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Harden: I was interested in the paper that you did on AZT’s effect on the neurological manifestations of AIDS. That whole area is of considerable interest. Do you want to comment on that?
Yarchoan: Yes. That was actually quite satisfying for me. What happened was we had a patient referred down from Memorial Sloan Kettering, who had AIDS, who had had Kaposi’s sarcoma, and who had had some documented neurologic dysfunction with AIDS dementia complex. And he came onto our trial. The trial involved two weeks of inpatient therapy, and then the patients received more drug as outpatients. The man was quite confused when he was an inpatient here, and was even having some delusional and paranoid ideas. He thought one of the nurses was trying to kill him by not giving him his AZT. We were quite impressed that, after he was on AZT for a bit, his thinking seemed to clear up, and he functioned a lot better. He had been on interferon before that for his Kaposi’s sarcoma, and interferon can sometimes cause some CNS [central nervous system] effects. As I recall, when he went back to Memorial, they had tested him and actually found some improvement in his psychometric tests. So, we were quite taken with this, but still thought it could be from stopping the interferon.
We had amended the protocol to allow us to treat some additional patients with AZT to gain some more experience with it. So, during this period of time, we recruited some other patients with neurologic disease. We knew that there was a lot of virus in the brain–this was actually shown by [Dr.] George Shaw in the end of 1984. We had this idea that once a patient became demented it was supposed to be irreversible, but based on this first patient we thought we might be able to reverse this. We recruited, I think, six or seven additional patients with neurologic manifestations. A few people with neuropathy appeared to derive some improvement, but it was relatively minor. We had one patient with a hemiparesis because of spinal cord involvement, and he did not improve much at all. But the patients with dementia generally improved, in some cases quite dramatically, and usually within eight weeks or so. We wrote up the initial four cases in the Lancet and then presented the information at a meeting. The neurologic community was quite surprised by this, and we were challenged aggressively at some meetings. The arguments were made that we were not neurologists, that dementia should not be treatable, the data were too good to be true, and that these were anecdotal cases. But it has subsequently been shown that, in fact, it does work and that there is a reversible component to AIDS dementia complex. AZT is actually one of the drugs that gets into the brain the best.
Harden: This is an argument for not cutting off AZT therapy completely.
Yarchoan: It is an argument against stopping it in such patients.
Hannaway: Would you tell us about how thinking on using combination therapies for AIDS evolved? There was a growing recognition in the articles that you, sometimes in collaboration with others, published in the late 1980s and early 1990s that HIV provides a number of opportunities or target areas.
Yarchoan: Yes. It became, as I mentioned, evident fairly early on that AZT as a single drug had but limited activity, and the other drugs that were being developed also appeared to have limitations in themselves as single drugs. We thought, for a variety of reasons, it would be worthwhile to combine them. The simplest reason was that they often had two different toxicities. In cancer therapy, if you combine drugs that have two different end-organ toxicities, you can often get more anti-tumor activity by combining them than with either one of them individually just because neither of the end organs cries uncle. We did this early on with AZT and ddC.
There were a number of other reasons to do it. There was some laboratory evidence that the drugs had at least additivity and perhaps even synergy. There was an idea that if resistance was a problem, it might be harder to develop resistance to two drugs simultaneously. In fact, with tuberculosis therapy, that is one of the reasons you give two or more drugs. We found that ddC had a very different toxicity profile than AZT. At the same time, we thought it would take some time to get a trial approved to administer both at the same time but that we could move quickly if we proposed alternating them. We were actually able to do that right within the Phase 1 study of ddC. This was a time that we had very good personal interactions with the FDA. We were able to get the FDA’s permission to do something that was really pushing the envelope a little. [Dr] Ellen Cooper was the person we were dealing with at the FDA. She was actually, I thought, very proactive during that period.
Then, after ddI was developed, we started to wonder whether it would be better to use the two drugs simultaneously or alternate them, and we did a trial in which we formally compared the two options. We found that people did much better combining the two drugs simultaneously at half dose rather than alternating the two at full dose. Over a period of time, people got the same dose of both drugs, but the way that the drugs were given made a big difference. Part of that is resistance. Also, part of it is because the two drugs hit two different cell populations, and this came out of some work that we had done in macrophages. Also, Mitch found the same effect in lymphocytes. In both cells, the thymidine-based drugs such as AZT work better in replicating cells because they are better metabolized to the active form. At the same time, ddI works somewhat better in resting cells. If we combined the two of them together, we were hitting both cell populations.. And we found some patients that, after over a year on simultaneous AZT and ddI, still had CD4 counts that were higher than when they started. So we had gone from 20 weeks of benefit to well over a year.
The question of whether it was better to combine two different targets rather than single targets came up again when the protease inhibitors were developed. They had very profound suppression of the virus, but resistance would often develop within about 16 to18 weeks. But if they were combined with the nucleosides, you were really able to suppress the virus. Actually, now you could suppress it to the point where there was so little viral replication that resistance was slowed substantially. This is a finding that was presented in a meeting about a year and a half, two years ago. So this is now the paradigm for how to treat the disease, to suppress the virus to the point where resistance development is slowed.
Again, even though the nucleosides were not ideal drugs, they kept patients going for a while. But, also, they provided the framework so that when the protease inhibitors were developed, the combination of the two gave very effective therapy.
Hannaway: Do you feel optimistic that this process of management with several drugs will have long-term success?
