Hope for HIV Prevention
Implantable devices that can slowly and steadily release long-acting antiretrovirals into the body are one novel HIV prevention strategy now in development. Find out how a team of researchers at Northwestern University co-led by Thomas Hope is studying one such device.
By Kristen Jill Kresge
Ever since reading psychologist Barry Schwartz’s book “The Paradox of Choice: Why More is Less,” I came to believe that we are often crippled by the number of choices in daily life. Do I want the whitening toothpaste, or am I better off with the anti-plaque? Which of the 37 varieties of laundry detergent will actually work the best? That is just the beginning.
The proliferation of online shopping only seems to add to the confusion that endless choice creates. A simple search brings up dozens if not hundreds of possible options for any item you seek. And studies indicate that the more choices there are, the less likely you are to be happy with your decision. In fact, some studies even suggest the proliferation of choices may make people overall less happy than previous generations. There are plenty of TED talks on this topic, not to further overwhelm you with choices.
But in the world of HIV prevention research today, the prevailing argument is that people need more options. That is to say, researchers think offering more ways to protect against HIV infection will lead to more people actually using a preventive strategy that works for them. There are already a few choices: condoms, of course; adult voluntary male circumcision; and oral pre-exposure prophylaxis (PrEP, the use of HIV drugs to prevent HIV infection), which has been shown to be over 90 percent effective at preventing HIV infection when used consistently. But researchers say that the barriers are still too high to get many of the people who are at greatest risk of contracting HIV to use any of these options consistently and correctly, which is, of course, the only way they are effective.
This is why researchers are moving ahead to apply for regulatory approval for the vaginal ring containing the antiretroviral (ARV) dapivirine, which was found to be 27 percent effective in pooled results from two large efficacy trials (see HIV Field’s Current Contours Show in Boston, IAVI Report, Vol. 20, No. 1, 2016). It is also why they are investigating whether a regular injection of antibodies that can protect against many of the HIV isolates in circulation, so-called broadly neutralizing antibodies, can protect those who aren’t willing or able to swallow a pill every day to stay HIV free. Another option is using long-acting ARVs that will be applicable not only for treatment but for prevention as well (see Longer-acting HIV Prevention Methods: Take Two Antibodies and Call Me in Six Months?, IAVI Report, Vol. 21, No. 3, 2017). These long-acting ARVs could be delivered orally, by injection, or via an implantable drug-delivery system that could self degrade or be replaced annually, similar to the implantable hormonal contraception devices that last for three to five years.
It is this type of implantable device for HIV prevention that is the focus of a US$17.5 million grant awarded by the US National Institutes of Health to researchers at Northwestern University in Chicago. The five-year grant is funding the Sustained Long-Acting Protection Against HIV program, involving 15 basic scientists and clinical investigators across 15 departments at the University’s Feinberg School of Medicine, McCormick School of Engineering and Applied Science, and Kellogg School of Management.
One of the project’s principal investigators is Thomas Hope, professor of cell and molecular biology at the Feinberg School of Medicine. The other is Patrick Kiser, associate professor in obstetrics and gynecology at the Feinberg School of Medicine and biomedical engineering at the McCormick School of Engineering.
Hope is a familiar face in HIV research and a rather colorful character. He often delivers presentations at conferences around the world clad in a Hawaiian shirt, and always with an air of joviality. But the work he and his group do is serious. Much of it involves understanding mucosal transmission of HIV and the critical events immediately following transmission that allow the virus to establish persistent infection. In addition to pushing forward the field’s understanding of the important interplay between HIV and multiple cell types, this research generates stunning, gallery-worthy microscopic images of the virus within the mucosal environment where infection is first established following sexual transmission.
Hope’s personality is perhaps most evident in the naming of Northwestern’s program to develop an implantable drug delivery system. “A lot of these trials have inspiring names like ASPIRE, ASCENT, et cetera,” he said recently at a meeting sponsored by the New York Academy of Sciences (NYAS). The program Hope co-leads is called the Sustained Long-Acting Protection Against HIV program, but it is the acronym that says it all. “We decided to take a more aggressive approach and call it SLAP HIV.”
