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A Vision of Hope: AIDS Research in the Coming Decade

On October 14, 2004, Project Inform convened "A Vision of Hope: AIDS Research in the Coming Decade," bringing together a panel of HIV clinicians and researchers to discuss the next 10 years of HIV treatment. The panel was moderated by Pulitzer Prize-winning medical writer Laurie Garrett. Panelists were Steve Deeks, MD, associate clinical professor of medicine at San Francisco General Hospital; Jay Levy, MD, director of the Laboratory for Tumor and AIDS Virus Research and professor of medicine at UCSF; Judy Lieberman, MD, PhD, of the Harvard Medical School; Mike McCune, MD, PhD, senior investigator at the Gladstone Institute of Virology and Immunology; Ed Tramont, MD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases; Paul Volberding, MD, professor and vice chair of the Department of Medicine at UCSF and chief of the medical service at the San Francisco Veterans Affairs Medical Center; and Martin Delaney, founding director of Project Inform.

Below are extensive excerpts from the panel discussion.

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Key Issues in Antiretroviral Management

Laurie Garrett: I went through some soul searching about whether or not to come out here from New York for this event because one of my dearest friends is getting married tomorrow in Ireland. I couldn't figure out how I could be here then be in Ireland in time for the wedding, but there are just too many people sitting at this table that I go back with way too far. In 1981, I was working for NPR in an office on Folsom Street (then known affectionately as the "Leather Belt") and several people at this table were the very first people who I went running to and said, "I heard rumors that there is a terrible new disease in San Francisco. What do you know about it?" You have people here who have been in the game that long and have shown that much dedication, and we are looking at about 300 years worth of work here! [laughter, inaudible comments] And I think that what I want to do before we get into the discussion is set the framework of what we are trying to do here.

We have reached a point where I have a classic chart that I usually show in my PowerPoint presentations, where you see the mortality curve in the world for HIV, and it is almost a straight line. From 1981, it just does this; and then you see the mortality for the United States of America, and it is going up and then at 1996 it plummets down, and then it is headed down around zero. As you all know, we do not have zero mortality but we are very low. What that table tells you is two things: First, antiretrovirals are working. They are not ideal or entirely perfect. Everybody who is on them is hoping for something a little better, a little easier, fewer side effects, not having to worry about cardiovascular disease, but they are, in fact, active compounds, which is something that we were not sure the FDA would ever approve. But the fact that they are working for you and working for your counterparts in the wealthy world is statistically insignificant in the global epidemic. So, globally they are not only unavailable but there has been absolutely no impact on the global mortality rate. This is clearly unsatisfactory. Now, we're in a global moment where this means that we have to move money around the planet, move drugs around the planet, so that these less-than-perfect drugs can get to everybody and everybody can have the same less-than-perfect experience." And not anyone is talking about the word "cure." Vanishing from the agenda amid true cynicism in many corridors seems to be an effective vaccine, and you have a kind of sense that everything is settling into, "Let's just make do with what we have, fine tweaked, and make less-than-perfect drugs and figure out how to make them cheap enough that people in most of the world can afford to have them."

Clearly, anybody who is thinking out of the box is trying to imagine what this pandemic would look like in 10 years, much less 20 years, and would have to say this is a highly unsatisfactory situation and a losing situation in the long run because we all know that drug resistance creeps up and the less-than-perfect drugs become useless. So, tonight we are going to try to get some creative juices flowing and we are going to try to think about what could take us beyond this highly unsatisfactory state of current affairs. Some might even argue it is an immoral state of affairs in that those who live in the countries that control currently (according to World Bank estimates) 71% of the global load have the privilege of surviving HIV while those who live in countries that collectively control less than 1% of the global load are doomed to a horrible death. Can we get out of this, both to improve the situation for those of you who are fortunate enough to live in the wealthy world and for all your counterparts throughout the rest of the world, who have no opportunity and no access at this time?

I think that the first thing we should just start with is the baseline right here of the protease era, the highly active antiretroviral therapy, combination therapy, whatever you want to call it, your "little pills." How have we progressed since 1996, just with the little pills that are available to those who live in the wealthy world--to make that whole therapy, ie, less "less-than-perfect"--and do we see a way to build from that modality in a better direction that would be significantly different for those who could afford it? Why don't we start with you, Steve?

CCR5 Inhibitors

Steve Deeks: I think that probably the most significant thing that has happened in the past 10 years (since 1996) was the identification early on that HIV enters T cells through a direct interaction with a receptor on the T cell called CCR5. That is observation 1; observation 2, made around the same time in 1996, is that people who do not naturally express R5 on their T cells did OK and, more importantly, often were not infected with HIV. So those two things led to the rapid development of molecules that now bind to R5 on people's T cells. We do not think it is going to be toxic because some people do not even have R5.... Beginning in January, we are going to see throughout the United States and Europe the introduction of these R5 inhibitors in a very big way, comparable, I think, to what happened in 1995 with the protease inhibitors, and I think these drugs will completely change the way we treat. So there are a lot of "ifs." Beginning in January, it's going to be very different.

LG: Before I move to the next victim, what is it about R5 now that looks more hopeful than our R5 experiment we had a few years back that proved to be disastrous, when we were talking about R5 as a decoy?

SD: Right now, we have the molecules, which in early human studies have clearly been shown to work. I mean, you can take these drugs, and they are not like T-20, but it sort of works in the same way, and I think a lot of you are familiar with the downside of T-20. These are pills you take once or twice a day and they clearly work in the short term but there's a big unknown--I will talk about this in detail later--in that a lot of people have a virus which enters T cells not through R5 but through something called X4, a second receptor in T cells, and it gets very complicated because some are thinking that this other virus is more dangerous than the R5 virus, and this is where we are going to need some thought.

LG: And are you worried about push-through mutations that ... Let me first, before we go any further, see a show of hands. Is there anybody in case ... we want this to be useful for everyone, so please, do not feel embarrassed, I just want to know. Is there anyone for whom the level of the discussion that we are already having is a little too . . . whatever, you would like us to be slowing down, define the things a little more? Is there anybody who is feeling a little lost or overwhelmed? OK. So, just to say a couple of quick things. We know that for HIV to infect human cells, it needs to attach itself to a receptor And one of those receptors, the primary one, is called the CCR5 or the R5 receptor, and what Steve is talking about is a medical revolution that may be taking place--we will see; we will find out in January, he says--when drugs that specifically affect the ability of HIV to latch onto the R5 receptor will be available. Right?