Yarchoan: That is a good question, and it is one that I have agonized about. I sometimes wonder, are we talking about tuberculosis in the 1950s when really there was a dramatic change and you could suddenly cure most patients, or are we talking about cancer in the 1960s, where you had one disease, childhood leukemia, that you could cure and many people thought that with combination therapy, we would be able to lick many other cancers. I think if we can develop other active drugs that target perhaps one or two more sites, and combine them with the drugs we have, we really might be able to start to move in the direction that a majority of people can live with this disease for a substantial number of years.
In terms of eradicating the virus, I am a little less optimistic, although I think that if you combine good anti-retroviral therapy with either the natural immunity or boosted immunity, that you may be able to live with this virus and keep it suppressed much the way we do with a variety of viruses. All of us are chnow.
Hannaway: People often refer to herpesvirus as something that most of the population lives with.
Yarchoan: Yes, chicken pox virus, for example.
Yarchoan: The other possibility is that we are going to get stuck on some of these new targets and that in three years we are going to start to get a wave of breakthrough as resistance develops to the available drugs in many patients. I am pretty optimistic that, as we identify new targets and get new drugs, we can continue to improve things. I have sometimes commented that we do not need to cure a disease, but if we can keep patients alive for 60 or more years, that is probably good enough for most people.
Harden: What I am hearing, too, is that you are coming back around to combining drug therapy with immunological reconstitution. Do you want to expand any on immunological reconstitution?
Yarchoan: Again, we have done some work in that. A number of years ago, when we became aware that this was a disease caused by a virus that was killing T cells, we felt that that the attempts to reconstitute the immune system would often be limited by the virus’s substantial efforts in killing whatever cells you wanted to reconstitute. Now that we are able to get the virus under control, it opens the door for efforts both specifically and nonspecifically to reconstitute the immune system. Again, people can argue over beers whether this is going to have an effect or not. I think Cliff Lane’s group is very nicely showing that IL-2 therapy, combined with anti- retroviral therapy, can make substantial improvements in CD4 counts. They are doing a trial now to look at the clinical benefits of this. It is not an either/or situation, but a situation of working on both and then putting them together.
Harden: Let us talk about how AIDS changed your overall career. Obviously, when you started, AIDS was not recognized, and since you got into AIDS, you have continued with it. You have been a senior investigator in the Clinical Oncology Program and Chief of the Retroviral Diseases Section in the Medicine Branch and now HIV and AIDS Malignancy Branch Chief. How have your actual activities changed, in terms of research and administration? Do you intend to stay with AIDS? Somebody in the last interview that we did shook me up. Somebody in another interview said that he was already thinking about what to do after AIDS.
Yarchoan: Let me just say it has given me great satisfaction–I was just thinking about that as Sam Broder and I are writing a chapter together, and we have been e-mailing each other back and forth. It has given me the opportunity to do what I really dreamed about doing when I was in college, to actually make a difference. When I get away from all the little daily imbroglios that go on here, it is very satisfying to feel you have actually made a difference somehow, even if in a small way. At the same time, I wish I did not have this opportunity in that this disease never appeared.
It is sort of funny in retrospect. I was training for a career that did not exist, and suddenly the career plopped down in my face. It was not clear to me what I was going to do after I finished my work in the Metabolism Branch, and probably if AIDS had not come in, I would have gone into more classic immunologic research. I was actually looking at a variety of different options at the time that I was finishing there.
Suddenly, an epidemic immunodeficiency disease came along, and I was lucky enough to be in a situation where I could expand my knowledge and learn more virology and more about drug development. I fell into a team led by someone I have great admiration for–Sam Broder. And Mitch was also a great teammate in our research. So AIDS has given me an opportunity to make more of a difference than I probably would have been able to do in other areas. Again, I wish the opportunity was not there, but I am glad I was able to do something about it.
Harden: How do you think AIDS has changed the NIH overall, the balance among the institutes?
Yarchoan: I am not sure I can really address that.
Harden: You have seen changes within your own institute?
Yarchoan: I think that, within the Cancer Institute, there has been an evolution. At first, people redirected whatever funds they could get their hands on to do AIDS research. Then the Institute was given AIDS money that went both to people working specifically on AIDS and also to people doing basic science that was related to AIDS. Then, when concern arose that AIDS money should go only to research directly linked to AIDS, NCI reprogrammed some work to focus either directly on AIDS or to not use AIDS money. These are changes that evolved over the last 14 years. But I really cannot address the larger issue of how much it has changed NIH or even NCI overall. There are a number of very dedicated people within the Institute and on campus who are interested in the disease.
Harden: You do not have a strong sense yourself, then, that AIDS has just taken over. As we said, there have been critics on both sides.
Yarchoan: No. I think there was probably a period of time when people would get AIDS money and use it for a research project that was somewhat related to AIDS. But the fact of the matter is that, because of the nature of AIDS, it meshes with so many areas of critical importance in so many fields of medical research that–I do not know quite how to word this–it has probably boosted medical science in general, even though it has posed an additional problem of focus. A lot of immunology has evolved during the study of AIDS. The study of retroviruses and retroviral vectors, T-cell immunity, apoptosis, and oncogenesis are other areas that have advanced. If you look at the study of retroviruses, you can see how it relates to the core of other fields, and people can go fairly quickly from retrovirology to a number of these other fields because they are so closely related. So, I know there are endless debates about whether some of the AIDS money was used on non-AIDS research and whether there was too much AIDS research, but a lot of cross-fertilization has come out of it, and that has to be good.
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