HIV Cure Research and Connecting to the Community: with Dr. David Margolis and Dr. Allison Mathews

Falk: So David, you of all people have been talking about HIV and cure for HIV. How close are we?

Margolis: I think that’s very hard to say. I think I expect to be working on this for the rest of my career. So we’re talking about years away. I think we hope that there would be a breakthrough or an advance that would really accelerate the process, but I don’t think we can live on that kind of hope. What makes me hopeful is to see the really steady and accelerating advance of the field from where just five or seven years ago really no one was working on this problem, this challenge. Now there are dozens of groups and hundreds of scientists and some drug companies around the world working on the problem, and I think everyone recognizes that it’s an extremely high bar and very challenging, but I think we can only know by taking the path to try to get there.

Falk: The immediate response to those in the community who think that we are withholding cure is that wonderful scientists here and elsewhere haven’t achieved a cure for HIV yet, although there’s hope in the future – and we’ll come to that and talk more about that. Is there also a perception though that there is information that’s being withheld? What kind of information do you think would be beneficial to get out into the community, more than what’s out there already?

Mathews: I think the information that is important to communicate to people is that we’re not purposefully withholding a cure for HIV from the community, but there is a process, a long process, that people have to understand about clinical trials. The 2BeatHIV project aims to use crowdsourcing contests – this idea of engaging the community in these conversations about HIV cure research and the process of clinical trials and how to protect participants and the community— as a way to then to dispel these myths about there being information withheld from the community members.

Falk: Tell us a little more about that program.

Mathews: Well, the name of the project, and even the format of doing crowdsourcing contests was all developed by community members through feedback that we got from people asking them: What type of name, and how should we reach people? So we decided to use “2Beat” –basically a reference to hip hop and music, but also this double meaning of having a goal and a target to beat HIV in the medical sense and also in the social sense.

Falk: Part of beating HIV, though, presumes that people know that they have HIV and that they’ve been tested for it. In 2016, is everyone who should be tested for HIV being tested for it?

Margolis: Well, certainly not. I think we’ve made some advances in that regard, but still, over many years now, about the same number of new infections happen per year, every year, than they have for 10, 15, 20 years or so. We have a lot of new tools. We have rapid tests that can be done with a saliva swab, but it’s really the process of overcoming the stigma, the fear, the information gap, and to engage the community with the health care system, to be able to deliver information, the appropriate messages, and access to testing, and if needed, access to medical care to allow us to really grapple with the HIV pandemic in a better way.

I don’t think we can expect people to come in to be tested if they think there’s going to be no help for them or nowhere for them to get treatment. There’s been a lot of advances in that regard as treatment is now so much better and so much more effective, but still there are a lot of barriers to engaging people in the medical system.

Falk: That’s really of concern, simply because of the now well-recognized possibility that one can prevent the spread of HIV with current therapy–not therapy in the future, but therapy right now. You’d really hope that everybody would want to be tested so that they wouldn’t infect folks and loved ones in their environment.

Mathews: I think part of getting that message out about getting tested is communicating this message that once you get tested, it’s not a death sentence – you can get into medication, you can get access to resources to pay for the medication. And also get the message out that taking medication can prevent you from passing it on to your partner, and that there is a pill called PrEP that allows people to prevent themselves from getting HIV. That message is not widely known right now, and it’s not being seen on public commercials, so the onus is on us as researchers and people who do community outreach to get that message out so that it will encourage people to want to get tested and not be afraid of what possible result would come from that.

Falk: What’s the role of the community then in passing that message along?

Mathews: The role of the community, I think, is making sure that they are involved in community-based organizations and getting more information about HIV and HIV testing. One of the things that I like about the crowd-sourcing contests is the idea that they are contributing their ideas on how to develop campaigns using music, art, and technology, and social media, to design campaigns that are culturally relevant, and that make these messages easy to understand, and easy to access. So that could be the role of the community, as really having a say in designing how those messages come out.

Falk: It’s true for patient engagement or citizen engagement in general. Patients and citizens always know the best approach to helping their own community, way better than we who are on the other end of the white coat.

Falk: Why Durham? You’ve spent a lot of time, Allison, doing your investigations in Durham. Why?

