Gaps in Drug Therapy Found to Help Some AIDS Patients
One is called the “Berlin patient.” Another is the “Washington patient.” A third is the “Bethesda patient.”
The three men and a handful of others were on the minds of AIDS researchers gathered here last week, because they have been able to achieve something that few others have--staying off expensive and burdensome AIDS drugs for long periods.
The men are walking advertisements for a new approach to HIV infections called structured treatment interruption, or STI, a controversial technique that at least some clinicians think can induce the immune system to combat the deadly virus.
STIs involve intermittently taking patients off their drug regimens in the hope that increased exposure to the virus during such periods will stimulate the immune system and thereby aid in control of the infection.
Although the approach has so far been tried on only a few patients, some researchers think it should receive much more intensive testing.
“We’ll see hundreds more patients tested in the next few years,” said Dr. Franco Lori of the Research Institute for Genetic and Human Therapy in Washington and Pavia, Italy.
STIs were but one of many themes discussed at the seventh Conference on Retroviruses and Opportunistic Infections in San Francisco. Others included new classes of drugs to expand the arsenal of weapons against HIV; new members of the older drug classes that are more powerful yet more readily ingested; and new insights into the long-term side effects of existing drugs.
Researchers were particularly excited about the gains that have been achieved to date and the prospects of even more drugs to come.
“We’re really seeing tremendous benefits from our current treatment approaches,” said Dr. Daniel Kuritzkes of the University of Colorado Health Sciences Center in Denver. “We’ve had a dramatic reduction in progression to AIDS.”
His colleague at the center, Dr. Robert T. Schooley, said: “Each new drug makes all the others more useful” by increasing the number of drug combinations available. “New drugs add value to older drugs, rather than replacing them.”
A Patient’s Experience Provided a Clue
The idea for STIs was planted last year when Lori reported on the Berlin patient, whose treatment with cocktails of AIDS drugs had twice been interrupted for a few weeks before it was permanently discontinued. Levels of the virus in his blood have not rebounded, as they have in virtually all other patients who have stopped taking their drugs.
Lori’s report was greeted with much skepticism, but many researchers apparently went home and tried it on a few of their own patients. “Last year, everyone thought we were crazy,” said Lori’s colleague, Dr. Julianna Lisziewicz. “This year, there are 34 abstracts about it” at the meeting.
To many people’s surprise, STIs seem to have worked in some cases. Lori reported on a middle-aged government contractor, called the Washington patient, who went through six periods without therapy before finally halting it successfully.
Dr. Anthony Fauci of the National Institutes of Health has reported another success, the so-called Bethesda patient, and a couple of other teams have had some success as well.
But they have also had many failures. Overall, only about one out of every three or four patients on whom the technique has been tried has successfully halted therapy.
The rationale for the STI strategy is that intensive treatment with HIV drugs reduces the level of the virus to such a low level in a patient’s body that the immune system “forgets” about the virus and doesn’t retain the capability of attacking infected cells.
When treatment is halted, the theory says, the amount of virus increases to levels high enough to stimulate the immune system into a protective reaction.
But high levels of the virus, of course, overwhelm the immune system and destroy the very cells designed to attack it. So the trick is to have enough virus present to stimulate the immune system without overwhelming it.
One key piece of evidence supporting the idea comes from a group of intensively studied Kenyan prostitutes who had been repeatedly exposed to HIV but had not developed infections, even after many years. But after they retired, six of the women became HIV-positive, Dr. Sarah Rowland-Jones of Oxford University reported recently.
The theory is that continued exposure to HIV stimulated the women’s immune systems sufficiently that the virus was unable to gain a foothold. Once their bodies were no longer exposed regularly to the virus, however, immune surveillance stopped, allowing latent pockets of the virus, which previously had not caused a full-blown infection, to multiply explosively.
The Kenyan women apparently had an unusual immune response to the virus that allowed them to reject it when they were continually exposed. Lori and Lisziewicz think a similar effect can be achieved by using less powerful AIDS drugs that allow some virus to be exposed to the immune system.
They studied two groups of HIV-positive patients. One group of 10 patients received the conventional cocktail therapy of three drugs, including a protease inhibitor, one of a powerful set of drugs introduced in 1995 that dramatically reduced progression to AIDS. The other group of 10 received a less potent combination of the drugs hydroxyurea and didanosine, which reduced viral levels, but not as sharply as conventional therapy.
Lori and Lisziewicz planned regular eight-week drug interruptions, or holidays, for both groups--although therapy was to be resumed if virus levels climbed significantly. All of those in the experimental group were able to make it through the first eight-week holiday, the researchers reported, but the majority of those receiving conventional therapy were not.
Dr. Bruce Walker of Massachusetts General Hospital released a study of seven HIV-positive patients in which conventional therapy was halted twice. Three of the patients were able to stay off drugs for four months before virus levels began to rise again.
The results provide “some powerful hints that we may be able to figure out how to harness the immune system against HIV,” Walker said.
