For certain HIV-infected individuals, the relative effectiveness of the drugs didanosine (ddI) and zidovudine (AZT) in slowing the progression of HIV disease depends on the duration of their previous AZT therapy, according to a recently completed study sponsored by the AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases (NIAID) and Bristol-Myers Squibb Company.
Our data suggest that AZT may be superior to ddI in delaying HIV disease progression among patients with advanced disease who have not taken AZT previously, while ddI may be the more effective drug among those with previous AZT use of at least eight to 16 weeks," says Margaret A. Fischl, M.D., of the University of Miami (Fla.) School of Medicine, a co-investigator of the study.
Dr. Fischl plans to present the findings of the study, known as ACTG 116A, in an oral presentation at the IXth International Conference on AIDS in Berlin on June 10 at 1:00 p.m.
The study results are based on data from 617 HIV-infected patients, all of whom had previously never taken AZT, or who had taken and tolerated AZT for 16 or fewer weeks. The study assessed whether ddI and AZT had similar effects in these patients in delaying new AIDS-defining conditions or death. Patients enrolled at 33 sites of the ACTG, four sites supported by Bristol-Myers Squibb Company and one regional center funded by the National Hemophilia Foundation. The ACTG is a nationwide network of AIDS clinical research centers funded by NIAID. Burroughs Wellcome Company provided AZT for the study, and Bristol-Myers Squibb Company provided ddI for the study.
Investigators enrolled patients with AIDS or advanced AIDS-Related Complex (ARC) with fewer than 300 CD4+ T cell counts per cubic millimeter (mm3) of blood and patients with no AIDS or ARC-related symptoms and 200 or fewer CD4+ T cells/mm3. CD4+ T cells are the crucial immune cells depleted during HIV infection. ARC is a symptomatic stage of HIV infection before AIDS when a patient has such symptoms as yeast infections of the mouth, unexplained fever or diarrhea, recurrent herpes outbreaks or loss of more than 10 percent of his or her body weight.
Participants were randomly assigned to receive daily either 600 milligrams (mg) AZT, 500 mg ddI or 750 mg ddI. Neither the investigators nor the patients knew which treatment a patient received. Sachet (powdered buffer) formulation was used for ddI. A 500 mg ddI dose in the sachet form is equivalent to a 400 mg dose in tablet form because of differences in absorption. Patients were followed for a median of 17 months.
Among 380 patients in the study who had no prior AZT use, 18 percent of those taking AZT developed a new, previously undiagnosed AIDS-defining condition or died within one year. In comparison, 31 percent of the AZT-naive patients on the 750 mg ddI dose and 29 percent of those on the 500 mg ddI dose developed new AIDS-defining conditions or died within one year.
Among the 118 patients with eight to 16 previous weeks of AZT therapy, the study investigators found ddI to be the more effective drug. For those patients assigned to AZT, 33 percent developed a new AIDS-defining condition or died within one year, while only 11 percent of patients taking 500 mg ddI and 17 percent of those taking 750 mg ddI did so.
The treatment comparisons between AZT and the two doses of ddI were inconclusive among the 119 patients with eight or fewer weeks of prior AZT therapy. Overall, the investigators did not find any significant differences between the effectiveness of the two doses of ddI.
In the study, patients assigned to AZT were more likely than those on ddI to suffer lowered blood cell counts, including granulocytopenia, a decrease in a type of white blood cell. Patients assigned to AZT had a low risk, similar to that seen among ddI patients, of developing severe anemia, a decrease in red blood cells.
Patients on 750 mg ddI were more likely to develop pancreatitis within one year than those on the 500 mg ddI dose or those on AZT. Study scientists did not observe any significant differences in the rate of development of peripheral neuropathy, a painful nerve condition, between AZT and ddI recipients.
"These data suggest that 500 mg ddI is better tolerated than the higher ddI dose and support the continued use of ddI 500 mg per day (400 mg per day in tablet form)," says Dr. Fischl.
The study began enrollment in October 1989 and follow-up ended in May 1992. NIAID released initial results of the trial in December, 1992. Physicians and others caring for HIV-infected patients can call 1-800-TRIALS-A to request further information on the study findings, including a more detailed executive summary document.
NIAID, a component of the National Institutes of Health (NIH), supports research on allergy, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.
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