professional nurse who will interpret them. Or in a slightly more innovative portion of this project, we're proposing to actually use electronic meters which automatically upload the data remotely. So no one's involved except for the patient themselves and a remote nurse who can interpret the data and then communicate with them over text message.

So we're hoping to use this opportunity to push the envelope a bit and to say how can this epidemic really teach us about the most efficient, the most convenient, and the most effective ways of delivering chronic disease care. We've known for some time that for example delivering HIV care through community health care is effective and more convenient and preferred by patients. I think this will be one of the first times where we can test that same model with another chronic disease, hypertension, which of course impacts 25% of the entire world's population. And potentially will have very far reaching impacts.

Brendan: It struck me that you're talking about how HIV reshaped the health care system in some of these countries. And now it's like an HIV care system. Or it does HIV care well but doesn't do other treatments for other diseases particularly well. And now we have another epidemic that's reshaping the health care system. I guess maybe could you talk about any parallels that you see between this and HIV, between COVID and the two pandemics or the two epidemics. And just the idea that it takes an epidemic to make some of these changes that could benefit people.

Mark Siedner: Yeah. I mean I think the glass half empty perspective here, which is I think in many ways a valid one is that we don't make change until an emergency makes us make change, until we're forced to make change. And in too many cases I think that both of these epidemics have revealed many weaknesses in our ability to one, provide health care effectively and efficiently, and two, to take care of the most vulnerable groups of people in our planet. And that's been seen time and time again with both of these epidemics.

If you look at the groups of people who've been most affected by both the HIV epidemic and the Covid-19 epidemic, you'll find the same risk factors. These are people who are lower income who have less access to health care, who are afforded less benefits of things like global vaccine supplies based purely on where they live and the global wealth distribution on the planet. And so I think there are some pretty strong parallels here in terms of who these disasters reveal are really suffering the most.

In both cases, but I think particularly for the Covid-19 epidemic, for those of us who also worked a bit on the Ebola epidemic and raised I think some calls then that are public health care infrastructure was really weak both domestically and globally, and that the preventative investments will probably pay dividends down the road. Even basic things like affording people access to things like diagnostic services and making sure that we have enough health care workers that are trained to diagnose disease and can make referrals for basic care. Coordinated systems of laboratory testing, all of these basic public health measures that I think were definitely revealed during the Ebola epidemic of the past decade I think largely went unheeded because I think what happens is there's a lot of attention that gets paid. Epidemics wane, memories fade, and it's onto the next thing. And so I think our public health preparedness and the weakness in our public health systems was revealed quite obviously, evidently, with this latest epidemic.

I think the real question we face now is will we learn from it this time. I think there's a reasonable chance that our pace of vaccination allows us some return to normalcy over the next few months if we do our jobs right and we get enough people vaccinated. And we don't learn that variants aren't going to overtake those vaccines and boosting won't work. There's a number of things that would have to happen to really push us back in the other direction. And we're all hoping that doesn't happen.

But if we do go on to a return to some level of normalcy, will we also remember this? Will we invest in our public health care systems? Public state departments of health have it massively underfunded in this country for decades, and they're almost non-existent in many foreign countries because they just don't have the funding to support it. That being said, the WHO and others have been asking for years for some basic funding support, training infrastructure development in most of the world.

So I think that the real question for us will be how do we respond to this. Will we make the needed changes, will we be wise enough to make the investments that we now know need to be made both domestically and globally. So that the next one comes, we will be better prepared.

Brendan: So just getting back to the grant that we were just speaking about, so this is work that is in progress now. And I wonder if you have any hopes for maybe some lasting changes that could come out of this. Or would you like to see remote care or community based care be more of an option? And maybe the technology, if you could talk about the technology aspect and how that fits in.

Mark Siedner: Yes. I think one of the real strengths to this project, which one, makes it more exciting, two, makes it more challenging, but three, I think positions it to have a lasting impact because that this project is really a partnership with the Department of Health. We have on our leadership committee we have this leaders on the Department of Health who are also advising the Department of Health at the same time about how to design the non-communicable diseases response program. And they every step of the way, every time we edit our proposal or protocol, it goes through them and they help weigh in about is this feasible, is this something the Department of Health will adopt if it's going to be successful?

And so it's a longer process. It's much it's much harder from a logistics perspective than is going out and doing a study, recruiting people and testing a hypothesis. But this painstaking process where we make sure that we're getting buy-in from our local partners and the people who eventually would adopt this system if it's successful I think and hope will give us the chance to say, listen, we accomplished our goals if we do. This did work or didn't. And this should be the response. And so I think we're in a position where if we do show something that's effective, our partners will be able to have the confidence to move it forward.

