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Simpler Therapy Is New Goal of AIDS Research

TIMES MEDICAL WRITER

AIDS, a “runaway epidemic” in much of the world, is rapidly becoming a chronic, manageable disease in the United States, experts said last week at the 12th World AIDS Congress here.

Hospitalization and mortality rates in the U.S. fell by 75% between 1994 and 1997, and the primary goal of AIDS researchers now seems to be tweaking out another 20% to 30% improvement in response to therapy. Their aim, according to conference co-chair Robin V. Gorna, is “simpler treatment, ever more effective, easier to take, with fewer side effects.”

Eventually, they hope to use drugs to cure the disease. “Cure of HIV infection is not a myth,” said Dr. Roberto Siciliano of Johns Hopkins University.

New treatment regimens introduced to the world two years ago at the 11th congress in Vancouver have been responsible for the decline in AIDS deaths. The key to these advances is the use of three or more drugs, with one of them coming from the remarkable new class called protease inhibitors, which block an enzyme crucial to the virus’ replication.

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About 80% of patients who receive the drugs have their virus levels reduced below the limits of detectability.

But the new drugs have also brought new problems. Hundreds of reports made it clear that clinicians’ primary concerns center on the massive daily doses patients are required to take, patients’ adherence to their medication regimens and the increasing incidence of side effects from long-term treatment.

Of the 20% who have not been helped by protease inhibitors, nearly all stopped using the drugs because of side effects that include nausea and diarrhea.

But perhaps of even greater concern--in addition to the drugs’ cost of $15,000 per person per year--are the strict regimens the patients must follow. They must take upward of 20 pills per day at precise times. Some must be taken on a full stomach, some on an empty one and others with large quantities of water.

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When on these regimens, “you have to plan, you have to be organized, and you have to be disciplined,” said Dr. Schlomo Staszewski of Goethe University in Frankfurt, Germany.

Some people set an alarm to wake them up during the night to take their pills. Others have computerized reminders to let them know when the next dose is due.

“How can you expect people to take all those pills, day after day, for years?” asked Dr. Bernard Hirschel of the Geneva Cantonal University Hospital, the conference co-chairman.

In fact, many don’t. A study by Dr. Allyn Nakashima of the U.S. Centers for Disease Control and Prevention surveyed 1,274 patients in 12 states. Two-thirds said they “always” take their medicines as prescribed. But after two years of treatment, just over half were still taking them as ordered.

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In another study of 248 patients in five U.S. cities, only 21% had not missed a dose. And failure to take the drugs leads to failure of the therapy.

Even health care workers, who should know the risks of HIV infection, often fail to complete preventive regimens designed to stave off infection after an accidental exposure. In a study of such workers in the United States, Dr. Adelisa Panlilio of the CDC found that 36% stopped taking the drugs prematurely. Most of them cited side effects as the reason.

“The fact of the matter is that drug failure is occurring and it’s occurring in about half of the patients” in combination therapy, said Dr. John Mellors of the University of Pittsburgh. “Over 90% of these cases are explained by adherence issues,” according to Dr. Julio Montaner, who runs the AIDS treatment program in British Columbia.

One of the main focuses of the meeting, therefore, was on new drugs and new formulations of old drugs that, in the words of Dr. Eugene Sun of Abbott Laboratories, are “tougher on AIDS and easier on the patient.” Some studies, for example, showed that twice-daily formulations of protease inhibitors work as effectively as the thrice-daily doses now used.

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But the greater interest has been in several investigational drugs, such as Glaxo Wellcome’s reverse transcriptase inhibitor abacavir (Ziagen), DuPont Pharma’s non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva), Abbott Laboratories’ protease inhibitor ABT-378, Gilead Sciences’ reverse transcriptase inhibitor adefovir dipivoxil (Preveon) and Boehringer Ingelheim’s non-nucleoside reverse transcriptase inhibitor nevirapine (Viramune).

All five can probably be taken once or twice a day.

Some researchers foresee a day when patients might be able to take only two pills a day. “We will have massive reductions in the number of pills patients will take,” Montaner said. And with all the new drugs that are being developed, he added, “we don’t have to hang our hat on a single peg.”

Treatment with cocktails of various drugs not only reduces the level of virus in the blood, but also increases the number of CD4 cells--a critical indicator of immune function--in the blood. Researchers are seeing “a tremendous recovery” of the immune system, one that many had not thought possible, said Dr. Brigitte Autran of l’Hopitale Pitie-Salpetriere in Paris.

