As a young physician working in South Florida during the early 1980s, Dr. Margaret Fischl struggled to find the source of mysterious immune problems among her male and female heterosexual patients of Haitian ancestry. When she read the initial reports of similar immune problems in gay men in California, she called the CDC to report her cases, but she says they didn't accept her conclusions because her patients didn't fit the profile of the mysterious disease being transmitted through homosexual sex or drug use. Eventually, the CDC named Haitian ancestry as a separate risk factor for AIDS -- stigmatizing and angering Haitians in the U.S. and abroad. Here, she recounts those events, and her trips to Haiti to investigate the disease there. Later, Fischl was one of the first researchers to discover the cancer drug AZT's effectiveness in treating AIDS patients. She describes those clinical trials and the criticism she faced from activists as doctors and patients learned more about the drug's toxic side effects. This is an edited transcript of an interview conducted Jan. 19, 2005.
- Some highlights from this interview
- Why the CDC didn't believe her patients had AIDS
- Tracking the AIDS virus in Haiti
- Uncovering AZT's effectiveness
- AIDS' impact on her as a young doctor
Do you remember the first encounter you had with a then-mysterious disease?
The first time I recognized when we were dealing with something very different and unusual was the early 1980s. We began to see infections that we should not be seeing in healthy individuals. They were infections that we were used to seeing in patients that had cancer chemotherapy, suggesting to us that their immune system was damaged, and we were trying to figure out what was going on.
How many cases were there?
In the very beginning, when we first started seeing cases, we were seeing about one or two a week, which was probably more than what other people were seeing in the country. [That was] likely related to the diversity of the population we were seeing in South Florida.
And this is before the first cases were reported in California?
When we were beginning to investigate the initial cases and trying to figure out what was wrong with their immune system, we picked up the MMWR [Morbidity and Mortality Weekly Report], and there were cases described in California and eventually New York. I'm reading it and saying, "This is exactly what we're seeing." We then immediately called the Centers for Disease Control and said, "We think we're seeing the exact same thing in South Florida," and described the population that we were seeing.
Their first comment back to me was they didn't believe me, because this was being seen initially predominantly in those of Haitian ancestry. They were concerned that something else was going on. They had a high incidence of tuberculosis, they had a high incidence of toxoplasmosis, and maybe that was knocking out the immune system. But as we were seeing the different cases, we were seeing Pneumocystis carinii pneumonia, which is the hallmark of AIDS as it was originally recognized. We were seeing Kaposi's sarcoma, which is the [skin] malignancy. We were seeing exactly what was being seen in other parts of the country. ...
I think in first dealing with the CDC, I have to say, as much as I respect them, they were fixed into how this was being transmitted. It was being seen among gay men and was sexually transmitted; it was being transmitted among drug users, so that was blood transmission. From my perspective it was sexual transmission and therefore heterosexuals, homosexuals -- at that point it really didn't matter. I didn't think there was anything particularly different. When you look back, it was just the total number of exposures is why you saw it originally among gay men, because the total number of contacts was so much higher.
Looking back with the CDC, they had a lot of difficulty. They began looking at all different types of aspects: Did they have unusual rituals in Haiti, voodoo rituals? Did they inadvertently have homosexual contacts? It took a while for them to accept that this was really heterosexual transmission, and I must say that was, from my perspective, an ongoing interaction with the CDC for a good five or six years. ...
… What was different about your patients, and why was that so significant in terms of the theories about who AIDS was hitting?
When you look at what was happening in South Florida, it was unique in several ways. We were seeing intravenous drug users; we were seeing gay men; and we were clearly seeing heterosexual men and women who had what was now described as AIDS. It let us know very quickly that we were looking at sexual transmission, and it went beyond a gay disease.
Now, the other thing is, once you saw it among intravenous drug abusers, you knew that it could be transmitted intravenously or through blood. We were also one of the first sites to recognize this among hemophiliacs, and that quickly let us know that blood products could become contaminated, and therefore could then be transmitted directly from blood transfusions. What it taught us quickly is the spectrum of how it could be transmitted and that it looked very much like a virus -- very much like hepatitis, for example, but not as infectious.
