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Goedert: I do not know. I think I have always been in the middle as to what the prognosis is. The people in the hemophilia community are only now coming around from the position that hemophiliacs are different. The realization is that, yes, hemophiliacs are different, but only because they are younger. That belief was based on the observation that few hemophiliacs had developed full-blown AIDS compared to the enormous numbers of hemophiliacs that were infected.
On the other end of the spectrum, immunologists, in particular, virologists, and maybe some of the clinicians, felt that this condition had to be inexorable and unstoppable. It seemed clear to me that there was a group of people, and I suppose my estimate of the portion has gone down from one third to 10 percent, that appeared to be doing not too badly immunologically for a relatively long period of time–what are now called “long-term survivors.” It is certainly true with almost all infectious diseases, and even with some malignancies, that a minority of those infected, but not an infinitesimal minority, does fairly well for a prolonged period of time. They are able, in the infectious disease world, to develop tolerance or enough immune response to control the infection and have a reasonably normal life expectancy. But I think I was out front in this.
The paper that I published in Science, was published for one, and only one, reason. It was the first clear evidence that of those people who were infected, many were going to get AIDS. Even in the gay community at that time, if you looked at the number of cases divided by the number of infected people you came up with 8 or 10 percent. In our cohort it was clear that 35 percent had gotten AIDS just three years after enrollment, if the proper actuarial technique was used. There was also this rank order in the three-year prognosis based on how long the virus had been in the community, with New York doing much worse than Washington, D.C., which did worse than Bob Biggar's group in Denmark. It was clear from whenever that was–it must been 1985 when we wrote that paper–that at least a third, and probably fully half of the people who had been infected, were going to get AIDS. But, again, from 1985 to the present day, it is clear to me that there is a portion of people who remain clinically well. That is what you would expect from the natural history of infections in human populations and in animal populations.
We continue to expend a lot of energy and a fair amount of in-house money [at NIH] looking for the immunogenetic factors that may account for the difference in disease progression and/or disease resistance. We view that as one of our highest priorities because it may have substantial implications for understanding not only the biology of how a person tolerates or deals with that kind of infection, but also some potential implications for the development of a vaccine or for learning what parts of the immune system must be stimulated in order to get some control over the infection.
Rodrigues: I want to ask you about the study that you did with twins. It seemed very intriguing. Have you continued research along this line, or has that particular project come to an end?
Goedert: No. It has not come to an end. It is most definitely ongoing. There is a rather interesting story about how that got started. I was invited by the Pediatric AIDS Foundation to go to a meeting in California on risk factors for pediatric AIDS and different kinds of immune response. We had reported, for example, that prematurity and low levels of anti-gp120, which is the part of the immune response that might be important in protective immunity, appeared to protect infants from getting infected by their mothers. Because of the time difference between California and the East Coast, the first morning I was there at a hotel on the beach I woke up very early. I took a long walk on the beach. I was trying to put together the things I had heard from the day before and make some kind of sense out of them. It was a good time for thinking; the sunrise was not quite over the Pacific, but coming over the mountains in Santa Barbara.
There had been one anecdote of twins being born that someone had mentioned, where one had been infected and the other had not. It seemed to me a possible way to distinguish when the infection occurs; whether it has already occurred before the woman goes into labor, in which case the chance of infection should be random for the first-born and the second-born twin; or whether, as I suspected, again wrongly, the virus was transmitted during separation of the placenta, in which case the second-born should be at higher risk because they are in the womb longer, they are exposed for a longer time.
Harden: Is it clear then that the virus does not cross the placenta to infect?
Goedert: Let me tell the whole story.
Goedert: The question was, if the order of infection was random you could say the virus must get across the placenta in a random order. If it was a non-random order of infection–if the second-born is at higher risk, or the first-born is at higher risk–then the transmission of the virus is non-random and it must occur during labor and delivery. Or else there is something funny about twins that we do not understand in terms of where the placentas are attached or whatever.
I recruited a young colleague at that meeting who was French. I thought we needed some French input to get the big European cohort studies and Projet SIDA in Zaire involved. It was clear we needed to get a big network since even the biggest studies would only have a few twins. So that is the origin of the Twins Registry, the one study I have worked on in which 99 percent of it was conducted by FAX machine. Without the FAX machine that study would never have been done. We literally faxed out invitation letters with forms, and people faxed the forms back in. Every day was like Christmas. I would come in here and there would be a FAX waiting for me, or maybe two, or three, or four, with more data. You never knew what was going to come across the FAX machine.
The startling finding was not that the order of infection was non-random, but that it was obvious from the start that the first-born twin was at much higher risk. That was because of the physiology of the second-born coming through the birth canal much more easily after the first-born had gone through. It was just intuitively obvious that the kids must be getting infected literally as they were coming through the birth canal.
But you could not disprove–and there were actually some more subtle suggestions in that analysis–that there were probably some children who were infected before the woman went into labor; birth weight discrepancies, the lighter child being infected, and so on. The study is ongoing.
Harden: You also looked at Caesarian section and found that that did not make any difference either.
