AIDS Scientists Fight Rising Tide of Resistance, Risky Behavior
In four days of intensive meetings, the 3,000 AIDS researchers gathered here last week for the eighth annual Retrovirus Conference saw little to be cheerful about.
True, some promising new drugs appear to be on the horizon, but none is expected to be the blockbuster that protease inhibitors were when they were introduced five years ago.
True, progress toward development of a vaccine against this fatal disease is inching forward, but even the most optimistic developers have given up hope that there will ever be a potent, protective vaccine such as those available for polio and other more common diseases.
And true, structured treatment interruptions still promise to reduce the burden of pill-taking and side effects among the HIV-positive, but perhaps only for a small minority of patients.
Meanwhile, as amply demonstrated by recent reports, the risky sexual behaviors that enhance HIV transmission are increasing, resistance to anti-AIDS drugs is on the rise, and large numbers of people continue to be newly infected each year.
“I know that people are always looking for a big buzz and a dramatic new highlight or finding to focus on, but . . . there isn’t one big thing that is happening,” said conference co-chairwoman Dr. Constance Benson of the University of Colorado Medical Center. But “there were a lot of interesting little things,” added her co-chairman, Dr. David Ho of the Aaron Diamond AIDS Research Center in New York City.
One little gain that has the potential to become a much bigger one is in the area of combating drug resistance. AIDS physicians now have 15 unique drugs to use against HIV, but some patients have already gone through all of them as the devious and resourceful virus developed resistance to each in turn.
A new family of drugs developed by the Belgian company Tibotec may provide a partial solution to the problem.
New Drug Keeps AIDS Virus From Replicating
Most AIDS drugs work by binding to the so-called active site of enzymes crucial to the reproduction of the virus. By clogging up that site, the drugs prevent the virus from carrying out its normal function. Protease inhibitors, for example, block the action of an enzyme that cleaves a large protein into two smaller ones.
But existing protease inhibitors bind to that site only relatively loosely. When the virus develops a mutation that changes the shape of the binding site slightly, the drug loses its effectiveness.
Two years ago, chemist John Erickson, then at the University of Illinois, developed a new family of molecules that not only fit tightly into the protease binding site, but that have the flexibility to hold on even as the enzyme rapidly shifts shapes in an effort to evade it. Erickson calls these molecules “resistance repellent.”
Laboratory tests show that the prototype drug, called TMC-126, and several related molecules have “an extraordinary ability to block replication” of the virus, even strains resistant to other protease inhibitors, Erickson said. In fact, it binds so tightly that they had to develop new assays to measure the binding.
The new compounds show no toxicity to cells in the laboratory and, so far, no problems in rodents and dogs. TMC-126 has been given to humans in a single dose in Europe with no problems, he added, and the company hopes to begin regular clinical trials soon.
“We have for the first time a very, very powerful protease inhibitor that could suppress resistant virus,” Ho said. “That’s pretty impressive.”
Tibotec has developed similar compounds that bind to reverse transcriptase inhibitors--the first family of AIDS drugs, including AZT, but one which has been notoriously susceptible to development of resistance.
Dr. Rudi Pawels of Tibotec reported here that a seven-day trial of this drug, called TMC-120, in patients who are resistant to other reverse transcriptase inhibitors, showed a marked reduction in virus with no significant side effects.
Resistant viruses are not the only problem with drug therapy. About 70% of patients develop a syndrome called lipodystrophy, marked by high cholesterol levels and redistribution of body fat. Lipodystrophy is produced primarily by protease inhibitors, but doctors have not known how. Dr. Andreas R. Miserez of the University of Basel in Germany and his colleagues have provided the first clue.
Mutated Gene Seems to Intensify Side Effects
Miserez and his colleagues looked at a gene called SREBP-1c that is involved in cholesterol metabolism. They discovered a mutation that makes people more prone to lipodystrophy. About 30% of people have the normal gene, while the rest have either one or two copies of the mutated form. Those with one copy show mild lipodystrophy when taking protease inhibitors, while those with two copies show a more severe form.
