The Age of Aids [home page]

interview: david ho

[photo of David Ho]

In 1994, Dr. David Ho discovered that what was then thought of as a latency phase -- when a person was infected with HIV but not experiencing any symptoms -- was in fact a period of continuous onslaught, in which the virus and the immune system are engaged in a pitched battle. Once he was able to measure the amount of virus in the blood, he learned that in fact billions of HIV particles were being produced every day. This breakthrough allowed Ho and his collaborators to come up with the idea for combination therapy -- treating a person with several drugs at once to suppress the virus down to undetectable levels. Patients near death rebounded dramatically after beginning what was called "triple cocktail" therapy, and Ho was named Time magazine's "Man of the Year" in 1996 for his work. In this wide-ranging interview, Ho recounts his breakthrough discoveries and his battles against the virus over the years. He also talks about the implications of combination therapy on the future of the epidemic and the importance of prevention efforts. "We have to bear in mind that during the years where this concerted treatment effort took place, approximately 2 million were treated. But during those years, another 15 million or so got newly infected." Currently Ho is executive director of the Aaron Diamond AIDS Research Center, where he is working on potential vaccine approaches, which he also discusses here. This transcript is drawn from four interviews conducted in New York and China in April and June 2005, and March 2006.

Tell us the story of how the first cases appeared. It was a complete mystery what was happening, wasn't it?

Sure, the initial cases were a great mystery to all of us who were in the clinics seeing patients. I remember that period vividly because I was a chief medical resident working at Cedars-Sinai Medical Center in the west part of Los Angeles. One day we had a young gay man who came into the hospital with all sorts of problems, but dominated by shortness of breath. It was clear that he had pneumonia, and it was severe pneumonia wiping out both lungs, and he was short of oxygen. When the diagnosis was made through a bronchoscope that went down and took some biopsies, it came back as Pneumocystis.

It was surprising, because Pneumocystis previously was only found in people who had immune system [was] damaged by chemotherapy or other drugs used to, say, stop transplant rejection. … He was treated for the pneumonia, and then we all realized, aside from that, he had a lesion in his brain, and that later was diagnosed to be Toxoplasma, which again is another organism that would only cause infection in people whose immune system was damaged. Later we learned that he had cytomegalovirus, or CMV, in his gastrointestinal tract.

So it seemed like he had a multitude of problems all occurring because of some compromise to his immune system, so it was a great mystery to us. But nevertheless, he was treated and was better for a short period. And then weeks later another similar case would come in, again in a young homosexual man. And it was in this way that some of the early cases in Los Angeles were witnessed at Cedars-Sinai Medical Center and UCLA Medical Center. …

For you doctors in the front line, at this point is a mystery like that alarming? Is it scary?

I wouldn't say that we were scared; we were puzzled. What was going on? Because if you could go to the medical textbooks, it's pretty clear that the kind of infections we were seeing were well described in cancer patients, in transplant patients and in patients who have taken heavy, heavy doses of steroids, for example, to suppress the immune system because they had lupus or some autoimmune disease. But in people who were born healthy and lived a healthy life and then all of a sudden came down with this sort of infection that was virtually unheard of? And so that immediately triggered the question, what was going on? …

Before long these patients start to die, don't they?

Yes. It was then clear after a few months that while you could take care of the acute complication that they were suffering from, once they're discharged they came back with again other problems or similar problems, and the early cases were all dying in a matter of a few months. So this was a lethal disease, the cause of which was completely unknown. …

In this period of mystery and puzzlement, what kind of theories were being kicked around?

In those very, very early days, there were a lot of theories. It ranged from something like a new virus or bacteria or some other bug that was being transmitted that caused the destruction of the immune system to the lifestyle of these men.

We have to bear in mind that during the years when this concerted treatment effort took place, approximately 2 million were treated. But during those years, another 15 million or so got newly infected, so we had a net loss of about 13 million infections by a virus that is lethal if untreated.

We know from their medical history that many of them had hepatitis B, syphilis and other sexually transmitted diseases, so there was a theory that they were being overwhelmed with too many infections and their immune system then crashed.

There was a theory that suggests cytomegalovirus, CMV, which is known to cause some degree of immunosuppression, was rampant in these cases and caused the immunodeficiency.

Some of the men had used nitrates, or poppers, and those were commonly put forth as chemicals that perhaps suppressed the immune system. So we were looking at a couple of dozen possible explanations. …

… What were the indicators that it might be a virus?

I think early on it was difficult to pin it on one specific possible cause. But given the fact that all these cases had a history replete with many different infections, ranging from hepatitis B to syphilis to gonorrhea to what used to be called the gay bowel syndromes, that is, a lot of sexually transmitted diseases occurring in the gastrointestinal tract, in the rectum, and infection was a strong possibility. But when we look at the textbooks to see which infection would cause immunodeficiency to this extent, that was very, very much missing in what we could find.

the cocktail

Part Two: Chapter Two A Radical New Treatment

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It was clear that we needed to evaluate the immune status of these early cases. Some of the blood samples were collected and were sent to the only clinical immunology lab that was available in L.A., in the west part of L.A., and that turned out to be the lab that Michael Gottlieb directed. And fortuitously, the lab had just developed these tests based on the use of a few new reagents called CD4 and CD8 antibodies made available only in the preceding few years.

It was through those measurements that a common denominator for these cases was found, and that was the CD4 T-cell number was low in all of these early cases. So we at least could tie them all together through that common feature. We still did not know why the CD4 T-cell was low.

But you now knew this was something that was a marker for the disease.

That's correct. …

Do any of those early patients stick in your mind? I mean, were they suffering terribly? Was it very scary for them that they were suffering from a disease that the doctors knew nothing about?

Oh, I think so. I think there's no question the patients were suffering from their opportunistic infections. Pneumocystis pneumonia could choke you, literally. Then the various opportunistic infections in the brain could cause seizures and other problems. It's clear that the patient's mouth is often covered with thrush. The intestinal tract could be affected by various bacteria or viruses, so they would have diarrheal illnesses. And, very importantly, the Kaposi's sarcoma is quite disfiguring, so they could have spots on their skin, on their faces. Even more dramatically, this virus, CMV, could cause destruction of the retina, and so it was clear some of them were suffering and losing their vision.

And bear in mind we're also talking about a population that has suffered discrimination -- gay men. Then some of them, because of the fact that they were coming down with a mysterious illness, were facing rejection from friends and family. So they're suffering at all different levels. …

How was the virus finally pinned down?

If one were to be logical about this, we knew the CD4 T-cell was destroyed, so there was the distinct possibility that the CD4 T-cell was the target of some infectious agent. … Our laboratory, and I would say about half a dozen to a dozen laboratories around the world, began to use T-cell cultures to see if we add materials from the patients, whether something could be propagated. It was in this manner that Françoise Barré-Sinoussi in Luc Montagnier's lab put a piece of a lymph node from a French patient into a culture and found that that culture would propagate what we called reverse transcriptase activity.