Was it was partly because of you that the CDC [named Haitians as a high-risk group]? …
In the beginning, when we were looking at predominantly heterosexual transmission, we were seeing this among those of Haitian ancestry, and I think the CDC had tremendous difficulty accepting the fact that this was transmitted heterosexually. Therefore, they were convinced something else was going on, whether it was practices that were happening in Haiti or in the United States, and therefore they actually developed a separate category that said Haitian was a risk factor.
That just blew up in the South Florida community. The entire Haitian community was very upset, and I don't blame them. The CDC came down here, actually wanted to interview patients, which they did do. They came into our clinic, and they were interviewing patients, and one of my patients came out and said, "I can't take this," and told me all the questions they were asking him and the potential accusations that were being made. I went in there and said: "Thank you. Please leave. These are our patients, and if you want to interview them, you have to respect everything that they're telling you, because if they don't trust you, they're not going to talk to you or even tell you the truth." …
Now, you went to Haiti at one point, didn't you?
Well, once we saw the outbreak, we were trying to understand what was going on, because in talking to the patients we realized that for the most part, they likely acquired this infection in Haiti. We wanted to go to Haiti to see what was happening in Haiti.
What did you learn from your trip to Haiti?
Going to Haiti was an incredible experience. When we went there, we went to hospitals. We looked at their medical records; we looked at their autopsy series. We realized very quickly that they were seeing AIDS at that time, and the extent of it was really incredible, the manifestations were incredible, and that likely children were affected as well.
The other thing that was happening also in South Florida is that we were seeing this among children that were born to mothers that had manifestations of AIDS so that we knew now that this was perinatally transmitted. The diversity of what we were seeing was incredible and introduced the full spectrum of how HIV as we know it today could be transmitted.
We gained a tremendous amount of insight into what was going on in trying to help the Haitian community in Haiti recognize what they were dealing with.
... What did you conclude?
In going to Haiti, the one thing that we found it just really reinforced was what the transmission pattern was and that it was very consistent. In looking at Haiti, we saw how this virus was being transmitted -- and I say virus now, because then we suspected it, but we didn't know that -- it was clear that in Haiti, for example, straightforward, that gay men went there to resorts and liked having sex with young men. There were no two ways about it: It was occurring that way.
There were also men and women that were heterosexual that were acquiring it. We could see connections even with some of the workers there that had been to Africa and worked in Africa and had prostitute contact in Africa. We could just see a pattern that was being set down. ...
What evidence did you find in your own research and studies that would at least seem to support the theory that AIDS came from West Africa back to Haiti, and then it was spread from there?
In the beginning, we did a fair amount of research in heterosexual transmission and looking at patients that were from Haiti as part of that study. Some of them actually traveled to Africa as part of their jobs and had sexual contacts in Africa, and they themselves felt that that's likely where they got the infection, because when they came back to Haiti, they did not have contact except within their family unit with their spouse. ...
How many cases did you encounter?
In the beginning, the number of patients we were seeing that we could relate to that were relatively small, because we were looking at patients that lived in Haiti that then came to the United States. We were looking at about a half dozen cases at that time, but that was enough, I think, for us to suggest that there might be a connection and that that really needed to be looked at in more detail.
Do you have a view on where it most likely started? Do you believe sexual tourists took it from the States into Haiti, or do you think sex tourists picked it up in Haiti and spread it back here?
I think when you look at everything taken together now that there are probably many ways this virus was transmitted, and that you really can't point to any one thing that resulted in the transmission. Just looking at South Florida and what was happening in Haiti, there were many factors going on. There were gay men vacationing in Haiti; there were Haitians going to Africa; there was likely drug use. And when you look at what we were seeing in South Florida, most of those cases initially among those of Haitian ancestry were acquired in Haiti. We had no evidence during the whole first 10 years of the epidemic that that was being transmitted in the U.S. among Haitians.
I don't think there was any one thing. I think there were multiple things. I think when you look at Africa, you are probably looking at the advent of air travel. And it didn't matter if you were a drug user, if you were gay, if you were heterosexual -- this disease didn't respect anything.
You said the Haitian community was enraged that they got labeled as the fourth risk category, but what actually happened to them to make them angry? Was it just that they were insulted, or were they suffering real discrimination from this?
