Stanford Report, January 14, 2004
|Three-drug combination found most effective in treating
By MITZI BAKERIn the largest comparison of highly active AIDS treatments involving multiple drugs given together, one specific combination proved to be the most effective way to combat HIV, the virus that causes AIDS.
The study, co-led by researchers at the Stanford School of Medicine and Massachusetts General Hospital, evaluated several drug regimens involving either three or four of the 19 HIV drugs currently available.
One three-drug combination proved to be significantly more effective at keeping the virus at bay than the other triple-drug regimens and, surprisingly, worked as well as the four-drug combinations. The findings were published in two papers last month in the New England Journal of Medicine.
"One three-drug regimen turned out to be so good that we couldn’t show that adding another drug was better," said Robert Shafer, MD, assistant professor of medicine, who was first author of the study that looked at four-drug combinations. Overall, he said, all the drugs turned out to work better than expected when the study began in 1998.
"Because of these results, it is clear that we should now be expecting starting regimens to be completely effective at suppressing virus unless there are problems in terms of patient adherence to the regimen or a patient can’t tolerate the drugs or has problems purchasing the drugs because of financial hardships or accessibility," Shafer said, "Failure should be the absolute exception, not the expectation."
The use of several anti-HIV drugs in combination has transformed HIV from a stark death sentence into something more manageable. The use of several drugs, each attacking HIV through a different vulnerability, helps prevent resistance that inevitably occurs over time with single-drug use. Prompt treatment with an effective drug combination can attack HIV while the virus is still vulnerable and before it takes its toll on the immune system, said Shafer.
While it was obvious that multiple drugs fight HIV better than any alone, no one knew if how they were combined made a difference. The team designed two studies to address this question involving nearly 1,000 patients followed for more than three years at 81 sites in the United States and Italy.
With the three-drug study, there was a dramatic answer: One combination prevented the virus from rebounding in 90 percent of patients, compared to 60 to 70 percent of patients given one of the other three combinations tested.
The cocktail that worked best included the oldest HIV drug, AZT; Epivir, known as 3TC; and efavirenz, sold under the brand name Sustiva.
The four-drug study — led by Shafer and Thomas Merigan, MD, the George E. and Lucy Becker Professor of Medicine — asked whether using an additional drug might potentially work even better. It also questioned whether the combination might be more toxic, in addition to being more expensive and more difficult to follow than a three-drug regimen.
After an average of 28 months, an intriguing finding came to light: The two four-drug regimens were more effective at preventing failure of the initial treatment regimen than each of the three-drug regimens except the triple-drug combination that worked best in the three-drug study. Upon further analysis, this same triple-drug regimen led to faster suppression of the virus than the two four-drug regimens.
In both studies, participants who began treatment with two specific drugs — the combination of didanosine and stavudine — had more drug toxicity problems, such as nerve damage and pancreatic inflammation. Shafer said this is the first time the toxic effects of these drugs have been followed in a large study of previously untreated patients.
This result led researchers to recommend that treatment of HIV infection should not begin with these two drugs, a stand that has been incorporated into federal treatment guidelines.
"A wall has been reached," said Shafer. "We have drugs that are so effective now that it will be hard to show in the future that another regimen will be more effective. We are now going to have to evaluate drug regimens based on factors like their tolerability, cost and availability." The goal for future treatments, he said, is to have even less toxicity, greater ease of adherence and lower cost.
The study was funded by the AIDS Clinical Trial Group Program, sponsored by the National Institute of Allergy and Infectious Diseases, the National Center for Research Resources, and the HIV Clinical Research Programme.