On a related note, we're actually using an implementation science framework to do this study. So as opposed to just being a pure clinical trial which its main goal is typically to say does this drug work in a vacuum. In a very well designed setting that maybe every patient is being followed every day and you have good oversight of every last thing that takes place, we're doing these within the public sector. We're evaluating not just whether it works but interviewing nurses and patients about their experiences with devices. What's working, what's not working. We're doing a costing and cost effectiveness analysis so ultimately we can advise the Minister of Finance if it's cost effective. So if it works, so what? But how much is it going to cost per patient to reduce blood pressure, to achieve blood pressure control. To eventually save lives because of reductions in heart attacks and strokes. So we're using a framework here that we hope will be able to be used not just to say does this drug A better than drug B, but does this program ultimately represent a sustainable intervention in the public sector. So I think that is our goal and we do hope that whatever we learn from this, whether it works or doesn't, it will be directly relatable to our partners.

In terms of the technology we are in the midst of developing the technology. We have some partners in South Africa, a company that actually makes [inaudible] applications and has been working with the Department of Health in a different province to develop actually child care and maternal care programs. And allow community health workers to collect data and report that data in real time the Department of Health. And so we're partnering with them to help develop a very similar application, but this time really focusing solely on blood pressure control which we're using essentially as a principle that this chronic disease method will work. But with the idea that maybe it would be expanded to others in the future.

So our current goal is to have various elements of this study. One would be kind of what we're calling a low tech innovation intervention, we're really people just get regular blood pressure cuffs at their home. We don't use much fancy technology but community health workers still involved. And then as I mentioned, a high tech version of this where the measurements are actually transmitted in real time using a cell phone technology to nurses who can review it without the need for additional visits.

Both of those strategies have risks and benefits to them. Technology is not perfect, especially in rural areas. The need for multiple visits by community health workers is not perfect in rural areas. And so we're trying to understand the trade offs between these various strategies. And hopefully find one that really works both for the patient and for the health care system.

Brendan: Hmm. Could you see a scenario where both of those approaches have benefits for different areas or groups? And maybe when you're proposing it to the Health Ministry saying look, for this area we found the blood pressure cuffs and a visit was really effective, but in the cities the transmitting over the phone network was more effective. And maybe having like a either or depending where you live that kind of thing.

Mark Siedner: Absolutely. And I think there's nuance to every class research study once you delve into the data. I think you can imagine a scenario where people with hypertension who also have maybe a child or a younger person in their home who can help them with the technology would be a reason why that there'd be certain groups of people that would do better with high tech. Whereas, as you mentioned, maybe distance the clinic. If you live very close to a community health worker, it's not that hard for them to get to your house, maybe they would benefit. And it's all of these issues.

And of course costs. So maybe they're similar or even equivalent, but one of them end up becoming more cost effective than the other. And you can say, well, the technology is getting more expensive but maybe not. Because if it decreases health care visitation, it actually may decrease health resource costs. So it's difficult to know exactly which one would work and which one wouldn't and for what reasons. But we're collecting all of these process measures and these things in the middle.

How many visits were made? How many times was a pharmacist involved? How many times did someone battery die? How many times were not able to get a cell connection and therefore they couldn't transmit. All of those intermediate steps for collecting that data as part of our protocol to try to help understand why does it work, why doesn't it work. And ultimately help clarify are there certain groups of people that would benefit from one versus the other.

I will say that ultimately in places like South Africa, in many countries in sub-Saharan Africa, there tends to be a public health approach which is that differentiated care, where certain people get certain things, is not always easy to deliver. Especially in rural resource limited settings. And they often follow relatively standard guidelines. So there are some sometimes difficult decisions to be made because you can't always have two or three different strategies. But our hope is that we're able to clarify what is the best strategy. And if there are reasons that they're better for some people versus others, let the policymakers decide the best way to proceed.

Brendan: It's interesting what you just said, let the policymakers decide how to proceed. How do you feel once you have your study, you've collected your data, you've drawn your conclusions, you deliver it. And then you kind of wait and see what happens. What's that like?

Mark Siedner: Well I think one of the most important responsibilities of scientists is to communicate their findings, appropriately, accurately, in an unbiased fashion. And to be engaged in policy decisions. But truly to allow policymakers the opportunity to ask questions, get the answers right, and make the decisions.

I think scientists I think have a really important responsibility to get it right. To express limitations, to express confidence intervals, and to say this is the range of results that we found. This is how to interpret them. And this is how not to interpret them. And to make sure that information is out there. But I do think there is a line there. And that line exists when I, as a scientist and not the person at the end of the day has to say we're going to put our money down and spend x billion dollars invest in this. My job is to say what would happen if you did that. And what's the alternative result if you don't. But not necessarily to say you should or you shouldn't.

And so I think we are pretty heavily engaged with our partners in trying to help interpret data in an unbiased way as much as possible. But I think we recognize the limitations of our role there. And it is to advise and to be clear and transparent and to recognize limitations but not to overstep those ballots.

Brendan: Well Dr. Siedner, it was a pleasure to have this conversation with you. Thank you very much for joining us.

Mark Siedner: It was my pleasure. Thank you for taking the time to speak with me.

Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.

Oby: To learn more about the guests on this episode, visit our website, catalyst.harvard.edu/thinkresearch.