Low, medium and high doses of the drug didanosine (ddI) had similar effects overall on the progression of advanced HIV disease in persons unable to take zidovudine (AZT) because of blood-related side effects, according to a study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and Bristol-Myers Squibb Company.
The trial enrolled patients with advanced HIV disease who were unable to continue AZT therapy because of significant drops in the number of certain white and red blood cells. Participants taking the three different doses of ddI showed no significant differences in survival or in the rate of development of AIDS-related opportunistic infections.
However, those assigned to the two higher doses of ddI experienced a greater rise in hemoglobin, white blood cell counts and the number of crucial immune cells known as CD4+ T cells than did those on the low dose. The clinical significance of the increase in CD4+ T cell counts is unclear, the investigators report.
Based on this analysis, it is not possible to reach a definite conclusion on whether increases in CD4+ T cell counts imply the effectiveness of a particular dose of ddI or merely indicate which patients are healthier to begin with, or both," says principal investigator J. Davis Allan, Jr., M.D., an infectious disease specialist at the New England Deaconess Hospital, Boston, and assistant professor of medicine at Harvard Medical School.
Patients taking the highest dose of ddI, 750 milligrams (mg.) per day, were more likely than those on the lower doses, 500 mg./day and 200 mg./day, to suffer from peripheral neuropathy, numbness, tingling and pain in the extremities, and pancreatitis, a potentially fatal inflammation of the pancreas.
This study does not allow a clear recommendation about the optimal dose of ddI in terms of effectiveness," says Dr. Allan. "However, the results indicated the 750 mg./day dose of ddI probably should be avoided in most HIV patients with advanced disease, particularly those at increased risk for pancreatitis, given the association of that dose with increased toxicity."
The results of the study, known as ACTG 118, were presented Feb. 22, 1993 at a meeting of the AIDS Clinical Trials Group (ACTG) by Dr. Allan and Victor De Gruttola, D.Sc., of the Harvard School of Public Health. The ACTG is a nationwide network of AIDS clinical research centers funded by NIAID.
Other recently completed NIAID studies compared the two higher doses of ddI therapy and AZT in persons with advanced HIV disease who had no previous AZT use, or who had taken and tolerated AZT for 16 or fewer weeks (ACTG 116A); and in persons with advanced disease who had tolerated AZT therapy for more than 16 weeks (ACTG 116B/117).
These new findings should be carefully reviewed by physicians treating persons with advanced HIV disease," says Daniel F. Hoth, M.D., director of the Division of AIDS at NIAID. "Together, the findings from the ACTG 116B/117, ACTG 116A and ACTG 118 trials provide physicians with a better understanding of ddI's utility in a variety of clinical situations."
For the study, investigators enrolled 650 patients with AIDS or advanced AIDS-related complex (ARC) who had fewer than 300 CD4+ T cells per cubic millimeter (mm3) of blood, as well as patients without symptoms and 200 or fewer CD4+ T cells/mm3. ARC is a stage of HIV infection before AIDS when the patient has symptoms such as yeast infections, unexplained fever or diarrhea, recurrent herpes outbreaks or loss of more than ten percent of his or her body weight.
Participants were randomly assigned to receive one of the three daily dosages of ddI as a powdered buffer. Neither the investigators nor the patients knew which treatment a patient received. A 500 mg. ddI dose in the powdered buffer form is equivalent to a 400 mg. dose in tablet form because of differences in absorption and is the currently recommended dose.
The median CD4+ T cell count among patients upon entering the study was 33/mm3. Participants had previously taken AZT for a median of 258 days. All patients in the study received preventive therapy for Pneumocystis carinii pneumonia, a common AIDS-related infection.
Physicians and others caring for HIV-infected patients can call 1-800-TRIALS-A, 9:00 a.m. to 7:00 p.m., EST, to request further information on the study findings.
NIAID, a component of the National Institutes of Health, supports research on allergy, immunology and infectious diseases. NIH is an agency of the Public Health Service, Department of Health and Human Services.