Hope spoke at the NYAS meeting about his team’s efforts to develop an implantable device to deliver the investigational ARV cabotegravir, an integrase strand transfer inhibitor with potent antiviral activity that is being developed by Viiv Healthcare. Cabotegravir is one of the first drugs to be developed simultaneously for treatment and prevention. It is currently being tested as both an oral formulation and an injectable in a large prevention trial. And the goal of Hope’s program is to advance an implantable cabotegravir delivery system to Phase I clinical trials by the end of the five-year grant period that began in 2015.
We spoke in detail about the program and its progress, and also the other projects he currently finds most promising.
Can you start by explaining the implantable drug delivery system that your group is developing as part of the SLAP HIV program?
Basically, to make it you more or less compress the drug into a series of pellets and then you put the pellets inside of a membrane that is made from a polymer that is designed to let the drug leak out at a certain rate. You play around with the different polymers and you use the one that allows the drug to be released at the rate you need for protection.
It is interesting because you basically start with shelves of beakers with stir bars in them and you put the different prototypes of the implant in the beaker. Then you take a little bit of the liquid out and put a little liquid back in, kind of pretending the beaker is like a little system, and by doing this you can figure out how much of the drug is actually coming out. And then you make adjustments. Once you get close to the amount of drug being released every day that you want, then you move things over into, for instance, different animal studies.
And why work with cabotegravir?
Even though there are many, many antiretrovirals, there are only a handful of them that can work for a long-term, sustained-release strategy because the drug needs to be very potent, and it needs to be cleared from the system slowly. Cabotegravir is one drug that that can be accomplished with. The others that might work, at least on paper, are the Gilead drug known as TAF [tenofovir alafenamidem or Vemlidy; a drug approved by the US Food and Drug Administration for the treatment of chronic Hepatitis B virus infection] and the new Merck drug that they call MK-8591, or as I called it at the New York Academy of Sciences meeting, unobtanium, because they are not really sharing information about it with anybody. I thought they would be mad that I called it that, but they actually thought it was funny.
And then did they tell you all about the drug?
Well, that’s a different story, but the scientists from Merck did tell me they thought it was funny that I said that.
So you couldn’t take any drug or combination of drugs and use a similar system to what you have developed?
Well it is really about the drug’s potency. The implant needs to be small enough that it is not obtrusive. If you had an implant that was the size of a can of beer and you could put it under your skin somewhere, then you could use any drug. But the problem is the drug has to be very potent because the size of the device has to be small. You could probably only put hundreds of milligrams of drug in the little implantable device, and ideally, for an implant, you are looking for it to hold enough drug to last about a year in order for people to be willing to go through the surgery to insert the device. You can take a pill every day, but this is something entirely different. You have to have the device surgically inserted and then it has to be removed or replaced, and that is much more complicated than taking a pill. So for people to be willing to go through that, there has to be a real benefit. Therefore it really is potency of the drug that is the limiting step.
If you were going to use a different long-acting antiretroviral, such as TAF, could you just change the polymer that controls the release and modify your device to work?
Some technologies are readily adaptable to other drugs, but ours is very specific. Some people have devices that are more of a solid matrix with little holes drilled in it, but because ours is really just a tube of polymer and because each drug has different characteristics, the polymer that works best for TAF is not going to work for cabotegravir. There are other technologies that are being developed that are more universally applicable. For example there is one that is basically a metal tube that slowly pushes the drug out of one end, and so with something like that, you could use any number of different drugs because you are just pushing the drug out of a tube.
Where are you now in the development and testing of your implantable in animal models and what are the plans for clinical development?
Well, we are very anxious…the nature of this grant is that we are supposed to have a Phase I clinical trial completed by the end of the fifth year, or at least in the no-cost extension period, so we are trying to meet that. Right now we are transitioning from beakers into rabbits, and then into primates to see if the way these things seem to perform in these idealized systems within beakers translates to the living animal. Those studies are ongoing right now.
Where does the device go in the body?
