San Francisco Chronicle - November 30, 2006
Sabin Russell, srussell@sfchronicle.com.

The experiment that eventually involved patients in 33 countries began in January 2002 and was halted at the beginning of this year after preliminary results showed that death rates were dramatically higher among those who interrupted their drug treatments.

A safety monitoring committee decided that it would be unethical to continue the experiment another four to five years as scheduled.

The study team led by the National Institutes of Health reports in today's New England Journal of Medicine that the 2,720 patients in the treatment-interruption group were 1.9 times more likely to die than those in the like-sized group who took antiviral drugs every day, as prescribed.

Those in the treatment-interruption group also ran a substantially higher risk of becoming ill from infections that exploit the immune system when it is weakened by HIV, the virus that causes AIDS.

The findings are bad news for those who hoped it was possible to manage HIV disease by carefully watching CD4 counts -- the level of infection-fighting white blood cells -- and taking the antiviral drugs only when that level fell to a threatening low level. Such treatment interruptions, in theory, could save billions in medical costs and spare patients the unpleasant, and sometimes lethal, side effects of AIDS drugs.

"For practical purposes, it is the end" for that strategy, said Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, which bankrolled the study. It was called the Strategies for Management of Antiretroviral Therapy, or SMART, trial.

Researchers who analyzed the data from the curtailed experiment made some surprising discoveries. Although 55 patients in the treatment-interruption group died, compared with 30 in the group that maintained the drug regime, only 8 percent of all deaths were caused by the classic opportunistic infections associated with AIDS.

The most common known cause of death was cancer, followed by cardiovascular disease and substance abuse.

UCSF researcher Dr. Donald Abrams, who enrolled about 100 patients from the Bay Area in the study, said it was difficult to generalize why more people died in the treatment-interruption group because the actual number of deaths was low. One possibility, he said, is that the virus itself, or the inflammation it causes, can harm patients in ways not yet fully understood.

Patients who interrupted treatment stopped taking their drugs if their CD4, or T-cell, counts were above 400. Patients with that level of infection-fighting blood cells do not typically show symptoms of illness. A T-cell count of 800 or more is considered normal.

If their T-cell counts slipped below 250, the patients would restart their drug therapy, stopping it when their counts went up to 400 again. On average, those who stopped taking drugs remained off the medication for 16.8 months. Those in the treatment-interruption group as a whole were on HIV medication one-third of the time during the experiment.

Hank Wilson, a San Francisco AIDS activist and long-term survivor of the disease, said it is too early to declare treatment interruption a failure. He uses his own treatment-interruption plan, which he would not disclose because, he said, what works for him might not work for others. He remains healthy, with a T-cell count of over 800. It once hit a low of 26.

Wilson noted that the overwhelming majority of patients in the study who interrupted treatment did not have ill effects. He believes that the data need to be examined more closely -- to determine, for example, if those who stopped treatment and experienced a sharp increase in the virus in their bloodstreams may have been using cocaine. The drug has been shown in laboratory studies to accelerate HIV proliferation.

"It's like pouring gasoline on a fire,'' Wilson said.

Drs. Judith Currier and Lindsey Baden of UCLA wrote in an accompanying article that the findings of the SMART trial were "definitive," but said there may be some circumstances where treatment interruption is appropriate.

One such instance would be when HIV infection is caught early, in the acute phase shortly after a patient contracts it, they said. These patients could live for years before the virus begins to wear down their immune systems, so it might make sense to stop the drugs after the acute infection is treated.

Women who take AIDS drugs before and after childbirth, but whose T-cell counts are high, might also be considered candidates for a treatment-interruption study, Currier and Baden said.

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