Reverse transcriptase is an enzyme of retroviruses, and that was the first indication that a retrovirus might be involved in this syndrome. They showed this reverse transcriptase activity as being transmissible in the tissue culture, and they also showed one electron micrograph of a particle that looked somewhat like a retrovirus. So that was just the first hint that a retrovirus was causing AIDS.

It was published in a prominent journal, and yet it was not convincing enough in 1983, when that observation was made. It was only in 1984, when more evidence came out from [virologist] Bob Gallo's laboratory that showed in fact it's highly transmissible; it's indeed a retrovirus with a morphology well documented and [isolated] from many, many cases; and linking it to an antibody test that helped diagnose who was carrying this virus who was not. …

What is a retrovirus as opposed to a virus? …

There are many, many different families of viruses. Viruses are tiny organisms that cannot survive by themselves. They need cellular machinery to replicate, to grow. Retroviruses is one family, and their unique feature is that they carry their genetic material in RNA form. But in order to complete its life cycle, it has to go through a DNA form. So it has the unique ability to convert RNA to DNA, and hence the term reverse transcription. …

So one way to look for retroviruses is simply to measure reverse transcription capability, and in fact that is how Barré-Sinoussi and her colleagues discover HIV. …

So now the hunt is over; now the battle begins. How do people set about trying to combat this virus?

Well, when Bob Gallo's lab published the four papers pretty much convincing the bulk of the scientific community that this new virus, which later was called HIV, was the causative agent, there was a great deal of optimism. We all recall the secretary of health [Margaret Heckler] at the time declared that a vaccine is just around the corner because of this seminal discovery. So there was a lot of optimism that once we identified the agent, we will figure out a way to conquer it, even though we know that the epidemic was growing.

By then, we knew the epidemic was spread throughout U.S. and was in Europe and certainly in Africa. There was a great deal of optimism that science would conquer again, would come up with the tools to make drugs and certainly would come up with a vaccine. A lot of people went to work right away to screen for drugs that would shut down HIV in the test tube. That took place at the NIH [National Institutes of Health], in many academic labs and in the large pharmaceutical companies. And in fact, within a year or two, there were a series of compounds found to be active against HIV, including the first drug, AZT, and that emerged very quickly.

[What were the early approaches to a vaccine?]

… If the scientists in the field could just look at vaccine development for other viruses -- smallpox, hepatitis B, mumps, measles, rubella, polio -- and say, "Well, what techniques were used to develop some of those vaccines?," there were three principal methods.

One was to take a live virus and make it weaker in the laboratory through an attenuation process. Well, that was kind of scary as a way of approaching HIV, to attenuate HIV. Since it's such a lethal disease, it was thought to be universally fatal at that point. So people quickly gravitated to the two [other] principal methods to be tried.

One is to do what Jonas Salk did for polio, and that is to grow up lots of virus and inactivate it in the laboratory to kill that virus. That's what we would call whole-killed virus vaccine, and such an approach was being planned. In fact, Jonas Salk joined that effort to use his standard technique to apply to HIV.

The other way is basically to follow the hepatitis B model. With hepatitis B, if you make the co-protein of the virus, what we call the surface antigen, and give that alone, it can induce protective immunity. So people began to work on the co-protein of HIV and hoping that eventually would turn into an AIDS vaccine. So such approaches were initiated in the year following the identification and confirmation of HIV as the cause of AIDS.

… What happened to that optimism? …

I think there was a clear dichotomy. The scientists were very optimistic in the sense that we have a new virus to work on, and it falls within a family of retroviruses, which we actually know something about. And so the retroviruses have certain enzymes, and we could target those enzymes and hopefully block HIV growth in the laboratory and probably in people. So there's that kind of optimism.

But on the clinical front, we know the epidemic was spreading. I would say the clinicians, the nursing staff and other health care professionals were confronted with a growing crisis that they had so many patients for whom nothing could be done therapeutically. So there was frustration on that side.

Drug discovery is a slow process. You have to spend years, typically, screening and then doing the development work to optimize a drug and then to test safety in animals and take it on. The drug industry would like to say that's a 10-year process. But we were confronted with a health crisis. And so already, early on, once the compounds were found to be active, there was a lot of pressure to move things along quickly, the so-called fast tracking of drug development. And you could see the government stepping in, especially the FDA [Food and Drug Administration], to try to say, "OK, how do we move some of these things that are found to be useful in the laboratory into the clinical arena?" And so for AZT to have been found in '85 and then to make it to clinical testing and eventually approval in two, three years is quite remarkable.

What was the process that led to AZT being discovered, because it wasn't designed for AIDS, was it?

No. AZT is a nucleic analogue. By that I mean it looks like one of the four building blocks for our DNA, and so AZT and other related nucleosides were designed as part of cancer chemotherapy. We know these type of compounds could affect DNA synthesis, and usually cancers involve cells that are dividing and would undergo quite a bit of DNA synthesis. Therefore, these compounds have the potential to be more toxic to cancer cells than to normal cells. So they were designed at then-Burroughs Wellcome for that purpose.

But once you want to screen all your compounds for a specific HIV target, you pull all of them. It was quickly found that AZT and several other nucleosides have activity against HIV, and therefore they could be pushed forward.

It makes sense, because HIV has to make DNA from the RNA template, and what AZT does is it interpolates into the growing DNA chain, and it serves as a false base. Instead of the regular base, it fools the body and puts in AZT. But its AZT has been modified, so it doesn't have an adapter for the next base to be added, so it just terminates the DNA synthesis.

Why was that not the final cure?

When AZT worked pretty well in the laboratory, it was put into clinical trials, and then after that initial study it was clear AZT was beneficial. It was slowing down the disease by a little, but not dramatically. People were living months longer, certainly not years longer. So it was clear to the scientific community, here we have a first drug that was beneficial, but it was far, far from being sufficient or optimal. Why? Well, we didn't fully understand until much later. …

You discovered that a healthy person can be infected with HIV, can carry the virus without actually having AIDS. …

… We were fortunate enough to jump right in in 1984, when it was clear that a retrovirus was causing this. So I was really at the right place at the right time on several occasions along this AIDS timeline. …

What you were referring to is that we very quickly tried to do some very obvious things. We thought this was a transmissible virus. The epidemiology taught us that people were passing this through sexual contact, and therefore the virus should be in seminal fluid, and we wanted to prove that, and very quickly, in middle 1984. …

What was surprising was that was done from an HIV antibody-positive gay man who was not suffering from any acute problems. So we were able to isolate the virus from this blood, from his seminal fluid, and establish the fact that there is virus in the seminal fluid. … He was somebody who was feeling well, had no symptoms whatsoever, and his CD4 cell count was lower than normal, but not dramatically low.

So we, from that one case, began to establish the fact that there's the what we call asymptomatic carrier; that is, somebody who carries the virus but does not suffer from any disease. And from that initial case and the subsequent work, it became clear that HIV could infect but doesn't cause problems until some years later, and there is a period where one is symptom-free but HIV positive, and potentially infectious to others.

People talk about a dormant phase of the disease. Can you explain [why] people used this term? You had a famous hunch that … it wasn't really working like that.

