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We went through this formal thought process before launching into a new area of research. The situation in AIDS was different from that in HTLV-1 leukemia lymphoma, because in leukemia, it appeared that once cells were infected, an antiviral drug would not be able to block the tumor process. But here was a very different situation in that the virus was continuing to go from cell to cell. So then we started to think about how we could block this process. The literature on other retroviruses, animal retroviruses, gave us a place to start. We did not know whether it would work or not, but we thought that it was certainly a logical thing to do.
Hannaway: Was Dr. [Hiroaki] Mitsuya also working with you and Dr. Broder?
Yarchoan: Certainly. He had actually come to work with Sam before Sam had moved up to the thirteenth floor of the Clinical Center, in about 1982, as I recall. Again, I may be off. It seemed to me he came around August of 1982. So he had moved up with Sam to the thirteenth floor, and then I went up there.
Hannaway: Can you describe how you went about this? You came to this decision, this is what we want to do. What sort of procedures did you establish?
Harden: Walk us through it.
Yarchoan: There is one point I would actually want to interject. It does not fit in here, but...
Hannaway: That is fine.
Yarchoan:...it is sort of in the same area. One thing I very distinctly remember was, when those first Science papers came out, [Dr.] Gene Shearer had been trying to look at some immunologic models of this new immunodeficiency disease. I think Gene is really to be admired for being a very basic research immunologist who with two feet jumped into this very murky area of a new human immunodeficiency disease. In retrospect, I think it is quite amazing that he was willing to stand on the edge of the cliff and jump. But he had been studying a cohort of gay men from the D.C. area who were relatively monogamous. When Bob Gallo was testing his initial HIV assay, he wanted some sera from gay men, and so he used some sera from Gene Shearer’s group of gays. I cannot remember the exact number, but about 60 or 70 percent of them were HIV-positive at the time. I remember after reading the Science galleys doing a rough mental calculation of the number of gays in the country and the percentage who were likely to be HIV-infected, and estimating that there were half a million to a million people infected with this lethal virus who did not know it. There was a weird feeling of having this cataclysmic information that the world was not aware of. I could not go out there and give a news conference saying that a lot of people are going to die and that it is a real crisis. But it was a very weird moment for me, feeling that I was privy to this information that had not perked through people’s consciousness yet. Then there were endless debates about how many of them would get sick and how many of those would die. Unfortunately, the more pessimistic views turned out to be correct. But it impressed me at the time how cataclysmic a disease we were dealing with.
Hannaway: This was in 1984, when you were reading the four papers together?
Yarchoan: Yes. What Sam first did–I think Sam deserves a lot of credit for pulling things together and moving forward–is to hold a small meeting. He used to have an office on the sixth floor, in the 6B corridor, and there was a little conference room there. Sam pulled some people together. We have tried to reconstruct who was there, but it has been hard. [Dr.] Peter Fischinger was one of the people that he called in, and I just do not remember who the other people were. [Dr.] Dani Bolognesi, I think, was one of them, although I am not a 100 percent sure. The meeting was to brainstorm about various and sundry strategies to stop this retrovirus.
What I remember from that meeting was that Peter Fischinger–he confirmed this when I contacted him later, trying to jog my memory as to who was there–had talked about treating patients with thymidine or some related compound, because there was evidence to suggest that that approach might do something. There had been work in the laboratory of [Dr.] Prem Sarin, who had been in Bob Gallo’s shop, that some rifampin analogs–rifampin is an anti-tuberculosis drug–had activity against other retroviruses. We thought that we would try to get a hold of some of these rifampin analogs, if any existed, and see if that strategy might work.
Meanwhile, Sam thought it was very important to get a clinical trial going. We had no idea how to even test if a drug was working in AIDS. What do you use to follow these patients? If they got completely better, you would know it was working, but the disease was relatively silent. People could be infected with HIV, as we now know, for a number of years without even being aware of it. Would the CD4 count go up? Would that be something to follow? It would be nice to follow the viral load, but there were not any assays for that. The best you could do was to culture HIV, and that was not quantitative. So we were struggling to try to figure how to even go about doing a clinical trial to test an antiretroviral drug.
During this time, Mitch [Dr. Hiroki Mitsuya] focused on the laboratory approach. Sam had Mitch try to develop an assay to detect whether a drug was working in the test tube. As I recall, initially Mitch went over and worked with [Dr. Mikulas] Mika Popovic and learned some techniques in his laboratory. Then he brought the virus back and started working in the laboratory in Building 10. He first tried to look at p24 production, or production of RT, the reverse transcriptase. A problem was that it was very hard to tell whether you had an antiviral drug or just a drug toxic to the cells.
Mitch had been doing some work with T-cell clones, and since HIV killed T cells–Sam and Mitch and I all batted these ideas around–it seemed that if you could block the killing of the cell with a drug, that would be a very nice test, because you could show that it was both an antiviral drug and that it was not toxic to the T cells. Thus this drug could let the immune system at least continue to live, and perhaps even grow. So that was a very nice model. Mitch had these tetanus-specific T cells, as I recall, and he tested them. But these T cells are very difficult to grow. You almost have to talk to them, and they are just...
Hannaway: Encourage them?
Yarchoan: Really hard to work with. Then Sam and Mitch got the idea of infecting one of these cells with HTLV-1, and they developed this T-cell clone that was actually very sensitive.
