NIH CLINICAL CENTER GRAND ROUNDS
Episode 2009-009
Time: 1:02:40
Recorded March 11, 2009
CONTEMPORARY CLINICAL MEDICINE: GREAT TEACHERS
Prevention of Transmission of HIV-1: Clues from the Early 21st Century.
The speaker is Dr. Myron S. Cohen of the University of North Carolina at Chapel Hill School of Medicine.
ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future – this is NIH Clinical Center Grand Rounds.
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ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds. On this special "Contemporary Clinical Medicine: Great Teachers" Episode, we're pleased to present a discussion on the topic -- Prevention of Transmission of HIV-1: Clues from the Early 21st Century." Our speaker is Dr. Myron S. Cohen, from the University of North Carolina at Chapel Hill School of Medicine.
We take you to the Lippsett Ampitheater at the National Institutes of Health Clinical Center in Bethesda, Maryland, where Dr. John E. Bennett, chief of the in the Laboratory of Clinical Infectious Diseases at the National Institute of Allergy and Infectious Diseases at the NIH will introduce our speaker.
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BENNETT: It's my pleasure and privilege to introduce Dr. Myron Cohen. I have known him for so many years that I have to look at the slide to remind myself his name in Myron Cohen. He began his career at the University of Illinois where he obtained his bachelor of science graduating summa cum laude and phi beta kappa. He went on to Rush Medical College where he was elected to the Honor Society in his junior year which is another important honor. From there, he went to the University of Michigan for his medical residency and on to Yale University for his infectious disease fellowship. He then went to the University of North Carolina where he is now the distinguished professor of medicine and as well as a professor of public health and microbiology and immunology.
He has numerous other titles. He's associate -- let me get this right. Associate vice chancellor for medical affairs as well as the director of infectious disease division director of the Institute for Global Health and Infectious Disease and director of the Infectious Disease Center. His academic career has been largely centered around sexually transmitted diseases, and more recently HIV with more than 200 research publications and peer review journals plus numerous articles and book chapters in addition to that he has been elected to the American Society of Clinical Investigation and the Association of American Physicians as well as being a fellow in the American College of Physicians and the Infectious Disease Society of America. His topic today is “Transmission of HIV-1: Lessons Learned from the Earlier 21st Century.
COHEN: Thank You. I’m going to use slides so let's turn them on. I went to a lecture recently where somebody's Power Point slides didn't work and the guy said, if I don't use these slides, it's going to be powerless and pointless. So I don't know that there is an academic physician in the United States who could do this without slides. The historians can do it. But let me start out by saying I have no conflict of interest and nothing to disclose -- which is good. Except and I have support from the NIH my entire career made all the work I and my colleagues have been possible. Being here is a pleasure because it's like the mother ship for research. So I want to thank the intramural and extra-mural programs for their support.
The title is self evident. We'll talk about HIV infection. I talk really fast. So I apologize in advance and already this is faster than anybody from North Carolina could understand. So if you're from North Carolina, or Alabama, I really feel bad. But this is what is going to happen. It's going to be like a breathless discussion. So let me -- you see the issue is clues from the 21st century. I’m not at the fast track to anything. I have been working on one problem for 30 years, it's sexually transmitted diseases including HIV. This is a picture of me many, many years ago. For those students I met with this morning, life goes by and this is what I looked like 30 years ago when the first cases of HIV were being described.
The objectives of this talk are going to include some brief mention of the current epidemiology of the disease, biological factors that have gotten us where we are and then I’m going to discuss our prevention strategies in detail. I’m going to leave time for questions 5 minutes early. There is a red clock directing me to that event.
So where are we now? We have at least 33 million people affected. 80% are in Sub Saharan Africa. We have at least 16 million people die of this infection. So it's consequences are in describable, really. The U.S. has a problem at least a million people infected and probably about 60,000 new cases a year. And this is not equally distributed. Washington, DC, of course, is very heavily hit by this and as you know, from the newspapers, urban Washington might have an HIV prevalence in some populations comparable to sub Saharan African countries and that's true of New York and urban areas. We have a fairly potent epidemic in the rural southeast as well this. Still remains in the United States an epidemic to some extent focused on men having sex with men but increasingly women of color are affected by this epidemic.
Where is HIV going? It's going to stay in Africa. One reason I use this is, I didn't anticipate -- I know for sure I didn't anticipate when I started out working on this problem for 30 years. My old friend and I talked about granular sites, part of the whole mix. You get caught up in a problem and it's going to go for a generation if not several. The time frames do become important. HIV will not leave Africa in my lifetime and probably not the student's lifetime. India has a very large epidemic but surveillance is very poor. So it's unclear how big it is. China has a big epidemic and the surveillance is poor. There are several million cases in China and China declared recently to my surprise, that death from HIV is the number 1 cause of death from infectious diseases in China. This is still a developing countries country that has a lost rural areas. To admit this in a country where HIV treatment is free, is pretty potent acknowledgement. And then Russia has a gigantic epidemic fueled by intravenous drug usage which is very, very popular in cities in Russia. This may go other places but we don't know where.
