San Francisco Chronicle - Monday January 30, 1989
Randy Shilts, Chronicle National Correspondent

Eight years into the AIDS epidemic, a time of cruel and bitter irony has arrived in the search for life-saving treatments.

Some of the most brilliant research in the history of science has been mobilized to battle the deadly disease - reaching into the heavens on the wings of the space shuttle, journeying into the tropical rain forests of the Amazon basin and foraging into the atom-size nooks and crannies of viral molecules.

But while science is making herculean efforts, the testing and release of effective treatments have been painfully slow.

A Chronicle investigation has found that precious time is being squandered by interminable red tape, inefficient administration and an obstinate adherence to business as usual.

Key elements of the problem are these:

-- The $100 million federal program at the National Institutes of Health for testing new treatments has become a "Bermuda Triangle" where proposals for drug trials sometimes disappear in the middle of a ponderous review process.

-- Delays in testing drugs have frightened many pharmaceutical companies away from relying on the federal testing system for fear that their treatments - and the multimillion-dollar investments in them - will be swallowed up by red tape.

-- Despite public announcements to the contrary, the Food and Drug Administration continues to limit access even to drugs that virtually all researchers agree are extremely effective in treating AIDS infections.

-- Some researchers no longer will participate in studies demanded by the FDA, saying the rigid requirements would force them to deny care unethically to suffering AIDS patients.

--Both as a matter of Reagan administration policy and as an effect of bureaucratic sluggishness, neither the FDA nor the National Institutes of Health has anything resembling the staff it needs to perform its designated tasks, severely slowing the testing and release of new AIDS drugs.

These problems have created a wrenching paradox.

Never before have researchers been so optimistic about their ability to tame the virulent human immunodeficiency virus - HIV - and stem the tide of death that has swept the world with the spread of the AIDS epidemic.

And never before has there been more pessimism about the ability of the government to perform its appointed tasks in testing and approving treatments for the hundreds of thousands who anxiously await some sign of hope.

Both of these developments must be measured against the grim deadline faced by those for whom effective AIDS treatments are an issue of life and death.

Between 1 million and 1.5 million Americans are infected with HIV, according to federal estimates; internationally, that number may be as high as 10 million, according to the World Health Organization. Virtually all of these people are expected to contract AIDS within the next decade if no effective treatments are found. Without new treatments, all face the likelihood of an agonizing death.

The fallout from these problems has been mounting chaos.

UNDERGROUND FLOURISHING

Lack of approved treatments has created a flourishing underground in AIDS remedies; thousands of HIV-infected people are traveling as far as to Japan to buy AIDS drugs and smuggle them back into the United States.

In California, researchers became so frustrated with the pace of NIH trials and FDA regulations that they prodded the Legislature in 1987 to establish a separate state drug-testing program and a "mini-FDA" that can approve drugs for use in the state.

Although conceding that some of the problems exist, Dr. Maureen Myers, chief of the Treatment Research Branch at the National Institute of Allergy and Infectious Diseases, counters that the federal government deserves credit for gearing up a research effort unparalleled in both speed and scope.

'SO MUCH TO DO, SO FAST'

"We have had so much to do, so fast," says Myers. "We have put together a clinical trial capability that is unprecedented in terms of the complexity of what it's doing, the speed with which we've had to do it and the highly visible environment in which we're doing it."

Adds Dr. Anthony Fauci, associate National Institutes of Health director for AIDS and the administration's top AIDS official, "The feeling of urgency is palpable."

Few could reasonably argue with the assertion that the NIH has set records in assembling its clinical-trial program and forging innovative drug development plans. However, AIDS advocacy groups argue that moving faster is not fast enough - especially when there still are many areas within the system that could be streamlined.

"Things simply could move faster at the NIH and FDA - the urgency just isn't there," says Martin Delaney, co-director of Project Inform, a San Francisco-based organization that provides information and lobbying on AIDS treatments.

"Somebody needs to put a blowtorch to the feet of the NIH and FDA," he says, "because these delays are costing lives."

Such charges are not new. The problems in mobilizing a productive governmental and scientific search for AIDS medications are almost as old as the epidemic.

THE EARLIEST EFFORTS

When AIDS burst upon the medical scene in 1981, it appeared in the form of a depressing array of rare diseases for which treatment research had been minimal. Therapeutic strategies that once worked for these diseases, such as aggressive chemotherapy for the Kaposi's sarcoma skin cancer, were inappropriate for patients with ravaged immune systems.

Virtually all the research performed on AIDS remedies in the first years of the epidemic was done by individual clinicians who were struggling to save their patients from the devastation wrought by this mysterious and brutal new disease.

"We had no help from federal agencies," says Dr. Ronald Mitsuyasu, associate director of the AIDS Clinical Research Center at the University of California at Los Angeles.

"In the early days, the only people interested in the treatment of AIDS were those of us treating patients and a very few pharmaceutical companies," he says.