That is a good question. It can kind of go anywhere but right now we are mostly thinking of doing something similar to what is done for Norplant and other hormonal implants used for birth control. Those devices tend to go in the inner arm, around the lower biceps. And the logic for that, although we have not been able to find out explicitly why they decided to put it there, is that it is a place that is not going to be exposed to outside impacts, you know, like being in a car accident and hitting it hard against the inside of the car or any other sort of bumping into something. It is a little bit protected in that place. But there has also been some discussion of putting it in the buttocks or in the small of the back.
You want it to be someplace where there are not a lot of nerves and you are not going to notice it. But right now as we are doing our acceptability studies, we show examples of it being like the hormonal, sustained-release devices and so it is in that same spot on the inner arm.
Is there also anything to be learned from the implantable insulin release systems that are used for treating diabetes?
Insulin is a much bigger molecule than these antiretrovirals, so while I think some lessons can be learned, like how the body reacts to implants and that kind of stuff, the actual functions of the devices are going to be very different for a human protein versus a small molecule. These drugs are very small molecules.
If you are trying to prevent against sexual transmission of HIV, how do you know how much of the drug needs to be in a person’s system to protect against exposure? Will cabotegravir released by the implantable device have a different bioavailability than if swallowed in a pill form or administered by injection?
So that’s the idea behind the animal studies. It all comes down to the systemic drug levels. When you take a pill, depending on the drug, either all of it gets into your system, or with some drugs, not that much of it gets into your system. And so the bioavailability is dependent on the drug getting through your digestive tract to enter your system. We do not have that issue with the implants.
And so the idea is after—we have to do all the studies, of course—but after a certain period of time, days or weeks, the drug would be spread throughout the body. We know from studies of oral PrEP and some other things, that sometimes these drugs concentrate in one part of the body and less in another part of the body, so that becomes important. You just have to have sufficient levels to provide protection, that is what it is all about.
Could you theoretically develop this type of an implantable device to allow the broadly neutralizing antibodies to be released over time, or is it really specific for non-protein, small-molecule drugs?
I do not think this technology with the membrane, where it releases the drug through the membrane, would ever work for broadly neutralizing antibodies. But people are developing technologies to accomplish this, it is just different kinds of technologies are required to make these things work.
Is there any interest in developing an implantable device for HIV treatment, or just for prevention?
You are absolutely right that this same exact device could be used for treatments, but in the grant program that is sponsoring this project, they were very explicit in saying you had to pick prevention or treatment, and because we have a lot more experience in prevention, we are focused on prevention. But the implant could easily be used for therapy.
What role is the management school at Northwestern playing in this grant? Are they involved in figuring out whether people would want to use an implantable device and how to market it?
So one of the things that the field is considering, and there is a lot of discussion about this, is how there have been all kinds of efforts to develop new products—vaginal rings, gels, et cetera—and then very often when it comes time to roll these new products out, the people that have to use them are not so excited about actually using a gel or a ring. Instead it is, “I would like this, but I don’t want it to be this way.”
So I think this program was set up really, very well. The first couple of years was a competition of different groups to see which one could develop a technology that made the most sense. And part of the decision process used to decide which of these technologies to advance into a Phase I clinical trial was going to be concerns about whether or not it would be used. If we have three technologies available that we can advance, and one of them people are excited about using for prevention, and the other two, they’re like, “I hate that idea,” then that would come into play. So the role of the School of Management has been in conducting acceptability studies.
Historically, as a hardcore scientist, I have not necessarily always been a big fan of this sort of work. But I am now convinced that it is of the highest level of importance. We need to start thinking about how we are going to get people to use these things and offer them the things that they are willing to use, otherwise we haven’t solved any problem.
Our number one guide in the management school, Bob Schieffer, is an expert in doing these kind of analyses. It starts with a focus group to get a sense of what people are thinking. Then you can turn that into hard science by doing something called a conjoint analysis and discrete choice analysis.
If you just tell somebody here are 10 things and say, “Which is your favorite one?” the responder might grab one, but then the next day they would grab a different one. And sometimes people don’t even know what they like or not. So instead of offering them—this is just one crude example—but instead of offering them 10 things to pick one from, you offer them the 10 different things two at a time. Then you can ask do you prefer this one or this one? This one or this one? This one or this one? And by doing this, some things become immediately apparent to analysts. One is that some people, like 15 percent of people, don’t know what they want so perhaps they can be excluded from the analysis. Then you can start to extract different information. Is their number one choice right next to their number two choice, or is their number one choice far superior to number two? These comparisons allow you to get this kind of information.
