New AIDS Drug Therapies Could Check Epidemic
For the first time since the AIDS epidemic began sweeping across America and the world, physicians think they may have the weapons to place them on an equal footing with the deadly virus.
While cautious about using the word “cure,” researchers gathering Sunday in Vancouver for the 11th International Conference on AIDS are optimistic that they can begin to bring the epidemic under control.
In new studies that will receive their first formal presentations at the conference, researchers have found that potent but costly combinations of new and old drugs can reduce HIV concentrations in AIDS patients to levels below detectability. This allows patients’ immune systems to rebound to health--an unprecedented accomplishment.
To their own astonishment, scientists are for the first time even talking guardedly about the prospect of eradicating the virus from patients’ bodies completely--a “cure” that once seemed hopelessly beyond reach.
“If you had asked me in January, ‘Can you eradicate HIV infection?’ I would have laughed in your face,” said Dr. Julio Montaner of the University of British Columbia. “But now we’ve been able to demonstrate that we can effectively suppress viral production. That is leading to a dramatic change in how we think about the disease.”
“We are at a crossroads in the history of the epidemic,” said Dr. Martin Shechter, co-chairman of the conference. “At past conferences, there was a lot of gloom and doom and bitter disappointment. The tenor of this conference should be one of cautious optimism. . . . People haven’t been this excited for a long, long time.”
The new treatments are so promising that some experts argue that everyone should have a yearly AIDS test to detect an infection as early as possible. When an infection is detected, said Dr. Douglas Richman of UC San Diego, physicians should attack it “early and hard.”
AIDS activists, however, argue that the new combination treatments, for all their promise, have a dark side as well. They have several powerful side effects, and their cost--as much as $16,000 a year per patient--puts them out of reach of many Americans, much less AIDS patients in developing countries.
“It’s a new hope for people with HIV, but a hope most of them can’t afford,” said Jeffrey Reynolds of the Long Island Assn. for AIDS Care.
Bleak Numbers
Although the mood of researchers has improved, the basic numbers behind the epidemic have only gotten bleaker in the two years since the last international conference. In the United States, about 650,000 to 900,000 people are infected with the virus--one in every 300 people over the age of 13, said epidemiologist John M. Karon of the Centers for Disease Control and Prevention.
About 55,000 Americans died of AIDS-related infections in 1994, the most recent year for which data is available, bringing the total to more than 325,000, Karon said.
But the U.S. numbers are dwarfed by those elsewhere. According to the United Nations, more than 90% of all HIV-positive adults live in developing nations. About 21 million people worldwide have contracted the virus that causes AIDS and about 7,500 new HIV infections occur daily. About 4 1/2 million people have full-blown AIDS, and more than 4 million have died from it.
In the past, physicians could do little for AIDS patients other than ameliorate symptoms. The drug AZT could knock down viral concentrations in patients for a time, perhaps a year or more, but the virus was generally able to mutate its way out of control.
Now, however, nine different AIDS drugs are being sold in the United States, five of them approved in the last six months. Six of the drugs, including AZT, are so-called reverse transcriptase inhibitors. These prevent the virus from copying its genetic material, the first step in making more viruses.
These drugs have provided short-term control of the virus, but HIV has always eventually found a way to develop resistance to them.
But three other new drugs called protease inhibitors have dramatically changed the balance of power.
The protease inhibitors attack another enzyme that is crucial to HIV’s reproduction. When the machinery of an infected cell manufactures the 17 proteins that make up the body of HIV, those proteins are all joined together in one long strand. They cannot form new viruses until they are snipped apart by a scissors-like enzyme called HIV protease.
The newly developed protease inhibitors jam the scissors portion of the enzyme so that it can no longer cut, thereby blocking viral replication.
Alone, these new drugs are not much better than the reverse transcriptase inhibitors. But when combined with two reverse transcriptase inhibitors in a three-drug combination, they produced an unexpected wallop.
Dr. David Ho and his colleagues at the Aaron Diamond AIDS Research Center in New York City were among the first to try the combination, usually using a protease inhibitor such as saquinavir along with AZT and another drug called 3TC. The combination did not help all patients, but in many cases it was amazingly effective, causing the concentration of viral particles in the bloodstream to drop below the limits of detectability by even the most sensitive of techniques.
“We are talking about a brand-new paradigm, which is to completely suppress virus replication,” Richman said. “If the patient suppresses it long enough, will the last embers of the virus become extinct so the [infection] is cured? We don’t know.”
The new drugs have “made an incredible difference,” said Christopher Griffin, 48, of Hollywood, who began taking one of the protease inhibitors the day after it won federal approval in March. “It’s the first time in three years I haven’t felt on some inexorable progression . . . toward mortality.”
