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Hannaway: You received these compounds that you were testing in this endeavor to find a treatment for AIDS with alphabetical labels?
Hannaway: So AZT, in effect, had the label of compound AS.
Yarchoan: No, it was just S.
Hannaway: Just S. But had there been the whole alphabet to test before that?
Yarchoan: We had not gotten all of the alphabet. It was really Mitch who was doing the laboratory testing. We divided our efforts, and I was initially focusing more on the clinical aspect. So, for a period of time, it was really Sam and Mitch who were involved in this collaboration with Burroughs Wellcome. Then I got brought in when it started to move towards a clinical trial.
Hannaway: So it was Dr. Broder and Dr. Mitsuya who were doing the in vitro testing.
Yarchoan: Right. Although we all worked together and bounced ideas back and forth. I would go to the library and think of some compounds and bring it to their attention, but they were doing the hands-on laboratory testing.
I do not think we tested all the drugs between A and S. I think we tested a number of them. I know B was one that they had tested. But my recollection was that Burroughs had a set of compounds and only sent some of them up, but these were coded. But I am not 100 percent sure.
Hannaway: But what other drug companies or sources was the laboratory getting compounds from?
Yarchoan: We were getting them from a variety of different sources. I remember going to Cliff Lane’s laboratory and getting some acyclovir, I think, that he had in the refrigerator to test. We were trying to pull in things from a variety of different sources. Some compounds we ordered from chemical catalogs. I think there was collaboration with one or two other companies that happened later.
Hannaway: With Abbott?
Yarchoan: I would have to go look in the old documents. I just do not remember which company they were getting compounds from.
Harden: When you got to the Phase 1 trials in July 1985, I believe, what happened? Would you walk us through the process?
Yarchoan: The trial included 19 patients. We treated 11 and Duke treated 8. My best recollection is that the draft protocol was originally written by people from Burroughs with a fair amount of consultation from Sam. We had sent down a copy of our suramin protocol, and then Sam had communicated to them things that we would have done differently based on what we had learned from that protocol. So it incorporated their expertise in terms of doing Phase 1 testing and such, and what we had been learning from the suramin study. We then made some changes to the study. The Burroughs researchers were also interested in having something done down there, I think, because they knew people at Duke and they could go across town and see the patients. So it was agreed that the protocol would be done at Duke and at the NCI, and we would take the lead on it.
We got the protocol through the IRB. Then my recollection is that the first patient–I may be off a day–came in on July 3 and was treated July 5, or something like that, up on 13 East. And the first treatment was an intravenous infusion. The first patient to receive AZT was from Boston. He had full-blown AIDS, he had had Pneumocystis carinii pneumonia, and he had about, 40 or so CD4 cells per cubic millimeter.
Hannaway: That is not many!
Yarchoan: The patient received an infusion that was for the initial testing for pharmacokinetics, and Sam and I sat around and watched as he got a syringe full of AZT. I remember that night he developed a fever, and we came in and tried to figure out what the cause was–was this drug toxicity or was it the disease. We could not figure out what was going on. The temperature was not high enough to stop the treatment, and it looked like it was consistent with some sort of minor opportunistic infection or a cold, and so we continued on. The fever then went away.
He perked along, receiving the drug three times a day intravenously. It was initially supposed to be a two-week protocol. At the end of the two weeks, we found that his CD4 count had gone up, and we did not know what to make of this. We knew that CD4 counts bounced around, but this was a bounce in the right direction. We thought we had enough to push the company and the FDA to extend the treatment, so we got an amendment to extend it for another two weeks. The CD4 count was up around 200 by then. It was also getting really tiresome to give this drug three times a day intravenously, and there was reasonable evidence from the animal studies that it could be given by mouth. So we got permission to amend the protocol to change to give it by mouth. The patient received another four weeks of treatment by mouth. His CD4 count did not get much higher. It bounced around and actually was dropping back down by the end of the eight weeks. I guess, in retrospect, we were also learning about resistance in that first patient, just the way the first patient with AIDS that we saw was like the whole epidemic rolled into one patient.
But he really felt a lot better. We also were doing skin tests, and we found out after a few weeks that his skin test–which is a way of measuring the T-cell responsiveness–had changed. He was anergic at the beginning of therapy, which means he did not respond to any of the four test antigens. At the end of a few weeks of AZT, he had a very robust skin test to tuberculosis. This was a PPD [purified protein derivative] test. So, again, in the sense that these initial patients were really textbooks–there was the tie-in with tuberculosis and HIV that we now appreciate in this patient. But we were very impressed that not only were the number of CD4 cells going up, but they were working.
Then we started getting concerned that this was an artifact that occurred just because we were immunizing him by giving him repeated shots. Normally you do not apply PPDs every few weeks. We found some articles related to this. The literature was pretty murky, but the sense we got is that if someone were truly anergic, they would not have a positive skin test to an antigen if you retested them a few weeks later. That made us feel fairly confident that this was something real. So we were excited about this patient, and we wrote to the FDA and Burroughs Wellcome.