I just remember one of the local channels called me up and was almost whispering on the phone and said, "Is it true Haitians brought in a deadly disease in the United States?" And I said, "That better not be your headline in tomorrow's paper." …
That discrimination happened quickly was very obvious. If you were of Haitian ancestry, you were easily recognized; you couldn't hide that. The community was very proud, very cliquish, and therefore they didn't want their own community to know what they might have or not. Therefore it would even interfere with them accessing care.
The whole thing was just really in the beginning somewhat of a nightmare, because we had to re-establish ourselves with the community; we had to gain their trust again. They had to see that our interest was helping them, understanding, having them work with us as we worked with them. It was hand in hand; we couldn't do this without them. They literally couldn't do it without us as well, and they had to learn to trust us, and with time they did.
There was an atmosphere of panic in the general public, wasn't there? All kinds of fears -- nurses wouldn't feed patients, policemen and firemen wouldn't touch suspected AIDS patients.
When you look back in the original description, this occurred among gay men and drug abusers, not a part of society that's championed. We had to work through all the routes of how it was transmitted. That the community panicked was real; that the health care community panicked was real; that everyone from firefighters to policemen panicked was real.
If a syringe was accidentally dumped in a parking lot, entire rescue units came in. I was called on the phone: "What do we do?" It was just really difficult, and I have to say the health community themselves panicked in a way. We just had to slowly teach them not to be afraid, and we led by example. …
As a young doctor, what kind of an emotional pressure did it put on you to be treating patients for whom you could in effect do nothing?
I learned very quickly that if you recognize the disease, we could treat it. We could get them through that acute infection. I pulled every stop that I could, I pulled on every knowledge base that I could, to treat infection. I pushed it to the absolute edge on how we treated patients -- very, very aggressive in doing it. And we won. We won small battles, if someone got out of the hospital with their PCP [Pneumocystis carinii pneumonia], that was a success story.
Then they came back with another infection. We worked again to recognize it and treat it, and that was a success story, watching it slowly evolve out, because leading the effort here, I also did the epidemiology. After I got to about 15,000 patients that died, I stopped counting numbers. It was very difficult.
It isn't really why I went into medicine, to watch so many people die, so many people being ravaged by this disease. And I say ravaged because it was. By the success of each individual battle, they could have five, six infections and be on multiple treatments. Then we just learned to put all the medicines together. How they took them all -- to this day I don't understand how they went through all of that, but they did, because they realized that there was no other hope, that this group of young physicians and nurses were dedicated to helping them when no one else was.
Then we realized that ultimately they were going to die, and some of the patients we got very attached to, got very attached to us. … They taught us incredible amounts. They taught us what courage really was. They told me if I wasn't there and if we didn't battle, then the battle was lost, that I was their hope, their courage, and then we just had to be there. So we just kept moving forward. Every time we would win battles, but we didn't win the war. Maybe one day we will. ...
The other thing that was very difficult, I traveled some years ago to India, and it was a fascinating trip. We saw a country that had poverty, that had leprosy in the colonies, and the isolation that they had there was very striking. When I came back from India, one of my patients [in the States] that I had followed for a long period of time -- and it was very apparent that we had tried everything we could. At that point we really couldn't treat him anymore, and the medicines were causing a lot of side effects, so he just asked me: "Should I just stop? Is it just time to stop everything?" And I said: "There isn't much more that I can do. I can just give you the same medicines, but you're not going to get much better than that." So he said, "No, then I want to stop." And then he said, "Well, I guess this is goodbye." I will never forget the expression on his face. It was nothing, for example, that I saw in India.
I mean, just the total loss of life, that his young life was over. That expression is something I will take with me forever. He knew I was upset, and he said: "You did not fail. I had five years I would never have had, and I thank you for that." Even to this day it's hard to even think back to that. ...
In retrospect, I think we rewrote textbooks on how to care for patients. They taught me what it really means to be a physician, that it's healing them and that it's healing them in many ways in the soul and the heart, and teaching them to die; that that is a process that you have to go through.
Then eventually treatment improved, and we had to teach them how to live, that this is not something that you're going to die with; that if we make a diagnosis of HIV, that is not a death sentence anymore, so it's now we turn around the other way.