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“We are now providing proof that indeed the immune system is not dead,” she said. “It can be restored even late in the disease.” Autran and others speculated that further recovery of the immune system, over a period of six to eight years, might permit patients to stop taking drugs and allow the immune system to keep the virus in check.

Some researchers think that complete immune recovery may occur even earlier in patients who began receiving combination therapy shortly after their initial infection, before the virus could wreak havoc in the immune system.

Dr. Bruce W. Walker and his colleagues at Massachusetts General Hospital in Boston have identified 19 such patients whom they will ask to halt treatment while physicians monitor them for signs of HIV’s return.

Hirschel has a similar group of patients in Geneva, where he hopes to conduct the same experiment.

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Perhaps even more surprising than immune recovery during treatment is the finding of some researchers that, even among patients who “fail” combination therapy--that is, whose blood virus levels begin to rise--CD4 counts remain high enough to provide protection against the opportunistic infections that are the mark of full-blown AIDS.

“Almost everyone you talk to has a couple of these patients. It may require redefining what failure means,” said Dr. Anthony S. Fauci, head of the National Institute of Allergy and Infectious Diseases.

Researchers get the chance to observe the encouraging effects of the new generation of AIDS drugs in only a small fraction of the world’s population, however. Because of the cost, these treatments are not available to 90% of the world’s 30 million HIV-positive people, allowing the disease to take a devastating toll. Even the cheapest combination treatments might be about $10,000 per year.

That is more than 16 times the $600 per capita annual income in the Ivory Coast, which like many African countries has a high incidence of infection. Treating only a quarter of the HIV-positive people in the nation of Malawi would require 84% of the country’s gross national product. In Uganda, it would require 61%.

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Worldwide, an estimated 30 million people have HIV or AIDS, including one in every 100 who are sexually active. The number of new cases of HIV continues to grow by 16,000 a day, with more than half of the victims under 25 years old.

In sub-Saharan Africa, one in every 13 sexually active adults is infected. And in certain countries, such as Botswana, the figure soars to 30% of the adult population.

Being able to treat people in those regions should be a priority, experts said, even though clinicians in developed countries are beginning to see some disturbing side effects of the new drugs beyond diarrhea and nausea. These are generally attributed to the use of protease inhibitors, although that link has never been firmly established. Drug companies, in fact, argue that the syndrome may simply represent a new side effect of AIDS--rather than the drugs--that clinicians are observing only because patients are living longer.

Dr. David Cooper of the University of New South Wales in Sydney, Australia, reported that nearly half of his 3,000 HIV-positive patients who are receiving protease inhibitors have redistributions of body fat and grossly elevated levels of cholesterol and triglycerides.

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“It’s a syndrome of peripheral fat wasting, changes in body shape, hyperlipidemia and elevated cholesterol in ranges where, if you saw a cardiologist, you would immediately be put on cholesterol-lowering drugs,” he said.

Some of the most disfiguring fat accumulations include the “protease paunch” on the abdomen and “buffalo hump” on the back of the neck.

Dr. Krista Dong of Brown University in Providence, R.I., reported similar, albeit less severe, complications in 118 female patients. About 71% of her patients said their breasts had gotten bigger, 71% complained of protease paunch, 47% said their limbs had wasted and 23% said they had developed a buffalo hump.

It is not clear how many people, if any, have stopped therapy because of these problems, but physicians may eventually be forced to change their prescribing practices. “In symptomatic patients with poor prognosis, the risk-benefit balance is clearly in favor of protease inhibitors,” Cooper said. “In asymptomatic infection, the risk-benefit is not known.”

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As many as 2% of patients receiving combination therapy develop diabetes, and some of those taking the protease inhibitor indinavir develop kidney stones. The stones disappear when they stop taking the drugs, however.

No one is quite sure how protease inhibitors bring about these effects, but Cooper made an intriguing suggestion. Using computerized databases that show the genetic sequence of human proteins, he looked for those that have a sequence similar to that of HIV’s protease.

He found two that were the best match, and both play critical roles in the metabolism of fat, cholesterol and triglycerides. If drugs designed to inhibit protease also inhibit these enzymes, Cooper said, they could produce many of the observed symptoms.

Researchers are looking forward to the next generation of drugs in hopes that new approaches can solve some of these problems. Some of these drugs, still in the early stages of development, block the sites at which HIV binds to immune cells or directly stimulate the immune system to increase its ability to fight off the virus.

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They still have a long way to go, cautions Dr. Robert Gallo, the co-discoverer of AIDS. “Despite great advances in therapy against HIV and the likelihood of additional anti-HIV chemical inhibitors being developed in the coming years, the problem of treatment for HIV-infected people is not solved.”


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