In 1984, hope flared briefly. Researchers at the National Cancer Institute confirmed the discovery of the AIDS virus. The identification of HIV at last gave investigators a single target at which to aim their anti-viral studies.

In what still stands as one of the great lost opportunities of the AIDS epidemic, however, Reagan administration budget officials continued to deny NIH researchers adequate resources with which to study AIDS. Just eight months after the discovery of the AIDS virus, for example, the administration proposed an 11 percent cut in financing for AIDS research.

Some scientists, meanwhile, openly doubted whether a treatment would ever be found, since past research into anti-viral drugs had been largely unsuccessful. Scientists such as the cancer insitute's Dr. Sam Broder, a pioneer in early treatment research, found it difficult to convince colleagues that it was worthwhile even to look for an AIDS cure.

"I told people that if you declare the patient terminal, you'll always prove yourself right," Broder recalled later.

AIDS treatment research was under way elsewhere. French scientists, who had the benefit of a year's head start in identifying the AIDS virus, aggressively tested drugs to fight both HIV and its related infections.

Although the French attempts largely were unsuccessful, the disparity between the French and American research commitment exploded into a major embarrassment for the federal scientific establishment in July 1985 when it was revealed that matinee idol Rock Hudson was being treated at the Pasteur Institute in Paris.

"Here was a celebrity who had to leave the country to get treatments because nothing comparable was being done here," says Mitsuyasu, one of the UCLA doctors who had secretly treated the actor before he left for Paris. "That brought a lot of attention to the lack of drugs in the United States."

WEAK INFRASTRUCTURE

Congress quickly forced money on a reluctant Reagan administration and demanded that the NIH gear up its research in the three principal areas of drug development - discovery, clinical trials and regulation.

Although the first phase of development - drug discovery - had traditionally been the exclusive domain of private industry, both the NCI and NIAID established pioneering programs to invent new therapies.

At the NIAID, the NIH agency that was given the principal mandate to find treatments, AIDS appropriations soared from $60 million in the 1986 federal fiscal year to $260 million for the current 1989 fiscal year.

Under intense pressure from both Congress and a deregulation-minded administration, the FDA announced new procedures to speed the approval of AIDS drugs.

The crash effort to find treatments, however, quickly spotlighted cracks in the nation's scientific infrastructure, notably in the ability to investigate new viral diseases.

The scientific challenge presented by AIDS is as basic as the differences between viruses and bacteria.

Bacteria have proved an easier target for therapies because they are independent life forms that live within a person, but exist separately from the organs they infect. Most antibiotic treatments, therefore, can single out the invading microbe for destruction without damaging the host.

A virus, however, is merely a strand of genetic information temporarily encased in a protein envelope. Viruses do not live independently and take on a life of their own only once they enter a cell and commandeer that cell's DNA. Viruses literally become part of the host cell.

This presents a much more significant medical problem, because therapies have to perform the tricky task of killing the virus without destroying the cell in which the virus is incorporated.

Early attempts to perform this feat in other illnesses were so discouraging that until recently many researchers felt that chemotherapy for viral diseases was decades away. By the late 1970s, many private pharmaceutical companies had significantly scaled back their anti-viral research.

"They started in the '70s, failed because of inadequate knowledge, and then they all ran away," says Dr. Robert Gallo, an NCI virologist who is considered to be one of the world's leading AIDS researchers.

RETROVIRUSES

Meanwhile, interest in retroviruses - the subgroup of viruses to which HIV belongs - also was slackening. It was a fashionable subject of research in the 1960s, but most of the world's known retroviruses in the 1970s were in animals. Most experts came to believe that if retroviruses were found much in humans, they probably were not causing much in the way of serious diseases.

The loss of vogue in both the areas of retrovirology and anti-viral drugs meant that there were fewer and fewer jobs or research grants for people who wanted to investigate those fields. Experienced researchers redirected their efforts into more orthodox studies and new scientists were not trained.

The Reagan administration's slashing of health and research budgets in the early 1980s only accelerated the decline of the nation's virological infrastructure.

"You can really see how this has created limitations in the scientific capacities of this country," says Dr. John McGowan, chief of the NIAID's National Cooperative Drug Discovery Groups.

"There's a lack of trained virologists, chemists, biologists who understand the nuances of retrovirus models and how to use them."

Laboratory capacity for viral research at universities and government facilities also plummeted in the absence of federal interest in basic health research.

"You go to AIDS labs all over the country and see everybody all crowded together," says virologist Gary Williams, a senior scientist at Alameda's Triton Biosciences. "They've got old, inefficient equipment. They could cut a lot of time off with new equipment and better labs."

RENEWED OPTIMISM

Even as despair mounted about whether effective treatments would ever be found for AIDS, the first glimmers of today's heightened optimism were beginning to flicker from one of the world's larger pharmaceutical companies, Burroughs-Wellcome.

