COLUMN ONE : Rethinking Priorities on AIDS : The infections that prey on those with damaged immune systems have been targets of little interest to researchers. The emphasis has been on finding a cure for the syndrome.
A recent international conference on the status of AIDS drug research here drew an overflow crowd of hundreds of medical professionals. But by the final morning’s session--one devoted to the infections that prey on people with immune systems laid waste by AIDS--the hall was virtually empty.
“I expected it,” said John McGowan, associate director for basic research and development for the AIDS division of the National Institute for Allergy and Infectious Diseases, the leading federal agency in AIDS research. “It didn’t surprise me at all.”
Throughout the scientific community, there has been little in the way of basic laboratory work or clinical studies toward finding or testing treatments for the opportunistic infections that plague and eventually kill most people with AIDS. And attracting researchers to the area has been a continuing problem.
The lack of activity reflects a belief held by most of those doing major AIDS research: that the greatest advances will come from developing drugs for the virus that causes acquired immune deficiency syndrome, rather than from drugs to treat each infection that accompanies the underlying condition.
Thus there has been a full-court press to discover and study antiviral drugs but far less interest in finding treatments for the virulent forms of cancer, meningitis, pneumonia and other infections that strike AIDS patients.
But that attitude is rejected by those who are infected or ill. For them, the most pressing and immediate concern is to survive with AIDS as long as possible by defeating each infection that develops.
“If you can give us two more years, you’ll have two more years where you can find your cures,” said Mark Harrington of the organization ACT UP (AIDS Coalition to Unleash Power).
The situation also frustrates primary care physicians who are on the front lines treating AIDS patients, and the National Institute for Allergy and Infectious Diseases (NIAID), which recently initiated a major push to ignite interest in the opportunistic infections arena.
“There is no question we need to do more,” said Dr. Anthony S. Fauci, NIAID director and the federal government’s director of AIDS research activities.
“From a scientific viewpoint, it’s obviously much more interesting and exciting to do the antiviral work,” Fauci said. “But you also must address the problem of what you do for those people who are already infected and whose immune systems have deteriorated. This is an issue of major public health importance.”
Experts say there are many reasons work in this field has been moving so slowly. First, they say, few known drugs are effective against many of these infections, which are rare in people with healthy immune systems.
Further, too few basic laboratory scientists or pharmaceutical companies are interested in looking for new drugs. The number of diseases involved complicates the search, and drug manufacturers often perceive the potential market to be quite small and not worth the effort.
“Where do the new (drug) molecules come from? They come from laboratories or companies that get excited about this kind of research,” said Dr. Daniel Hoth, director of the AIDS division of NIAID.
Hoth said: “Researchers in academia will get excited about testing these drugs (in humans) if they sense the challenge is doable, but the major problem is that there aren’t a lot of drugs out there. The fundamental issue is that we need to find new molecules.”
Researchers also noted that it would be discouraging to conquer one infection with a drug that is available now only to have an infection of a different nature strike in its stead.
“We need to put people with AIDS into remission” by finding a way to restore their damaged immune systems, said Dr. Robert T. Schooley, an AIDS researcher at Harvard University and Massachusetts General Hospital.
Until that happens, Schooley said, “each successfully treated infection will add a little bit to life expectancy, but in a lot of ways, it’s just exchanging one cause of death for another. I wish life were simple enough to believe that treating the opportunistic infections would make the disease go away. But it isn’t.”
He likened the situation to leukemia years ago, before therapies were found to place that disease into remission. Those afflicted with leukemia also were vulnerable to life-threatening infections.
“As the antibiotics got better, we were able to keep people alive longer,” he said. “But unless we were able to put the leukemia into remission and have the immune system returned, the patients would all die of infections anyway. In AIDS, the tempo is slower, but the process is the same.”
Nevertheless, there has been at least one dramatic instance of a drug already in use demonstrating a significant ability to extend the lives of AIDS patients.
That drug is pentamidine, used to treat pneumocystis carinii pneumonia, which was killing AIDS patients with brutal swiftness. A group of San Francisco physicians showed that it can stave off even a first episode of pneumocystis carinii when it is taken in aerosol form as a preventive measure.
And now, virtually all individuals infected with the human immunodeficiency virus (HIV) whose immune systems have begun to show signs of serious deterioration--placing them at great risk of developing pneumocystis-- are advised to take aerosol pentamidine.
“That was a major breakthrough,” said Harrington of ACT UP. “It refutes the whole argument that we can really save lives only by treating primary HIV.”
NIAID, recognizing that too little attention has been paid to opportunistic infections, recently initiated several efforts in the area.
The agency plans to sponsor a “drug discovery” group with the single goal of looking for new drugs. Such groups have been operating in the antiviral area since 1986.
Typically, a group involves a partnership of academia, industry and government, drawing upon the resources of dozens of drug companies and about 100 different institutions. The agency has slated $3 million this year for the work on opportunistic infections.
“Should we discover a compound that looks promising, then we will have the capabilities to develop it and bring it into human trials,” McGowan said.
And the agency’s community-based AIDS research program, which involves primary care physicians who treat AIDS patients, within the next few months plans to begin trials of known drugs to determine if they could be used to prevent any of the opportunistic infections.
The physicians are eager to participate in this overlooked aspect of AIDS research, said Dr. Lawrence Deyton, director of the program.
“The most important thing on their minds is: How do I keep my patients alive longer?” Deyton said.
Unlike academic researchers, who are primarily concerned with the behavior of the virus and how it affects the workings of the immune system, “doctors in our program are primary care providers,” Deyton said.
“The scientific questions they are going to ask are going to be of primary clinical concern. They’re asking different kinds of questions in a different setting,” he said.
“These docs are different in their emotional makeup,” Deyton added. “They’re not as interested in publishing, or in winning the Nobel Prize. For them, the rewards are truly exhilarating when they can make these little inroads.”
Deyton said that the first trial will seek to find a way of preventing toxoplasmosis in the brain, a life-threatening parasitic infection seen with increasing frequency in AIDS patients.
As with other opportunistic infections, many people are exposed to the organism that causes toxoplasmosis , but only those with damaged immune systems become ill; others who have been exposed to the parasite have developed antibodies to it. The trial will seek to identify those at risk and to administer them low doses of those drugs usually used to treat the disease after it develops.
“If this turns out to be effective, we’re going to be sparing a lot of people a very serious infection,” Deyton said.
Similar trials will try to prevent mycobacterium avium , or MAI, a tuberculosis-like condition that frequently strikes in the later stages of AIDS. It is a frequent cause of death and disability in AIDS patients and is difficult to treat.
“There’s a certain pessimism about MAI because we’ve known about the organism for a long time, but it has so far resisted efforts to find a meaningful therapy--even before HIV disease became common,” said Dr. Paul Volberding, an AIDS researcher at San Francisco General Hospital.
Dr. Michael Gottlieb, the Los Angeles immunologist who identified the first AIDS cases in 1981, is planning to conduct his own trial of an anti-tuberculosis drug to see if it can prevent the onset of MAI. His work is being sponsored by the maker of the TB drug.
Gottlieb finds himself in an unusual position, having seen both sides of the AIDS research dilemma. In the early years of the epidemic, he was affiliated with UCLA and took part in antiviral studies. Today, having severed his ties with the university, he is in private practice, treating primarily AIDS patients.
“Research on the virus itself is the big win,” he said. “When I was in academic research, like most researchers, I focused on the virus. But now that I’m in full-time clinical work, I realize the importance of finding and testing new drugs to treat these infections which contribute so heavily to patients’ suffering. My perspective has changed.”