SD: In clinical trials.

LG: In clinical trials. Now, the question I was asking is, we know that at a certain point in the course of the disease process HIV switches from latching onto the R5 receptor, it mutates to take on a form that latches on to a different receptor, called the X4 and, typically, that form of HIV is more dangerous. Now, if we start introducing widespread use of R5-inhibiting drugs, will we promote this mutational cycle so that we actually end up creating a monster?

SD: And that to me is the single most important question that I think, at least in the therapeutic field, we will be dealing with over the next few years. And half of the people, half of the data, suggest that if that switch occurs, it is no big deal, it is not that different from getting drug-resistant HIV. The other half suggests it is actually a very big deal. Not only is that virus not responding to your drugs, but it is most dangerous to you, and figuring that out is going to require doing the studies.

LG: OK. Paul Volberding has been treating people with HIV since 1981 and he probably has been involved in as many clinical trials along the way as just about anybody around in the HIV game. Starting with the question I originally asked: Just looking at the baseline of the drugs that we have out there right now and what is immediately in the pipeline that will affect people who live in the wealthy world, do you see any real big steps in the near future?

Easy Dosing

Paul Volberding: Yes. I am going to take a different path than Steve did. What has been said is hugely important. There is no question that it is actually a change in the treatment paradigm of initial treatment with the possibility that new classes will be available, with the potential to maintain the health of people who are increasingly resistant to the drugs. It is all involved in the development of classes of drugs, and the CCR5 ones are the next that are coming along. I guess I would say if I had to say what is the most important development between 1996, the first part of the epidemic, and now, it is the increasing ability to deliver therapy in incredibly compact modes. It is not rocket science, perhaps, but to those who--and some of you have done so yourselves--go from the era where you were taking handfuls of pills three times a day, worrying about food or no food, and extra water or not--to today when, as you well know, you can take a couple pills once a day and that is it. Yet it is as potent as anything we had in 1996. Again, it is not science but it is in terms of lowering for people who otherwise would not have an ability to get on and stay on treatment, and we know what we have to achieve in terms of continual adherence to medicines, such that I would argue it is incredibly important for patients in San Francisco and it is also part of what is happening to revolutionize how we think about the rest of the world. The fact that we have compact simple regimens that, at least in many parts of the world, are also really cheap and that we recognize increasingly some of the toxicity that used to be so common in some regimens is now less so. We dream about the possibility of creating access among the people that you mentioned. So I would say, in terms of the real global impact, it is the simplification of treatment and the reduction of toxicity that have the possibility to create a real impact.

LG: So make the drugs easy to take, cheap, and with fewer side effects.

PV: Less toxic, yes.

LG: Those are the key features of what happened in the post-1996 era?

PV: I had a patient who did well on these drugs where his T cells were very high when he started antiretroviral therapy, and together we decided that it would be OK to take a break from treatment, and he was off treatment for almost a year. It was an important period for him, and when I restarted him on therapy, he had gone from the protease era to the modern era. He could not believe that this was his antiretroviral regimen, with so few pills. It really meant a lot.

Incentives for Pharmaceutical Industry

LG: Marty, you were dealing with the pharmaceutical corporations, since some of them were a whole bunch of little companies before they all turned into five giant megalopolises. And you have been dealing with the FDA for 22 years, in one battle after another, and we have now seen a set of scandals emerge that deeply cut into the profit margins and the level of willingness to go out on a limb and take risks on the part of the major pharmaceutical companies. I mean, Vioxx is only the most recent of a long litany of things that have hurt their bottom line and there are rumors of the CEO of Merck being asked to step down, and he has personally been the key element supporting Merck's vast expenditures on HIV vaccine, and there is just a sense that the industry is getting gun shy. It is one thing to come up with something in the lab. It is another thing to carry it through with the fiscal risks involved to the point where it might actually go before the FDA for licensing. What is your sense of the situation right now? How bad or good may it be? And what do you think are the primary concerns or roadblocks in that system?

Martin Delaney: I think it is a question that we face. You know, as activists, we constantly struggle with this. The pharmaceutical industry does all kinds of things that we would just like to wring their necks over, in terms of pricing of the drugs and in terms of how they deal with the public, the advertising. There is a long list of things that we all would love to attack, and do attack.

On the other hand, if we push that too hard, then we push them out of the field because they tend to feel that "this is not a very attractive market." There are already 20-some drugs for it and where most of the problems already exist is really globally, around the world in places where they basically are not going to make money on these drugs. They are going to have to sell them for as close to their raw costs as possible or the business gets taken by the generic companies instead. So when you put those pieces together, and there isn't a whole lot of incentive for companies to stay in this, and I think there are a few things going that probably do that. On the one hand, we are critical about the companies joining together and buying up four or five companies, but one of the effects of that has been that there are now a few companies working in the AIDS field that have developed drugs for every one of the drug classes available. Overall, I think that is probably a good thing because it means they are committed. They have several products on the table and in development, so it is not like they can just walk out of this business anymore. If they had just one drug, it would be easy. But at least a few of these large companies now are very deeply imbedded in this and they are going to stay there. I think, though, this is a problem that cannot be fixed just by us as advocates of the public. I think that there is a government relationship, too. Government has to provide incentives for these people to stay involved in this. Without that, there isn't a heck of a lot the rest of us can do.

LG: Yes. What I hear from some of the CEOs I have spoken to from Glaxo, Pfizer, Bristol-Myers, and so on is, "Why in the world should I invest a couple hundred million dollars in trying to make an integrase inhibitor drug that represents a whole new model that we're not exactly sure how the FDA will handle? What biologicals should be examined? Will the FDA approve it? What constitutes safety and all this? Why should I risk all that when it will barely be on the market and the world is going to say it's morally right for Cipla to steal it, to put out a generic version? Where is my marketplace? Tell me why I should stay in this game?"

