New Strategies Fuel Optimism in AIDS Fight
After a long, cold winter of disappointment, disillusion and discontent, a warmer, more optimistic wind is wafting through the AIDS research community.
Despite a drumbeat of recent reports indicating that AIDS is a more dangerous and aggressive foe than most had believed, many researchers are more optimistic about the chances of fighting the disease than at any time since the discovery of AZT, the mainstay drug of current AIDS treatment programs.
That optimism--clearly present in Washington earlier this month at a national AIDS meeting--arises, in part, from the discovery that the virus is surprisingly vulnerable to new combinations of antiviral agents and to a new class of drugs called protease inhibitors.
But perhaps even more important is a fundamental and dramatic change in researchers’ ideas about how the HIV infection should be attacked--what scientists call a paradigm shift.
Clinicians are abandoning the standard model of HIV as a simple infection that can be treated with a single drug in the same way that a bacterial infection is cleared up with an antibiotic.
Instead, they are seeking inspiration from the field of cancer therapy, where a single tumor is aggressively attacked with a “cocktail” of different drugs that each exploit a unique vulnerability of the cancer cells.
Clinicians couldn’t adopt this shotgun approach to AIDS before because they had only bullets--AZT and two other drugs--that targeted the same viral weakness. But the new discoveries reported at the Second National Conference (on) Human Retroviruses and Related Infections have suddenly stocked their armory.
The Washington meeting was “clearly a much more upbeat meeting than the last several international meetings have been,” said Dr. David Ho, director of the Aaron Diamond AIDS Research Center in New York City. “Now we have more tools, better drugs, better assay development--the field has matured a lot. A lot of hard work that before didn’t translate into anything meaningful is now (paying off).”
“I think there is genuinely more optimism,” said Dr. Jack Killen, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases. “There were a lot of loose ends coming together (at the meeting). It’s beginning to make some sense, and to provide a rational framework for (therapy).”
“I think the investigators are more encouraged than ever before,” said Dr. David Feigal, director of the antiviral drug products division at the Food and Drug Administration. “Some are so excited . . . that they would just as soon skip clinical trials and start using these new drugs immediately”--something, he added, that is prohibited by federal law.
Critics cautioned, however, that the promising studies have not been in progress long enough to determine if the new drugs actually prolong life, and they warned that most of the new drugs are very expensive. Others said that researchers may be overoptimistic simply because there was so little good news in the past.
“I don’t think that things are any different than they were six months or a year ago,” said Dr. Irvin S.Y. Chen, director of the UCLA AIDS Institute. “There has been steady progress on a number of fronts, (but) if there has been change, it is psychological.”
Dr. Robert T. Schooley, an AIDS specialist at the University of Colorado Health Sciences Center--who organized the Washington meeting--agrees that “psychologically we definitely have turned a corner.” But he believes that a substantive corner may have been turned as well.
“Whenever scientists have a plausible hypothesis--and tools that can be used to test it--they feel much more excited than when they are wandering around not knowing what the game plan is,” he said.
And the FDA’s Feigal added: “I do think there has been some real progress. Sometimes all the little things do add up.”
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In 1994, AIDS became the leading killer of young adults in the United States, accounting for one in every five deaths among those aged 25 to 44, researchers from the Centers for Disease Control and Prevention in Atlanta reported here. There were 80,691 new cases of AIDS in 1994, said Dr. John Ward of CDC, but the number of new cases is leveling off, growing by only about 3% per year. “The epidemic is slowing, and we can take comfort in that--but small comfort,” he said.
According to new World Health Organization figures for 1994, women accounted for half of all new AIDS cases for the first time. In Africa, according to WHO, three women now develop the disease for every two men.
In the United States, where men account for more than three-fourths of the cases, women are beginning to catch up. The number of new cases among women is increasing by 17% annually, mostly as a result of drug use and heterosexual contact, according to new CDC figures.
Women also seem to develop full-blown AIDS more quickly than men and to die at an earlier age, for reasons yet to be determined, according to a December study by Dr. Sandra L. Melnick and her colleagues at the infectious diseases institute. In general, she found, HIV-positive women were both younger and sicker than men when they entered treatment programs and were more than twice as likely as men to die before developing AIDS-associated conditions, such as Kaposi’s sarcoma or Pneumocystis carinii pneumonia.
