Hello, I'm Chris Beyrer. I'm a professor of epidemiology at Johns Hopkins at the Bloomberg School of Public Health, and I'm here to talk to you today about PrEP, the state of the science. So why do we think pre-exposure prophylaxis is going to matter in the global and US response to HIV? We have to look at the current epidemiology of the epidemic to do that, we'll do that together. And then we're going to talk about PrEP, pre-exposure prophylaxis, as primary prevention, and then some of the efforts in preparing for coming PrEP access era. So In terms of the global pandemic, we have had almost 40 million deaths from AIDS, making it really the most severe infectious disease epidemic of modern times. Last year, in 2015, over a million people died of AIDS. There were about 37 to 38 million people living with HIV infection, and most importantly, if we're thinking about prevention, we had 2.1 million new infections. So that is a real problem. Less than half of people living with HIV were on therapy at the end of 2015. It's now about 18 million overall. But only 20 countries are implementing PrEP. Those include the US, which was the first country to do this, France, which has looked at intermittent PrEP. Only two countries in Africa so far, South Africa and Kenya, and then a few others. So the PrEP access era is really just beginning. When we look at what is happening with treatment coverage and with AIDS deaths, there's very good news. And that is basically that we've seen a steady increase in HIV treatment numbers. That's this curve. And that has been happening, coincidentally, with the decline in deaths from AIDS. So that is really wonderfully heartening news. But when we look at prevention, when we look at rates of new infection, things are not so encouraging. So what you have here is from the 2015 UNAIDS report looking at new HIV infections worldwide in the last five years, from 2010 to 2015. Some modest declines, but overall what you're seeing is basically incidence is flat. And in Eastern Europe and Central Asia, that's predominantly Russia, it's markedly increasing. When you put that all together and look at the global curve of the epidemic of new infections, this is a slide, actually from Tony Faucci, you can see there was a rising epidemic. Then a very encouraging decline, which led a lot of people to think that we were getting control of global HIV infections. But in the last five years, basically, new infections have been flat. And that is why we think if we really want to see a decline in new infections, we have to have new and more potent prevention technologies and certainly, one of those is PrEP. Now, PrEP has been considered really for people at high risk of HIV acquisition and exposure. And what that means in much of the world, and certainly what it means in the United States, is the key populations, the people who share two features. One is that they are the most likely In the population to acquire HIV. And the second is that they are the least likely to be receiving appropriate services. So that includes gay, bisexual, and other men who have sex with men. In the US, that population is the largest and represents the largest number of new HIV infections. Sex workers of all genders, people who inject drugs of all genders, transgender women who have sex with men, who are the most disproportionately burdened of any population worldwide. And then women and girls in the southern and eastern African hyper epidemic setting. And then people who are the uninfected sexual partners of people living with HIV across all kinds of relationships, heterosexual, same sex, male, and trans. And then of course, adolescents from all these communities. So adolescent men who have sex with men, adolescents who are injecting drugs, adolescent transgender women. When we look at the proportion of new infections worldwide that are occurring in key populations, we see that this is not just an issue of the US and Europe. This really is happening everywhere. This is a slide from the World Health Organization that's looking at the attributable fraction, the proportion of people, new HIV infections, in key populations, as a component of the overall epidemic. So you can see right away, for example, that in Africa, it's 43% of new infections are in key pops in Ghana, over a third in Nigeria, a third in Kenya. Even more so in Iran, this is mostly injection drug use. Look at China, more than half of new infections are in key populations. Most of that are men who have sex with men, and some injection drug users, the majority in Australia, 70% of new infections in the US. And when we look at that, this is data from the CDC, US Centers for Disease Control, it's up through the end of 2014. So it's the most current data that we have. What we see, which is very encouraging, is that heterosexual contact is in a slow decline. New infections among injection drug users are low and also declining. And the one component of the US epidemic that's still expanding is male to male sexual contact. And that is why we think we need PrEP. There's a great regional disparity to this epidemic and of course, an ethnic and racial one, unfortunately. So what you're looking at here is, again, recent data from the CDC, it's by region. You can see that the South is the most burdened region in the country. And this pink color is African American men who have sex with men. And you can see that they are enormously disproportionately burdened. So that's a huge public health challenge for us. And we think PrEP may play a role in helping to address it. So PrEP as primary prevention, and what do we mean by primary