…Well throughout the 1980s we knew quite well that HIV could affect the person and not cause disease for many years, in fact as long as a decade or more. …And that lulled us into thinking that HIV wasn't so active for a long period of time….

When we talk about dormancy in the course of HIV infection, there are two parameters that should be discussed. First is, there is no doubt that when we talk about dormancy as related to a clinical aspect, one could go for years with HIV without showing any signs, overt signs or symptoms. That is clear-cut.

But does that mean that the virus is dormant? That's another matter. So we call that clinical dormancy versus viral dormancy. … We now know that they're not equivalent. …

So what is happening is that we now know, based on work done in the late '80s and early '90s, that in fact the scenario is the following: HIV comes in; it infects the person; it replicates, grows at enormous levels all the time continuously if the person is not treated. That has a continuous onslaught on the immune system, and so these important CD4 T-cells gradually deplete in the body of the infected person. …

So you have many years [when] the virus is attacking the immune system and slowly destroying it. But the manifestations in the person do not occur until many years later -- in fact, a decade later. So there is no viral dormancy, the virus is very active, but there's a protracted symptom-free period when the virus is actually causing relentless destruction.

… Describe the hunch you had about how this might be working and how it turned out that [University of Alabama's George] Shaw was working on very similar lines.

… Beginning in the late 1980s, my laboratory was beginning to try to grow the virus from as many cases as possible, and to grow it from blood cells, grow it from plasma, which is the fluid part of blood. There was a study that we ultimately published in 1989 that said to me and my colleagues that we could actually isolate the virus rather easily from every person who's HIV antibody positive, and we could isolate it most of the time not only from the white blood cells, but we could also obtain it from blood. … Some of these people from whom the isolation was made were symptom-free. So that began in the late '80s to tell me and my colleagues that there was more virus replication than the earlier observations.

And then in the ensuing few years, our group now began to use more sensitive techniques called PCR [polymerase chain reaction] to quantify amount of HIV. And George Shaw's groups began to adopt PCR techniques, and several other groups did similarly. People began to measure, in clinical material, more and more HIV.

That set the stage for us to think, well, in fact, how much HIV is being made? And the opportunity to really address that in a concrete way came in 1994. The reasoning is quite straightforward: By then, we knew that for most of the time, if you take an infected person and measure the amount of virus in his blood, there could be some variations, but it's going to be a variation around a mean. So overall it seems to be pretty steady. So you have a fixed concentration of virus in the blood. That's what we call an equilibrium, and an equilibrium is maintained by production balanced by clearance. These two must be approximately the same in order to maintain that equilibrium.

So we made the argument that if we now have a way of abruptly stopping production, we could actually look at the decrease in the virus as a reflection of clearance. … In 1994, by then we had worked on protease inhibitors, and they emerged from the lab to enter the clinic. We had the chance here to put one of the protease inhibitors into patients for the very first time.

It was in the setting of that treatment trial [that] we observed the dramatic decline in the viral amount in blood. We fortunately, because of the hunch, or actually years of experience, designed the experiment so that we could quantify the rate of decrease very precisely in the first 10 days of therapy. That allowed us to use math, a little bit of calculus to determine the clearance rate. Well, if you had a clearance rate, you also had the production rate at equilibrium, because those two were approximately equal.

So we did a very nice clinical study involving mathematicians, chemists and a whole consortium of people. And to our surprise, at a meeting in the summer of 1994, I bumped into George Shaw and a third colleague, and in dinner conversation he and I both realized that we had similar data. … By October we both were at a conference and had the opportunity to present our data. I went first, he went second, and then it was pretty convincing to much of the medical community [and] the scientific community as well. Those papers were quickly published in Nature in January of 1995. …

[What did this discovery mean for treatment?]

The consequence of that obviously is central to thinking about how HIV destroys the immune system, but also it has great ramifications for therapy, because HIV is an error-prone virus. As it replicates it makes mistakes. Now, that may not be all bad, because mistakes allow HIV to generate new variants, some of which will allow it to survive in the presence of drugs, survive in the presence of immune attack, so that's actually an advantage to HIV. When we know how much virus replication is going on and we know the error rate with which the virus makes mistakes, then we could begin to calculate what HIV would do if we applied drug pressure, and from those type of calculations came to the conclusion that it's inevitable for HIV to develop drug resistance if you give it one drug at a time. However, if you start to combine the drugs and try to force the virus into a corner using multiple drugs, it is exceedingly difficult or statistically improbable for HIV to become resistant to all the drugs simultaneously. That for us formed the foundation of thinking about combination therapy.

That was in 1994, '95, and by the middle of 1995 we had taken that concept very quickly into practical testing of combination of drugs, at that time typically three drugs. We set up several studies in mid-1995, and by mid-1996 we were able to show that for the first time we could drop the virus down so that it's not detectable and keep it down for a year or more. That was what was later hailed as the major advance in HIV therapeutics. …

What was it like for you personally when patients started taking triple cocktail and you saw the results?

I think it was of course very gratifying. We had in 1994 already been very pleased with the outcome of giving protease inhibitor to patients and seeing dramatic decrease in viral load, but the single drug led to only short-term benefit, because then the drug-resistant virus would emerge after several weeks or several months.

But by 1996 we saw that the response with combination therapy was rather dramatic and sustained. That was the difference. What also was impressive was the level of immune restoration was much greater. For the first time we see some deathly ill patients totally recover after two to three weeks of good therapy, and we had within our own clinical studies several patients who had essentially no CD4 T-cells left and were thin, wasted, no longer very functional, and some even bedridden. To have those cases return gradually over a few weeks or a couple of months to a state where they would return to work is certainly impressive. So this in the field has been termed the Lazarus syndrome by some folks, and that is true; there are a number of such examples where people got out of their deathbed after a few weeks of therapy. …

You also had The New York Times [Magazine] in '96 running a story called "When Plagues End." There was a sense that this thing is manageable now. But did you find that combination therapy meant that there were no troubles ahead?

No. We always felt that combination therapy was a great step forward, but it was far, far from the end. First of all, we wanted to continue to explore, when we dropped the virus to undetectable level, is it just hiding below our detection, or is it continuing to go down, and would it go down to nil? Very quickly by '97, '98, we realized it wasn't going down to zero so that HIV was eradicated; in fact, it was settling down at a lower level, and so we weren't able to cure HIV infection. That remains a goal. However, we don't have the tools to achieve HIV eradication presently. And of course we know that the therapies that were applied for American patients would be very expensive to use in developing countries, not to mention all the logistical challenges.

… What happened with the drug resistance? …

Another problem associated with combination therapy was that initially it was very complex, so the complexity made it harder for patients to stick with the regimen. And if enough of the doses are missed, then the drug levels could dip down, and that would allow HIV to begin to break through and become drug-resistant. We were seeing some of that. This was compounded by the fact that drugs had side effects that patients don't like, so occasionally some people would even voluntarily take a partial drug holiday, and that also added to the problem of drug resistance.