Mathews: Part of the reason that I’ve done a lot of work in Durham is because I’ve lived here for a long time, and I believe that in order to do effective community engagement you really need to work with people who live in the communities and who know the communities well. But the other part of it is that Durham is the third highest county in North Carolina for HIV infection rates, and number nine in the country for AIDS-related deaths.

Falk: Wow.

Mathews: So even though we’re a small city, we actually are pretty impacted by the HIV epidemic. It’s very important for us to really concentrate our efforts on thinking about how our experiences with the HIV epidemic might be unique from other bigger cities like Atlanta and New York and LA and San Francisco.

Margolis: But in a lot of ways Durham is very emblematic of the south, which is a really heavily affected part of the country for the HIV epidemic currently. A lot of the issues that are important there are really important across our part of the country.

Falk: One wonders then, whether real preventive efforts should be targeted in those areas.

Falk: Walk me through how you prevent HIV.

Margolis: Well, there are a lot of tools to prevent HIV. You mentioned one of the recent advances by Mike Cohen here at UNC, showing that treatment of people with infection prevented spread of infection. But obviously, the most simple prevention method is to have safe sex with barrier methods of contraception which can also prevent spread. Allison mentioned PrEP, which stands for Pre Exposure Prophylaxis—so this is the use of anti-viral medicines by people who aren’t infected yet taken close to the time when they might be exposed, and the use of those medicines has been shown to prevent transmission from an infected person to the person who is taking PrEP.

There are now studies and experiments going on trying to develop different kinds of PrEP that are easier to use, and perhaps safer and more long-lasting; medicines that could be applied topically, and now medicines that can be taken once and last for many weeks and even months, similar to the idea of taking birth control pills to prevent an event for a long period of time.

There can even be the use of anti-viral drugs immediately after an exposure to prevent the establishment of an infection—that’s a difficult thing to do but can sometimes be useful.

Then of course ultimately, if the research community could develop a vaccine, that’s another big goal of the HIV research community that many people have worked on for many years, and there are still advances going on and hope that we will get to a more effective vaccine. There is a vaccine that was used in a study in Thailand and was barely effective, but it did prevent about 30 percent of lowering the risk of transmission. It’s sort of a starting point. Another recent development is the use of special antibodies that are very broadly protective against HIV that may be either developed for administration or if we could teach the immune system of people to make these antibodies on their own, that would essentially constitute a very effective vaccine approach.

So there’s a lot of tools. One of the bigger challenges is to figure out how to effectively use these tools in the community to have the best effect.

Mathews: One of the things that has always been a challenge is not just that we have these advances in medication, but also making sure that people have access to that medication and can afford it. There’s a lot of barriers and red tape that people have to go through in order to be able to see the physicians and be able to get access, insurance to cover the medication, and understanding that it’s important to continue to take the medication.

We’ve been putting out messages that people should use condoms, and make sure they use medication, but it’s also a matter of really addressing some of the structural and social aspects of that, like access to health care, and access to education, and transportation. That also would help prevent HIV – prevent the spread. And also making sure that we coordinate efforts between HIV prevention, treatment, and cure. Researchers and outreach workers and physicians—just making sure that everything is coordinated.

Falk: Let’s have a specific example, if you would. How would you use the 2BeatHIV approach to get out the message that PrEP even exists?

Mathews: Well, one of the things that we have done previously is have a contest where we had community members submit art, music, poetry—different types of creative material reflecting on a particular problem. That problem for the first contest that we did was to raise awareness about HIV cure research through a campaign. So they submitted their ideas and their creative material, and then we selected one, and we pulled some of the best submissions to then create promotional materials and campaign materials that would then be further disseminated throughout the community.

Then we also hosted a lot of different events with community partners throughout the year that raised awareness about HIV cure research, and partnered with organizations so that they would also benefit from being affiliated with the University and being affiliated with the project. So I would do something similar to that with trying to develop some type of community-based, community-sourced messaging around PrEP, to design some type of campaign that was community-built.

Falk: I wonder how many of well-educated health professionals know that PrEP exists, let alone members of the community. It’s a substantial advance in so many ways, and I’m not sure that our average medical student or even practicing physician knows that it exists.