MD: Well, their marketplace is in America, Europe, Canada, some parts of South America, and Australia. I think there are enough paying customers for them, but they are not going make the kind of worldwide profits that they once envisioned. I think they have got to realize it is still a profitable market for them. If not a billion and trillion dollar market, at least it is one in which they make hundreds of millions of dollars on every product each year.

Ed Tramont: There are other ways to get at it as well. I mean, we have had the experiment now; it's called Bioshield. Everyone know what Bioshield is? There is no market for an anthrax vaccine, which is a bioterror agent. No one will take that vaccine unless there is perceived risk and you are waiting for a catastrophe like we had with the flu vaccine. You could not give away enough flu vaccine last year and now you cannot get enough of it. So what they came up with was Bioshield, and what the government has basically done is guarantee the companies a market. There is a way to do that. Obviously, you have to have a lot of public support to do something like that. So I mention Bioshield to people and they go, "Yeah, yeah, yeah, we need that!" It gets a little harder when you get further away from that because what do you do when the new drugs we're talking about are for chronic arthritis or renal disease [for which drug companies do make profits]?

There is another aspect where we can make a difference, where I think government can make a difference. We are trying to take away a lot of the expense that they incur with developing drugs. We were talking about the trust that has to exist between the companies and the government, and I can tell you that the trust is pretty low. It is really low. If you think you don't trust the government, the companies don't trust government! And, if you think it's bad with drugs, let me tell you, it is really bad on the vaccine side.

LG: Right, and we are going to get there. Without pointing too much further down the path, there are many in the international sector who say, "Look, we're actually in the pharmaceutical industry, we're in a market failure." It happens to be an industry where the classic principles of Adam Smith do not work because, if they did, you would be making products for the largest number of people who need products, and that is exactly the opposite of how the pharmaceutical industry is moving right now. And so, we have a larger topic but it is outside the sphere of this discussion unless some of you wish to raise it in your questions later. And what I would like you to think about is something Ed mentioned: Some of the targets that can be raised that are targets on the virus itself, for which we have products in the pipeline already. But there is another whole flip way of looking at HIV and that has to do with thinking about the fact that this is a microbe that gets into a body and that the way the body responds to the invasion of the microbe may offer some potential treatment clues down the road. And that takes me to Jay Levy. Jay, take it away!

Immune Response

Jay Levy: I was hoping you were not going to leave us without having the hopes to consider. I'm a trained virologist (and Laurie you're doing a great job: You know this field quite well). I was called in to look at people who were naturally able to fight infection, whether it be polio, herpes, or one of those, and we started studying all kinds of viruses and realized it is not so much the virus as it is the ability of the body to ward off the infection mainly to control the infection, and from these long-term survivors, which for something like polio is 99% of the people do not show signs of being infected with polio. With HIV, on the other side, there is 5-8% that live what we call 10 years without any signs of it, but we have got several people who are 26 years documented; one sample collected for a hepatitis study here in San Francisco in 1978 showed they already had antibodies, I mean, they probably were infected in '77, but they are perfectly healthy young men and they are able to control the virus that is in their system. They can control it by their immune system and what we think is a natural immune response. So, what you are asking (no matter what you are looking at) is, "Can we repeat that type of protection for individuals who are already infected?" And we will get to it. When asked, we are talking about all these drugs--15 drugs now, more drugs--targeting the same receptors as others, some targeting other parts of the virus, but with very little attention given to the immune system. Companies do not want to go into this because it is going a long way to get a product. However, the positive side is that the immune system is so important for other diseases--autoimmune disease and cancer, not only HIV--once we decipher how it works and how it is protecting to control HIV, you can use that for other approaches to disease and the few enlightened companies--of which there are very few--are not willing to look at it. Better is the support from the NIH that says, "We believe in hosted immune responses. Show us something!" So later in the day, we can talk about what there is, but I just want to say that the drugs are toxic. If you have got a natural immune response, you do not have any toxicity. People are living very well.

People come to me with Chinese herbs and say, "Take these herbs and bring the immune system back." And you have to say, "Well, what do they do to the immune system?" "Well, they activate the immune system." Well, you do not want to just openly activate the immune system. Those of you who follow the field know that can be dangerous and you want to be able to selectively do that. The people who study the immune system will be able to monitor what--natural products, maybe--will give a good immune response to people who are infected. That is the area, the "new horizon," that I think is opening up as we learn more and more about the disease.

LG: I wonder what you make of the increasing evidence that one of the places HIV colonizes that gets missed, of course, in blood testing and so on is the gut; and you raised the metaphor of polio. We know that polio latches on to M cells in the gut and that it is fundamentally an enteric virus, although it may show up all over the body. I wonder if you see any real significance in the recent set of findings related to HIV in the gut and what that might mean on the event horizon for treatment?

JL: I think the big surprise, which isn't a surprise when you talk to a hard-core immunologist, is that the gut is the largest immune system. But for HIV researchers, we are always finding surprises that we find so obvious, but you have to let them catch up. So, yes, the gut has a lot of infected cells because it is just hard to pick. If you can find a way of preventing infection locally, if you are willing to get to the gut ...

One of the other groups that is really terrific to study is people who have been exposed many times and are not infected. Steve mentioned some of these people lack the CCR5 receptor for the virus, so they can be infected by other HIVs, but we have some people who are astounding to us. They actually are very risky, do not care if they get infected, and they cannot get infected! And when we study them, they have a natural immune response against the virus. You heard or read about prostitutes in Nairobi or in New Guinea, where 10% of the prostitutes never get infected yet have the same number of clients, and there seems to be some natural immune response. Some of it may be targeted but my own opinion is that it is some kind of a natural or innate response.

Now, it is interesting that if they are convinced to leave the profession, and if they come back two years later, a certain number of them get infected. What we have learned is that you need to have been exposed to HIV within a year to maintain this result. After a year, it goes away. We're talking about certain cellular immune responses. That is a fantastic group and that is the most encouraging for a vaccine, for a vaccine that prevents any infection. So it says the human body is capable of doing that. Let's just explore it more and figure out how to do that.