The key to the new treatment paradigm comes from remarkable studies about the replication and infectivity of HIV. These studies were made possible by sophisticated new molecular biology techniques that allow researchers to conveniently measure the amount of the virus in the blood for the first time. In the past, they have had to guess at viral activity by counting white blood cells, which provided only an indirect--and often misleading--view of what was happening.
Ironically, virtually every bit of information that the researchers have deciphered has not only contradicted the conventional wisdom, but seemingly also should be cause for extreme pessimism.
Scientists had believed that HIV undergoes a short burst of replication when a person is infected, then hides out in the immune system for perhaps three to 10 years. Full-blown AIDS, it was thought, develops when some as-yet-unidentified stimulus triggers a new burst of replication that overwhelms the immune system.
This scenario supported the idea that treatment with antiviral agents could be delayed until the virus re-emerged and the first symptoms of AIDS appeared. It also gave comfort to researchers attempting to develop vaccines that would stimulate the immune systems of people already infected with HIV, providing a boost that would allow the virus to be swatted down when it re-emerged. At the end of January, the FDA gave permission for full-scale trials of one such vaccine, developed by Dr. Jonas Salk of the Salk Institute in La Jolla.
But that scenario is apparently dead wrong.
The virus does replicate rapidly immediately after an infection, but much more intensively than was thought. As a result, newly infected individuals “are far more infectious than scientists previously believed,” 100 to 1,000 times more infectious than they are throughout the remainder of the disease, said Dr. James M. Koopman of the University of Michigan.
During the first two months of an infection, Koopman said, the chances that a gay man will pass on the virus to his partner during sex are about three in 10. After the first 60 days, in contrast, the odds drop into the range of one in 100 to one in 1,000.
What makes that high infectivity troubling, Koopman added, is that the newly infected individual has no symptoms and that the presence of the virus cannot be confirmed biochemically for at least 60 days. Such an individual, he said, is “a walking time bomb,” especially if he or she is sexually active.
Perhaps even more disconcerting are new revelations about HIV activity after that initial period. Contrary to the notion that the virus hides out in the immune system and effectively lies dormant for years, two new studies demonstrate that the virus actually is engaged in an all-out war with the victim’s immune system on a scale that is unprecedented in infectious diseases.
Every day, 100 million to 1 billion new viruses are produced in each patient’s body, which pumps out 1 billion new disease-fighting white blood cells to battle them, according to studies by Ho and Dr. George M. Shaw of the University of Alabama in Birmingham. It is this high rate of reproduction, the researchers now believe, that allows the virus to mutate and develop resistance to drugs.
The same intense warfare happens in a normal viral infection, but that skirmish generally ends in few days, with either the virus or the immune system emerging victorious. If the immune system wins, the patient returns to health. If the virus is successful, as often happens when the influenza virus attacks the elderly, the patient dies.
With AIDS, however, it’s a stalemate that persists for years, until ultimately the immune system succumbs.
An HIV infection “is like an acute infection that never ends,” said Dr. Ashley Haase of the University of Minnesota School of Medicine.
Added Dr. Anthony Fauci, director of the infectious diseases institute: “The immune system must be incredible and remarkable to have the ability to keep up.”
But after a while, the immune system runs out of steam. HIV does not.
It is at this crucial point that many researchers now believe that the symptoms of AIDS first appear. At first, the body is not able to fight off opportunistic infections while holding the virus in check. Eventually, it can no longer continue the stalemate and the body is overwhelmed by the virus.
As depressing as this scenario appears, it has also triggered optimism because it provides the first strong evidence why existing treatment approaches do not work and points the way to better ones. “This stuff . . . has really changed how we view the disease and has made us think about treatment very, very differently,” Ho said.
Because the immune system is already apparently running full-bore in HIV-positive individuals, Ho and others speculated, efforts such as Salk’s to stimulate the immune response may be foredoomed. The current concept of delaying antiviral therapy until the onset of symptoms also needs to be rethought.
“Does it make sense to let this virus replication go on for years and years before we start to treat?” Ho asked. “Do we do that with cancers? No. The same type of treatment should go on now (for HIV)--the earlier the better.”