How did we get here? This is what I really worked on mostly. There is a -- how many are familiar with this formula? How many have never seen this? I knew the truthful answer would be helpful. This really simple formula is very instructive. Beta is efficiency. Infectious agents have to go from one person to another. What is the probability at the will occur? It varies with different agents. D is duration of infectiousness. How long does something remain contagious? For most infectious diseases D is pretty short. People have a window of infection. They transmit or don't and then it's gone. For HIV the duration of infection is very long helping it drive the epidemic and C is the number of people exposed and in HIV this is a volitional number. You have to be in a situation where you're exposed at the right moment in time to the right person. So it's counter-intuitive in a way.
How many saw the movie, Outbreak with Renee Russo? Remember she and Dustin Hoffman were confronting a virus that was going to kill the entire species. The reason the species survived is because they got in the helicopter with the vaccine they made while getting remarried. They got remarried, fixed the problems in the relationship and made a vaccine in a very short period of time and saved the species. The problem is, the agent that they were describing, it kills the host too quickly to sustain a gigantic epidemic so D becomes too short and beta is probably too inefficient. So, these are the numbers we have to worry about. We are trying to get row less than one to implode the epidemic. So we have to focus on bait a how do you calculate beta? How infectious is somebody? That's clearly determined by the concentration of the virus. Not the concentration in blood for sexual transmission but the concentration in general secretions and genotypic and phenotypic factors that make one virus more contagious than another. The different viruses are not all the same in their ability to go from one to another. Then susceptibility is not uniform. Some people have hereditary resistance. Some people have innate resistance is some people have acquired resistance. But acquired is very, very rare.
So this is what this looks like. So here is semen. If you're looking at sexual transmission and cellular virus and free virus in the semen and then it has to get through a lot of barriers to find a cell that will accept HIV. That cell has to have receptors cd4, dc sign and maybe a few others. Ccr5 is really critically important. So the virus uses its envelope to find the r5 cell and a transmission event occurred. If you put semen in a vagina of a macaque, this can occur in 30 minutes. The window of opportunity for prevention is some settings is very small. Once a cell is infected, the virus will be handed off to other cell types with the right receptors and then the person is HIV infected. 99% of the time, in a swarm of virus, the virus can use lymphocytes or macrophages. But the transmitted virus will use a macrophage. It's called the r5 virus and what it's so heavily preferred is still not determined.
There are strong genetic influences. That ccr5 receptor can have a deletion in a particular place. If have you that deletion, you're subs susceptible to HIV. So the density and polymorphisms can increase or decrease the probability you will acquire HIV. If you occupy the receptor, it's possible you had be less susceptible. A guy tried to do studies that are debated about receptor occupancy. So the ligands if they occupy the cells, maybe they will be less susceptible. Then there are responses that are know are compatible. For infectiousness, there is a lot of genetic work that controls viral peak and viral set point and we know 3 genes affect viral set point. So that's a very hot area in HIV.
So genetics affects the transmission. But the one thing we are pretty sure of is shown on this slide. The probability of a transmission event. If you look at the concentration of HIV in men and try to predict the probability, if you get too few copies, transmission probably won't occur. If the copy number increases, the transmission event achieves much high are number. HIV transmission is not homogeneous, it's heterogeneous and time. Can you understand me at this the rate of speed? I’m going to talk faster. [laughter] So, this is from a recent study about the transmission event. So I talked about the idea that the concentration of virus makes a big difference and then we see 9 the transmission event and then we see a swarm of virus shown? Green. And most of those viral copies and the swarm is huge. It is 100,000 copies. Many of the copies are defective. But some are healthy. When transmission occurs for reasons we don't understand, 82% of the time, only one virus causes transmission. So many viruses could cause transmission but one has caused transmission. We don't understand the bottleneck. What is special about that one virus? Why does that one cause transmission? When multiple viruses cause transmission, it's 2-3 viruses and they are not equally -- there is a -- they are linked together in a particular way.
We recently looked -- this is sexual transmission in a paper. We looked at intravenous drug users because we thought it would look different. We looked at 10 so far. And those 10, 8-10 had one variant and all the viruses were using the r5 receptor. This is preliminary data but there is something special about the r5 and about restrictions of how many viruses either restriction or elimination of all the other viruses. And we need to understand this to be successful. Now, this looks a lot different if you look at it from an epidemiologist point of view. There is a route of exposure and then the probability of a transmission event this. Is a blunt view. Mom to baby, about 30% chance unless you intervene with drugs. The epidemiology is easy because you have the mom and the baby. Needle sticks in blood. High risk, very easy to determine. You have the needle or the unit of blood and you have the person who or might get HIV. But sexual transmission is much harder to understand. Because you have to ask people about their sex lives and they don't necessarily tell you the truth. That's a big problem.