prevention? That's an epidemiologic term, and that means prevention before infection. So for example, reducing someone's viral load after they become infected has important secondary prevention benefits. But PrEP is about uninfected people staying HIV uninfected. So what did the data show? Well, this is a summary slide, and what it shows is most of the PrEP efficacy trials, and some effectiveness trials, that have been done. At the bottom here, in blue, is topical PrEP, by which we mean either vaginal or rectal use. So, not oral use of pre-exposure prophylaxis. And then here is oral. Most of these are trials with TRUVADA, which is the two-drug combination of tenofovir and emtricitabine. A few, like the Thai study in injection drug users, was actually done with tenofovir alone. Most of these are daily oral TRUVADA trials. The exception to that is the French IPERGAY trial, which was an on demand use of PrEP. A dose before sexual activity, right around the time of sexual activity, and two doses within 48 hours after. And what you can see here, this is the line of union. So anything that crosses this line was not Efficacious. Anything on this side of the line didn't work as protection at all. And if a dot with a bar is on this side of the line, there was efficacy. So the people on this arm were protected from HIV infection. These are the 95% confidence intervals, so that means that this is statistically significant. And, as you can see, IPERGAY, the PROUD study which was an effectiveness study of daily oral Truvada in gay men, men who have sex with men in the UK, the Partners study which looked at discordant couples in Kenya. So that's either men or women with an HIV uninfected sex partner and we're looking at the PrEP efficacy and the partner did not HIV. The partner study also looking at discordant couples, all of these show consistent, and very high efficacy 86, 86%, and so forth. Coming all the way down to the first trial that really showed efficacy, which was the Iprex trial, that was daily oral Truvada among men who have sex with men and transgender women. It showed 44% efficacy, but this was an intent to treat analysis. When you looked at people who actually had measurable drug levels onboard, the efficacy was much higher. And that's true of all of these. The Achilles heel of PrEP is adherence. When people are adherent, the efficacy looks way better than this, and it's well over 90% in most of these studies. So, iPrEx continued after the trial results in what was called the open label study. So this is, basically, after a trial which has been placebo-controlled and where people were randomized to drug or placebo, you then, if you show efficacy or obligated ethically to offer to intervention to everyone who was in the trial. So, what we're looking at here is basically, after the IPrEx trial everybody's still uninfected was offered PrEP. Now, we're following people going forward. And now they know that they're getting drug, they know that they're not getting placebo and they have been counseled that it works. And what you're looking at here is the analysis of the efficacy of the drug from a post-hoc perspective, so in other words, after informing people. And comparing that efficacy with the blood levels of drug. So, what you see is that there were very high infection rates, about 4.7 infections per 100 people per year. So that's a very high incidence if no drug was detected. So in other words, if these people offered PrEP didn't take it, they got no protection, and this was a very high risk population. People who had blood levels consistent with two tablets per week had some protection about 2.3%. So had about halved the incidence but still wasn't very good. If your blood levels were consistent with 2 to 3 tablets per week, it was again better 4 tablets or more. So if you're taking 4 or more doses a week, there were no infections, and that was very statistically robust. So what this data tells us is that PrEP really works, it worked spectacularly well If you take it. Insufficient use has some effect. And of course, if you don't take it at all, these were very high risk people. Now importantly, people always ask the question, well doesn't PrEP encourage unsafe sex? Isn't it more likely that these people will stop using condoms or have more receptive anal intercourse events. It turned out that condomless receptive anal intercourse, which is the thing that we're most worried about, actually fell across this trial, both for people on PrEP and people. And we think that that probably was a result of the counseling in the study, and the fact that people were provided free condoms. So at least at this point, there's no evidence of what is called behavioral disinhibition. The idea that PrEP is going to ramp up sexual risk taking. However, the authors did conclude, and I think this is an important point, now this is a direct quote from the paper, Bob Grant is the lead author, our study shows that uptake is high when barriers to PrEP supply is eliminated. So keep that in mind, uptake is good but we have to deal with the barriers. Then we had these data. This was last year in September, the lead story in the New York Times, which is basically the results of a very important study done by the Kaiser Family foundation. Now, this is important because this is actual world implementation, this is not a trial. But what happened here was that Kaiser had, it's an insurance provider of course, an HMO, about 650 people or so offered PrEP through their insurance system after PrEP was shown to be safe, and efficacious, and after FDA and CDC approval. What your looking at here, this