It became clear that while the initial studies were able to drop HIV to undetectable levels for almost every patient in the beginning, some would not have durable results, and that's because of the gradual development of drug-resistant virus, and that continues to be a problem that we face today. …

When people talk about the "immune system crashed," what is the immune system?

The immune system is a complicated defense against foreign invaders. It consists of many different types of cells. There is a part of the immune system that we call innate -- these are things that would zap the bugs as they enter our bodies. There would be these what we call neutrophils; they are kind of white blood cells that would simply gobble up bacteria. The innate system, we're learning, is actually very, very complicated, and it's a more primitive part of the immune system that not only we have, but the mouse has, and certainly even much, much lower animals like a fruit fly would have.

But there is a more complicated part of the immune system called the acquired immune system, which has memories. It has memory because once it sees polio, it remembers what the poliovirus looks like, and if it should come again it would be whipped out very quickly. That part, again, is a mixture of many different cells, what we call antigen-presenting cells, a cell that would capture the invader and show it two different limbs of the immune system. There's the B-Cell limb and the T-Cell limb.

The B-Cell part, most people have an inkling what's going on. B-Cells turn into plasma cells that make lot of antibodies, and these antibodies are basically large proteins that recognize different organisms and different things, and our repertoire for that is truly amazing. We could recognize thousands and thousands and tens of hundreds of thousands of different invaders. The immune system is most remarkable. And so the antibodies latch onto bacterial viruses and inactivate and help clear them. …

The T-Cell cannot be viewed as a single cell. The T-Cell is a collection of cells in the acquired immune system; it's the part of the immune system that has memory. And there are many subsets of T-Cells. One subset is what we call helper T-Cell, and they have a marker on the surface called CD4. In fact, that is the target for HIV. So this helper T-Cell is very important in interacting with B-Cells, with what we call antigen-presenting cells and with other killer T-Cells. So it is a coordinator or orchestrator of several of the key immune responses. And so if that cell is depleted by HIV, one could have a multitude of immunological consequences.

Then there's another large population of T-cells with CD8 marker on the surface, and these have the ability to recognize foreign invaders and kill the cells that are producing the foreign invaders. …

HIV does not replicate in 99.9 percent of the cells in the body. It's very strategic in homing in for helper T-cells that have the CD4 molecule on the surface. By knocking that cell off, it could cause havoc throughout the immune system, because this helper T-cell is a very important orchestrator of the immune response.

Explain how the virus works. …

HIV as we know it now goes through its life cycle in about 24 hours. It has this ability to bind to some cells in our body, because HIV will bind specifically to the CD4 molecule on the surface of the T-cell and use that as a receptor. Once it does that, HIV the co-protein changes shape a little bit and binds to a second molecule, which we call the co-receptor. Then these two interactions would result in a dramatic change in the conformation of the co-protein. So now HIV could directly fuse with the target cell.

When the two membranes fuse, the internal contents of the virus are then injected into the cell. So now HIV penetrates into the cell; it has a core. This core has got to come apart. Within this core, HIV has this genome which consists of two strands of RNA. So the genetic information is carried, and these are two identical strands in most case. The virus now has its own machinery nearby to make, from the RNA genome, a copy in the DNA form. This is the step we call reverse transcription. It would make a copy of the DNA, and then the first copy of the DNA would be copied into a second complementary strand, so that in this fashion HIV converts its genetic information from RNA form into something that our cells know about, which is double-strand DNA.

Then HIV has a way of transporting this newly synthesized DNA into the nucleus of the cell, which is the central part of the cell where the chromosomes reside. Once it gets in there, HIV has a different enzyme to basically make a cut in our chromosome DNA and insinuate -- or what we call integrate -- the newly synthesized viral DNA into the chromosome or the cell. Now HIV becomes part of the host cell. From there the host cell doesn't know whether that piece of DNA is foreign, so it uses its own machinery to make HIV's various proteins. And so HIV will make lots of proteins, some RNA. Then what happens would be all the viral protein would rally to the surface and aggregate and assemble. Then what happens is we see the virus particles bud out from the surface.

A lot of this could occur by HIV hijacking the cellular machinery. So HIV only carries a few of its own important enzymes to do its own business, and the rest of it is completely dependent on the machinery of the host.

[How fast does the virus replicate?]

… From an infected cell we know that thousands, perhaps even 10,000 progeny particles could emerge. Now, that's in the laboratory, and so it's easier to define that, but we could also show that in infected people, this infection, this life cycle continues every day, relentlessly. HIV essentially goes through one generation per one to two days and would produce from an infected cell thousands of progeny. Therefore, in the body, we're talking about not just millions but billions of particles made in an infected person every single day. …

Is it true that a retrovirus [mutates more often]?

In general, a retrovirus, as it converts RNA to DNA, is more error-prone; that is, it makes mistakes. It's like a typist who's obviously trying to copy something but occasionally would make mistakes. Doing reverse transcription, it's much more error-prone than the process of going from DNA to RNA in our cells.

So it's a problem for retroviruses, but it's also an advantage for retroviruses. This error-prone nature could lead to self-destruction, but also lead to creation and more variance -- more mutations -- and novel variance. Darwinian evolution tells us if you have more variance, the fittest will survive. It's an adaptive mechanism.

The other thing about reverse transcription is that it doesn't have a repair process. There's no proofreading function, if you want to make the typist analogy. It makes mistakes, and it doesn't go back and check. For our genetic information to go from DNA to RNA, we make fewer errors, and also, we have a proofreading function that would fix the mistakes.

So this turns out to be a good and a bad feature for HIV. Some forms would be lost because of mistakes, but new forms would be created, and that will confer an advantage to viruses like HIV.

Does this make it exceptionally difficult to come up with a vaccine to prevent it?

It is one of the major obstacles to a vaccine development, because HIV grows so much, replicates so much, because it makes mistakes so much, we're multiplying two high numbers, and consequently, we are not confronted with one HIV strain out there. We're confronted with a huge array of HIVs throughout the world. They are all related, they all have common features, yet there's so much variance out there.

This poses an additional challenge for those of us who are trying to come up with a vaccine. It is not just trying to prevent infection of one strain, but it's a multitude of strains. …

What are the phases of the virus's life cycle that you could target [in] your attack?

Well, we now have 21 drugs to treat HIV infection, and they could be divided into three categories, with a fourth possibility, I think, on the horizon. The first part is reverse transcription and represented by the first drug, AZT. That of course is blocking the conversion of genetic information from RNA to DNA.

The second part that emerged in the 1990s is actually the last part of the viral life cycle. As viruses are budding out, within these particles there's a chemical scissor which we call protease that must cut the proteins. So the big chunks could be broken down into smaller pieces that fit nicely together to assemble in infectious particle. If you gum up that scissor, it's unable to cut, and therefore the cell will make progeny virus, but they are dead. Such agents [protease inhibitors] were developed in the early '90s and found to be active in patients beginning in 1994. So those are the two principal categories.

