TAKING A BREAK.

Patients with HIV flirt with a pause in their treatment, but at what cost to their health?

IT'S NOT SURPRISING that for many people with HIV the notion of stopping their medication altogether--at least for a prescribed period of time--is extremely tempting. For most people with the virus, effective therapy means taking dozens of pills a day at strictly regimented hours, often with severe dietary restrictions mid, unfortunately, debilitating side effects that range from vomiting, diarrhea, and fatigue to physical deformities. On the other hand, these patients are still alive to complain about it.

But a drug holiday, as such breaks are known, is no longer just an idle dream. There is cause to believe that temporarily stopping treatment might have clinical benefits. Some researchers even believe that stopping and starting drugs can elicit an immune response to HIV that, they theorize, might eventually eliminate the need for therapy altogether. The idea even sparked enough interest among AIDS activists to lead to an April public forum in San Francisco on the topic, sponsored by Project Inform, a treatment advocacy group.

"The overall take on this is that drug holidays are at least feasible," says Tim Horn, executive editor of PRN Notebook, an AIDS journal. "Some studies showed that after two or three interruptions, the virus took significantly longer to come back up, suggesting that it did boost HIV immunity."

But the growing popularity of drug holidays has alarmed some doctors, researchers, and public health experts, who worry that taking the breathers, also known as structured treatment interruptions (STIs), is a recipe for viral disaster.

"There is nowhere near enough information yet to just take people off drugs in the hopes of stimulating an immune response," says Howard Grossman, a New York City physician with a large HIV practice. "It is all theoretical." Grossman rarely takes patients off therapy--and then only if the drugs are failing completely or producing unbearable or dangerous side effects.

The idea for drug holidays first became an issue in 1996, when a recently infected patient in Berlin began combination HIV therapy. Within days the amount of virus in his blood plummeted from high to undetectable levels. But soon after, he developed a bacterial infection and went off medication for about eight days. During that time his viral load rose but did not rebound to a high level.

The "Berlin patient," as the unidentified man became known, returned to his regimen, maintaining undetectable levels of virus despite developing hepatitis A. Soon afterward he stopped therapy permanently, and once again his viral load did not rebound, hi fact, it remains undetectable to this day (although HIV was found in his lymph nodes, so he is hardly "cured" in the traditional sense).

The news sent shock waves through the global HIV research network, and soon clinical trials to test STIs began in several countries. In February at an AIDS conference in San Francisco, data was presented for 18 patients who went off therapy for at least two months. The reports further fanned the flames of interest in the subject while also increasing anxiety among some doctors and researchers.

One widely publicized study came from Veronica Miller, MD, of Frankfurt, Germany's Goethe University in May 1999. Thirty-nine patients with viral resistance to many HIV drugs went on a two-month-plus holiday before beginning new multidrug regimens. Following the break, the HIV in 24 patients was unexpectedly found to have reverted to a so-called wild-type virus, meaning it was once again sensitive to standard drug therapies. When they began their new regimens, 19 of those 24 saw the virus in their blood return to undetectable levels, compared with just one of nine people who did not experience a reversion to the wild-type virus.

Franco Lori, MD, of the Research Institute for Genetic and Human Therapy, housed in Washington, D.C., believes that carefully structured and monitored treatment interruptions might create an environment in the body whereby the immune system, through repeated raising and lowering of viral levels, learns to identify and effectively control HIV in the body. The theory is that by maintaining undetectable levels in the blood, the body is unable to mount an effective response.

But not everyone is convinced. The prospect of T-cell counts failing in the absence of drugs to hold off the virus is enough to put off even the most adventurous patients. But the biggest fear is the development of viral resistance to the drugs the patient is starting and stopping. This has not seemed to occur in most controlled clinical trials, though the possibility of such resistance is very real and could occur if people attempt to take a drug holiday without the supervision of their doctor.

Grossman notes that the results seen in the Berlin patient have never been duplicated, that most trials to date have been too small to generate significant data, and that there's no evidence to prove that STIs are beneficial. "If the body were to mount an effective response to HIV, it would do so during the initial infection, when the immune system was still intact," says Grossman. "It hasn't worked, but it keeps coming back as an idea because people are frustrated with what we have now."

Indeed, says Grossman, drug holidays fill a longing in patients who are weary of adhering to a strict regimen of drug taking. "We are telling people what they want to hear," he says. "Everyone wants to go off drugs. Give them half the chance, and they'll come running through the door."

Still, Grossman concedes that STIs might prove useful for people newly diagnosed with HIV infection whose T-cell counts remain high. "In those people it might be good to keep the virus suppressed for a few months, then take them off drugs and let it come up again, and then hit it back down," Grossman adds. "It's kind of like treating a herpes virus or like chemotherapy, where you don't keep people on drugs constantly. You hit them hard, then back off a little. But we just don't know." Several large trials of STIs are currently under way to determine the merit of such a theory.

One of Grossman's patients, Spencer Cox, a treatment advocate himself, recently took a nine-month holiday against Grossman's recommendation. "I was failing everything, and I was so sick from the medication, I just decided to stop," says Cox. But after nine months his viral load went from 100,000 to 650,000, and his T-cells fell from 200 to just 24. A panicked Cox went back on a six-drug combination therapy. Apparently he too had reverted to the wild-type virus: His T cells are now back up over 200, and his viral load is a manageable 400.

Needless to say, such wild swings in response to drug holidays have created confusion and possibly unfounded hopes. Until more research is completed, the long-term benefits and risks of drug holidays will remain unknown. Still, the prospect of having the body finally exert some control over the virus remains a tantalizing one. "Somewhere along the line we seem to be priming the immune system to control HIV," says Horn. "But we need more studies to see if this will prolong survival and, indeed, let you function against HIV without therapy. That's everyone's ideal."

Find more drug holidays and links to related Internet sites at www.advocate.com

David Kirby is a regular contributor to The New York Times.