is a paper by Jonathon Volk is about two and a half years of PrEP prescriptions. This was a very high risk group of people followed for 36 months. There were a number of person years of observation. They offered PrEP to everybody in their insurance system who met their risk criteria. But in fact, 99% of the people in this insurance system, and this is mostly data from Northern California, San Fransisco, but 99% were men who have sex with men, no new infections. So, that is absolutely spectacular, and these data from a real world. Clinical population of people meeting risk criteria and being offered prep by their providers, shows unusually, that the effectiveness of this intervention looks even better than the efficacy. That does not happen so often in medicine. These are data from Gilead Pharmaceuticals, this is the company that manufactures Truvada and has the patent for it in United States. And this is their prescription data through 2015, and this was presented at the International AIDS conference In Durban, South Africa last summer conference, full disclosure, that I was the international coach there for. And what you're seeing here, is that early on, there was a relatively slow uptake of PrEP and then there has been a real take off. A 700% increase or so, up to about 80,000 Americans now on PrEP. So that is really impressive, and that is very encouraging in terms of the PrEP era beginning. But keep in mind, the CDC's estimate of the number of people who meet risk criteria and should be offered PrEP in the United States is about 1.2 million. So when we look at that this is about 6% of the people who actually meet criteria for PrEP are on it and we are really just starting. Now, I think there's some important issues to think about when we think about the US epidemic and particularly, the severity of the epidemic in men who have sex with men of color, particularly African American and Latino men. This is the group with the highest rates of new infection and so far, anyway, the PrEP uptake in this population has been relatively low. And where we've had adherence data that has not been good. It's been a less than of other ethnicities and races, including white men in the US. So the HIV Prevention Trials Network, the HPTN really tried to address this with a very important study. This is HPTN 073 looking at uptake and use by black MSM in Washington, DC, Los Angeles and North Carolina. They had a relatively modest size, about 226 African American men who were HIV negative, who met risk criteria. About 92% completed the study. The adherence was about two-thirds. And you can see here that among men who accepted PrEP the incidence was much lower, still high but significantly lower, among men who declined PrEP, 7.7% became infected in the course of a year. That is an extraordinarily high rate of HIV infection. But the good news here is that the men who did accept PrEP, did rather well taking it. And this study really used a culturally competent four component behavior intervention that was designed by the investigators who were all African American gay men. Really this is the first study to be designed and led by a group of African American gay investigators and it really shows the importance of cultural competence in PrEP. And I want to also say that we're thinking about, and there's a lot of effort around PrEP potentially for another population at very high risk. And that is transgender women. Who had sex with men. So, who are we talking about? Transgender women who have sex with men are a population who are assigned male gender at birth. So, these are generally biological males at birth, but who express a female gender identity and have a female gender expression. So choosing to live as women and having an identity as transgendered women. This is a group that shares the biological risk of other men who have sex with men, because they very commonly engage in receptive anal intercourse. But also have a number of behavioral risks that are more like other women. So they end up being a very important risk group. There's very little data on PrEP for transgender women. And really, the only study where we have significant numbers of transgender women was that first trial, the iPrEx trial. Out of about 2,500 people, there was a subset who were transgender. And I won't go into details in the interests of time and the data, but just to say, unfortunately, that the uptake was relatively low. The adherence was very poor in this group. And there was no ability to see efficacy. So this did not work as well for transgender women as it did for other men who have sex with men. And so this is an area really of important research. Nevertheless, all these data taken together led to a very important new recommendation from the World Health Organization. And while we're on this slide I just would point out that this Bangkok to Tenofovir Study which did not look at Truvata but rather single drug. Tenofovir is the only PrEP trial we have in injection drug users. It's was in a large population of people who inject drugs in Thailand, men and women and this also showed efficacy. So the good news here is that PrEP does look like it works to prevent acquisitions and in injection drug users, and remember that these are people who typically have dual risks, they both have risks from injecting and needle sharing, but also sexual risks for HIV acquisition. So in 2015, the World Health Organization put out a new guidance. And this was a two part guidance on when to start anti viral therapy and when to use pre-exposure prophylaxis for HIV. And this is very important. In the US, we don't necessarily