Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 10 - November, 1993

TREATMENT ISSUES (TI): Can you tell us about the meeting in Madison?

MARTIN DELANEY: The purpose of the meeting was to bring together various forces engaged in discussions around AIDS research towards the question of how should it be managed - should the federal research effort be structured differently, are there inherent problems in what we're doing? And more or less, where are we? We brought together the tops in government, the Faucis (Anthony Fauci, Director of the National Institute of Allergies and Infectious Diseases), the Broders (Samuel Broder, Director of the National Cancer Institute), some Congressional representation, representatives in industry, a number of activists who've been vocal on these issues, Kristine Gebbie (the White House "AIDS czar") and university-based voices that have been speaking out on these issues. The goal was to see if there was anything these folks could agree upon as a first step toward proposing change. The first two-day meeting was largely aimed at getting a snapshot of what people agreed on.

We got agreement on a list of scientific questions, as well as a list of organizational and structural questions. Our goal was simply to find where we could agree, and I was happy to see we drew up consensus on a number of those points.

TI: And what were those?

DELANEY: Well, on the "do-ability" of the problem itself. The agreement that people believe we can solve and manage this problem.

TI: And that was agreed on by most people?

DELANEY: That was universally agreed upon. And Broder even challenged us to take it farther and agree that we could literally remove the virus (HIV) from the body. People weren't quite willing to go that far.

TI: Of course, that's at odds with some of the pessimism that came out of Berlin that seems to pervasive.

DELANEY: It very much is, because the pessimism that came out of Berlin frankly was not based upon data. It was based upon emotional reaction and politics. One of the good things of the meeting was to confront some of that pessimism. The other areas of agreement got down to specific questions of funding, management practices, management styles, and specific problems of the government-industry interface. Now there's going to be a second meeting in Boston on November 22 to 23. In the meantime, four working groups have been put together which break up the areas of agreement from the first meeting. The working groups are attempting to draw up programmatic recommendations for how to address these problem areas that everybody agrees upon.

TI: Obviously, if everything was truly wonderful in the AIDS research effort, something like this would not be needed. What's wrong with the government's AIDS research effort?

DELANEY: AIDS research, like biomedical research in general, is not managed under the best accepted principles of project management and goal accomplishment. There are methods for managing basic research and discovery that are employed in industry and other parts of the government for managing work into the unknown. We've seen it in the space program, in military programs, and in the computer and other high technology fields. It's my belief that those technologies of management are not employed in biomedical research. There's a sort of profound belief in this notion of watering the garden - that we don't know where the answers are going to come from, you can't force a solution. So you water the garden freely.

TI: What's wrong with that?

DELANEY: It leaves far too much to serendipity, and it assumes that this process will somehow fairly distribute things to the right places. I don't think it does accomplish that. We've learned from industry and other fields in science that you're much more likely to accomplish a goal when you establish goals, develop strategic plans, continually scan for your knowns and unknowns, establish hypotheses to test and develop your knowledge - to push it forward a step at a time in a rational fashion. I don't see that happening in AIDS research.

TI: What research effort would be a useful model to look at?

DELANEY: A lot of the military research has been far more focused and much more likely to produce results. The grossest examples, of course, are in weapons development and weapons delivery. Folks like to think that was all some sort of engineering project over the last 50 years, but in fact, if you go back from 1940 and see where they went, they pushed the envelope in every imaginable aspect of our knowledge of physics.

TI: Are you satisfied with the current leadership of the federal AIDS research effort?

DELANEY: I believe in the need for stronger leadership, and by that - I don't mean a dictator, I mean a different process more than necessarily different people.

TI: But isn't the job of the people who are in charge to really develop an effective process?

DELANEY: Absolutely. And if I must be asked, yes, I think they fail to do so. Now the question, though is why? On the surface, they will argue that they don't believe in the other models - that they believe we must just sort of water the garden freely and maybe a flower will grow.

TI: Some people also argue that the current leadership has been there, now for seven to eight years, and that the longer you're there, the more you become embedded and part of the system and thus cannot really develop substantial changes.