A third category emerged more recently, and that is, we began to understand how HIV binds to the receptor, then the co-receptor, and then fuses with the cell membrane. One could now target that process at one or several of those key interactions. And there is one licensed drug that blocks the entry, or penetration, step.

But of course in my description of the life cycle, there is also another step, and HIV basically takes the newly synthesized DNA and inserts it into the chromosome of the host cell. That step is also amenable to attack, and drugs, I'm quite certain, will emerge in the next few years directed against that particular step. …

Tell the story about the woman from Africa [who spoke at the 1996 International AIDS Conference in Vancouver]. What did she ask?

It was an African woman in her 30s, and she was there as an invited guest to talk about the situation she faced in Africa. Of course there was already all the hoopla surrounding combination therapy. And she posed it quite simply: "What does this mean for us? Our fate is the same. You're talking about therapies that cost hundreds if not thousands of dollars per year, and yet we don't have the resources to buy an aspirin pill for our headache sometimes." And so I just remember sitting in the audience listening to her, being very moved by her comments and realizing that it's going to be a real challenge to help people living with HIV in Africa and such developing places.

The other thing was that we realized the epidemic was continuing to spread, and drug therapy alone would not put an end to the spread of this virus, and we had to begin to focus on the vaccine side. From that moment, I can tell you that, for myself, we wanted to continue the work on therapeutics, but we also wanted to [get] back to the lab and think about what role our institute could play in vaccine development. …

We cannot continue just to treat patients as they become infected. We know at that time and presently the new infection rate was approximately 5 million a year, so the number was just increasing so rapidly. Yes, by developing a drug to treat the infected we could reduce mortality and morbidity; however, the real solution to this epidemic is to curtail the spread of the virus, and that is done through education, through implementation of measures that would block transmission, such as condoms, needle exchange and such measures, or, most effectively, if we could come up with a good vaccine that would block transmission. As scientists, that I consider to be our major mission in the prevention area. …

… Do you want to characterize and describe some of the theories of AIDS denialists? … What was out there and was available for them to grab on [to] if they wanted to say that HIV was not the cause of AIDS?

I think this is a long subject if you want to discuss it properly, but the denialists were aided by the fact that in the mid- to late '80s, we weren't finding a lot of HIV, and so HIV was present in relatively small amounts, and yet the destruction of the immune system was so severe. It really enhanced their story. As techniques got better and as the studies were done, that apparent paradox was resolved, but the denialists were stuck, and they kept saying it's not the case in the face of mounting evidence. I mean, if HIV doesn't cause AIDS, then how would anti-HIV drugs lead to such dramatic improvement in one's well-being? And that's only one example. There are plenty of examples to do away with this ridiculous theory.

But of course some people have been reading nothing but literature from this particular group, and unfortunately I think in surfing the Internet, [South African President Thabo] Mbeki was greatly influenced by their writings and came up with the idea that maybe HIV is not the cause of the problems that the South Africans were facing. Certainly by the time of the Durban conference, he was still openly questioning whether HIV was the cause, and at the opening ceremony, he in fact said the cause of AIDS was poverty.

Now it's somewhat rhetorical. Obviously poverty is at the root of the problem, resulting in many of the high-risk practices, but fundamentally we all knew HIV is the cause. And for a president of a country that had the largest number of cases in a country, he could not afford to adopt that attitude, and particularly as the leader of sub-Saharan Africa, he could not afford to take that attitude. …

[What did you say at the Durban conference in response?]

… I had this opportunity to give the plenary lecture the next morning, and as I walked up to the podium and thanked the convener, I showed my first slide, which is a picture of the virus HIV. I was going to talk about HIV pathogenesis, but I used the opportunity to say, "Ladies and gentlemen, this is the cause of AIDS." And with that the audience applauded loudly, knowing that I was referring to the thinking of President Mbeki.

We were just in Brazil, and some of the government officials that were behind their program in the late '90s said that they were encountering from WHO [World Health Organization], USAID [United States Agency for International Development], resistance to the idea of providing treatment to the developing world. People would say if you started a program you won't have the money to sustain it, and therefore it's irresponsible to be talking of treatment. Do you remember encountering or coming across that kind of thinking in the late '90s?

That kind of thinking, that we cannot deliver antiretroviral therapy to the developing world, was quite prevalent throughout much of the late 1990s. I think Durban changed that. I think there was a school of thought that [said] the task was simply too great, the challenge too daunting and the cost too high, and [so] why bother? You cannot do it well. You don't have the infrastructure; you don't have the trained professional staff; you don't have the money to pay for all these therapies. But Durban changed the nature of that open dialogue to say: "Why not? We need it, and this is the right humanitarian thing to do." …

It certainly wasn't led by the South African government. It was the physicians and the scientists and the social workers and what have you who gathered there who began to ask why not. That led to the movement. And of course WHO and such agencies completely turned around in the subsequent years. …

[Were you aware that the Bush administration was developing PEPFAR (President's Emergency Plan for AIDS Relief) before it was announced?]

We were all aware that the government is studying the situation, will have its own plan. I guess I was pleasantly surprised by the magnitude of President Bush's commitment to this problem. I thought with his political views he was going to not take HIV/AIDS so seriously, so the announcement of the $15 billion commitment for AIDS certainly was welcome news, and the fact that he would take it on in such a serious manner was certainly well received by all of us. …

Just briefly on the president's plan: $15 billion now on the table for five years but targeted to 15 focus countries, most of which are in Africa. When you look at that and look at the next wave of the virus, do you think the money is being allocated properly?

Well, there's no doubt that the chosen sites are countries with a desperate need and with a heavy caseload, so there's nothing to criticize about site selection. Yet you could say, well, there are many other countries that are equally deserving of this kind of assistance. But of course, again, there are limitations as to the available foreign aid from the U.S. for this particular problem. Next-wave China, India could account for 20 million cases, something like that, and that's huge, because that would be a number approaching the current caseload in Africa. But arguments could be made on the basis that these two countries have greater resources than Africa. So I think it's a tough, really tough call, and no matter what decision is made, there will be detractors. …

Do you think more money is required?

It is my own feeling that if any citizen in the developed world, if they would just take five, 10, 15 minutes to understand the reality of this problem and to appreciate the scope, the magnitude of what we're faced with, would come to the conclusion that $15, $20 contribution per person toward the global fight [against] AIDS in the developing world is surely more worthy than many other projects we fund with that kind of money. …

In the early part of this decade, what was the [Chinese] government's attitudes towards HIV?

I think China had its first case in 1985, and somebody returned from a foreign country, so he did not acquire HIV infection domestically. The real first epidemic occurred in 1989; a cluster of injection drug users in the Yunnan province in the south was identified. Initially there was a great deal of disbelief, so the blood tests were repeated, and they came up again positive.

Then it was quickly realized that on the other side of the border there was an epidemic linked to Burma and ultimately to Thailand, and HIV was coming through together with the heroin trade. But you have to realize that injection drug users are a fringe population. There was this thinking that well, yes, it could occur in this population, but not in the general population, and so the problem did not receive a great deal of priority.