A team of Swiss researchers reported enrolling 100 patients in a trial of treatment interruptions. Preliminary results from the very small number of patients who have already gone through three drug holidays were “modestly encouraging,” the team said.
What is the difference between those whose viral load rebounds immediately and those in which it doesn’t? The key difference, Lori said, is that the patients who responded positively had much stronger immune systems, as did the Berlin and Washington patients.
Those findings led him to suggest that perhaps the way to help those on conventional therapy is to stimulate the immune system with an AIDS vaccine rather than with the virus itself. If a potential vaccine could provoke the same response as a viral resurgence, it might make it easier to halt drug treatment.
At the Aaron Diamond AIDS Research Center, Dr. David Ho and his colleagues have, in fact, already tried the treatment with four patients--using an experimental vaccine called Alvac 1452. When treatment was interrupted, two of the patients were able to go 68 and 85 days, respectively, before treatment had to be resumed. The other two patients, in contrast, went only 13 and 23 days.
The treatment “seemingly had some impact,” Ho said, “but the numbers were so small that we can’t take away any firm conclusions.”
“This study raises a glimmer of hope that even in chronically infected patients, there is the potential to re-create an immune response directed against HIV itself,” said Dr. Calvin Cohen of Harvard Medical School.
Lori and Lisziewicz plan a larger study in which they will vaccinate HIV-positive patients with genetically modified immune system cells, produced from the patients’ own blood, that mimic the appearance of HIV-infected cells. The cells provoke a more powerful response than existing vaccines in monkeys and in human volunteers who are not HIV-positive, they said. The tests will begin as soon as they receive clearance from regulatory bodies.
Lori cautioned, however, that “we don’t have the recipe for this yet.” He and others argued strongly that treatment interruptions should be attempted only in controlled trials and that individual physicians should not risk their patients’ health by attempting it on their own.
The desire to interrupt therapy stems from the need to take many pills every day, the high cost, the growing number of complications caused by the drugs and other problems.
One of the first complications of drug therapy was abnormalities in lipid distribution that have produced deposits of fat in unusual places, such as “buffalo humps” on the neck and “protease pouches” on the belly. Researchers previously believed those effects were caused by protease inhibitors. But new results suggest that is not necessarily the case.
Dr. Carl Grunfeld of UC San Francisco said he believes such “lipodystrophy” is linked instead to reverse transcriptase inhibitors--the first class of HIV drugs to be developed--particularly the recently developed drugs lamivudine and stavudine. Both came out at the same time as the protease inhibitors and many patients just happened to be put on both those and the protease inhibitors simultaneously, he said.
But “we should not be rushing to implicate any drugs,” he said.
Osteoporosis Emerging as a Side Effect
Another emerging problem is osteoporosis, or loss of bone density, associated with treatment. Grunfeld said 20% of his patients taking cocktails of AIDS drugs could be classified as having osteoporosis and that they were a different group from those with lipodystrophy. Several other groups reported similar findings. Osteoporosis increases the risk of bone fractures and breakage and HIV-positive patents may need calcium supplements and, for older women, hormone therapy to minimize risk.
Because of the changes in lipid levels associated with drug therapy, including increased cholesterol levels, researchers had feared that patients would be at increased risk for heart disease. That does not yet appear to be the case, however.
A team from the Kaiser Foundation Research Institute in Oakland reviewed records of all HIV-positive Kaiser patients in Northern California and found no apparent increase in the risk of heart problems. But Dr. Ian Frank of the University of Pennsylvania said that “atherosclerosis develops over years” and that “we should not necessarily expect to see an increase in [heart attack] rates in a group of individuals who are, in general, young and at otherwise low risk.”
Clinicians hope that side effects will be less of a risk with several new drugs discussed at the meeting. The drugs may also reduce the burden of taking large numbers of pills everyday.
* Glaxo Wellcome reported results with a new drug, called Trizivir, that is a combination of the older AIDS drugs AZT, 3TC and Ziagen. The pharmaceutical firm found that Trizivir is as effective as the three drugs taken individually, and that it can be administered in one pill, twice a day.
* Abbott Laboratories reported results with a new protease inhibitor called ABT-378 that is 10 times as potent as existing inhibitors, yet appears to have few side effects. Researchers said the side effects were so mild that patients receiving ABT-378 in clinical trials often called the investigators to complain that they were receiving placebos.
* A new protease inhibitor produced by Bristol-Myers Squibb called BMS-232632 proved as effective in clinical trials as the older drug nelfinavir, even though it is administered as two pills taken only once a day. Existing protease inhibitors require as many as nine pills per day. “This is a much easier bridge to cross” for patients trying to stick to their drug regimens, said Dr. Ian Sanne of the University of Witwaterstrand in South Africa.
Not all of the news was good, however. Merck & Co. withdrew a scheduled paper on its next-generation AIDS drug, MK-944A, because monkeys receiving the drug developed kidney abnormalities. Merck said all 100 human patients receiving the drug had been switched to other regimens.