DELANEY: Well, I think it's essentially true that the longer you're in a spot like that, the more baggage you bring to it. Some of this stuff starting to happen right now - certainly talk about strategic plans. Well, that's fine, except where was it in 1986? It's being forced on them politically, and I think reluctantly. I don't believe their heart is in it right now. So yeah, I support change in leadership.

TI: Dr. Harold Varmus has been appointed to head the NIH (National Institutes of Health). Are you optimistic about his leadership?

DELANEY: No, I'm not. As you know, I sort of stuck my neck out in opposing him and raising questions about him. And the principle reason for that is, when you get down to these arguments about how research ought to be managed, I think he frequently has been outspoken on the opposite view. He is not viewed as someone who looks to strong central leadership.

TI: And how about the President himself? Do you believe he's provided any real leadership in trying to attract the best and the brightest?

DELANEY: Up to this point, I would say the President has simply not given any attention whatever to it. So far, there simply hasn't been any clear leadership from the Administration in any form. Now, we're getting a lot of signals, like participation in our meeting and the support we've had from Shalala and Phil Lee. It seems like they want to do something, but I think they clearly haven't put the time into figuring out what they want to do.

TI: Let me go back - you voiced optimism that it was, indeed, possible to develop effective therapies for HIV. What are you basing that on, and what particular therapies - or lines of therapies - do you see as most promising?

DELANEY: I think there are really two basic points. One is that I think there is general agreement on the cause of the disease - unlike cancer, in which you're dealing with hundreds of different diseases, there's just no comparison to where we were or even are on the war on cancer. We're infinitely ahead of that. Secondly, even though we don't understand every last bit of pathogenesis - that doesn't bother me, because frankly, no disease that I can think of historically has ever required a perfect understanding of pathogenesis - the existing therapies --I think the general consensus is that they do have some activity against the disease.

TI: You're talking about the nucleosides? (AZT, ddI, ddC)

DELANEY: I'm saying the combination of anti-viral therapy, opportunistic infection therapies - each of those areas has shown some ability to modulate the outcome, change the time parameters, etc. What that says to me is that we're on the right track and that we're essentially in an engineering stage here. We're not fishing in the dark. What we're trying to do is build upon small knowledge to make larger gains. One of the great hopeful things about this epidemic is that we see any activity at all in response to anti-viral therapy. There's a bundle of studies out there that show there's some gain. Maybe it's a six-month gain used at a certain time in a certain way - whatever that gain is, that tells us that this goal, I think, is attainable. There are ways to slow [viral] replication ... to me, it's an engineering problem of how do we do that and there are several very promising avenues out there that are moving on that.

TI: Are you optimistic about the protease inhibitors?

DELANEY: Yes, mostly because of our experience with Merck so far has been pretty sober and solid.

TI: Merck was actually pessimistic about their own drug (L-697,661) despite promising reports about convergent combination therapy.

DELANEY: I like them a little more than the others in that regard. So I'm very hopeful about that. Protease inhibitors open up the potential for a broader kind of synergy in combination. Also, I'm encouraged by the progress that's going on in gene therapy right now.

TI: Any particular therapies or are you just talking about areas of research?

DELANEY: There are several technologies involved in that that I'm very hopeful about. There's a whole focus going on in immune-based therapies right now. It's very encouraging. Not because it's instead of anti-viral therapy, it's because we're working on another part of the problem, and that's progress to me. And opportunistic infection drugs are improving with each year.

TI: Tell us about the work in immune restoration that was led by Jesse Dobson (of Project Inform).

DELANEY: The areas that are under the most development right now are cellular transfer, be it from a twin or a non-matched sibling-cell transfer from another species, technology for doing things that will be in human beings before November. We're talking about a methodology that will allow the transfer of HIV-resistant stem cells from other simian species without rejection. It's another approach to gene therapy, but a much easier way. The whole cytokine area is kind of exploding - both in terms of correcting inappropriate cytokine signalling and replacing with some of the signals that seem to be missing. TI: What is the status of the Interluekin-2 (IL-2) trials?

DELANEY: We're very pleased by the most recent data coming out of the IL 2 trials. There's reason to believe that they're coming upon a better way to use it, and it's supported by a limited number of cases with Lane's [Cliff Lane at the NIH] work, but we also have quite a bit of similar work done out here and in Stanford and in Larry Waite's group. We are seeing in both groups substantially elevated overall levels [of CD4 counts] and trends sustained for a long time. So that's significant. A number of individual physicians are duplicating Cliff Lane's protocol right now.