Griffin, who developed AIDS in October 1993, was hospitalized late last year with three different AIDS-related infections and feared that he was beginning the “downward slide” toward death, he said. But now he feels much healthier and far more energetic. Six weeks ago, Griffin said, he felt the strength to begin running as part of his regular exercise program.
While his T-cell count is still very low, it has risen significantly--from 30 to 90--while the amount of virus in his blood has dropped. He feels so much better that his whole outlook has changed, Griffin said.
“It’s like you’re driving one direction and stop and go back the other way,” he said, describing the turnaround. “I’m really astonished.”
‘Reason for Optimism’
If the drugs can affect the terminally ill so dramatically, they should be that much more effective in the newly infected, researchers reasoned.
To test that theory, Ho, Dr. Martin Markowitz and their colleagues at the Aaron Diamond Center last July found 12 men who had been newly infected and started them on combination therapy. Today, the team can find no trace of the virus in the men.
“These combinations really are powerful,” Ho said. “There is a lot of reason for optimism.”
Ho plans soon to attempt to wean some of the men from the drugs to determine whether, in fact, the virus has been eliminated. If it has not, he plans to try a four-drug combination.
The combination therapies are so promising, Richman said, that everyone should get an HIV test as part of an annual physical examination. If they test positive, he said, they should immediately begin a combination treatment. “We have to hit it early and hit it hard,” he said.
The drugs may be even more effective in newborns, whose immune systems may have greater recuperative powers.
Dr. John Sullivan of the University of Massachusetts Medical Center in Worcester has used the combination therapy on two 10-week-old infants who were clearly infected at birth. Now, a year later, the virus is undetectable in the two infants and the level of their antibodies against the virus is falling, a strong sign that eradication may have occurred.
Many researchers caution, however, that the AIDS community has been optimistic in the past, only to have its hopes shot down when the virus came up with new tricks. Some are particularly nervous when researchers talk about the prospects for a cure.
“I refuse to say that word at this point,” said Dr. Richard D’Aquila of Massachusetts General Hospital in Boston. Perhaps it is more appropriate, said Dr. Roy Gullick of the New York University Medical School, to talk about “turning AIDS into a long-term manageable and treatable disease, much like hypertension and diabetes.”
Even that may be going too far, said Jules Levin, executive director of the National AIDS Treatment Advocacy Project. “It is premature to as yet accept the notion that we can, in fact, ‘eradicate’ HIV or are about to turn it into a chronic, manageable disease,” he said. Such suggestions, he said, “are based on an incomplete and small body of research.”
Nonetheless, he fears that many physicians will make the mistake of treating patients with only one drug rather than a combination, thereby impairing their survival. “We need a proper balance of these two extremes,” he said.
Potential Problems
Even if the drugs work as advertised, there are still a number of potential problems--including the cost. The new regimen costs $12,000 to $16,000 a year. That puts them out of the reach of most AIDS patients around the world. “A majority won’t have access to them at this time,” said Dr. Daniel Tarantola of the Harvard School of Public Health.
Even in the relatively wealthy United States, the cost will be a problem for many patients. Medicaid will cover the cost, but AIDS activists suggest that many patients will have to quit their jobs and sell off valuable possessions to become eligible for it.
And then there are side effects and dosing problems. One of the protease inhibitors causes nausea in a quarter of the people who take it and interferes with the activity of 23 other common drugs. Another causes kidney stones in 4% of patients. Some drugs must be taken on a full stomach, others on an empty stomach.
And patients must be religious in adhering to their regimens. Missing a day or two or taking less than the full dose, experts fear, may well allow new resistant strains of HIV to emerge.
“Triple therapy is going to be tough for people to take for 20 or 30 years,” said drug researcher Edward Scolnick of Merck & Co.
Beyond the current drugs, researchers see a wealth of other possibilities for new ways to treat the disease. Researchers announced earlier this year that certain cytokines--proteins produced by white blood cells--can block infection of cells by HIV.
It may be possible to infuse these proteins into recently infected individuals to block the spread of the virus or to develop synthetic analogues that work even better.
Researchers have also announced the discovery of receptors on white blood cells that are crucial for the entry of HIV into the cells. Drug developers have high hopes that they can identify simple compounds, perhaps even vaccines, that can clog these receptors and keep HIV out.
So, as researchers gather in Vancouver, their optimism is largely unbounded. Fifteen years of hard and expensive research appears to be ready to pay off. “We really are entering a new era for the treatment of HIV,” Levin said.
Times staff writer David Ferrell contributed to this story.