When you look at how drug therapy works today, you know the virus hits CD4 cells, the main part of the immune system. It then goes into the cell, and it converts from an RNA virus to a DNA virus, and then it gets actually into the heart of the cell, the nucleus of the cell, and it integrates into the very DNA makeup of that cell. If that cell is stimulated, it then uses the network of that cell to make itself again, so then it converts itself back to an RNA virus and makes hundreds more. It attaches to the cell again, and it bursts out. In looking at how now you block that virus, you can block it at many steps: at attachment, at converting to an RNA virus, at getting into the heart of the cell, and then when it converts to DNA and then back to RNA again.
…Looking at what AZT does it actually blocks the virus in its ability to rebuild itself…. AZT works at one of the earlier steps, after it gets into the cell and starts converting from an RNA to a DNA virus….
Can you describe the clinical trial you did with AZT, how that worked, how that was set up, and what happened?
Those were the early Phase I-type studies that looked at escalating doses of the drug to pick out the best dose to use in future studies. Then the next phase study was a Phase II study, and it now asked the question, does this drug work?
We designed it as a placebo-controlled trial, because there was no therapy at that time, and we wanted the answer to be very straightforward and clear: Does it work, or doesn't it? We enrolled patients that had AIDS, advanced disease, and were concerned that perhaps the drug was being used too late and may not be as effective very late in the disease. We therefore also included patients that were at earlier stages of disease.
That was the design of the study. It had AIDS patients, it had AIDS-related complex patients, and it was designed to get the drug versus a placebo. A Data Safety Monitoring Board [DSMB] was set up, and we decided that the most important thing was survival benefit; that's what we were looking at at this point. We decided that that was the appropriate thing to ask for: Could we attain it? We hoped so. We didn't know. It was the first drug, but in designing a good scientific study, that is the way it should be designed. We then also said that we would also look at the immune system; we would also look at the incidence of recurrent infections, that the other thing it might do is slow it down. So that was our secondary look at the data.
When you set up these groups, is it kind of difficult to decide who gets a placebo and who gets the experiment to work?
When you design the study, it's a randomized study, like flipping a coin decides who gets placebo and who gets the drug, and it's blinded, so as an investigator I did not know who was being treated with a drug or who was getting placebo; and as a patient you did not know; as a pharmacist dispensing the drug you did not know.
As an investigator, you treated everyone as if they were getting the drug, because if there were side effects, you had to proceed on the basis that they were getting the drug, and you had to therefore change the dose of the drug, ... interrupt what they were getting. If that was placebo or drug you didn't know, but you had to pace through it as if all patients were getting the drug for the safety of the patients. ... If the drug showed to be effective and it had survival benefits, then you would set it up in such a way. If you hit a certain statistical level, which would be that it wasn't by chance that this was happening, then the Data Safety Monitoring Board would recommend that the study be stopped because you had an answer. For example, if it showed that zidovudine or AZT was better than placebo and patients were living longer, [then] you had your answer and what you wanted to do, and therefore it was not in the best interest of the patients to continue them on placebo, and therefore they recommended to stop it.
So when the trial's over, the board intervenes. How did you report it to the profession, and how was the news greeted?
Once the Data Safety Monitoring Board recommended that the study be stopped because it reached statistical significance, at that point the sponsor accepted that, discussed it with the investigators, and the study was stopped at that point. What happened is that the data was fully analyzed to describe everything that was seen in the trial: It described the survival benefits; it described that it actually slowed down the disease; it described that it improved the immune system; it described that it worked well in patients that had AIDS; that it also worked in patients that had AIDS-related complex or earlier disease. There was even a trend that suggested it was working better in earlier disease. At that point the group got together, and we wrote it up and published it, and went for broke and went to the New England Journal [of Medicine]. I was delighted to lead the whole thing, to write that up and get it into the New England Journal.
What was the response from the profession?
The reaction from the medical profession was really astounding, was very positive. It was considered an amazing breakthrough that moved very quickly. It showed that one could develop a treatment against what now we know was a virus, HIV; that that could be done. Therefore, it was a critical step showing that one could actually get at the cause of the disease HIV and actually treat it itself, and begin to reverse it. Then drug companies developed more drugs; we began giving two drugs together, and then eventually new classes [were developed], and [we began] putting three drugs together.