TI: Are you concerned about the toxicities with some of these cytokines?

DELANEY: With any of these drugs, sure. With all the cytokines, the challenges are in the rational way to use them.

TI: There's been a lot of discussion about IL-12. What do you think?

DELANEY: IL-12 is sort of the cytokine "du jour" right now in terms of its signals, its secondary pathway in immunity based on natural killer cells and interferon. It needs to be studied. I'm hesitant, though [that] it's going to be the whole answer. But it's another tool for fine-tuning the immune system, and I think the sooner we get it into studies, the better.

TI: What about another "treatment du jour," the whole area of so-called "anti-oxidants"?

DELANEY: Well, one could argue in a cryptic way that all cell death is due to oxidated stress - that's the way the body kills cells, through oxidated stress. So in that sense, anti- oxidants certainly make a lot of sense. Now again, it's the question of when, how much, and how far you can get from that approach. It's symptomatic treatment on a cellular level, and yeah, I think it may be helpful. It may slow cell death and cause a little less harm on the cellular level, but eating beta-carotene alone or pentoxifylline, as far as I can see, is not producing dramatic changes in outcomes. Should it be done? Of course it should.

TI: What about pentoxifylline?

DELANEY: I wouldn't discourage it, either. It seems of all the therapies we've looked at, it's one of the things that have the fewest downsides. So it may make sense.

TI: And how do you evaluate the nucleoside analogues?

DELANEY: My sense of nucleoside analogs is largely unchanged from what it's been for the last three years. If you look at what Concorde said, it simply fine-tunes our knowledge of how to use these things. All of us know people who've used nucleosides and had toxic effects and didn't see benefits. But I also hear of people who use them and did well, we really felt they benefitted for long periods of time. The weight of the evidence is, [that] these things, while imperfect, are tolerable in a lot of people and seem to be helpful in some of them.

TI: Let me go back to the federal research program. The new position of the Office of AIDS Research Director has not been filled. Is there any individual that you think would be appropriate for the position?

DELANEY: I think that's probably the toughest question out there right now. None of the candidates I've heard mentioned frankly excite me for this position. And the recommendation I've made so far is that: we not be limited in our thinking of people who are star producers in AIDS; secondly that it's eventually an administrative job, and what we need is a good politician and a good administrator in there; and third, I'm not even sure it's a medical researcher. The scientific calls should be coming from this advisory panel. Beyond that, what we need is a slick bureaucrat - an excellent bureaucrat.

TI: Someone who would manage a research bureaucracy.

DELANEY: Right. For me, that could be a behavioral scientist as easily as it could be a physical scientist, or it could even be someone who isn't even from the scientific field.

TI: Or someone like the First Lady - hypothetically - who has the ear of people who would really make that person credible.

DELANEY: That's right. Absolutely.

TI: Are we setting that person (OAR Director) up for failure in the sense that he or she still has Tony Fauci, who opposed the changes and who's going to be running a big chunk of AIDS research dollars. In a sense, they'll be two competing operations.

DELANEY: Yes. I think there's some real potential for problems in the structure. Especially because you're taking this secondary structure, the one that Fauci will run, is run by the guy who used to run the whole show. Intrinsically, I think that's a formula for sort of a two-headed monster here. But also I don't know a good way around that. I'm not suggesting that they should throw Fauci out or something. I'd be happy to see Fauci spend more of his time in science.

TI: And less in administrative.

DELANEY: Right.

TI: How does the government maximize the efforts of private industry in AIDS research?

DELANEY: Well, I think the first thing it needs to do is ask them. I think it's done a very poor job of sort of sitting down with industry and asking what it needs to be better involved in this. I was really struck last week when you saw Clinton on television, pulling togetherb the leaders of Ford, GM, and Chrysler announcing this government-industry collaboration to create cars that will get 80 miles per gallon. Well, you know, where the fuck is the collaboration with the President and industry on AIDS? Why isn't he there with the head of Merck and the head of Burroughs and these companies announcing a similar collaborative effort?

TI: A good question to end on. Thank you for your time.
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