LG: Well, Judy Lieberman ... I mean, we have had these very isolated examples of individuals who seem to have some kind of an immune response to the virus that actually is protective, as opposed to the initial viremia antibody push response, but they are really, really rare! They have not seen us with other infections ... I mean, this is like rabies, pre-Pasteur rabies--virtually 100% kill, no natural human immune response to rabies--and partly this tells us this is a very, very new virus in our species and it is still a very new and baby epidemic, and partly it tells us that we are up against a very tricky enemy if we are going to try to come up with any of the immunological tools, whether they be the classic old-fashioned vaccine we used to think about or something radically different, to deal with it.

Reason for Optimism?

LG: Recently, we had the very disturbing findings regarding enhancement, showing some things that seem like they are working may actually be enhancing the capacity of the virus to infect the body by stimulating the immune system. That is something Jay brought up in saying, "You don't want to just take some herbs because somebody says it beefs up your immune response." That might actually be, in the case of HIV, bad for you. I wonder, if you look out upon the event horizon, what do you see that immunology can bring to the table, realistically?

Judy Lieberman: I guess I am a little more pessimistic, but there is some hope. The immune system is so complicated and so regulated that I would say, even though there has been a tremendous effort to try to understand the immunology of HIV for the past 20 years, I do not think we can really understand it. We do not really understand what is the problem? In HIV infection, you have both aspects of tremendous immune activation and also immune deficiency, and it is very hard to disentangle what we need to do immunologically to have a therapeutic impact on the virus. There is some indication that some species of monkeys have very high levels of virus replicating in their bodies but they do not become sick with SIV. We do not understand really why those monkeys do not become sick. I mean that the classic teaching would be that they must be controlling the virus, but those monkeys are making a lot of virus. So it seems in some aspects that they are somehow ignoring the virus, that their immune systems are not being activated by the virus. Somehow, we have to figure out how to quiet down the immune system, the general sort of inflammatory part of the immune system, but at the same time maintain the function of the immune cells that are actually recognizing the virus and destroying it. And that is a real paradox. How can we on one hand quiet down the sort of nonspecific part of the immune system and at the same time keep the specific part going strongly? But the piece of hope I would mention is that, even in the last year or two, we have really learned incredible things about how the immune system is regulated and I think that there are opportunities for applying some of those new understandings of the regulation of the immune system for really intervening. And I think there are opportunities there, where the immune system could be harnessed as an adjunctive therapy.

But I also want to make one other point. Basically, there are a lot of viruses we become infected with that our bodies can live with, like the virus that causes infectious mononucleosis or cytomegalovirus in most people. I think there is hope, if we can treat HIV aggressively at the beginning, that we could turn it into the kind of virus that we can live with, that our immune systems can live with.

LG: You brought up the question of SIV, the simian immunodeficiency virus, and its infection of African green monkeys in the case of SIV-2, and just to back up for those in the room who might not be quite up on the table where we are right now, let me just point out that, when you talk loosely, as many health food stores, do saying, "This will activate your immune system," well, what is an allergy? It is a hyperactive immune response incorrectly directed against something you should not be freaking out about, whether it is egg whites or poison ivy or whatever. Simply activating your immune system is not the way to go. It is an incredibly complicated, orchestrated system and you want to make sure that the conductor is activating the right string section or the right oboe at the right moment. And what I think Judy is trying to say to you is that we do not really understand enough of the basic biology of the immune system to feel confidant that this is the drug we want to punch through and develop and that people should be mainlining in order to get over HIV. You raised the question of SRD and we have been hearing ever since I can remember in this epidemic, "Why don't we just round up zillions of African green monkeys, which are not an endangered species and so on, and try to figure out why they can have viral loads in the billions and it never seems to bother them or make them ill in any way, shape, or form?" Do you think that we should have a major push, a huge all-out effort, to try to study the African green monkey and SIV?

JL: Yes, I think that there should be many more focused immunological studies in primates to try to understand pathogenesis because you can intervene there and see what effect it has in a way that is hard to do with people.

LG: Well, Mike McCune, if I could be so bold as to describe your research as indicating that you know how to take incredibly complicated problems and come up with a research design that pits a finite set of issues against each other in a way that results in some advancing of understanding and you seem to be a real master at this. [audience laughter] I wonder if you would look at this ... you're supposed to smile! I just paid you a compliment. I wonder if you look at this sense of massive complexity in trying to figure out the host response, if you can see on the event horizon, looking out five to ten years, some way to begin to tease this out in a meaningful way.

Mike McCune: You ask such good questions! First, I am sorry I was late. I was at one of the less and less frequent AIDS research fundraisers before this and I plead good cause ... You know, I took a sabbatical in Paris last year, my first year away from this city in the past 20 years, and I have been working with Paul and others to see patients with HIV in the clinic and I am not as pessimistic as Judy was, but I am actually getting pissed off. I think that the drugs are OK, but they are not working as well as I would like to see them work and a lot of the stuff that I have been doing and spending time thinking about tends to do with drugs. So I figured I would take the year off in Paris thinking about what to do with this question about immune responses because we do know a little. When CD4 cells go down, we do not even know if the total body CD4 compartment has gone down, and it's 20 years since the discovery of the virus. So I worked with a fellow named Simon William Hobson, who, if any of you have had an opportunity to meet, is a wonderful fellow who likes to talk. So what we did all year is talk. I am an immunologist and he is a virologist, an evolutionary biologist, and I started out as a fan of the immune system and he a fan of viruses, and we sort of switched chairs about midway through the year because I came at the problem with a peculiarly Western approach, which is that the only thing that exists is that which happens, and that which you can measure, OK? And most of our discussions about immune responses deal with that which occurs. I think you were referring to this: If you have an active immune response, then it is active, right? So, in the positive connotation and in the setting of HIV, in fact, you need to have a really active immune response because we quantitate it like no other bug. We all know you have 106 virological mayhems with what Simon calls "106 Varian parts per mil." Do you know what that amounts to in the way of protein? Let me take a gander at that: It is about nanogram quantities of protein and your body responds to it actively by making milligram quantities, a log order higher quantities, of antibody per mil, and does it help? Of course not. I mean, we all know it is really not doing much at all but the amount of protein that is there and the amount of antigen that is there is actually very small compared to... does anyone want to take a guess at how many bacteria we have in each of our large intestines, which we just live with right now? [audience laughter] I mean, it is a huge number, it is 10 or 12 gram quantities per mil, and the genome complexity of those bacteria are actually larger than yours. Yet, what do you do? You coexist! It is very cool, okay? So the immune system is there to coexist. Now this is some of the San Francisco PC kind of thing but it is there, too.