Harden: We have been talking about the differences in why people go into medicine. I had asked you about people who are interested in both clinical and basic research. We were talking about Dr. Gallo as someone who does not want to do clinical research, but you were pointing out that he thinks like a clinician.
Yarchoan: We have interacted with him on a number of occasions. During that period in June of 1984, we attended his annual laboratory meeting, which, at that time consisted of about 30 people meeting in a room in one of his contract laboratories. It was truly a laboratory meeting with a few international collaborators, rather than the big, international meeting it is right now. That was the most incredible meeting I have attended in my life. We heard all of this unpublished information about HIV and retroviruses, and it just completely opened up that field for me.
But it always impressed me there and in other places that Bob–in spite of the fact that he leads a basic science laboratory–does what I would call translational work, and he can think of clinical things and draw laboratory associations from them. He is very good at that, and he keeps his clinical thinking and clinical connection in a way that is, for me, quite remarkable.
Harden: Now, when we stopped the tape a minute ago, before we started this side discussion, you were walking us through...
Hannaway: We were talking about how Dr. Mitsuya had developed a clone.
Yarchoan: Right. He had developed this clone. Meanwhile, I was trying to think of what else we could do to move towards a clinical trial. As I mentioned, I had been collaborating with Brian Murphy before on the influenza project, and I used to eat lunch with him and some of his colleagues. Sometimes [Dr.] Jay Hoofnagle, who is another virologist, would join them. And that particular day, Jay Hoofnagle came in. I remember saying, “We had this meeting about HIV, and we thought about using some rifampin analogs. Do you guys think that this would have a chance of doing anything?” The answer I got was, “Yes, it could work. Might as well try it.” And Jay Hoofnagle said, “As long as you are trying that, why don’t you try this drug suramin. It is an extremely potent anti-retroviral agent.” I said, “Sounds good. Thanks for the tip.”
So I went up to the library, and I remember trying to look up suramin. I thought it was spelled something like “cerimen,” and I could not find it. I finally called Jay back and said, “Jay, how do you spell the name of this drug, and do you have a reference on it?” I cannot remember if he spelled it for me or gave me the reference. I tracked down this article by [Dr.] Eric DeClerq in which he showed that suramin was an inhibitor of the reverse transcriptase of murine retroviruses. I brought it to Sam’s attention, and he said, “Let’s get a hold of this and test it.” I do not know where he got a hold of it, but somehow he did. Mitch and Mika tested it in the laboratory, and it turned out to be active against HIV. So we started writing a protocol.
This was a drug that had been given to patients before. At the beginning, we were most interested in testing drugs that had been used in humans before. The reason was that doing so would cut out what we thought was two years of animal toxicity testing, GMP [good manufacturing practices] production, and all the rest of it, and we could get a trial going soon rather than two years down the line.
So suramin was great in that respect. It was a drug that had been used in people before, although it was not used in this country, and it worked in the assays that Mitch was setting up. Sam and I worked together on writing the protocol. One thing I remember is that we did get a lot of support in terms of things moving quickly, and it certainly helped that Sam was the Associate Clinical Director and knew how the system worked. My recollection is we started writing the protocol in June, and I think it was August 6 of that year that we treated the first patient. So it took us about a month and a half from concept to treating the first patient.
Harden: What is involved in writing a protocol? I presume it is saying just what you intend to do and how many patients and so on, but there is bound to be more. I know that you have to go through an institutional review board.
Yarchoan: Yes, and the process has actually become more complicated since that time. At that time, you had to write down a pretty detailed blueprint of the experiment, defining what you were going to do, although you could give yourself a range of doses and leave some things undefined. Ideally, it should be written, so that, if after writing it you got hit by a truck, someone coming along could take that protocol and follow it. It had to go through the Institutional Review Board of the Cancer Institute. Since suramin was an investigational drug in this country, we had to get access to the drug. Someone had to file an IND, an Investigational New Drug application, with the Food and Drug Administration, and they had to approve the experimental use of the drug and to approve the protocol if it was the first IND application. That was basically what had to go on during that period of time.
Harden: While you are working with this first Phase 1 part of the trial, are you in close contact with somebody at the FDA [Food and Drug Administration], or is it more that you get the approval, you do it, and then it goes back.
Yarchoan: As time evolved, we actually started working reasonably closely with the FDA, calling them up periodically and even meeting with them. But I was not personally involved with the FDA at that time. My impression was that Sam spoke to people at CTEP [Cancer Therapy Evaluation Program]. For the NCI, CTEP are the people that generally hold and file the INDs. There is a regulatory part of the CTEP that has expertise and experience in pulling together INDs and filing them with the FDA. They really acted on this one very, very quickly, and they got the company that made this drug to let us cross-file with them so we could use all the background information that they had.
Hannaway: The animal trials and things that they had done previously.
Yarchoan: This drug was used in Africa as a treatment for onchocerciasis. The company then filed the drug with the FDA, and the FDA gave us very rapid turnaround on it, so that people really did get a sense of urgency and moved things along.
Hannaway: How did you recruit patients for the trial of suramin?
Yarchoan: They found us. We wrote the protocol and...just to backstep a little bit, one of the real issues was, again, we did not know how we were going to monitor the patients. At the time, there was someone in Bob Gallo’s laboratory who was trying to develop an assay to measure one of the proteins of HIV, p24, but that assay really was not yet working. We wrote the protocol to use this assay, but it turned out that it was not developed enough when we began the protocol. But we gave ourselves leeway to do other things.
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