The New York Times

Wednesday, February 8, 2000

THE DOCTOR'S WORLD

Promise and Peril of New Drugs for AIDS

By LAWRENCE K. ALTMAN, M.D.

SAN FRANCISCO, Feb. 4 -- In less than four years, the euphoria over the success of new drug combinations to treat AIDS has yielded to the sobering challenge of dealing with the drugs' complications and failures.

Death rates for what had been an invariably fatal disease have dropped significantly since the introduction of combinations of protease inhibitors and other drugs. Many people with H.I.V., the AIDS virus, including some who were near death when they began taking the drug combinations in 1996, continue to lead more or less normal lives, though they must take a number of pills at specified times throughout the day, at costs that can exceed $10,000 a year.

And a short course of drugs can stop transmission of H.I.V. from a mother to her newborn, though this important gain is not being delivered in many countries for lack of money and public health services.

But the unflagging optimism that AIDS scientists displayed at an international meeting on AIDS in Vancouver in 1996 was absent at the Seventh Conference on Retroviruses and Opportunistic Infections here from Jan. 30 through Feb. 2. One reason is that the infection is spreading through many parts of the world. Another is that many of the participants at the conference were doctors who treat infected people for whom the drug combinations have not worked as well. No one knows for sure how many they are: reports range from 30 percent to 70 percent.

A major cause of drug failure is H.I.V.'s uncanny knack of mutating to become resistant to drugs. Thus, the greatest challenges now are to develop novel classes of anti-H.I.V. drugs and new members of older classes that are active against resistant virus. At this year's conference, there were strong hints, from the very earliest stages of research, that such potent new drugs could eventually be developed, and experts greeted the reports with cautious optimism.

But since AIDS was discovered in 1981, there have been few breakthroughs.

And the findings reported here, meeting officials said, represented incremental progress, not major advances.

Drug companies now market 14 anti-H.I.V. drugs and a number of other drugs for the array of infections that occur as potentially fatal complications of AIDS. That small arsenal is an indisputable advance over the early days of the epidemic, when there was no effective therapy for H.I.V.

The relative abundance of AIDS drugs has created greater need for expertise in prescribing the vast number of combinations. Dealing with the complexity of H.I.V. treatment "is something that cannot be expected of physicians who don't do it most of the time," said Dr. Robert T. Schooley, a meeting official who is an AIDS expert at the University of Colorado.

Many AIDS doctors said they had often been confused about which anti-H.I.V. drugs to prescribe and when to start them. Many experts favor beginning treatment almost as soon as H.I.V. is detected, long before symptoms of AIDS develop. Others favor waiting longer because of the difficulties in adhering to the rigorous drug regimens and the growing number of side effects. Additional confusion can occur if resistance develops and creates a need to change drugs.

Doctors must now also be alert to an increasingly complex web of drug interactions. The web can inadvertently increase or weaken the potency of drugs taken for other conditions, promote development of resistant viruses, reduce chances of successful long-term therapy and cause harm in other ways.

Doctors are learning to tailor therapy for each infected person by using new tests that detect the genetic patterns of H.I.V. resistance to various drugs.

They also monitor the amount of H.I.V. in the blood to determine the effectiveness of therapy.

When combination drug therapy began to drive the amount of virus to levels below the limits of detection in such tests, many doctors and others jumped to the conclusion that the virus was not replicating in the body. A prevailing opinion is that replication of the virus must be suppressed as much as possible.

But Dr. Daniel Kuritzkes of the University of Colorado, an invited speaker at the meeting, said, "It is easy to get lulled into a false sense of security that just because you can't measure something, it is not there."

That point has become clear in the last year as researchers have gained compelling evidence that viral replication still occurs, although slowly, even when tests show no detectable virus. Now a major question is: will slow replication have a long-term adverse effect on what now appears to be successful therapy?

Growing recognition of the hazards of long-term drug therapy has created another area of confusion.

Two years ago at this meeting, Dr. David A. Cooper of Sydney, Australia, first reported that many patients receiving anti-H.I.V. therapy had developed unusual collections of body fat that created paunches and buffalo humps on the backs of necks. Then the complications grew to include metabolic changes like elevations in cholesterol and triglycerides that could increase the risk of heart disease.