LG: Do not tell the Office of Homeland Security! [audience laughter]

MM: But it is there to allow you to coexist with all the stuff that is on you and in you.

African Green Monkeys

MM: And nobody has ever counted the absolute number of African green monkeys, but they represent just one of many groups of monkeys that live in Africa. The incidence rate of infection that occurs in adolescents usually is anywhere between 40 and 80%; it does not say most of them are infected. And so you could probably take a gander at that, it might be many of them or maybe as many of them living with multiviruses as there are people living with HIV, which is to say that, in high viral loads, you need the right number because often it comes down long before the adaptive, the so-called "active," immune response kicks in because often it comes down and they are perfectly happy.

So the question to ask is, "Should we study all of them?" No, you cannot do that, really. It is not physically possible and there are always these naysayers, I know, from having spent years working with animal models, who say, "Well, it is not really relevant to human disease." And in fact, it is a start, I agree. It is a start. So the way that I am thinking about this now is that we do need to really understand the immune system. We need to get down to the kind of tabulation of its composition numbers that we have not allowed ourselves for structural reasons yet to do. We need do it in, yes, African green monkeys. The same virus that causes disease or does not cause disease in an African green monkey can cause disease in another species of monkeys. So we could begin to do experiments and ask the question "Why?" in a very descriptive sense. I think, actually Jay has alluded to this, the drug companies, which I know well, do actually have their ulterior motive, and that is to make money, and they have seen money in the setting of inflammatory and antiinflammatory agents. What I have discussed just now is that it would be very nice to put it in a very short capsule, it would be very nice to be able to teach our immune systems how to coexist with HIV. And inflammation appears to be something that we do not wish to have, and so there are therapeutic interventions that now allow us to dampen inflammation in people. Judy alluded to an incredibly important series of findings about five or ten years ago in immunology, which teach us how the immune system keeps things from being active. In fact, that is probably the most important part, this stuff of regulation, regulatory T cells. They probably are antigen-specific and it is highly likely that there are interventions now that we could use, and I think it must be the case in nonhuman primates first to suppress immune responses in such a fashion that we can ask the question, "Does this situation now lead to the lack of the disease progression?" The main thing I am thinking about is to take animals that do not get sick and understand how to make them sick, but much more interestingly, to ask the question in those who normally would get sick, "What modifications can we make in the immune systems to prevent that from occurring?" And then go straight with, in many cases, GMP or in some cases off-the-shelf drugs, into people. I have been asked, "Would you imagine this to be a preventative vaccine?" I think down the road this actually could be, but in many folks with HIV now, it is possible that if you had a durable way of modulating the immune system in such a fashion that it was no longer as active against HIV as it now is, then you might have a disease modifying the intervention that could very much slow disease progression.

LG: OK, but I want to ask you and Judy the same question. You worked with Simon William Hobson and one of Simon's major contributions to the field has been that he did a kind of experiment that is unbelievably tedious work, unbelievably difficult, where he took what is called histology slice by slice of the spleens of people who had been infected with HIV and he found literally microscopic slice by microscopic slice, that they were different HIVs, that as you went literally distances that would be at our level the equivalent of going from that chair to that chair, you had totally different viruses colonizing. Now, that implies one sort of good news, which is that the immune system is exerting a lot of pressure. It implies that the virus is trying to mutate, that everywhere it is trying to find a way to outlive some sort of immunological pressure that is not successful but is successful enough to force the virus to keep trying to adapt, to keep trying to change itself to outwit whatever is in its immediate environment, its immediate ecology. That might be good news. On the other hand, you said, "Well, maybe we would not have a preventative vaccine." Well, most vaccines are not actually preventative. You actually do get the microbe in your body, like polio, but the vaccine keeps you from progressing to the disease state. The question is whether we ever get to the point where we peacefully coexist, like the monkey, with HIV in our body or is it possible that what Simon William Hobson's data is saying to us is that this virus is still actively and constantly trying to mutate to outwit whatever we throw its way and it would be foolhardy to try to go down that path. Judy?

JL: Well, I think antiretroviral drugs actually let you coexist with the virus. That is what they are doing.

LG: But you develop resistance.

JL: But I think what we have learned in the past five or so years since then is that, even though the virus becomes resistant to any one drug, the resistant virus is less fit than a wild-type virus and if we target enough things at once, we can actually get to a situation where there is not a lot of viral mutation, where the virus is being controlled. And I think that is very optimistic and I think that we will do better with time.

LG: OK, I have one last question, and I want to remind everybody, if you have questions, you should have written them down. Put your hand in the air and one of the volunteers will come and get your card and bring them over here. So jot your questions down while I have one last question. I am going to direct this to Paul and Steve. This is a clinical trial question.

Cultural Sensitivity

LG: A while back, we had quite a huge controversy when Marsha Angel, who at the time was running The New England Journal of Medicine, attacked certain types of AIDS clinical trials done in Africa saying that the standard of care ought to be exactly what it is in the United States and that target therapy ought to mimic what is available in America. It was sort of a consensus ethical response that she was off the wall, that the whole point is to make things affordable and available to as many people as possible, and that mimicking this very expensive American model did not make sense in Africa. But we are really moving to a point where there is more and more pressure to conduct our clinical trials in endemic countries, to do more collaborating with African colleagues in particular, but also colleagues in other developing parts of the world, and to find ethical ways to test entirely new concepts--whether it is an integrase inhibitor or a CCR5 blocker or whatever it might be--in populations where the whole clinical model is so radically different from what we have available here. And when you couple that with the financial pressures and the drug industry to try and come up with cheaper and cheaper ways to get things through clinical trials, it is a very attractive idea to push into Africa, to push into developing countries for your clinical trials. How do you see this? Do you think it is possible to escalate in that direction with a research model and still come up with things that end up getting FDA approval and end up being drugs we can use right here at home? Paul, you were nodding.