So the transmission probabilities in this article that I was part of in 97, this can't be right. We don't believe that it takes hundreds if not thousands of episodes of intercourse for a transmission event to occur would make you think this is very inefficient. But then how would you get an epidemic with 33 million people infected? I need to resolve the tension between myself. Having written this article I don't think is right, I’m sorry. And now what do I think is right? The other point is anal intercourse. It's not really male to male transition. It is when anal intercourse is involved. It's very efficient. The rectum has a lot of cells that can receive HIV. So this is a very efficient event. These events we need to get under the hood a little bit. This is a national study in South Africa in boys and girls at different ages and the prevalence of HIV. And when you look at a 15-year-old population there is a low prevalence in boys and girls. But as time goes by, by the time a girl gets to be 21, just about anywhere in sub Saharan Africa, she had about a 30% chance of acquiring HIV. 1-3. That's like unbelievable if that was going on in the United States everything would stop. Now, when you interview these girls, and you say how did you acquire HIV at this kind of rate? They don't have more episodes of intercourse than American girls. They don't have anal intercourse, by their history. They are doing nothing different than American girls. There is something we really don't understand about South Africa. Certainly we know these girls are more likely to run into a man who is HIV infected. A girl in the United States has a 1-10,000 chance of having unprotected intercourse or less with a man who is infected. A girl in South Africa probably has a 5-10% chance.
When you look at the age these girls are having sex with, it doesn't pan out. These girls say they have sex with men 4 years older than they are. That's the same number we see in the United States. So, there is something we don't understand about this very devastating point that we really need to understand in our lifetimes. So one of the hypothesis that is very popular I think is true is that infectiousness and susceptibility are variable, they are heterogeneous.
So for infectiousness, the stage of disease makes a big difference. I'll show you a slide in a second. General track changes make a difference. Genetic factors make a difference. For susceptibility, there are factors that affect that and among the STD universe, the factor that attracted the greatest attention is HSV infection. It sets the stage for a person to be more susceptible. There is a study just published today which is an excellent study, and he very carefully looks at acquisition of HIV and he argues that about 20% of HIV acquisition can be ascribed to chronic or acute HSV infection. This doesn't mean we'll be able to deal with HSV. We are talking about HSV2. Jeff is in the first row trying to make a vaccine. A applaud that effort. This contribution to HIV is really important.
So the way this looks is like this, here is what we think it looks like. Somebody is minding their own business and they don't have HIV and then they get acute HIV. There is unrestrained replication of HIV in the blood and in the genital tract. These are the copy numbers of HIV measured. Billions of copies. So the transmission probability isn't 1-3,000 when you have billions of copies. The transmission probability is 1-10. 1-20, 1-30 without anal intercourse. Then, viremia is lowered. This imaginary red line is so low that this person is no longer contagious. But most people achieve a set point that renders them still contagious and then the person goes on with their life unaware that they have HIV infection. They still are sexually active. They get another STD and then they become more contagious again. So they have windows of hypercontagiousness and intermittent contagiousness and during the intermittent we expect them to transmit HIV more efficiently. And the cofactors play a role. You might have gonorrhea and HIV. So when you have gonorrhea you will give the next person gonorrhea. And then that next person will become susceptible to HIV much more than if they hadn't gotten gonorrhea. If a man has sex with a woman who is uninfected with gonorrhea, he has an 80% chance of giving the woman gonorrhea in 80% of intercourse. 50% of women with gonorrhea are not symptomatic. The man with HIV gets gonorrhea and then becomes more containing us and helps to drive the epidemic. People with AIDS don't know they have AIDS oftentimes early on. They have much more viremia and more contagious again. So we think that anywhere from 8-40% of all the HIV transmission events occur from people with acute infection. This is going to be important when we talk about prevention. Because people with acute infection are generally invisible. So they are invisible.
How can you do prevention on somebody invisible? Then the rest of the transmission events, about another 20-30% must come from people with AIDS and the rest comes from people in the middle. This is from work that shows you numbers. These are people with the established HIV and this is the HIV RNA in blood and this is the number. A lot of copies. 150,000 copies, higher than the United States. This is blood of people with acute infection. The median copy number is more than a million. This guy has 2.5 billion copies of HIV. And so you can imagine that these people are very contagious. Let me just put in a plug real quickly for global health. We work in Malawi for more than 20 years. And the point is you can make a lot of discoveries working in resource constrained countries much more quickly than you might be able to do in the United States. We have a clinic where we see 100 patients a day and half of the people are HIV infected. So you have STDs and also HIV infection. So this is the called the center where we see patients. We help with another clinic, called the lighthouse where we manage 10,000 people with HIV. This is our research center. These are the labs. There are 4 pods labs that make it possible to do this work in Africa that translates to discoveries that are important in the United States and our service function is important. This is a library we helped to build. And this is the UNC home page. It's a virtual library. You can get any article at UNC off the web from the UNC. And there is a full-time librarian with a uniform. If you're a basketball fan, you know everything is about this Carolina blue color and this librarian wears this uniform to show she is getting her salary from this service function. I want to put a plug in for global activities not independent of discoveries. That help the entire species.
This is not going to be exhaustive. We only have 50 minutes. I would argue there are 4 times or windows of opportunity to intervene. We are at a cross roads of a massive number of people with HIV infection and we have seen the full spectrum of this catastrophe being played out. So we have no option but to try to intervene. There are 4 windows of time.