Last week, the list of long-term complications of anti-H.I.V. therapy expanded further. Teams headed by Dr. Cooper and Dr. William G. Powderly at Washington University in St. Louis reported that many infected people had developed thinning of bones from osteoporosis, which can increase the risk of fractures. Though no one knows how often drug-related osteoporosis affects H.I.V.-infected people, the number appears substantial.

The cause of the fat, metabolic and bone abnormalities is unclear and controversial. Initially, the problems were linked to one or more of the protease inhibitor drugs. Now the reports are conflicting. Some say other AIDS drugs can cause the problems. Still others contend that the changes result from H.I.V. itself, the aging process and factors unrelated to drugs. The variety of abnormalities probably have more than one cause, the participants said. For now, the abnormalities seem to correlate best with the length of anti-H.I.V. therapy.

The complications have discouraged some people from starting therapy early in the course of infection. Also, many who experience the complications want to change drugs in hope of reversing the effects. But deciding which mid-course correction to make can be difficult. Meanwhile, studies are beginning to determine whether lipid-lowering drugs known as statins, which lower the amount of cholesterol and body fats, will reduce the risk of complications.

To Dr. Cooper and others, the confusion reflects the price paid for the Food and Drug Administration's decision to license drugs faster in response to a public health emergency. Because many AIDS drug trials lasted less than four months, the complications were not recognized earlier. The lesson for the future, many participants said, is to monitor the long-term effects of such drugs more carefully.

There was general agreement on one point: the need for further laboratory research, epidemiology and rigorously controlled clinical studies to better define the complications and find counter measures.

Since combination drug therapy began, there has been great concern that taking "drug holidays" would increase the risk that the virus might develop resistance. For many, the concern has proved real.

But anecdotal reports that a rare individual could stop therapy and not have H.I.V. return intrigued scientists. A few researchers began testing a concept that cycles of starting and stopping drug therapy might strengthen the immune system and help people battle H.I.V.

Dr. Bernard Hirschel's team from the University of Geneva reported a modest reduction in the replication of H.I.V. after a small number of participants stopped drug treatment for three cycles. The participants took combination drug therapy for eight weeks and stopped for two weeks to test the concept, known as structured treatment interruption.

Dr. Patrick Yeni of Bichat Hospital in Paris was among the speakers who said the preliminary findings from the Swiss and other continuing studies were inconclusive. "Obviously we need much more data before we can recommend such a strategy," Dr. Yeni said.

Dr. Kuritzkes said there had been "no demonstration to date that these transient boosts actually have any benefit" in staving off development of AIDS or simplifying therapy. "It is not yet certain that this is going to be a fruitful strategy," Dr. Kuritzkes said.

Dr. Anthony S. Fauci, who directs the National Institute of Allergy and Infectious Diseases, said the limited available findings suggested that "if there will be any success with interrupted therapy, it will be among those treated within weeks after they became infected." Even in that small group, only a minority of such people might benefit, Dr. Fauci said.

Nevertheless, he and others say the hope is to identify the immunological factor that allows such rare individuals to fight off H.I.V. and to manipulate it into a therapy to benefit those who do not have it.

Standard anti-H.I.V. drugs are directed at two areas in H.I.V.'s life cycle: the protease and reverse transcriptase enzymes. The drug action makes it difficult for the virus to replicate.

Now researchers are developing a novel class of anti-H.I.V. drugs that strikes a different area, blocking the entry of virus into cells. Twice daily injections of T-20, the first member of this class known as entry inhibitors, showed that it could work in people with viruses resistant to other anti-H.I.V. drugs.

The preliminary success with T-20, which was developed by Trimeris Inc. of Durham, N.C., will probably spur a search for other entry inhibitors that can be taken orally, participants said.

Reports about entry inhibitors were greeted with cautious enthusiasm because as experimental drugs are tested, researchers often encounter hazards that delay or stop progress. Some experimental drugs that showed much promise at last year's meeting have since fallen by the wayside.

As if to underscore the point, Merck & Company, the drug maker, canceled a report scheduled for this year's closing session because scientists recently detected unexpected kidney damage in rodents given one of its experimental protease inhibitors. Human studies of the drug have been put on hold, a Merck spokeswoman said.