The company was among the first to test its patented drugs to see if any inhibited the reproduction of HIV. What struck Wellcome's vice president for research, Dr. David Barry, was how many appeared to stop retroviral replication in the preliminary screening.

"Normally, you'd have a high hit ratio if you get just one substance out of 100 that worked - but of the first 100 compounds we tested, a dozen showed some activity," recalls Barry.

"That told me that this virus was weak, that it would be more amenable to chemotherapy than other viruses," he said.

One substance was particularly effective, a drug that was among many labeled in an alphabetical series - Compound S. In February 1985, three labs had confirmed that Compound S, later to be called AZT, was active against the AIDS virus.

Three months later, the substance was first tested in human patients for safety. By September 1986, proof of the drug's potency was dramatically demonstrated, to such a degree that within the record time of seven months, the FDA had licensed AZT as the first drug approved for the treatment of HIV disease.

AZT remains an imperfect treatment. Because it suppresses not only HIV but the bone marrow's ability to make new blood cells, its use cannot be tolerated by many patients. Its effect on AIDS patients appears to wear off after about 18 months of use. New toxicities, such as damage to muscle tissue, are only now turning up.

But the emergence of AZT therapy stands as a landmark in the history of AIDS treatments because it demonstrated that HIV could be thwarted and that, with diligence and luck, science might triumph over AIDS.

But today, nearly two years later, it remains the only approved AIDS drug. The long-promised future generations of drugs have never appeared. The pipeline is clogged.

LIKE THE ANTIBIOTIC ERA

This is the central irony of the AIDS story today. Because so much money and research are now being thrown at AIDS, most researchers do not doubt they will succeed in finding treatments that can save the HIV-infected. Moreover, their work could well reshape forever humankind's relationship to viruses.

Scientists do not talk of curing AIDS but of finding long-term treatments that can allow HIV-infected people to live longer and, eventually, enjoy a normal life span. AIDS treatments now in development would function like insulin does for diabetics. Insulin does not cure diabetes, but it does keep the condition in check, prolonging the diabetic's life.

"I'm optimistic for therapy (for AIDS) in the near future," says the NCI's Gallo. "AIDS will be the beginning of medicine comparable to the antibiotic era that penicillin opened."

What troubles researchers, however, are the problems in quickly translating their scientific advances into practical assistance for AIDS sufferers.

Scientists frequently point to the problems encountered by the aerosolized form of pentamadine, an antibiotic, as typical of the bureaucratic morass which has delayed the application of ground-breaking science that could save lives.

As early as 1983, researchers at San Francisco General Hospital and Memorial Sloan-Kettering Cancer Center in New York started developing machines that could turn pentamadine into a mist to be inhaled to thwart Pneumocystis carinii pneumonia, the largest single killer of AIDS patients.

In 1986, the Sloan-Kettering researchers were imploring the NIH to put aerosolized pentamadine into its clinical trials program. Their proposals, however, never moved out of the byzantine NIH bureaucracy.

Sloan-Kettering's own trials showed that aerosolized pentamadine had dazzling success in preventing Pneumocystis. Because the drug was so effective, the doctors did not believe it was ethical to conduct controlled studies in which some patients were given placebos rather than the pentamadine treatment.

The NIH, which normally conducts such studies, never did these tests either. The FDA has not approved the treatment because it traditionally demands a placebo-controlled study before approving a drug.

This has stalled the approval of aerosalized pentamadine for a year.

Although the FDA is expected to approve a limited release of the drug under tight restrictions within the next few weeks, scientists say the delays have exacted a terrible price in human suffering. The financial cost has been staggering, too: U.S. Representative Henry Waxman, D-Los Angeles, has estimated that release of aerosalized pentamadine last year could have saved a significant portion of the $400 million it cost Medicaid to take care of Pneumocystis sufferers last year.

Such stories have left doctors despairing, even as scientists now contemplate breakthroughs of historic proportions against all viral diseases.

"When I started pushing the government to develop AIDS treatments, it was late 1981, there were only 90 cases in the whole United States," recalls Dr. Marcus Conant, the researcher at the University of California at San Francisco who first discovered the existence of the AIDS epidemic locally.

"Today, there have been almost 90,000 cases in this country, but one thing hasn't changed, and that's the lack of urgency," he says. "Until we get that urgency, the bodies will keep piling up."

Tomorrow: Drug Discovery -

Space Flights and Designer Drugs

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PHOTO CUTLINE: (1) Demonstrators virtually shut down the FDA headquarters in Rockville, Md., last October / ASSOCIATED PRESS, (2) Martin Delaney of Project Inform / BY ERIC LUSE/THE CHRONICLE, (3) Isabelle Gaston worked on blood isolation at the Bio Hazards Facility at UCSF's AIDS Immunobiiology Research Laboratory / BY ERIC LUSE/THE CHRONICLE CAPTION: PHOTO (3)

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