First, we spent most of our time, not most of our money, but time, trying to keep HIV-negative. The unexposed person should not become exposed and to do that we had massive campaigns worldwide. The abstinence, behavior change and condom programs. Needle exchange programs. All are designed to keep you from getting exposed. Or keep you healthy at the time of exposure so you don't have an STD so you won't acquire HIV readily. We know that these things make a contribution. We know abstinence works but it's really hard to keep people abstinent forever and sometimes you think you're in an abstinent or a monogamous relationship, you might learn you're not. Concordancy is problematic in Africa where there is a couple where the woman is monogamous with the man and wants to have a baby. But the man is not monogamous and the man is HIV infected. Discordant couples play a substantial role in driving the epidemic when these transmission events occurs. We know male and female barriers work. Condoms are reversible. When they are used properly they work great. The problem is to get people to use them 100% of the time and properly. That doesn't work if you're in a couple trying to have a baby.
Circumcision works. It's a barrier where the removal of the foreskin reduces the probability of an HIV transmission event by 60%, maybe 70%. But it takes some real -- you're not going to get circumcised -- you don't go to a bar, meet somebody and decide circumcision a really good -- it might be too late at the moment of the meeting to decide it might be a good idea. If you're circumcised, congratulations. If not, it takes a lot of action to become circumcised.
Now the trials are obviously not double blinded but they are very compelling. And they are over and circumcision works always the question is, can we circumcise our way out of the epidemic. Will the Chinese and Indians go for this? Can we circumcise enough African men to make a difference? Many models have been done. Circumcision is going to be more popular. What role is it going to may in the long run, I can't say.
What about the STDs? It's the debate. There are 7 trials to try to treat STDs so the people who have been treated have been rendered STD negative and should be less susceptible. Own -- only one trial may aid -- made a difference. Either they don't amplify HIV transmission but I’m 100% sure they do amplify HIV transmission. So the more logical conclusion is that the interventions are inadequate. You have to treat just the right STDs at just the right time in just the right people with very effective drugs for the right direction of time. This is very hard to achieve. So NIH sponsored a very large study called -- I’m looking at the program officer with my eyes right now and in that trial, they were trying to give people herpes treatment for people who were HIV-negative to show that they could prevent HIV acquisition. And they gave this drug but what they learned is that it wasn't as potent as we thought. It doesn't suppress inflammation, and we learn that some of the people weren't taking the pill at all. And these are problems with doing the trial prevention for STDs. So they are really important. There is tremendous benefit to treating STDs but to treat STDs to end the HIV epidemic is unlikely. It's all in your court. We need that vaccine to make some difference.
There is a trial ongoing. And I think it will be an important vaccine to make but the challenge is very great. So the next moment in time is the moment of exposure. So now you told your children and your patients, don't get exposed. Don't get exposed. But then, they are going to get exposed. And this is the window of time that you don't want to confront. So here is what happens. So there is HIV-negative person and they are exposed and a transmission event curse and there is a window where the -- occurs -- is invisible. And then there is a ramp up viremia and the virus becomes visible and during ramp up viremia, the problem is some of the viral particles integrate into the cells and form a latent pool. We know how to get rid of all other pools of HIV and replicating cells and in all compartments of the body, we can deal with HIV replicating. What we can't deal with is the latent pool. What renders HIV incurable disease is this pool.
Now the NIH is about to have an RFA. There was a science article by a consortium of people arguing we must work on the latent pool. That's the way to cure HIV. And I believe NIH -- I don't want to speak for NIH but I think they have been soliciting information about how would we attack this problem. And so I think in the next generation of scientists, they will work on the latent pool and I think they will make a contribution. So the latent pool grows and grows and grows and the host kicks in in mystical ways we don't understand but I'll get back to that, and then there is a set point. If you have a high set point, you live a much shorter life and you're more contagious f you have a low set point, you live a long life and you're much more contagious. Sought set point is important. About 18% of the set point can be determined by genes. And we don't know what the genes do but we know the probability plays a role. Those genes make a big difference in where the set point is. And to understand those genes is a very important topic.
Now, what happens is, that is bad, one bad thing is the pool and the integration of the virus. The second bad thing is when the host sees the virus, the virus is confronted by cda t-cells. And those cells, their goal is to eliminate the virus. But it's the very rare time in just the right genetic background where the cda t-cells force the virus down a pathway where its replication unfit. Most of the host, the vast majority, the cda t-cells fail. And we have a paper coming out in JEM that shows what happens is you can see escape mutants when you sequence the virus. You look at the cells week by week after acute infection and you see the virus escaping. And the virus escapes -- this is at Oxford.
So you see the virus escaping and once it escaped you're going to have mutation that is will keep going and going and you're not going to control the virus without antiviral drugs. Neutralizing antibodies form very late and don't play much of a role in any of these event and not a lot of hope in the role of neutralizing antibodies in what we are talking about. I couldn't come here – Jeff Cohen said don't come here without a sequence slide. Here a sequence slide to show you can do this. You are sequencing one gene at a time and now we're looking at the semen. And 3 things can happen in the semen. You can have equilibration or you can have compartmentalization where they take off in different directions or what only happens in the semen, you can have amplification. What happens here is that it never happens in the blood. The compartment is small. Target cells are small in number and you get one virus replicated over and over and over again. This has only been reported in semen.