PV: It is obviously a big chunk of the question. I think that I see ethics as always in part determined by cultures, and I think it is a very difficult challenge to say what the perspective is for somebody who has done all of his work in San Francisco to be able to come up with a single answer to a question where the cultures that we are working in are so different. I do not think it is impossible and I think there have been examples where trials have been done in Africa and Asia, where the results have been very important here and this includes the Thai vaccine trial. It was a trial that did not work but it was a good trial and it was done in a manner consistent with the ethics there. I think the issue of what kind of standard of care needs to be provided and for how long it needs to be provided is not just an ethical question but, in effect, a practical question. I'm kind of getting out of this directly, but I think only way to imagine doing it is not in a patronizing way, but in a very direct way to allow the responsibility to be with the people who are part of that culture, who understand what is going on and for us to play a facilitating role rather than a directing role.

LG: Steve ...

SD: Well, this is a little beyond my expertise, but I think I will use some personal observations to answer it, and there are two issues here. One is: "Who is asking the question?" and "Who is answering the question?" In San Francisco, I collaborate with these networks and the people in those networks design these questions, and these questions that they look at are not relevant to my patients. So we end up asking our own questions locally. I look to the expertise of these experts to help me answer the questions, and I think that same thing should play out elsewhere. NIH and the Europeans and the United States, and some other countries, have developed a capacity to do rigorous local research and to determine the truth. But these groups do not necessarily know how to figure out what are the best questions. So we just need collaborations with those who are working in a country in the context of a certain cultural situation, seeing patients, who can ask questions and then turn to the expertise of the NIH and so forth to help answer them. And that I do not think is being done as well as it should be.

LG: OK, the first pile of questions to come to me are all directed to Judy. [audience laughter]

JL: Can we use targeted gene therapy against HIV? Can we use this naturally occurring phenomenon in all of our cells to block HIV infection? In fact, we found that we could. So that was pretty encouraging and we and others, a number of groups have worked on this, also found that we could silence the expression of almost every gene in HIV and you could use them together and you could also silence things like the R5 receptor that we were talking about earlier. So you could silence host genes that cannot mutate or you could silence viral genes or you could take a page from drug therapy and make a cocktail of small molecules that could silence multiple genes at once, and in fact, we found that--if we took, say, a small drug that silenced the receptor and another one that silenced HIV genes--we could completely suppress HIV infection in at least tissue culture. So this field has really moved rapidly, and it was three years ago that it was found that this worked in cells in our body and already the first INDs have been filed to start clinical trials using this drug, but there are a lot of problems. One of the main problems is that these small molecules do not naturally get into cells in the body. In a tissue culture, it is easy to get them in, but not in vivo. However, we have been very interested in harnessing this for HIV, or to make a microbicide, and we have actually found a way that we can direct these drugs into cells in live animals only into cells that are infected with HIV. So that provides two nice things: One is that you can get the drug where you want it, and if you only target infected cells, then the toxicity of the drug is going to be a lot less.


JL: Okay, so RNA interference is something new. It will be a while before it becomes a drug for HIV, but I think there is a lot of promise whenever you have some new mechanism of possibly treating disease and a lot of people think that this is like a whole next new class of drugs that is going to come into play. We found that, in the cells that are responsible for transmitting HIV, we could silence the expression of the receptor that is involved in transmission for weeks at a time, actually for as long as we could keep these cells growing in the body. So that was pretty exciting and that caused me to think that the main problem in making a microbicide is that you have to remember to use it before you have sex. If you could protect cells in the genital mucosa, for long periods of time, perhaps you could develop an agent that you would not have to take just before you have sex. So we have been very actively working to see if we can harness this new phenomenon as a microbicide and we have figured out a way to get it to work. We have used them on mass models--that is sort of the first place you look. We have been able to silence the expression of genes throughout not only the epithelium but very deep into the tissue, and we just tried for the first time a herpes infection model in mice. We challenged mice with a lethal dose of herpes virus and on the first try we found we were able to protect the mice. So I am very ...

LG: Have you tried an anal epithelial exposure?

JL: No. I think there are a lot of things that have to be done. I know nothing about how you formulate these compounds to make it into something that might be useful. We have to look very carefully to make sure there is no toxicity, that it does not cause inflammation. So this is really hot off the press. We just started doing it ...

LG: You heard it first here! [audience laughter]

JL: I mean, the same principles would apply to sexual transmission to women and to men. I do not think there is any difference.

OK, so there was one other thing about ...

LG: Testing microbicides.

JL: No, the point of treatment at the point of infection ... [crosstalk] What I think is that ... so the immune system is very good at recognizing small amounts of foreign proteins but when you have very large amounts, like Mike was talking about, where you have nanograms of HIV protein circulating in the body at any time, it cannot tell what is foreign and what is self. And so things that are there in a huge amount become ... the immune system learns to tolerate or to ignore in some ways. For HIV, I think it learns to ignore it in a wrong way, but it does not ignore it in the ways in which it should be ignoring it. So I think that the key in my mind is to try to reduce the amount of virus that is disseminated in the body and that the earlier you can suppress the virus, particularly as soon after infection as possible, probably the better. I think the truth is we do not know whether that is, in fact, the case from clinical trials.

FS: It looks like Jay wants to make a comment.

JL: I just want to say that there may be people here who have participated. We had what is called an Acute or Early Infections Program at San Francisco General and through Options Project, and it was fantastic. The unfortunate news is there are a thousand new infections in San Francisco every year and what we are able to do is exactly what Judy said: Look to see if therapy very early--that is only when virus is present, before there have been antibodies produced, which would suggest an immune response--will influence the course of the infection. We are able to look at a variety of immune responses, some natural immune responses, to see if that will permit these people to become what I talked about earlier, long-term survivors. So this is an incredibly important group of subjects and I have to thank the San Francisco community for being so active in allowing us to answer these questions.