pay so much attention to WHO recommendations. We follow, CDC guidelines but in the rest of the world, this is absolutely critical to getting Ministries of Health to make change and reform. So the recommendation is that oral PrEP containing Tenofovir. Should be used as an additional prevention choice for people as substantial risk of HIV infection as part of combination HIV prevention approaches. Now when WHO makes a recommendation, they always state the strength of the recommendation, in this case strong. And the quality of the evidence, and in this case high quality evidence. So that's pretty much the gold standard, that's about as good as you're going to see. And that is one of the reasons why we really hope that PrEP now begins to be rolled out. Just to go back, if you look at this recommendation it says, people at substantial risk of HIV infection. So what does that mean? All 6 billion people on our planet or a relatively small number of people? WHO happily importantly did make a recommendation about what they mean by substantial risk. So it is provisionally defined as HIV incidence greater than 3 per 100 person years in the absence of PrEP. So if you remember from the study we looked at of African American MSM, the men who did not take PrEP had an incidence above seven. So immediately, you ask the question. Would African American men who have sex with men qualify, at least as a risk group for PrEP? And the answer is yes. Obviously, there is individual tailoring always. Not everybody in that demographic group is necessarily at risk. But, if you have an African American sexual active gay or bisexual man in your clinic, that is somebody to talk to about PrEP. Now, HIV incidents above three has also been found in addition to men who have sex with men in transgender woman, as we were saying, in heterosexual men and women who have a known HIV infected partner. Particularly, though through our untreated and not virally suppressed. So a number of populations really meet this criteria. Interestingly, if we look for example in Baltimore. Among injection drug users the rate of infection now is well under 1%. So injection drug users, at least the great majority of them in Baltimore would not meet this WHO criteria. So, what else can we say about PrEP? Well it's not just numbers, right. First of all, needs to be a risk assessment, particularly for gay and other MSM. Focus on that highest risk for HIV acquisition, and that is unprotected receptive anal intercourse, URAI. And we have to remember that when we say unprotected and for those of us who have been in this field a long time, unprotected is synonymous with condomless or it used to be. Now things are changing because unprotected doesn't only mean receptive anal intercourse without condoms. It can mean. PrEP, is protective. If we actually look at the data on the effectiveness of PrEP, and compare it to what we have on the effectiveness of condoms, which has never been done in a randomized trial, because it's not ethical to do so. PrEP has higher effectiveness than condoms. So when we say unprotected sex, do we mean without a condom or without PrEP? And when we say protected, do we mean both condoms and PrEP? Or just condoms or just PrEP? And that is a very important conversation that we need to have with each other. In public health, in clinical care, in science, in providing clinical services, but also with our clients and with our patients. The same is true about where we are with viral suppression. If HIV infected people are sustainably virally suppressed, is condom-less sex protected sex because it's protected by antiviral therapy? This was the Swiss statement from several years ago and it now is really a movement that people have embraced and including very highly regarded clinicians and scientists to say antiviral therapy is protective. So where are we now in thinking about prep for individuals, for people, for actual human beings? Well, we're starting to see some data on people's feelings and emotions and experiences of being on this new intervention. So I showed you the data from Gilead that Showed this extraordinary increase in up-tick. That up-tick really happened after 2013. So 2014, 15, 16, we really starting to see use increase. What are people reporting? Well, PrEP users report some important additional benefits. The first is feeling safer during sex. Having less anxiety, having less fear of HIV infection. For many gay men they report that, since they've been on PrEP, it's the first time in their adult lives that they've been able to have sexual encounters without the fear of HIV acquisition. People are reporting less HIV stigma. And for example, less concern about having sex with positive partners. So less of that division between infected and uninfected men. And maybe most importantly people are reporting stronger relationships. Not an undermining of relationships because of being able to have the sex you want, but stronger relationships because PrEP encourages conversations and more honesty before, during and after sex. That is an important part of, of course, all of our lives and of sexual health and emotional health. Insights from behavioral economics are helping us understand some of this a little better and it suggests that part of the reason why PrEP's additional benefits are strongly felt is because they have salience meaning they're relevant to people's lives and they are experienced in the present. That's important for reward. It's not some distant thing that this will keep me from HIV. It's that I can have sex now and be less afraid tonight today. And that's important from a behavioral