So the moment of time I described, that's the transmission event. The goal of the prevention field is to stop the transmission event. So here is your option. You can modify innate immunity. We don't know how to do that. That's a hot topic. Somebody is studying innate immunity and if we know how to modify that, that would be good. We could make a vaccine. Only two ways to do it, neutralizing antibodies, there a search for those by the gates foundation and the NIH organization and then there is cell immediated immunity. And then there is antiviral therapy. Okay, the vaccine strategy, this is what we like to do. This is one I have already showed you. Exposure, infection, set point. But if we made a vaccine that put neutralizing antibodies in the vagina and the male genital tract, they would never get HIV because the antibodies would be so protective to cause sterilizing immunity. We don't know how to do this but this is a big challenge. And labs -- two different consortiums are trying very hard to find broad neutralizing antibodies and develop a strategy to make those effective in reality. What most energy has been spent on is the ctl response and that idea is simple. If we could blunt ramp up viremia, the host might be healthier. And if we could blunt ramp up viremia, then maybe the person's peak viral load would be so low they wouldn't affect the next person.
So massive efforts have gone forward to develop vaccines that would have a prepared host with a ctl response that would essentially do what is on this slide, blunted, peak and set point. And there was a lot of support for this idea and still is because of work showing here are animals that have gotten a vaccine and the red is like the unvaccinated animal. The blue is the vaccinated animal and some of the animals have a reduced peek and a reduced set point. Unfortunately this is not sustained but it's hopeful. So the step trial used this model to go forward to test a vaccine and the step trial failed to make a vaccine that offered protection from HIV. So a lot of different reasons there is not time to talk about right now. But the conclusion from this shouldn't be frustration.
So I want to make an uplifting point. We learned a lot from this clinical trial. We were missing key elements necessary for a vaccine to work. And I don't think -- my conclusion is, we absolutely have no choice but to continue to develop the science required for HIV vaccine. If it takes 1,000 years, this needs to go forward. That's my first point. My second point is that this year, the last 2-3 years, there’s a tremendous number of new ideas about the number of cells necessary and their quality and what they need to do to control peak and set point viremia. This information ought to help advise the next generation of vaccines. I’m not saying we have a vaccine made that uses all the information we have learned, but the work of Bruce Walker's group shows you two dichotomies, which Walker's group shows that ctl response can be very effective in the right hla background and Andrews show you what escape looks like. It's potent thinking through the problem. I get to work with this group and it's been a very successful collaboration and done a lot of work not to make a vaccine but to enable the development of vaccines. So I thank NIH for their support for this kind of vaccine effort. So the next idea is about antiviral treatment.
So vaccines for HIV we don't know how to make but we know how to make antiviral drugs. We started out with one drug in 88. We now have 22 drugs and the 22 drugs are really affect itch. So I’m going to talk about how these drugs are being used to prevent HIV. So we have 3 options. Treatment of the infected person, preexposure prophylaxis and post exposure. These are 44 monkeys living in Atlanta. They are exposed to HIV rectally every week. And if you don't -- if you do nothing all the monkeys get infected over one or two weeks. But if you give them daily antivirals, you prevent them from getting infected. Now it's given every day, not really pre-exposure but really pre- and post-exposure. And if you give them a high dose of injectables none get infected. These 44 monkeys led to a massive effort. The massive effort is shown on this slide. These 44 monkeys are powerful.
There are all these trials of antiviral drugs all over the world. Some with this alone. Most with ftc. We'll get to gels in a second. There are 21,000 people enrolled in clinical trials decide to prove that pre-exposure prophylaxis will prevent an HIV transmission event. Some are supported by the NIH, and some by the CDC and the first trial results should be available in 2010. Most people think based on the monkeys, this will work and there will be pills available to prevent HIV. The problem is how will we employ those pills? Who will take the pills? How will reemploy these pills? And will there be complications we don't recognize? We are excited about ccr5. R5 transmission. This is work from my colleague where she gives a human the r5 blocker and then measures the concentration in blood plasma and surgical fluid and vaginal tissue and you see this stuff gets there very active supply it stays in the vaginal fluids for 3 days. And it stays in the blood for 3 days and you can find it in the tissue for more than a day. So this is potentially a really important adjunctive drug it to prevent HIV transmission event.
Now Pfizer has not been wild about making this available for a whole bunch of reasons. But we see there will be drugs using our -- r5 blockers. There are others coming along. We see there will be r5 blockers as part of this discussion. Because r5 transmission has been so popular. One danger is that we'll start seeing x4 transmission, that we haven't seen yet. Now, the other alternative is gels. So these are the antiviral drugs in a gel formulation. Here is the same atlanta monkeys, they are different but they live with them. These monkeys get HIV and it's a nadvantage mall model. They get this in a vaginal model if you put this the gel in you get complete protection from HIV transmission. That's acquisition. This is incredibly important for the microbicide field. That field is vibrant and here say list of a lot of different drugs being used and I would just say two worse about -- words about this. First, a drug that's not an antiviral called pro 2,000 works. It caused about a 30% reduction in HIV acquisition in women and in women who didn't use condoms who wanted to get pregnant, 80% protection. Not published yet. And in addition, these women had healthy babies. 650 live births during the use of this stuff. Now, because people are so excited about antivirals, they are not very excited about pro 2,000 and another study is going on that will be ready in november. But if the second study is finished, I would think this could become potentially really important.