And then beginning in this period, from '92 to '96, when the caseload increased dramatically because of the blood-selling practice in the central region of China -- but remember that the epidemic was only recognized in retrospect. As it was developing, it was invisible. …

So there was a general belief, as many countries went through, that this is a problem that affects somebody else's country, but not ours. This is not unique to China. I think many countries went through a typical denial phase before accepting this thing and then the full political [will] to want to fix the problem. …

Only in the past two years, I would say, I sensed a dramatic turnaround, and I certainly see, in terms of rhetoric and in terms of action, full political commitment, at least at the central government level, to want to fix this problem. That, I think, is very gratifying, the recent change.

[Why did the government's attitude change?]

I think there are probably multiple reasons behind it. I would like to think that many agencies that have been doing work in China for a number of years finally had the impact felt. I would include some of our own advocacy work on that list.

For example, in November '03, we organized a very important conference in Beijing and brought former President Clinton to the table to speak to the audience and to speak to the Chinese leadership. The dramatic turnaround was at least temporally correlated with his visit. Within weeks, the leadership in China demonstrated its commitment to this issue by visiting patients in Beijing Hospital as well as patients in rural villages in central China. Thereafter, all the policy changes were spot-on. So there's at least that temporal correlation.

But I think a very dramatic event in 2003 also had something to do with it, and obviously that was SARS [Severe Acute Respiratory Syndrome]. SARS broke out in early 2003, spread through China and the world. Initially the government perhaps treated it without the transparency that the Western countries expected, but in April of that year, it took charge and had a dramatic turnaround and demonstrated to the world that it could fight this epidemic with a great deal of force. And to everyone's surprise and amazement, SARS was brought under control by that summer.

I think it was a loud wake-up call for the country, and it turned the attention of the leaders to health problems for the first time. … As they looked at SARS, they looked at the burgeoning HIV epidemic and said, "Wait a minute; by comparison, SARS is dwarfed by AIDS, and therefore this has to be a higher priority." …

So what was it doing, and was it actually translated to the local level?

For example, the government's putting out directives about tolerance, on-discrimination. It's changing the laws to protect the infected. It's making a commitment to provide free treatment and free testing, particularly for the patients living in the poorer areas. And I see a great deal of effort going on to prevent the further spread. So educating the masses is becoming a priority. Treating the patients with good combination antiretroviral drugs is becoming a priority.

So in the last two years, as I travelled throughout central China and southern China, I could see the changes myself, and see the changes in the attitude. But China's a huge country, and in provinces such as Hubei and Yunnan, you have much more progressive views than in a province like Henan, which I think is still more conservative and more closed. …

In terms of this commitment to get the drugs to the developing world, … from a scientific viewpoint, what are the challenges at play here?

In the developing world, including many regions in China, there are lots of challenges trying to administer good antiretroviral therapy. In the U.S. we have over 2,000 drugs to choose from. Here in China, a short while ago there were only four domestically made drugs; now there are six, so the combination that you can create using the limited number of drugs is also quite restricted. The therapeutic options are few in number here in China and in the developing world.

Cost becomes a major consideration. In the U.S., because of insurance and government assistance programs, it's not a major factor, but the cost here is a major factor. So for a physician to think about treating a particular patient, or for a person who is designing a program to treat many patients or to intervene with the mother to block transmission to the child, it makes a huge difference in terms of what type of weapons you have in your arsenal to work with. …

So you have millions on treatment; then the program is ended [after] five years. What happens then?

I think if you have a program that's not sustainable and patients all of a sudden have to stop after benefiting from ARV treatment, that's very cruel. We know that in the U.S., in the course of conducting research, if you found something that was effective, you have a moral obligation to continue it one way or another. I think that same moral obligation exists. It's not a legal obligation, but I believe there's a strong moral calling to go out there and find a way to continue it.

I think in the end you have to appeal to all these assistance programs, whether it's the PEPFAR from the U.S., the Global Fund [To Fight AIDS, Tuberculosis and Malaria] from the U.N. or large foundations like Gates, Rockefeller, etc., whether they would be willing to step up and help sustain the programs.

And the scientific risks if people go off treatment in terms of the virus?

I think the downside of going off treatment completely is not as huge as going off treatment partially, because partially would result in the emergence of drug-resistant virus. If you go off completely, you simply don't get the benefit of therapy; that is, virus replication will return, destruction of the immune system will continue, and that ultimately would lead to the downfall of that infected person. You sort of return him to his prior status, and that must be very frustrating, must be very cruel to that individual.

… Talk about your research on the vaccine.

Well, for the past five years we've been working on vaccine development. We have a team that's making a series of different kinds of HIV vaccines, and for the last few years we have taken two of them from laboratory research to clinical development and have gotten U.S. FDA approval to move them into human testing in New York.

One of them, the first one, has been in clinical trials for the past 18 months, and another one entered trial about three or four months ago. We have no idea whether these will work or not in protecting against HIV infection, but we are going through the phases, and at this stage we are simply assessing the safety of these vaccines. When we determine that these are safe enough, we will move on to the Phase II study to determine whether these are stimulating the immune system in a proper way. If we pass that milestone, we would then move it to a trial to assess whether the vaccine protects or not.

We're working on a series of these. But ultimately, when you think through what vaccine development entails, at some stage you're going to have to test it in a location where there's a fair amount of HIV infection ongoing, and where you could conduct a rather sizable trial involving thousands of subjects to be followed for several years. You think through the logistics of that, and you realize you'd better start preparing for that. You've got to prepare [for] success and gear up for that some years before.

It was because of that sort of consideration we picked the southwest region of China, because there is still a lot of new infections, particularly among the injection drug users, and we could go in and use that population as a study population for vaccine. So we've been thinking about that as part of our long-term vaccine strategy. And we've been thinking about if we were to do that kind of clinical trial in south China, we also have to address production issues of our vaccine in China and clearing the Chinese FDA so that we have the proper approval from the authorities to go ahead and do so. ...

Scientifically, in layman's terms, what's your strategy for the vaccine?

The first two vaccines are called DNA vaccine and a vaccinia-based vaccine. The DNA is simply a circular piece of DNA into which we have engineered a number of HIV genes, and when this DNA is inoculated into, say, the muscle, the muscle cells would make the HIV proteins but without making infectious HIV, so it's perfectly safe, and these proteins would be shown to the immune system and tickle them to get a proper response. So that's the first vaccine.

The second vaccine is to use a vaccinia, which is nothing but the smallpox vaccine which was used to help wipe out smallpox. So it's an attenuated smallpox virus, and we could engineer the same set of HIV genes into this vaccinia and use it as a carrier. And now when you inoculate this vaccinia onto the skin or in the muscle, it will make some proteins, including the HIV proteins, thereby stimulating the immune system. ...

Let me ask you to respond to something that [Samaritan's Purse President] Franklin Graham said when he was talking about the vaccine and his work on this. He said: "The scientists, they want a vaccine that's 100 percent effective or close to it, that's just like polio or something. But actually, when you talk about HIV/AIDS, it's a moral problem, and you have to change people's behavior." ... How do you respond to that?

