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Science in a fishbowl

Dr. Fauci on combination therapies, vaccines for AIDS

From the May 1997 ACP Observer, copyright 1997 by the American College of Physicians.

By Deborah Gesensway

BETHESDA, Md.-When it comes to advances in understanding and controlling HIV and AIDS, the last year has been one of both great hope and great hype. Scientists have been lauded for transforming a fatal infection into a controllable, if chronic, disease; yet in the next breath, they are accused of creating unrealistic expectations among desperately ill people.

Most dramatically, evidence has recently shown that a substantial proportion of those who can comply with a complicated regimen of different drugs—11 have been approved by the FDA, including four protease inhib-itors since December 1995—can reduce the amount of HIV in the blood to below detectable levels. These new combination therapies, colloquially known as "cocktails," have been tested for only about 18 months, so their long-term effects and safety levels are unknown. For other infected people, the cocktails appear to fail altogether. But the rapid influx of new knowledge about how HIV infects, replicates and destroys human immune systems is spilling out of the labs and into the offices of doctors who need to transform the theories into practice.

At the heart of this extraordinary research endeavor for the entire 16 years of the disease's history is Anthony S. Fauci, MACP, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. Dr. Fauci, 56, a Brooklyn, N.Y., native who has spent his entire 28-year career in the labs and offices of NIH, was awarded the John Phillips Memorial Award for distinguished contributions in clinical medicine and named a Master of the College at this year's Annual Session in Philadelphia.

Dr. Fauci received his medical degree from Cornell University Medical College and completed his residency at New York Hospital-Cornell Medical Center. Although administration consumes much of his time, Dr. Fauci remains active in the lab, concentrating on identifying the nature of the immunopathogenic mechanisms of HIV infection and the scope of the body's immune responses to the AIDS retrovirus. Dr. Fauci spoke with ACP Observer about where AIDS research heads next and about the challenge of conducting science in a fishbowl.

ACP Observer: What is going on in the field of AIDS research that is most exciting for clinicians?

Dr. Fauci: Obviously, the thing that has attracted the most attention has been the great potential in the use of combination therapies, particularly those that include the protease inhibitors, in the treatment of HIV-infected individuals.

We must be careful, however, because the hype that this has gotten thus far may have caused some to inappropriately and incorrectly assume that the battle and the war is won. That, I think, is a dangerous assumption. We do not know how good these drugs ultimately are going to be.

Q: What are the caveats?

A: Although in a reasonably large percentage of individuals the virus falls to below detectable levels in the blood, what we don't know is how long this is going to last. Does this mean that the virus has really been cleared from the body or is it merely being suppressed in sanctuaries like lymphoid tissue? Also, there is the danger that you will induce the evolution or emergence of resistant strains of the virus. There's the question of the ability of the patient to tolerate these regimens, a question not only of compliance but also of cumulative toxicity. These things do not get considered when people get caught up in the euphoria of the so-called breakthroughs. As we know from experience over the years with infectious diseases, it is dangerous to be declaring that a disease is cured and over until you have substantial experience with the therapies.

Q: Is AIDS different fundamentally from other infectious diseases?

A: There is no clear answer to that. HIV is extremely unusual and very rare in that most viruses either kill you acutely or you completely clear them from the body. There are some exceptions to that rule, for example, herpes viruses, but there is no infection other than HIV where the overwhelming majority of the people who get infected have chronic persistent replication of the virus for years and years.

We have very little experience with retroviruses affecting man, namely viruses that have the ability to integrate their genome into the genome of the human cell. Most infections target a particular organ and destroy the cell, but do not integrate their genetic material into the genes of the cell to essentially propagate forever.

Q: You have written quite a bit about long-term non-progressors. What is it about these people that makes them important to scientists?

A: The very fact that there are long-term nonprogressors who can live for 15 and more years without any deterioration of their function tells us that this length of survival is possible. If they did not exist, we might say, 'Well, nobody can survive.' And, we have shown very clearly that the long-term nonprogressors are a heterogeneous group. Some of them are long-term nonprogressors because their virus is weak or defective. Others have a very potent immune response. So we use these people almost as an experiment of nature to guide us to come up with studies. Why is replication being contained? What about their lymphoid tissue? Why is it different in people who have advanced disease?

Q: In addition to the research leading to the combination therapies, are there some other advances that warrant further attention?

A: There are a number of very important advances in the basic science of understanding how the virus works—for example, the discovery of the co-receptors for the virus, and those molecules on the cell surface that the virus needs to bind to enter the cell. Those discoveries this year were probably as or more elegant than some of the treatment discoveries, but people better understand a cocktail that makes people better, so they get a distorted view of the relative importance of the science.

Understanding how the virus works lays the framework for developing more targets for drugs and vaccines. It is the fundamental science upon which the more flashy therapy studies emerge.

Q: What about vaccines vs. therapy?

A: Developing a vaccine is the only surefire way to put an end to the epidemic—most of the people who need the drugs will never get them. We are not going to substantially decrease the amount of resources that are being used on treatment, but any new increases in resources will favor vaccines, basic science and immunology.

Q: NIAID dedicates more than half its total budget to HIV and AIDS research. As a result, are there other infectious and immune system diseases getting short shrift?

A: Everything is relative. I would not say that other diseases are not getting a lot of attention, but our institute has expanded four times its size since I became director, and most of that was HIV-AIDS. That is appropriate when you have a new disease that is out of control. You can make an argument that if you poured as much money into malaria or some of the other scourges of the developing countries, you would be able to essentially wipe those out. However, there is no guarantee that this will be the case.

On a positive note, the response of the scientific community to HIV and AIDS shows what can be done when substantial resources are garnered together. Look at the story of the protease inhibitors. It started with basic virologists working on HIV identifying the protease enzyme, structural biologists crystallizing the enzyme, the development of an inhibitor for that enzyme, the translation of that into a drug, the clinical trials of the drug, and then the rapid approval by the FDA. Something that in the past may have taken 20 years to do took place within just a few years.

Q: What's the role of the practicing physician in all this?

A: The practicing doctor is the natural beneficiary of these consortia of government, industry and academicians working together on science. All of us are working for the goal of translating this to the private doctor and ultimately the patient.

It is particularly challenging for the private physician to keep up with the appropriate state-of-the-art approach to an HIV-infected individual. It is our responsibility to provide that information to private physicians, and to make these guidelines and consensus recommendations flexible, living documents, as it were, that change quickly. But it is the private physician's responsibility to be aware that they are in a rapidly moving field that is going to require constant updating and alertness on their part as these guidelines evolve.

Q: How does the close public scrutiny of everything related to AIDS affect your work?

A: It does not change what I do, but that is one of the reasons why my job is so difficult. Some days I am hated, some days I am loved. Some days the activists call me a hero, the next time they call me a murderer. I got used to that a long time ago. A lot of people ask me about public opinion. Public opinion is not my first consideration. I care about what is correct, what is scientifically appropriate, what is ethical and what is good for the public health.

Q: But how do you keep focused on the science when you are working in this kind of an environment?

A: You are now talking about science in a fishbowl. With HIV, because of the enormous public scrutiny, little things get blown up, and things tend to get distorted. For example, were this a disease that was not getting as much public attention, you would not see nearly as much publicity about the combination therapy until it was signed, sealed and delivered. If the disease were of less public interest I do not think you would see the kinds of extrapolations toward declaring victory before it occurred. No doubt we have made great advances this year, but it has been as much of a media phenomenon as anything else.

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