The other trials are mostly using antivirals, especially this drug and those can be put in a ring that sits in a woman's cervix for a month and the stuff is soily leached out of the ring. So this topical antiviral approach is likely to be effective. The rings are likely to work.. And so there is a lot of excitement and enthusiasm in the prevention field saying, we know how to make antivirals. We know they are really important and they are going to do something to these infectious events. The thing is, we don't understand the public health implications yet but I'll be shocked if we don't have positive results from these trials there. A trial going on right now in South Africa of the gel interrupted that will be ready pretty soon. So what if you didn't have a vaccine and you didn't take pre-exposure prophylaxis? What do you do then? That's post-exposure. That's pretty state forward. We can't do a clinical trial to prove it works for a variety of reasons. If you're going to use post exposure prophylaxis, it's a big emergency and you need 28 days. Failure occurs if you delay therapy and especially after rectal intercourse and our biggest problem with post exposure prophylaxis is health care workers don't know enough about it. They are not sure how many days they should wait. So we have a campaign to make health care worker aware of the urgency of starting post exposure prophylaxis there. Is a website devoted to this. You're looking at how the exposure occurred isn't significant.
You always want to start therapy within 72 hours and then you try and get more information and if you decide exposure is negligible stop. If you decide it's significant, you go forward and you give 28 days of therapy. People who have been traumatized and raped, that's not the place to discuss efficacy data. You start the stuff front loading and then make a decision later about are you going to continue for the full 28 days or stop? It's a very special time and we need a lot more effort to make sure people who need this get it. In the US, this is a modest problem. In South Africa there is a rape every 7 minutes. So to deal with this Africa really quite important.
So the real 900 pound guerrilla, the whole discussion is about treatment. And the question is, does treating HIV -- if you treat somebody with HIV infection, do you render them less contagious? And that is a topic worthy of great discussion. Because it bee lies the idea that we should try to treat our way out of the epidemic and the question is, what is the evidence to support that? In any way feasible? So the first idea is transmission events themselves. You can't treat your way out of the epidemic if you're not treating people. What percentage of people in the United States who are HIV infected know they are? Less than half, probably. What percentage of people in South Africa who are HIV infected know they are HIV infected? 12%. So, we have a situation where we 29 have very good drugs and really easy to do tests to take two minutes but most people have not been tested. And the problem there is very straightforward. There is discord in couples where there is ongoing transmission in the couple and it is couples have never been tested and it's a disaster. So there is a door-to-door household study in Kenya and Uganda screening hundreds and thousands of people and they find a lot of people with unrecognized infection as you expect, and within those people, they -- within those index case, they fine find a lot of partners who are negative.
One of the big misconceptions is if you have HIV infection, you're partner has it. You ask an African person, they don't want to get tested. They say, of course I have it, I have sex with my partner. About half the time there will be a discord in partnership ongoing. So transmission from couples, transmission who don't know their status, testing critical. This is from a CDC study where they looked at the transmission from people aware of there their status and unaware. So aware of infection if you look at the people unaware of their infection, they accounted for more than half or expected to account for more than half of the new infection. So not testing people, people not knowing their status further contributes to the HIV pandemic. This is my only animated slide and I’m very proud of it. See how everything is moving? This could get your attention because of the mass movement. So this is like a risk pyramid and the deal is this, I think most people would accept that acute infection is very contagious. But the duration of time during which your semen has increased HIV is 12-13 weeks. So the question is, how much can you contribute to the HIV pandemic with that window of time? As I said, in one study it was argued it was 7% of all the cases. In another it was argued it was 43% of all the cases. At some range. But it's important. But the most important group must be the 30 million people with HIV infection not on treatment who don't know their status. And if we can't test those 30 million people, there is no way to intervene with anything if we don't know they are HIV infected. So Frasier modeled this over and over again. No matter how many times, it's always the same. People with HIV infection that don't know their status are most important.
Now the question we have to ask as scientists is, what about the 2 1/2 million people receiving antiviral therapy? Are they less contagious? A fellow of mine led the Swiss in a declaration and the Swiss declared these people are not contagious. And the conclusion of that declaration was, I'll show you the basis for that. The conclusion came from this kind of thinking. The first conclusion came from biological plausibility. Many like this have been done. If you look at semen before you start antiretroviral therapy you can find HIV there. Some of the drugs concentrate in the semen and then you have trouble finding it once you start the therapy. This is one person out of 114 people on one occasion. But people might shed HIV and their cells are always infected. You didn't cure anybody, you just concentrated the antiviral in the secretion. But this kind of biological plausibility helps people to believe that you're rendered less contagious. And you suppressed the blood viremia.