LG: OK now, this huge pile is all for Steve. [audience laughter] You might want to jot these down. There is a little overlap, so there are a lot of questions wanting to know, "Are there ways to block the binding of CXCR4?" "Can R5/X4 binding inhibitors prevent infection altogether, and thereby act as a sort of vaccine, if you will?" "How far along are we with AND O70, which is an X4 antagonist, and what seem to be the big obstacles for that one?" "Does concern that CCR5 directed treatments might push for the breakthrough of mutants that go to X4 pertain also to the possible use of CCR5 in microbicides?" "Has Schering, the company, determined what caused the heat irregularities of the first CCR5 study?" My goodness! That is awfully inside baseball! [audience laughter] OK, I will leave it at that.

SD: All related questions. So with regard to what we said earlier, HIV can enter through R5 or X4 and most people are infected with R5, and R5 only. We are not sure why that is but it does argue that R5 inhibitors might be a great thing for prevention and might be something to use in microbicides, and I think there is a paper that came out in Science today about a microbicide which has an R5 inhibitor.

Audience member: Yes ...

SD: OK, so it actually works in the same area. So great question, lots of interest in using drugs which bind to R5 or somehow interact ... or there is interaction between the R5 virus and CCR5 in preventing transmission. Now, we probably do not need X4 inhibitors at that point, but once R5 enters, over the next several years in many people--not everybody--R5 switches to X4 and, as we were saying earlier, the X4 virus may be particularly virulent. So why are we wasting our time with R5 inhibitors when the people who are most desperate, who are getting sick, have X4? The reason is that if you bind, if you cover CCR5, we do not think people will get sick. We do not think you need your CCR5. People who are born without a functional CCR5 would live forever, well, you know, would live a long time ... [audience laughter] and in general do not get HIV. But if you take out the CXCR4 ... if you take a mouse and you take out its CXCR4, they do not do so well. It is an extremely important part of what T cells do. The drug companies are very nervous to develop drugs that basically block something we all think is very important. There is one drug, and someone referred to it as the AND O70 drug. It actually is now in phase II through the ACTG. It is being studied; it is being studied very slowly. Everybody involved is very concerned about toxicity but that drug class is moving. It is two or three years away before I think you will be able to see the type of action that we are going to see in the next few months with the CCR5 inhibitors.

And the final question with regard to the Schering heat problem, which I am pretty sure was a heart problem, is that the CCR5 inhibitors have been shown (1) in Schering's case to cause arrhythmias, an irregular heart rate--long pauses during the cycle of the heart beating--and of course, that made everyone quite nervous. Nobody has quite figured out why that happened; they threw the drug away, and came up with Schering D, which evidently does not do that, but the Schering D drug, the Pfizer drug, and I think the GSK drug--three big drugs being developed now--have been pretty much shown not to have this heart complication, so we think they are going to be OK.

LG: Alright. Now I have a set of questions and I am not really sure who to direct them to. I am going to put them to the panel and they all come from people who are thinking about their own health right now. They are asking, "What ever happened to structured treatment interruption? Have we given up on that? Does it work? What should we be working on in that direction?" "Should we be thinking about what is happening to the rest of the organs in our bodies?" Several of the people are asking, "We want to know, in the long run, what is happening to our cardiovascular system? What is happening to deal with acute fatigue? What is happening to deal with lymphadenopathies and HIV-specific lymphomas and brain function problems, memory loss?" How can we avoid these questions and do we have any way of sorting out really effectively at this time? How many of them are asked because we have an HIV patient population that is living long enough to be middle-aged and, like most middle-aged people, losing their memory, and some of the other things they worry about that are specific to taking the drugs or specific to the virus? So I guess I am asking you clinicians here on the panel to take this on. Paul, why don't you start?

Structured Treatment Interruptions

PV: Let me start with the treatment interruptions, although Steve has spent the bulk of his career working on aspects of this. The trouble with treatment interruption is that people use the term to mean very different things and the approach that was popular for a fairly brief period was the idea that if you stopped the drugs, if your virus was suppressed and you stopped the drugs and allowed the virus to come back up, then your immune system would react against the virus; it would become stronger and then you could start the drugs again and you would have the benefit of that strengthening the immune system against the virus. And that has not worked. There has been no study that convincingly shows that it does really anything and there have been some down sides to taking that kind of an interruption. The way that a lot of us now are approaching it is through operational research, which is if your T cells are really high and if they have never been really low when you stop the drugs, a number of trials now have shown that you can go for a long time--months or years--before you have to restart the drugs. The T cells take a long time to decline and that is leading to what I think is one of the most interesting questions again of when to start therapy, because for a long time when we worried about the drug toxicities, the cost, the trouble with adherence, the resulting resistance, the argument was, "Let's wait as long as possible before we start because we do not have to use them early. They will work later on." But we now realize that if you do that and later on decide to stop your drugs, your CD4s may come right back down to that level. So you've lost some ground. And there has been one study, a preliminary study, that suggests that the strategy of treating for periods of time very early in the disease may actually allow you to maintain your T cells in the safe range and over the course of years, not having to be on a drug very much at all. So that is the kind of treatment interruption that is a strategic operational one that has nothing to do with immunology but, again, could be a strategy that would swing the pendulum back to very early therapy. It just shows that we do not know what we are talking about! [audience laughter] ... that we change our minds all the time.

LG: Jay?

JL: Yes. I am glad Paul mentioned "early in infection" because I was talking about the first six months of infection, where we do have people coming in. If you start therapy, you are able to stop and then the virus comes back but at nowhere near the level you would see initially, and they can go for a long period without drugs. We do not know. We are just starting to do that but in the few cases that we have looked at, it has been very impressive. But eventually the virus comes back because the immune system does get destroyed. So I want to put a note in that the more creative approach is, as Paul said, operational and to treat these individuals with HAART therapy and give them interleukin-2--which allows me to put a note in about immune-based therapies. Interleukin-2 will help raise the CD4 count, help CD8 cells function better, and then immunize. So first we are doing IL-2 in part and we are going to see what happens. I think they are going to do better, or they are going to go a little bit longer without having to resume therapy, and actually the French have a very small study that was reported which suggests that is true. But I would imagine if we had an agent, not a vaccine, but one that can arm the immune system to fight the virus, and treat with HAART so the viral load goes down, you give them interleukin-2 to bring immune cells back--because most of them are naive; they have to be shown that there is virus around because the virus has been suppressed--and now you immunize. And that combination, I think, is going to be very powerful and may work in chronic infection as well. So these are operational in the works and I hope we can get them under way in the near future.