The mutated gene “is very easy to test for,” Miserez said, making it possible for the first time to predict who will be most susceptible to this complication. Although therapies to prevent lipodystrophy may eventually arise from the discovery, he added, the best course now is to aggressively treat those with two copies of the mutated gene with cholesterol-lowering drugs.
A new protease inhibitor now being studied may alleviate some of the cholesterol problems associated with AIDS therapy and may also ease dosing problems. Most protease inhibitors require patients to take several pills at least twice daily.
But a new drug called BMS-232632 can be taken in only one dose per day and is as effective as other protease inhibitors, said Dr. Kathleen Squires of USC’s Keck School of Medicine. Studies of 480 patients, she said, showed good protection against the virus at doses only 10% to 20% as large as those required with nelfinavir, another protease inhibitor. The new drug was also effective against viruses resistant to other members of the class.
Equally important, the drug appeared to have no effect on cholesterol and other lipids, Squires said. And only about 17% of patients receiving it developed diarrhea, compared to 55% of those receiving nelfinavir.
Some researchers have hoped to reduce the burden of pill-taking by having patients take planned drug holidays, an approach called structured treatment interruptions. But results presented here show a very mixed response. Dr. Bruce Walker of Massachusetts General Hospital reported that four of 14 patients who stopped taking drugs for periods of three to six months were able to keep their virus in check. Dr. Martin Markowitz of the Aaron Diamond AIDS Research Center reported that three of 15 similar patients were able to keep their virus in check when they stopped drugs--but two of the three had a genetic variant known to help people naturally resist AIDS.
And others noted that his study involved only patients who began treatment shortly after detection of the infection.
In such a case, treatment began before the victim’s immune system was exhausted by combating the virus. When drug treatment was stopped intermittently, the victim’s own immune system was able to combat it because it was only exposed to a relatively small amount of virus. Some researchers call this phenomenon autoimmunization.
“But how relevant is that for the 99.9% of patients who are chronically infected?” asked Dr. Antony Fauci, director of the National Institute of Allergy and Infectious Diseases.
Fauci also reported on 10 newly diagnosed patients who were able to keep virus levels low by following a regimen in which they took drugs every other week for 10 months. Patients consider this program “a big advantage because 50% of the time they don’t have to take drugs,” he said.
Two of the patients, he noted, stopped for longer than a week at least once. Both times, virus levels rebounded, but they were able to bring it back under control. Fauci noted that researchers had seen no sign of drug side effects in the patients yet. But he cautioned that more time and larger trials will be required before such a regimen can be more widely adopted. “We don’t want people to do this on their own.”
Possible new hints for treatment and prevention also emerged from several studies that looked at women who seem naturally resistant to the virus or who do not pass it on to their infants even when they receive no drug therapy.
Three different groups--two in England and one at the U.S. Centers for Disease Control and Prevention--studied small groups of women who did not contract the virus even though their husbands were HIV-positive.
Dr. Ann Duerr of the CDC and her colleagues, for example, studied the wives of 24 HIV-positive men. They found that the wives’ blood contained a protein that, in the test tube, blocks replication of the virus. The other two groups found the same thing.
All three are now trying to isolate and identify the protein--which seems to be produced by white blood cells called macrophages--in hopes that it could be used in therapy.
A similar protein may be present in the placenta, some other researchers believe, which may be why three-quarters of HIV-positive women who are pregnant give birth to HIV-negative infants. Dr. Bruce Patterson of Children’s Memorial Hospital in Chicago reported that he and his colleagues have isolated a protein from placental tissue, called leukemia inhibitory factor, or LIF, that is extremely potent at blocking HIV replication in the test tube. The name results from the fact that the protein has a mild anticancer effect in mice.
No one knows yet what LIF’s normal role in the body is, but it binds to special receptors on the placenta and on macrophages.
A small Michigan biotechnology company called Virion has made enough of the protein for 2,000 doses and plans soon to begin testing it as a potential vaginal microbicide to protect women from sexual exposure to HIV.