So our goal now is to have unmeasurable copy number in the blood. If you have 50 copies in the blood and you have this kind of data, this person is no longer contagious. So this declaration was made and it attracted a lot of attention and a lot of argument. That led to them further looking around. You can look at retrospective studies and they say when you treat people, the index case, their partners are less likely to get infected. And then these studies say if we are following a couple where one person is infected and the other person isn't, and we treat the infected person and follow them for two years. No randomized control. We don't see transmission events. In those two years, we stop transmission. But the problem that I would emphasize is, we don't know what happens after two years. So we might have two years of benefit and then 5 subsequent years of resistance transmission. If you see my point.
So this short-term observational studies are a problem. Then population studies arguing that a population benefitted or didn't benefit from the population receiving a lot of antiviral drugs. So, this plausibility study, plus all this stuff renders us concerned that we might have to treat or might treat our way out of the epidemic. So NIH is supporting a large trial that I’m involved with. This is in 9 countries that ask two questions. Is it good to start antiviral therapy earlier than higher cd4 cell count? So they start at 350-550 cell points. Are they benefitting something we think they will. And then everybody gets therapy when the cd4 cell. The trial is the about the couple. You're enrolling 1,700 couples and the end point is the partner not the person receiving the drugs. So give the drugs to the patient. You follow the partner and you say, if this really works, the partner will not get HIV and this study is powered to see a 30% difference in the couples. The study goes on for 5 years or 6 years. It's going on so long to make sure you get a durable benefit. The study is you're measuring viral load every few months. So if the patients aren't taking their drugs you'll know it because their virus will go up and you'll see whether it escaped from the drugs or from not taking their pills. We think this is a pivotal study in proving a belief system. I can tell you there is a belief that this works. So much believe that people don't want the trial results. And this comes up in utopian modeling. So make a model where you can make almost anything happen if you have the right assumptions. And I think that this model in Atlanta is ultimate utopia.
Test everybody in Africa today. Treat everybody right now regardless of their cd4 counts. No for rationing of drugs and the epidemic will go away by 2020. If this really happened and the model is correct, treatment is the solution to the epidemic. But obviously, you can see all the problems. We don't have enough drugs, not enough personnel, we don't know how to find the patients. But there is a summit meeting that we will go to it who to discuss this model and strengths and weaknesses on May 5. And I think you'll see this in the newspapers a lot and it's called test and treat. It's a movement to stop rationing, stop thinking about it. Just do it. I’m ambivalent having worked on this for 30 years, it's like, okay, on the one hand I believe this is true. On the other hand, I think it's really important to prove it. Because if we are wrong, and we put the species awash in drugs and it will take a long time to take a step back. Are the assumptions realistic? Can we accomplish this? So the big challenge now ending on time, the big challenge now t we had tremendous HIV treatment success. 22 antiretroviral agents available and two million people -- probably 3 million receiving HIV therapy but 7 million more need therapy today even when you ration the drugs for cd4 count. HIV prevention lags behind treatment. And HIV prevention is never treatment except in moms and babies.
The biggest success is the mom/baby story. One reason the mom/baby story was so successful to prevent transmission is that the physicians and health care workers bought into this instantly. There was one community, a treatment community and a prevention community and they were in the same community. But in the United States and other countries, the treatment community is different than the prevention community and I don't think we can really succeed unless we marry these communities.
Lastly, I'll end with what is next? So here is a prediction. What you're going to see in the next little while. First of all, transmission of HIV, we're going to understand this better and better and better with more details, especially in drug users. That's a group that hasn't been studied. We can't really make a vaccine unless it prevents drug born and sexual transmission. We are going to see tremendous attack of the latent pool. I anticipate big grants to deal with this both from gates and NIH and others. From prevention of HIV- if pro 2,000 second study works, that should be rendered available to women now. You have hundreds of thousands of women in Africa wanting to give birth who don't have anything to do to prevent the acquiring HIV because the partner won't get tested but the women could start using pro 2,000 and they like it. They found it desirable. I don't know why. I am not a woman but the point is, that women in this study like the pro 2,000.
For treatment of HSV2, I told you about 039. It didn't work. There is another trial to treat an index case and that result will be made available in July. One of the problems -- they treated discordant couples, HSV. The problem is this has a real antiretroviral affect so the benefit may be an antiretroviral affect as much as a herpes benefit. This will be announced July 16. We have the prep trial and the first results in 2010 if we are lucky. We have microbicide trial in 2010 in we are lucky and we have earliest results in 2010 if we are lucky.
And then we have NIH commit to more vaccine trials including a trial that I think is scheduled to go forward at some way in the future. This is an epidemic that has gone on for a very long time. But for infectious disease specialists, Legionnaires disease and SARS and these other things, we dealt with them for a short period of time and they were really a big deal and they were gone. HIV came along and it was really a big deal and it's not gone and it's not going away. But I do think that now at this point in time, there are real -- it's a really exciting moment in time to do HIV research in treatment and prevention and in trying to cure the infection. I thank you the NIH for all their support for all the investigators for all these years and thank you for listening to this and i'll answer any questions. Thank you. [applause] And I’m like that was like no oxygen. Like basically I need to be hospitalized now. I need to be admitted right now. Questions?