Goedert: There was a slightly lower risk of infection, and, in subsequent analysis, the risk has been found to be significantly lower in those that were born by Caesarian section. Even in twins born by Caesarian section, the first-born is at a higher risk than the second-born. We attribute this as most likely due to what we call ascending infection, in that most Caesarians are not done electively. The amniotic fluid has already broken through and the children are already exposed. The child who is in contact with the cervix and close to the birth canal is already exposed to that. There is some evidence from the perinatal herpes virus literature that if the babies are exposed for at least four hours they are likely to get herpes, if the woman has active herpes. We think that there can probably be some ascending infection up into the uterus if the woman is in labor for at least four hours, which is not uncommon at all.
But there was a little lower risk in the first analysis and, in subsequent analyses, the risk was appreciably lower with Caesarian section for both the first-born and the second-born twin.
Harden: That is an interesting study. Is it ongoing?
Goedert: Yes. We have had an extremely good response. We now have, I think, 200 sets of twins and two sets of triplets enrolled. We have the luxury now of just analyzing those who are prospectively identified. There are some statistical reasons why it is hard to deal with those whom you find out about because one is infected. You never have any negative-negative sets if one twin had to be infected in order to come to medical attention. But we have, I think, 115 sets of twins in which we can just analyze those that are identified because the mother is infected. You get a better handle on the absolute risk because you have, in theory at least, the universe of twins that were born to infected women.
We are coming to the end of our questions relating to your papers. But
before we stop, Dennis, do you have other questions you want to ask?
Goedert: Sure. I do not know if it can be called a study. It was a Sounding Board piece, which is an uninvited editorial in the New England Journal of Medicine. This was at the time that politics was preventing even doctors who wanted to from readily testing their patients for HTLV-III, now known as HIV, antibodies. The rationale for limiting access to this test was, first, the potential for discrimination and other kinds of adverse activity, which was a real consideration. The second was that in theory nothing could be done for the patients who were found to be infected. The pressure, which was very successful in some communities, was to use the test only for donated blood and plasma. The wording was always very careful to specify that the donor was not being tested, the blood was.
Meanwhile, there was a raging epidemic with numerous people going around not knowing whether they were infected or not. It still makes no sense to treat everybody the same in terms of their education. The educational approach at that time, which was rather successfully promulgated by gay men, was the same for everybody–“Everybody should use condoms.” There were also some other recommendations, such as finding out if the person had been sick, and so on. It was not clear then, and it is still not clear to me now, what kind of educational campaigns are successful and what are not. We have indirect anecdotes and so on, but, although I do not consider myself a scientist, I do consider myself somewhat of a social scientist. It is very dissatisfying not to have a clear picture as to what kind of education is helpful or successful and what kind potentially may even be harmful. You could, in theory, tell everybody to use condoms and in theory–I do not think it is likely–you could promote sexual activity.
The Sounding Board piece basically said there is an objective way to define truly “safe sex," and that is no sex; masturbation, in which there is no contact with other people; and a completely monogamous relationship with another person, provided both have the same HIV antibody status. It is very explicit not only that both people are negative, but also that both people could be positive. I think it still never has been shown that there are adverse consequences from two HIV-infected people having sex with each other. But in order to do that, you then had to apply the antibody test to this counseling and definition purpose.
The points of the
We have continued to confront this in the hemophilia couples where the men are almost all infected and the women are almost all uninfected. What can those people do? Not much. That is a tragedy. But to tell these people that they can just use condoms borders on perpetrating a fraud. I think when the rubber meets the road, so to speak, ultimately they say, “If you have intercourse, then at least use a condom.” Then you are making it clear that it is a second order preventive activity. It is not research–it is opinion–but it is rational opinion, I hope.
Harden: But the kind of research that you did put you in a position to make such kinds of recommendations, or be asked to, at any rate, more than someone who was simply looking at a test tube.
Goedert: Yes. I always enjoyed being close to the firing line, close to the fringe. While I wish there were more people like that, I think the whole system, the whole field, is too timid and too sluggish. At the moment I am frustrated by the vaccine trials. Where are they going? Are they going anywhere? Are we being too timid?
Harden: It has concerned me for some time that subunit vaccines do not seem to be being investigated, not only in AIDS but in some other areas too. Will we ever have any kind of a vaccine given how fast this virus mutates, and what should we be doing? If you feel frustrated by what is happening, what do you think might be effective? Will it be subunit vaccines? Will it be whole virus vaccines, live or dead?
Goedert: I am not a vaccinologist, but I heard a telling comment at a meeting I was at within the last week, “You could learn a lot from your failures, but if you don't try it, you don't have any failures.” I am not close enough to the subunit vaccine work to be completely discouraged. The people who are working on it are probably discouraged, and maybe I should believe in their discouragement, but even those people, I do not think, are completely discouraged. I believe that we will have a vaccine. I found very exciting the recent report of the SIV vaccine that used a deletion mutant. It deleted one of the regulatory genes from SIV and really had a very successful challenge, not only with the homologous strain of SIV, but also with a virulent strain of SIV.
Let us consider the subunit vaccine. We will never know which way to go on subunit vaccines until we try them more. Although I am not a vaccinologist, unless there is good reason to think that the person's risk of becoming infected might be increased, or their infection enhanced, we will never know what does not work until we get out there and try it.
Harden: Let me ask you an epidemiological question. Last Sunday in the New York Times there was a discussion of the new National Research Council [NRC] report suggesting that we could reduce the incidence of AIDS to low levels by targeting zip codes where there are a high number of infected people. Have you heard about this?
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