Well, I don't disagree with what he's saying. I think vaccine is some years away. What do you do in the meantime as the epidemic rages on? So what we can do today is to educate the public and to have that knowledge, modified behavior and lower risk of HIV transmission. I agree that there's a moral obligation to do that, and that must be done as much as possible, as widely as possible.

On the other hand, I think we all realize that changing behavior is most difficult. Yes, we could achieve limited degree of success, and that we must aim for, but it isn't going to completely stop the epidemic, whereas if we could truly come up with a highly protective vaccine, we could achieve that goal in the long run. So I think in fact what the world needs is sort of a public health solution through mass education and so on to the current crisis. ...

What about the role of the influence of the Christian right movement in the implementation of the Bush administration's program?

Well, I think it's OK to emphasize the fact that abstinence, for example, is very important to fight the sexual spread of HIV infection. There's nothing wrong in emphasizing that and in urging people to delay the beginning of sexual activities. But we also know there are limitations to that, and the human behavior could be modified only to an extent. When the behavior cannot be modified, I think you have to look at it with a practical eye.

Condom distribution, condom use we know can prevent many sexually transmitted diseases, including HIV. In the same vein, needle and syringe exchange could lower HIV transmission in injection drug users who share apparatus. So what is the greater moral obligation here? Many of us will look at stopping HIV transmission as of paramount importance, and we would urge the inclusion of measures that actually work, and I think we will consider stopping the spread of this deadly virus as the greatest moral obligation.

Is there a new strain [of HIV]? What is it, and why does it matter?

We saw in early January a man who was referred to us because he had been found to be newly HIV positive, and he had a number of tests throughout 2003 to show he was HIV negative, because he was a gay man with a number of sexual partners. He became ill in the latter part of 2004, not feeling well, and in the process of being worked up, he was found to be HIV positive for the first time. He was referred to Dr. [Martin] Markowitz in our institute and as part of the routine workup for a new case of HIV infection.

His virus was characterized. It was then quickly realized that his virus was resistant to nearly all the drugs except for two. And at the same time, his CD4 T-cell measurement showed that he had already progressed to AIDS despite his fairly recent infection. His CD4 cell was down to 85, and then within weeks it was down in the 20s. And he was feeling lousy. It was clear from his history that his infection could be as short as four months or, at the longest, it was 20 months.

So he had developed AIDS in four to 20 months, and his virus was resistant to nearly all the drugs so that you couldn't form a routine combination to treat him with. In addition, when his virus was characterized, it behaved very aggressively in the laboratory. ...

It was after a couple of weeks of studying this situation that Dr. Markowitz brought it to my attention, and we then brought it to the attention of the New York City Department of Health to say, "This is a unique situation." They studied it for a couple of weeks more, and they made the decision they needed to issue a health alert and conduct the press conference, which they did, and announced it to the world.

Why does it matter, and what does it tell you about the virus?

Well, I think the observation is not unexpected, because multiple-drug resistance has been described; rapid progression has been described. What is new in our case is the convergence of those two phenomena in a single case and in a man who also has many, many sexual partners. So there's a great deal of concern about whether this is the beginning of something bad. Now, nobody is saying for sure it is, but we certainly thought that the description of this case to the world was very appropriate.

So whether this marks the beginning of a new phase I don't know. But in time all of us fear that there will be a virus strain that will be resistant to our therapeutic arsenal and that if that were to spread aggressively, it would be a major setback in terms of our fight against HIV/AIDS. ...

If you imagine this virus having a character, what would its character be?

I have a lot of respect for this foe. It has beaten us again and again for a long, long time. And having studied it, I know it quite well, and I find it remarkable that it's so strategic in striking a key cell in our immune system. I find it so remarkable that it could grow continuously, nonstop, for years and years in an infected person, and in that process the virus that began the infection is very different from the viruses that finish the infection, because HIV has this great propensity to mutate, and so it basically continues to survive in that host by making mutations to constantly escape from the immune system. And now if we throw in drugs, it in some cases manages to escape from that as well and emerge as drug-resistant forms.

So we have come to appreciate how tough this virus is -- and of course on the global level to see it spread from just a few cases in 1981 to now, cumulative[ly] speaking, infected 70 million people, of course killing off some 20 million already, leaving 40-some million living with a lethal infection.

So that's how I see HIV, that despite some of the advances that the scientific community has made, despite the development of many drugs, we still are looking at a virus that's beating us, certainly on a global level. So there's a tremendous respect for what this virus could do. And remember, its genetic information is only 10 kilobases, 10,000 of these nucleotides put together. It's exceedingly small, and yet it's capable of doing so much. ...

... If you look five, 10, 20 years down the road, is this virus something that's going to be a part of us for generations, or are we going to be able to control it, manage it?

Well, I think if you look at the extent of the spread of HIV, there are 40-some million people with the virus at the moment. We know the rate of increase is approximately 5 million new cases per year. We still don't have a vaccine. We have drugs that are very helpful, but we don't have a cure.

So to me, it's clear that I'm not going to see the end of this epidemic, and it's also pretty clear that my children won't see the end of this epidemic. Even if we come up with a cure or vaccine tomorrow, just think about the time that would be needed to implement all these measures widely throughout the world. And even with that optimal scenario, it would be decades before this fight is won, and we're certainly, unfortunately, not in that situation. ...

... In the mid-'90s, you saw this death around you, and you responded with science that provided a treatment, kept people alive. ... There has been a push to have the same kind of success in the developing world as we have seen in the West. Where is that coming from, an d how realistic is that desire?

Speaking as an American scientist/physician, and seeing the success of therapy in this country and then traveling abroad and witnessing the continued devastation of HIV/AIDS, it's very frustrating, and you want to apply the solutions that you know do work in the U.S. to the developing countries. ...

As you know, there [had] been a concerted effort shortly after the great success here in the West to move the medicine to the developing countries, and that culminated in the so-called 3 by 5 program driven by the World Health Organization.

I must commend that effort for having treated approximately 2 million infected individuals during the three-year period that it took place. It did result in something that was very positive for the therapy effort.

But the human response, it's a compassionate response.

I think it obviously is the right thing to do. We ought to treat more and more people in the developing world. Of course it comes with a big price tag, and we have to think about that, and we also must think about what we need to do overall, and that is to cut down transmission and work more on prevention to slow down the growth of this pandemic.

We have to bear in mind that during the years when this concerted treatment effort took place, approximately 2 million were treated. But during those years, another 15 million or so got newly infected, so we had a net loss of about 13 million infections by a virus that is lethal if untreated.

If you do the simple math or the hard, cold math, it tells us we need to slow the spread of the virus as much as we are trying to treat those are who are infected.

Do you think global treatment programs have been oversold?

I still admire the compassion; I still commend the effort to treat. But we live in a world of limited resources, and as you ramp up treatment effort, there is no doubt that some of the prevention efforts would be jeopardized. My own sense is that treatment is rather dominant right now. Prevention was beginning to surface to the top, but because of the treatment ramp-up, it has dropped again.