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COHEN: Jack's point is this is a total mess. We don't have enough money for anything. What is the affect on antiretroviral availability. I think it's going to be bad. I think it's going to get harder and harder to get sufficient drugs in. One of the students asked me this morning, what are we going to do? We are putting so many people awash in pills that they are going to take forever and the pills aren't free. And who is going it pay for this? Right now America is paying for 2/3 of the global HIV treatment and care. In other words, it's our tax dollars through programs that we are paying for this and we are broke. But on the other hand -- we are very broke. But to not deal with this allows massive spread of the disease. For every person we treat, 6 more people get infected. If we do nothing at all today, there is going to be 100 million people with this infection in 10 years. So we really have an emergent -- and if treatment does act as prevention, which it probably does, it becomes important to find people and treat them. So I think we are weighing pay now or pay mass amounts later. And the pay later is not about our paying. It's about disruptions of society. It's about like Russia and other places getting incredibly messy because too many people die of HIV.
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COHEN: So this young lady is saying, this is not a good idea to treat everybody. You're going to Geneva with me. What are you doing on May 5? She is saying, this sounds good but what are you going to do about the cost? What about 20-30 years of therapy? Is this durable? What about the toxicity and people who aren't adherent and then resistant and then it files your whole population which we know is possible. Excellent question. I agree. That's why we are doing this to understand the benefit and the toxicity.
QUESTION: Wonderful talk. Thank you very much. My question has to do the discordant couple trial and the question of the ethics of not treating the uninfected participant in an era when these prophylactic drugs may show efficacy.
COHEN: I’m going to repeat the question. He is saying, what is your obligation -- and the situation comes up not in frequently. When we council the people, we have couples counseling. We don't say welcome to our study, please have unprotected intercourse. We say welcome to our study, use condoms every time. And don't get pregnant. 39 and don't get this disease. So the power calculations are way, way down. Like it's empowered to see very few -- 88 transmission events over 5 years in almost 2,000 couples. That's very few transmission events. However, what can happen is what about post exposure – pre-exposure is probably not something that would be appropriate for the partner except under very special circumstances. For example this comes up with the partners who wants to get pregnant and the physician says if you don't want to get HIV, we'll treat you and your partner and we'll let you get pregnant. But the pre-exposure prophylaxis -- you would be treating the negative and not the positive person. But let me just -- let me just then it comes up in the post exposure prophylaxis if the condom breaks and then we do get the post exposure prophylaxis if they request it.
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COHEN: if it works great it's still always better to treat the person who uses the drug and not the person. These are complementary universes. We hope by treating the person, the Swiss declaration would be true. If it's not, then your vision will become very important. Other questions or comments? Going once. Going twice. It's like an auction.
QUESTION: Could you just say a little something about sub type differences and how that might impact –
COHEN: So Jeannie's point is, HIV is not all created equal. And we have had trouble understanding the disequalibriums. Bc play as big a role in asia. We have b here. Many people, think there must be something about b that is not as efficient as c. One thing about b for example is in the swarm, b will be x4 and r5. Whereas c is locked into r5. It never becomes x4. So mathematically, when you're exposed to a c person you will see more r5 virus. Twice as much maybe. That's one issue. Second is, a and d progress at different rates. D progresses faster than some other strains. So you have a disease progression with higher viral load potentially driving more transmission. A has special features too. We just stretched the surface of differences but I am believing that they are not created equal which is -- is that the answer you wanted? That was the rhetorical question. I’m glad I could say I think clays are different. I think c is important. A lot of work is done on d but c is filling the planet. I’m holding you prisoners. There is free pizza there. Last question. Anybody else?
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COHEN: I think in my own mind, this is my mind, the following is true. If pro 2,000 works, I think the company that makes it will get a lot of support and it will be used not for everybody but in sub Saharan Africa for girls who want to get pregnant. You will see it available in that niche market if the November trial starts the first trial. One problem with the pro 2,000 is there is no excitement about it because everybody is waiting for the antivirals. If the antivirals work, I think there is sufficient commercial support that they will make it available, make it a product quickly. They spent a lot of time and money formulating the gel and ring. The gates foundation are international partners for many years and if the rings work and we are doing a ring study as many others are and if the gels work I think so the pharmaceutical industry will get behind this. And it will be very exciting. A woman would have a thing she could use. It would be a big revolutionary event. Other questions or comments? Ed? Thank you for listening. Thank you.
[Applause]
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ANNOUNCER: You've been listening to Dr. Myron S. Cohen of the University of North Carolina at Chapel Hill School of Medicine discussing Prevention of Transmission of HIV-1: Clues from the Early 21st Century as part of the NIH Clinical Center's "Contemporary Clinical Medicine: Great Teachers" series, recorded March 11, 2009. You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link, or by clicking the "View Videocast" link for today's podcast at the Grand Rounds podcast page at www.cc.nih.gov/podcast/grandroundpodcasts.html. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America’s Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I’m Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.