Until now, however, early treatment was impractical because there were not enough effective drugs. For example, one major study of AZT, the so-called Concorde trial, demonstrated that early treatment with the drug did nothing to prolong survival. But new results from the Washington meeting suggest that the armamentarium may expand rapidly.
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The only approved drugs for treating AIDS now are the so-called nucleoside analogs, including AZT, ddI and ddC, all of which target one viral enzyme. The problem has been that HIV variants that develop a resistance to one of these drugs usually develop resistance to the others at the same time, so combinations have generally been disappointing. One exception, reported last week, was a trial in children that showed that a combination of AZT and ddI was much more effective than AZT alone.
Researchers were particularly pleased to hear results from two American and two European clinical trials, which show that another antiviral agent, called 3TC or lamivudine, greatly increases the potency of AZT when the two are used together.
“The interesting thing is that 3TC would have been of no value as a single agent,” said the FDA’s Feigal. “That product was just about abandoned . . . (because) it was not very effective as monotherapy.”
But even more than the success of the multi-drug approach, scientists are encouraged by what they see as the first visible weakness in the AIDS virus. In mutating to escape 3TC, the virus apparently becomes more susceptible to AZT, increasing that drug’s effectiveness.
One key implication of this finding, experts speculated, is that even with its great ability to shift its structure and escape destruction by mutating, HIV may have limitations in the number of new forms it can assume--and may thus be susceptible to attack with a barrage of drugs.
Perhaps even more promising were several studies with a new class of drugs called protease inhibitors, which attack a different HIV enzyme than does AZT. At least seven protease inhibitors are now in clinical trials in humans and at least two more are being studied in animals. Results presented at the meeting for two of the drugs indicate that they are 10 to 20 times more potent than AZT at suppressing HIV replication and that they have fewer side effects.
The drugs are “clearly superior” to nucleoside analogs, said Dr. Martin Markowitz of the Aaron Diamond Center, but the results should be even better if the two different classes of drugs are used in combination. “I’m interested in using the best protease inhibitors and the best nucleosides (together) in clinical trials.”
Researchers are also optimistic that the discovery of a protein in saliva that blocks the entry of HIV into cells can be translated into a drug that will inhibit infection. Studies of long-term survivors of HIV infections may lead to the identification of other proteins that also control AIDS replication, and these may lead to new treatment regimens.
Scientists are beginning to see hopeful parallels between AIDS and cancer. Treating most cancers with just one drug, for example, usually provides only short-term benefits and leads to recurrence of the disease--just as does treatment of AIDS with AZT alone.
If a patient with Hodgkin’s disease is treated with vincristine alone, for example, “you’ll see tumors shrink and then come back--and not see any substantial impact on the length of life,” Killen said.
“But if you take that drug and put it together with three other drugs in a regimen, it cures people with Hodgkin’s disease,” he said. The same is true for many other cancers as well, including lymphomas, leukemias and testicular cancer.
“We need to devise combinations of drugs (against HIV) that work by multiple mechanisms of actions,” he added. “When I get optimistic about clinical stuff, that’s where it’s coming from.”
Already, there is buoyant talk among researchers about launching a trial combining AZT, 3TC and at least one of the protease inhibitors. “The outcome of that trial is going to be the key to our future planning,” said Dr. William Paul, director of the office of AIDS research at the National Institutes of Health. “We’re all very excited and hopeful about the idea.”
Adds Schooley: “Now I think we clearly have a new game plan we will be working on for the next year or two. It gives you a sense of purpose. And it gives you a lot of hope that we’ll do significantly better than we have so far.”
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New Attack on AIDS
Taking their cue from the war on cancer, researchers now believe that the best way to halt an AIDS infection is to overwhelm it with a mixture of drugs that attack at different stages of the virus’ life cycle.
New Attacks on Aids
A. Protein from saliva blocks infection of cells.
B. Drugs such as AZT block conversion of viral RNA into DNA.
C. Protease inhibitors block production of proteins for new viruses.
How Aids Occurs
1. Virus enters cell and protein coat is removed.
2. Viral RNA is converted to viral DNA
3. Viral DNA is reproduced.
4. DNA is converted back to RNA.
5. Viral proteins are produced.
6. Proteins and RNA are combined into new viruses, which multiply, and are released from cell into the bloodstream.
Note: Drugs that block other reproductive steps are also being tested, but clinical results have not been reported.