That, looking at it from the simple mathematics perspective, is concerning, and I still think we need to focus heavily on prevention, of course, through education and [harm] reduction, but also through scientific methods such as using drugs to prevent transmission, the development of [microbicides] and vaccines. …

If you look at PEPFAR [the President's Emergency Plan for AIDS Relief] and the Global Fund [To Fight AIDS, Tuberculosis and Malaria], there is $20 billion or something on the table, most of it focused on treatment.

A lot of it [is] focused on treatment. Of course some of those funds would also go and benefit certain prevention programs, emphasizing abstinence and condom use and such harm-reduction methods, but the principal amount is going for the therapy effort. ...

Why do you think that is?

I think it's human nature to want to help those who are already afflicted with the disease, and we in general are very bad at going after prevention of diseases. We don't need to just talk about HIV/AIDS. Whether it's hypertension, heart disease, strokes -- all of those -- we just do a poor job on the prevention side. This extends beyond health to environmental issues and what have you, so it in part is a reflection of human nature. ...

... The perception [of the antiretrovirals] is that you go on the drugs, and you are going to live a normal life forever. What does the data show, as far as you know, in the developing world?

Well, let me first say that ... in this country, people are getting the impression that infected individuals could live for decades. The drugs are plentiful; they are getting better, simpler, and associated with fewer side effects, so there is an impression that life could be extended indefinitely. But that's with the best therapeutic options available.

In the developing countries, it's quite different. Brazil is fortunate in that they make many drugs themselves. They do not make all the same drugs that we have available, so I think the therapeutic options compared to the U.S. would be more limited in Brazil.

But Brazil is much better off than most developing countries. The way I see it, in Indochina or in China, the therapeutic option at times is only one. You have your front-line regimen which is typically quite simple, with three drugs, but there is no backup. When you fail that front-line regimen, you have no other options, so your life may be extended for only a few years. ... You are going to have to look at the treatment outcome location by location, because that's entirely dependent on therapeutic options.

Has that been adequately explained when these large global treatment programs have been sold? Do you think the people who are getting these drugs [to populations in the developing world] know that, that that's what's in the cards?

I don't think so. I don't think the downstream consequences have been well explained. But does it change what you should do? Probably not, because your actions are benefiting the people you treat. Whether it's only three years or nine years or several decades, it's still beneficial to go on these.

But in the interest of full disclosure, I think people who get into the developing countries should be thinking about what is front-line therapy and what backup options are available to the patient population.

... What is a second line, and why does one need it?

Well, no matter what regimen we use to treat a patient, it is unlikely to be perfect. The drugs sometimes don't work as well. Sometimes the patients don't take 100 percent of the drugs, so there are adherence problems. Then there are times when there are side effects, and you have to stop the drugs. There are chances for HIV to break through and replicate while the person is taking the treatment regimen. When HIV replicates, it mutates and has a chance to escape from those drugs, so drug resistance would emerge.

Now, the majority of the patients over the first few years would be well suppressed, and you don't have such an emergence of drug resistance. But with the passing of time, the chance of drug resistance will increase. When enough time passes, you will have a bunch of patients who will have failed the drug regimen because of drug resistance. In that case, if you are in the U.S., you change your drugs because you have more therapeutic options. You can use drugs that still work against those viruses and once again suppress HIV as a person continues to do well.

In a developing country, you could be faced with no other therapeutic option, in which case the HIV will replicate and damage the immune system, and the person will continue to progress and then succumb to opportunistic infections.

So this raises pretty big moral questions about the extent to which we should be trying to treat in developing countries.

Our effort has been largely focused on the delivery of the front-line drugs. You probably have heard from the Clinton Foundation [that] they delivered the front-line drugs for as cheaply as a little bit over $300 per person per year. That's great work.

Downstream, we need to think about how to deliver the backup treatment regimens, and they are not so easy. They involve drugs that are more complicated and newer, and there are intellectual-property issues to address.

Much of what we have been talking about is for the simple front-line regimen, and we all know from the U.S. and European experience, when you want to treat somebody and think about the long-term outcome, you need your entire therapeutic arsenal that we have available here, but they don't in the developing countries. In some respects, that's an area that hasn't been discussed that much, at least among the lay public.

It's uncomfortable?

It's uncomfortable. We are still dealing with step one, and these are step[s] two and three. Perhaps it's coming, and it will come for the 2 million that have been treated under the 3 by 5 program. A fraction of them will need a backup regimen in time.

Let me ask you about the treatment in developed countries, and particularly here in the States. There is the impression that ... it's not that big of a deal: You take these drugs. To what extent is that really the case, and to what extent has that perception created a sense of complacency?

It's largely true that if you are an American patient, one way or another, through private insurance or through government assistance, one could get drugs, and generally they are the best front-line drugs. They are now quite simple, so it's easier to adhere to the regimen.

Over the last five years in particular, the regimens have been modified so that they are associated with fewer side effects, so people tolerate them actually quite well, and the success rate is pretty good in keeping the virus down for many years.

It is true that many, many American patients have benefited from the regimens, but that therapeutic success is a very important cause of complacency in America when it comes to HIV/AIDS. It's no longer an urgent problem. In certain places, at certain times, it's disappearing from the public consciousness. Now when we hear about HIV/AIDS in this country, it's more about what's going on abroad, particularly in Africa. Yet it's still a serious viral infection that can kill, and yet the U.S. new infection rate hasn't gone down either. So the epidemic continues to spread in this country. We have to work very hard to address this complacency problem in the West. ...

Do you still see [a] commitment from the federal government to fund the kind of research into HIV that you have seen over the past couple of decades?

My own view of AIDS funding from the federal government in the U.S. is the following: When Bill Clinton became president, there was a substantial increase in AIDS research support through the NIH [National Institutes of Health], and that continued after Bill Clinton, when [George] W. Bush took over. But in the last four, five years, the total NIH funding has been quite flat, and so has the AIDS funding.

There has been a shift in priority. There has been a growth in funding to support bioterrorism work, and to some extent that has taken away money from other areas -- not just for HIV/AIDS, but many other areas. But that, as you know, is a national priority defined by Bush. There is no doubt that the funding level for AIDS research is much lower, much tougher now, quite appreciably, and everyone is feeling it.

So it is harder, but I should still say that the funding in the U.S. is a lot better than, say, in the European Union or countries like Japan, where they have money, but they are not putting HIV/AIDS as a high priority.

Obviously the terrorism is part of that, but is it also the case that it doesn't seem to be a problem anymore to most people?

Right. It depends on which perspective you wish to take. If you take a narrow perspective and look at the situation in the U.S., the situation is not as dire, and therefore we could decrease our research allocation to this disease. You could say that's the attitude that many of the European countries have taken. So I could understand that.

But if you take a few steps back and look at the big picture, the epidemic is worse than ever, and therefore who is going to work on it but countries with the resources -- the U.S. and Europe? Diseases do not obey manmade borders, so we need to address these transmissible viruses as if they are a global problem that would affect us no matter how we draw up our borders.

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posted may 30, 2006

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