Meanwhile, the second patient that we had treated at this dose had severe Kaposi’s sarcoma, and this Kaposi’s progressed while he was on AZT and he had a minor CD4 count increase. There was another patient that was treated down at Duke. He started at about 200 CD4 cells, and his count went up a little bit. And there was a fourth patient that we treated that started with five CD4 cells and went up to 10, then dropped back down to five again. So, in retrospect, they all moved in the right direction. But it was just this first patient that really looked like something.
Then we went to the second dose, in which I think we doubled the dose. And six out of six patients at that dose had an increase in their CD4 cells. At a certain point, we did the statistics. And around October, we realized that we were having statistically significant increases in the CD4 cells. It was just over the level of being statistically significant. We were, at that point, very, very excited that we really had something. The one reliable test that we had at that point was the CD4 count. We did not have any truly accurate viral load studies. We had a culture technique, but it was hard to know what it was telling us, and the results were coming in all over the board. But it was the immunologic changes that impressed us–they were relatively small, but they were always in the right direction.
Harden: You are presenting a picture of seeing through a glass darkly and just trying hard to find a way.
Yarchoan: Yes. We have used the analogy of seeing a ship in the fog. You see these patterns and you are never sure whether there is really a ship coming or just eddies in the fog.
Hannaway: That is a good analogy, and probably a good way to think about it.
Yarchoan: We were excited but did not want to be too excited. Both for ourselves, and also because we felt then, and have always felt, that to try to give false hopes to patients is a highly unethical thing to do.
Hannaway: Had you recruited these patients by a talk on NPR or by other means?
Yarchoan: No. I think, again, these were recruited largely from calling up other academic clinicians, like [Dr. Jerome] Jerry Groopman, who, I think, sent down the first patient from Boston. Walter Reed was a source of some patients. Basically, there was this small community of people who were doing AIDS research, and you could call some of these people that had clinics and say, “Please send me a few patients.”
Harden: One of the other points that we have seen in all these interviews is that there is no question that the response to AIDS at this point was grassroots. This was not anything being directed by some higher authority. But you knew the people who were interested.
Yarchoan: That is very true. Just one of the things was that it was not clear what sort of safety precautions you should take. I was worried about working with HIV in the laboratory. And we were trying to figure out what precautions were needed. What were the rules? There were no written rules. I remember calling [Dr. Bernard] Bernie Poietz, who had discovered HTLV-1 working with Gallo. He had been a housemate in medical school, and was now up in Syracuse. I called Bernie and said, “What are you guys doing for it?” He sent me some guidelines that he put together, and we set up some procedures in our laboratory that fit the guidelines that they were using. But there were not any formal biosafety procedures for working with HIV at the time.
Harden: Do you remember, when we were talking about the first patient in 1981, and I said it was probably too soon for the panic. But, during the time of your clinical trials with suramin and AZT, I believe that [Dr.] David Henderson had set up some epidemiological rules in the Clinical Center. Did you find the staff or the nursing staff or the housekeeping staff or any of the other staff to be very nervous about dealing with these patients?
Yarchoan: Not too much. There was a certain amount of nervousness. There had been, by the time we did that trial, a reasonable amount of work that had been done with HIV in the clinical setting. Ed Gelmann had been doing some trials with Kaposi’s sarcoma within the [National] Cancer Institute, so that there were AIDS patients coming into the institute. NIAID had been treating some patients. There were levels of anxiety that ran the spectrum, but, I think, in retrospect, the staff really behaved very professionally at that time when dealing with the patients. But I think everyone had some level of concerns about it
It was potentially a scary situation. We were dealing with a virus that either was 100 percent lethal or something less than that, that seemed to lead to a very miserable death, and that you could spread to close family members or at least spouses. There were reports of needlesticks in some health-care workers leading to HIV infection, but it was still not clear whether that was how they were getting infected. Also, there were so few laboratories that were working with concentrated virus that the risks in the laboratories were really an unknown factor, because you just did not have a large denominator. There were a number of people who were quite concerned about it. But people were generally quite professional in the clinical setting.
Harden: Let me just ask one other question as long as we are on this topic. We have talked to some people who experienced pretty negative responses among friends, even co-workers, because they were working with HIV. They encountered people who would not shake their hands. They told of visitors who would get up and leave the dinner table when they learned that their hosts did research on AIDS. Did you or your family have any negative consequences in that way?
Yarchoan: No...but then, I did not talk too much around our child's nursery school about being an AIDS researcher.
Harden: But your kids were very little too. They were not at that, say, junior high age where...
Yarchoan: Right. We actually did not advertise that fact in the school setting. With people whom we know as scientists, it was generally a good thing to be working on AIDS. We just did not want our kids to be affected by people who might have weird impressions about it.
I think some of the other investigators who were not dealing with AIDS tended to view AIDS as something dangerous. A few investigators would tease me sometimes about not wanting to come into our laboratory or borrow our equipment. But I personally was not exposed to a lot of that.
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