Falk: David, what are we going to be able to do to improve current therapy for HIV, or is it really as good as it can be?

Margolis: I think as far as the effectiveness of stopping the virus from growing and spreading, and allowing the immune system to recover, and keeping people healthy, therapy is about as good as it can be. Therapy is essentially one hundred percent effective in one hundred percent of people who are able to get the pill and take it every day. The major advances that I think we will see are really in the delivery of those medications. Medications that can last for longer periods of time, or perhaps, for instance, an injection or an implantable device that you would get, only a few times a year for at least some people who need that type of treatment.

Falk: What then is this strategy for HIV cure? You use the interesting combination of words, “kick and kill.” What’s that all about?

Margolis: Well, that’s not my term and not my favorite one, but it is quite colorful and descriptive. Current therapy stops a virus in an infected person from being able to grow and spread within the body, but it doesn’t eliminate the virus in the infected cells. There are what we call so-called “latent reservoirs” of cells that contain virus, and if therapy is stopped, if the person goes off medication, the virus can turn on again and start to recreate disease all over again.

This is why people need to maintain a steady adherence to therapy, which really, for many people who are infected in their twenties or thirties, could be decades and decades of every day medication.

The idea is to try to eliminate this latent reservoir left over, small amount of virus, which is really very rare inside the body in people who are HIV-infected, but on effective treatment. And the challenge is, when the virus is in this latent state, it’s essentially invisible to the immune system because there are no viral proteins being expressed. An infected cell doesn’t look any different than its neighbor, healthy, uninfected cell. So that’s where the kick and kill comes in.

The kick is understanding how we can affect the virus inside the cell so that it turns on again and sort of unveils itself, unmasks itself. And that infected cell then becomes vulnerable, and then the kill is essentially an immune kind of intervention to deliver an immune response that recognizes these rare cells, sees them, and clears them.

Falk: You’ve just been awarded a wonderful NIH grant. The first of these was the NIH funding for CARE in 2011 and now you’ve been highly successful in getting that program refunded. What’s the goal of this current application? Why did you just get 23 million dollars to continue your fantastic research?

Margolis: Well, we got 23 million dollars because we have a lot of smart people working really hard, and the problem is very difficult. At the beginning of the program, in 2010, 2011, there was not really a whole lot of history to HIV cure research, so we were really developing the field from scratch, trying to understand more about how the virus remains latent, how to reverse latency, and make the latently infected cells vulnerable, how to measure these things, both in the lab and the clinic, because they’re both very rare, difficult to detect events. And how to model this, both in the tissue culture dish in the lab, and in animal models with HIV infection.

Over the five years we’ve made some progress, but all of the parts of the program need further refinement and improvement, but we’ve now gotten to the point where we’re beginning actually first two clinical trials, two clinical experiments where we’re trying to put the kick and the kill together in a patient in a very controlled, careful way, not expecting to actually cure anyone, but trying to actually see if we can measure for the first time, chipping away at this reservoir, and making it smaller and moving towards the direction of cure.

So our funding for this next five-year period is to essentially keep moving the field forward, both reversing latency and making infected cells vulnerable, measuring these effects in models and people, and a new and interesting tool using an antibody that’s engineered to be different than a normal antibody, but it has the ability to bind both an infected cell and any immune cell, not just an immune cell that recognizes HIV but any cell that’s floating around, and direct that immune cell to kill the infected cell. So these are called DARTS because they are dually active, redirecting antibodies.

Falk: These grants are typically five years long. Where are we going to be in 2021, or 2022?

Margolis: I hope that by that time, we will have experiments in animals that show significant clearance of latent infection, and perhaps cure in some animal models, and that we will be doing several clinical experiments on the small scale, testing advanced ways to reverse latency and clear latent infection. I expect that once we move forward and start to make some advances, we’ll discover some new challenges that we don’t know about yet, but we’ll just have to deal with them as they come up.

Falk: The fun of science.

Margolis: That’s right.

Falk: Thank you both for spending time with me today. Thanks so much.

Mathews: Thank you.

Margolis: Great to be here.