And then other choices are also very important. A good example is choosing between your favorite restaurant and your second favorite restaurant. The second favorite restaurant is across the street. Your first favorite is a 20-minute drive. You want to go to your favorite restaurant but it is raining, so you decide to go across the street. And then the next week the situation is different and you make a different choice. This example shows that the context of the things you have to consider when you make a big decision, or a small decision, are complicated and so you need to try to measure all of those things.
With the School of Management we’ve found a goldmine in my opinion. These people did this sort of work as a profession, they were successful and were able to retire, and now they are teaching the next generation by working in the School of Management. They can take those approaches and apply it to this very important area. Other people are of course doing this too, including the commercial firms that actually run the surveys.
I think that has been one of the several really neat things that have come out of this project that I was not anticipating.
Do people really need that many more choices when it comes to HIV prevention?
People often cite birth control as an example, in part because it’s sexually related, and in part because what actually works in getting people to use it more is having a choice of what method they want.
Back when there were very few choices, birth control was less successful. Now, there are all these different choices, even internationally, like rings, for example. Rings for birth control are much more popular in South America than anywhere else. In other parts of the world they aren’t used at all. In the US, I think contraceptive rings make up less than 10 percent of the market, maybe eight percent. That is still enough for the companies to make money on it, but it is not the top choice.
What we really need for HIV prevention is to offer people options. The implant is an option for individuals that are not good at taking pills every day. Some people are good at taking pills every day, whether it is for blood pressure or anything else, and other people are not. And bizarrely, if you do not take the pill, it doesn’t help you. From inside the bottle it can not do much.
What other areas of HIV prevention research are you involved in?
Right now I think we have the best science ever happening in our lab, and one thing that I think is very relevant is that we are doing some work on injecting broadly neutralizing antibodies and learning neat things about how they distribute in the body. We inject them into a macaque and watch how they distribute. By doing this, we are learning all these new ways that antibodies get to mucosal sites and the brain that nobody knew about before.
Some other work that I am really excited about is that we are finding there are all these unique interactions between antibodies and mucins [glycoproteins] in mucus that can add to antibody function, and in some ways, even change the functions of the mucins.
We are excited about being able to contribute to HIV prevention.
So does that bode well for the antibody prophylaxis studies, perhaps?
I am excited about those studies. I have to admit, a few years ago I was less enthusiastic, but the system has gotten so good at producing these antibodies at lower costs and modifying the antibody with certain mutations that make the antibody persist for a long time. I think some of that work that has been going on for a while is really coming together nicely.
Speaking of the interaction between antibodies and mucus, it reminds me of how your lab creates some of the most stunning images of the virus. I never knew mucus could be so beautiful!
It is really fun to have these pictures of what we do because people can look at them and kind of get a sense of what is going on. Your average person can appreciate those pictures more than, say, a flow cytometry plot, or a bar graph, or something else abstract. With the pictures you can show them that the green dots are viruses and all of the sudden they can visualize what is going on. So it is a nice space to operate in.
Perhaps a gallery showing is in your future?
We have thought about it and we have been involved with some of those. They had a show at the American Society of Cell Biology and they sold the pictures for charity. We gave them about 10 of our pictures and they used them all and they sold them all. So we do that a little bit. It’s fun.
You are also training and collaborating with early career researchers in Kenya, one of whom we profile in this issue. What inspired you to establish those connections?
I think it is very important, and we have to do these things. It helps establish contacts and collaborations because they have local knowledge that is important. They can help us to get highly relevant samples. We haven’t progressed that far yet where we are worried about this, but if we make a vaccine, we want it to work in Africa, and in the US, and everywhere else, especially in places where there is more transmission occurring. And there are differences in these populations that we have to understand and address. So these kinds of international studies are really important in the long run. One of the things we are doing is just trying to compare mucosal environments between volunteers in the US and Nairobi, Kenya. We are also trying to transfer some of our technologies to Kenya, and one of the cool things is they just got a microscope like ours, so that is exciting.