economics perspective. People also reported is that it's empowering people to have greater control over their own HIV risk. Because remember, if you are taking PrEP, you don't have to compel your partner to do anything. They're not necessarily taking PrEP. There's less reliance on that insertive partner to use a condom or to take their ART or to accurately disclose their status. You are owning the prevention. And that also, of course, is important for women. This is a woman controlled intervention for the women who are taking it. They don't need male permission necessarily and they don't need to disclose. So that's very important in the gender dynamics of HIV prevention and, of course, that is relevant for cis women and trans women. So what about access? And what about where PrEP is happening? Well, we have a problem in the United States in particular. And that is, of course, that we have an Increasingly, a minority epidemic of HIV, an epidemic that is concentrating in the South, and an epidemic, unfortunately, that is concentrating in areas of the country where people have less access to healthcare. So this is from Aids View. Wonderful resource out of Emory University led by Patrick Sullivan. That does very careful granular looking at HIV burdens by county, in every county in the United States. And what you can see. The darker colors represent more infections, is that HIV is concentrating in the South. This is where it's concentrating. In the early years, it was a bi-coastal picture, but that is not what we see now. And of course, the areas that have not rolled out the Affordable Care Act and have not done Medicaid expansion is also much of the same area. So the people we want to protect the most, are the least likely to have access to PrEP. This, again, is looking at HIV disease burden and now just specifically at the Medicaid expansion states, those are these, and at the states that have not expanded Medicare, and you can see unfortunately we have a close to a perfect storm. A misalignment of where the epidemic is, and where people have access to health insurance and healthcare. So the PrEP era is really just beginning. Let's linger on that slide for a little longer. And we have an enormous task in front of us. If this new, potent intervention, and you've seen the efficacy now and the effectiveness of PrEP, is going to make a difference in the US epidemic and is going to make a difference globally, it's going to have to make a difference in this part of the country, and that means of course that folks who live here and who are at risk are going to have to have access to PrEP. Right now, that is limited, much too limited, and it's not having the public health and human impact that we would like to see. If this is a boutique intervention for wealthier segment of the population who have good insurance and good access to health care, it will not have the impact of controlling the US epidemic that we want to see. This is a very exciting time to be working in HIV prevention. In addition to PrEP, we have a number of other interventions in the pipeline and there are a number of adherence strategies out there, because as you remember what we said earlier, adherence is the Achilles heel of PrEP. How are we going to do better with that? So for example, there are a number of mobile apps that people are using to try and improve adherence. Next PrEP and others is looking at additional drugs for PrEP, the study looked at intermittent PrEP. It may be that the current recommendation of daily oral Truvada, or daily oral tenofovir containing regiments, is not a great fit for some people. They may be better off with an intermittent dosing, and also would be kidney sparing which is one of the concerns with PrEP. There's a great deal of work on the topical PrEP, the microbicides both vaginal and rectal, we just have a phase two trial MTN 017 of a rectum microbiside that could be use by men, women, and transgender women who practice anal intercourse. It was somewhat disappointing but this is an important are of research. There are a number of intravaginal products including impregnated rings that have shown consistent but low efficacy and so this is an area of tremendous effort right now. And then, of course, there are things like injectable, PrEP injectable ARVs. Also, antibody studies passive immune studies the amp trial that is underway right now and there are some new HIV vaccine products also out there, being investigated, big trial just opened in South Africa and so the future looks really bright for new prevention tools but I think the most important takeaway message is that. We already have one new one that is PrEPed. It works if you use it. And what we need to do now is really on PrEP access, adapting PrEP to the populations who need it the most, working hard on adolescents, on minority folks at risk for HIV. Now, transgender women who have sex with men, there is an enormous amount of work to be done in using this new intervention, and having it really help control HIV and protect our clients. Let me just end by thanking and acknowledging a number of people, my own group here at Johns Hopkins and collaborators here in the School of Nursing, Jason Farley, Stef Baral, Toni Poteat, a number of folks we're working with. But also colleagues who share data and slides, Patrick Sullivan at Emery, a number of others. And let me also thank the funders of this work, the Johns Hopkins Center for AIDS research, the Bill and Melinda Gates Foundation, amfAR, and these are all grants to the Center for Public Health and Human Rights of Johns Hopkins. Thank you for your attention.
