CHAPEL HILL, N.C. -- The National Institute of Allergy and Infectious Diseases has stopped an AIDS drug clinical trial early because researchers have found a three-drug "cocktail" including the protease inhibitor indinavir significantly reduced AIDS symptoms and prolonged patient survival compared to a combination of two drugs.
Known as AIDS Clinical Trials Group (ACTG) 320, the study was being conducted with 1,156 people at 40 sites across the nation. An independent National Institutes of Health monitoring and safety board, which had continuous access to patient information, recommended halting the study even before all patients were enrolled because results were so dramatic.
The University of North Carolina at Chapel Hill School of Medicine enrolled 97 patients, which was the most in the United States. UNC-CH was among four centers that completed a study last year showing that indinavir, when combined with zidovudine (ZDV) and lamivudine (3TC), both significantly reduced AIDS virus levels in patients and boosted levels of CD4 cells, the infection- fighting cells the virus attacks and slowly destroys.
Volunteers in ACTG 320, randomly assigned to different treatment groups, all had CD4 cell counts below 200 per cubic millimeter of blood when the study began, while a normal count is above 500 per cubic millimeter.
"This new study is the first clear demonstration that, as we expected, the three-drug cocktail actually improves survival among patients and reduces progression to AIDS," said Dr. Joseph Eron, assistant professor of medicine and associate director of UNC-CH's AIDS Clinical Trials Unit. "It is extremely comforting to know that this approach to treatment will offer patients clinical benefits. These very exciting results renew our enthusiasm for this approach, which now clearly is the best treatment we have available."
Others involved at UNC-CH include Dr. Charles van der Horst, associate professor of medicine and director of the AIDS unit; Dr. David Wohl, research fellow in medicine; and research clinician Janet Groves.
Nationwide, researchers found 63 "disease progression events" -- including AIDS-related illnesses and deaths among patients receiving a combination of ZDV and 3TC, Eron said. Among patients receiving those two drugs and indinavir, they found only 33 such events.
"There were 18 deaths in the double-therapy arm of the study vs. eight deaths in the triple- therapy arm," he said. "No major differences were found in either safety or toxicity between the two treatments, and study medications were well-tolerated."
Indinavir, a protease inhibitor, works by preventing protease enzymes from cutting up proteins needed to form viruses, Eron explained. The envelope, or outer coating, of the virus still develops, but the core cannot, and therefore the resulting virus is not infectious.
Drugs such as ZDV and 3TC work by inhibiting an enzyme called reverse transcriptase. That enzyme enables the virus' genetic material, or RNA, to convert human genetic material known as DNA into more virus.
The Food and Drug Administration approved use of the combined ZDV and 3TC in November 1995, in part because of a national study Eron led and published in the New England Journal of Medicine. Indinavir has been approved for about a year.
"The people who should be thanked and congratulated for this study and others like it are the people who participated in the trials," Eron said. "They not only have done something that will improve their own care, but they have volunteered to do something that will clearly improve the care of many patients afterwards.
"Treatment with the triple-drug therapy is not easy because of the large number of pills patients have to take and the commitment they have to make to stick to the therapy," he said. "They are the real heroes here."
Glaxo-Wellcome Inc. of Research Triangle Park manufactures ZDV -- formerly called AZT -- and 3TC. Merck & Co. owns rights to indinavir.