Is it fair to say that AZT was the first steppingstone on the path towards the increasingly successful cocktail approach you were claiming?
In looking at the first study, the one thing that came out quickly is that the virus wasn't totally knocked down, and as long as the virus could still replicate or grow, it pushed against that drug and developed resistance so that drug did not work anymore. Therefore, for the development of new drugs that were coming out, it became very obvious to some of us that one drug wasn't good enough, and therefore we started combining drugs together. We combined newer drugs with AZT and then looked at two drugs together and showed that it was better than AZT alone, which was critically important.
Some people were very skeptical initially, because we were combining drugs together in the same class of drugs, and they were not entirely sure that that would work. But we had other disease processes in which that likely would work, and there were laboratory studies that showed when you put the two similar-class drugs together that it was synergistic. ... It had an added boost together, which was very critical in that one really needed to push this virus. Then the whole industry started developing different classes of drugs, and I think the next big step after that was then combining drugs together from different classes.
How did the AIDS activists greet the advent of AZT, as a successful at least beginning?
Looking back at the whole epidemic and working with patients and everything and looking at the success of AZT, that was latched onto by patients in an incredible way. When we discovered that this virus quickly developed resistance, we could then see the utter disappointment and almost anger in some of those patients, because here they suddenly had a success story, and it was taken away from them.
We had to again work together, telling them that this was a step, movement forward. It was again another battle, and it was moving forward; that it wasn't the answer; it wasn't the cure. It didn't mean we wouldn't stop looking for a cure, but it was a step and that they had to work with us, because the FDA moved very quickly to approve this drug AZT.
It was given at too high of a dose in the beginning; there was a lot of side effects. We picked up on that very quickly, did studies that looked at lower doses, and I would teach both patients and the health care professionals [that] in moving so quickly, we don't have all the answers, and as more studies came out, we learned more, and therefore we adjusted how to give the drug, how to dose the drug, how to put them together.
It wasn't a bad thing that happened; it wasn't mistakes that were being made; it wasn't untruths that we were saying. It's that we didn't have all the answers, and therefore one had to be cautious that we could change our minds in two weeks or a month when we got more data and knew better how to work with these drugs. But we had to approach it this way because it was such a devastating disease. It was saving lives.
Some of the patients became very activist and very angry, and nothing was good enough, fast enough anymore. They were concerned that these drugs were toxic and that they were causing cancers and everything else. As it was all unraveling, I just remember at a big conference someone stood up and said, "Dr. Fischel, would you take AZT?" I said: "No. Why would I take AZT? I don't need it." He said, "Just to take it just to show that it's safe and it's OK and you're not going to die of cancer." I said, "I'm not going to take AZT; I don't have HIV/AIDS." I said, "It doesn't cause cancers, and I'm not going to take that to prove it to you." You could just see the anger that was there. …
You just had to understand their frustration. They were dying; they were devastated by this disease. It had just incredible effects on them, and you just had to learn to accept that, not to be angry back at them, to understand them. …
[What did you learn about AZT and mother-child transmission?]
The other area that was very important with AZT is that once we understood what its impact was for adults, it also really led the way to looking at this in infants. ... We looked at the transmission pattern among mothers that had children and could see that not all children became infected from mom, and that there was not a complete transmission during pregnancy. It slowly evolved out that about 30 percent of mothers transmitted HIV to their children. …
The drug went very quickly into those early trials that looked at preventing transmission from a pregnant woman to her child in placebo-controlled trials and showed in the initial trials, like we did with the first big study with AZT, that it blocked perinatal transmission, and that was an incredible breakthrough. ... You have a medication in hand that could potentially prevent perinatal transmission, and therefore one entire part of the epidemic literally could be stopped. ...
If AIDS had a character, what would you say its character was?
If I tried to describe this virus, I would say it's incredibly smart. It is meant to survive. It is like almost the ultimate demon that's immortal. I hate even saying it that way, but it has all those characteristics. It can change its face; it can change what it looks like. To knock off treatment, it gets into the DNA makeup of a cell. It can hide there; it can quietly sit there and rest there so that the drugs we're using don't get at it, and if you stimulate that cell for any reason, it will wake up and turn on again, and if you take therapy away it will roar back again, to keep infection going. ...