LG: And we also had a series of questions about side effects and how to distinguish between side effects caused by the drugs versus those caused by the virus versus those that are just age-associated in the individual, and you know, I have to say, I remember the annual retrovirus meetings, the American-based meeting on AIDS each year, and I remember a few years ago when the organizers of the retrovirus meeting thought that these rumors of lipid-associated problems were so unimportant that they were relegated as posters for people to look at posted on the wall and none of them were oral presentations. There was quite a hue and cry about that. People got very angry about it. Now, in the last retrovirus meeting I was at, it seemed like that almost half the papers presented had to do with cardiac problems, cardiological complications, how to treat coinfection of hepatitis C and HIV, on and on, and there was this sense that, "Oh, my goodness! As a physician, you have one complicated patient problem here." So, Paul, you are the clinical leader at the table!

PV: Again, Steve knows these things as well. It is really an interesting field to be working in. First of all, I had the experience of giving a talk on AIDS to the first- and second-year medical students last week and I asked them how many of them could remember themselves before AIDS. None of them could remember before AIDS; they have all been born after this. When I look around the room, assuming that a fair number of you are living with HIV, you are about 24 years older than you would have been when I first started seeing patients. So, you know, we are all the same age, actually--55 or so--and we are getting to an age where, HIV besides, we are coming into a risk of cardiovascular disease. So there is the aging of the population of people that is a factor. There is no doubt that some of the drugs that we have used can cause problems. There is no doubt that some of the drugs can cause the elevation of some of the blood lipids, and I think that there is no doubt that is going to add to your own risk for cardiovascular disease. There is no reason it should not. And then there is the issue that Steve and Peter Hunt have been working with, which is that there is a good deal of immune activation; there is inflammation that is a constant part of being chronically infected. And there is more and more data to suggest that inflammation is a very important part of cardiovascular disease risk. So I think it would be too simplistic to try to take one of them out. I think they are all in play and we need to have really multifaceted approaches in trying to manage these problems.

LG: So, Steve, it is a big ol' damn mess?

SD: It is a mess! I mean, no, we talk all the time about heart problems and other drugs, increased cholesterol and you get accelerated heart disease and inflammation. Straightforward. I mean, it is clearly happening. Fat redistribution, likewise lipodystrophy, clearly happening. Lots of people studying it will have answers hopefully in the next few years. But there is a whole list of complications that no one is talking about and I actually think it is because it seems vague. Fatigue, right? Memory loss: "Yeah. OK, I am middle-aged and a little fatigued but I do not see ... my T cells are normal, my viral load is undetectable, but I just don't seem to have the energy that my friends at this age do." I personally think that, in my clinical experience, that there are these other things going on as a consequence of either long-term infection or long-term exposure to drugs that have dramatic impacts on the quality of life and they are things like fatigue and malaise, and weight loss. And I have found that a lot of my patients are very frustrated because they come and I say, "Well, I don't know what that is." I cannot do a blood test to see what is going on or even confirm that is happening and I don't really have a reason for it and have no interventions. And I think that the field needs to pay attention to this. It is a very large problem in San Francisco because people in San Francisco have been on drugs longer than anyone else: AZT 1989 onward, this is a city where we have had a lot of exposure to drugs and I think a lot of complications are the consequence and I hope that those involved in toxicity research would begin to pay attention to these rather vague but important complications.

LG: Jay.

JL: Just a quick comment. The virus itself can do a lot of this. We know the virus affects fat cells; the virus goes to the brain. We don't get antiretroviral therapy there to the level that may reduce it and one of the concerns I think of any therapist in your clinical treatment is that you live long enough and then you get Parkinson's disease and the secondary effects on the brain by the virus. The virus infects the heart; the heart infects the kidney, so it is a tradeoff. You are treating but obviously, as discussed today, you want to try to get drugs that are not going to give you these side effects.

LG: I want to go to you, Marty. This leads into a question that one individual from the audience put forward. It was not that long ago--really less than five years ago--that we were being told the human genome revolution was going to result in tailor-made targeted personalized medical care and that we were going to have Marty Delaney's genome--Ayyy! [audience laughter] And we were going to be able to target all medical care to that genome, right? And anybody who made those claims is running away from this as fast as they can, running in the opposite direction. How do you see this whole question of (1) trying to more personalize the health care, and (2) deal with the balancing act of (a) trying to be ahead of the resistance cycle of the virus, (b) keeping your lipids in order, (c) keeping you from getting a heart attack, (d) keeping you from losing your marbles, and on and on!

MD: Essentially I would take this, I think, a little differently than the other panelists have. I think if you look at, for example, going back to your earlier question. If you look at the cohort studies that have followed thousands of people in one clinic versus another over these last several years, they have had a darn tougher time trying to tease out what the effect is on heart disease and some of these other issues because, as I think you correctly said, the population is aging and changing with it. So you have got all of these factors going on at the same time. I think actually we do a disservice to people with HIV, making you worry about everything under the sun, you know? I think sometimes we as treatment educators probably give you more information than you want and more information than is even healthy for you because you begin to live your life worrying about every possible side effect and everything that happens as you grow older and every little bit of disease. Everything is not the way you want it in life and your life becomes about HIV disease and analyzing everything from that perspective. Well, and I have memory losses; I have fatigue for the last several years; I had a heart bypass last year. I am HIV negative, you know? And I am 59 years old, too, and that is why these issues are happening in my life and to some degree, I think it is why they are happening in other people's lives here as well. So I think you have got to find where is the balance of what is this life doing to us, you know. The polluted air we breathe and the crappy foods we live on, you know, and everything else--the quality of our water. I just think that it is important not to assume and interpret everything in your life from the perspective of HIV disease because it only is going to make you crazy!

LG: Well, I feel like we just hit a point where we could talk all night but our time is up and it is getting hot in here! I don't know if the air system is working. But I want to thank all of you for being such a lovely attentive audience and I hope that this was helpful for you.