Patients with advanced HIV disease who have received prolonged therapy with zidovudine (AZT) and who continue taking AZT alone or switch to either zalcitabine (ddC) alone or a combination of ddC and AZT have similar clinical outcomes overall. The combination therapy may be more beneficial than continued treatment with AZT alone for a subgroup of study participants, according to results from a study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).
For the study, investigators assessed the relative effectiveness of the three therapies in HIV-infected patients in delaying clinical disease progression, defined as the development of a new AIDS-related condition or death. When looking at all study participants, the researchers observed no significant differences between any of the three treatment regimens.
Margaret A. Fischl, M.D., co-chair of the study, AIDS Clinical Trials Group (ACTG) 155, and director of the Comprehensive AIDS Program at the University of Miami School of Medicine in Florida, plans to present the findings on behalf of the study protocol team at the IX International Conference on AIDS in Berlin, Germany, on June 10.
The data from this study point out important issues for the design of future clinical studies and treatment strategies for HIV disease," says Dr. Fischl.
The study results are based on data from 991 patients, all of whom had previously taken AZT for six months or longer, with a median duration of 18 months. The study enrolled HIV-infected people with 300 or fewer of the crucial immune system cells called CD4+ T cells per cubic millimeter of blood (mm3) if they had HIV-related symptoms and patients with 200 or fewer CD4+ T cells/mm3 with or without AIDS-related symptoms. At study entry, 83 percent of the patients had symptomatic HIV disease.
The participants were randomly assigned to one of three therapies, given three times a day: 200 milligrams (mg) AZT or 0.75 mg ddC or a combination of both drugs. Neither the investigators nor the patients knew which treatment participants received.
When analyzing the relationship between the patients' pretreatment CD4+ T cell counts and the activity of the different therapies as specified in the study design, researchers found that patients entering the study with 150 to 300 CD4+ T cells who received the combination therapy were less likely to get a new AIDS-related condition or die than patients taking AZT alone. In this same subgroup of participants, investigators found no significant differences between ddC alone and AZT alone or between ddC alone and the combination regimen.
These data suggest that patients with advanced HIV disease and CD4+ T cell counts of 150 to 300 cells/mm3 who have previously received long-term AZT therapy may benefit from combination therapy with ddC and AZT, rather than continued monotherapy with AZT," says Dr. Ann Collier, M.D., Clinical Director of the University of Washington AIDS Clinical Trials Unit and co-chair of the study.
The probability of patients entering the study with 150 to 300 CD4+ T cells/mm3 remaining alive and free of new AIDS-defining conditions at 12 months of follow-up was, respectively, 95, 88 and 86 percent for the combination, ddC and AZT groups.
For patients with pre-treatment CD4+ T cell counts of 50 to 150/mm3 or 50/mm3 or fewer, the investigators observed no statistically significant differences in comparison of the three therapies. Other subgroup analyses performed did not find any differences in clinical outcomes among the three regimens.
The investigators noted no overall differences in survival among patients in the three therapy groups. In the higher CD4+ T cells groups, too few deaths occurred to draw definitive conclusions about survival benefits afforded by any of the therapies. Patients on the combination regimen with pre-treatment CD4+ T cell counts of 50/mm3 or fewer showed a trend towards a higher death rate that was not statistically significant.
During the study, the probability of a patient suffering a severe side effect within 12 months was 45 percent for those in the AZT group, 40 percent for the ddC group and 49 percent for the combination group.
Patterns of severe side effects differed among the pre-treatment CD4+ T cell groups:
- Severe side effects were uncommon among patients with 150 to 300 CD4+ T cells/mm3 at study entry, and no significant differences were noted among patients in the three treatment arms.
- Among patients with pretreatment CD4+ T cell counts of 50 to 150, an inflammation of the mouth known as stomatitis was significantly more common in the ddC group (8 percent) than in the AZT group (1 percent) or the combination group (2 percent).
- Among the patients with fewer than 50 CD4+ T cells/mm3 at study entry, a common side effect was a decrease in the white blood cells called neutrophils, seen in 41 percent of the AZT group, 35 percent of the combination group and 18 percent of the ddC group. Severely elevated liver enzymes were seen in 14 percent of the AZT group, 5 percent of the ddC group and 4 percent of the combination group.
Peripheral neuropathy, a painful nerve condition of the hands and feet, of moderate or worse degree was significantly more common in the combination (22 percent) and ddC groups (23 percent) than in the AZT group (13 percent).
The study was conducted at 35 units of the ACTG and 16 National Hemophilia Foundation centers across the United States. The ACTG is a nationwide network of AIDS clinical research centers funded by NIAID that conducts studies to evaluate the safety of new drugs, drug combinations and vaccines in adults and children at various stages of HIV disease. Hoffmann-La Roche Inc. provided ddC for the study and Burroughs Wellcome Co. provided AZT for the study.
"Our findings suggest the need for more information on the effects of combination regimens in early stages of HIV disease, and on whether intervention with combination therapy after a much shorter duration of AZT therapy in advanced disease can help HIV-infected patients," says Dr. Fischl.
Combination therapy is being investigated further in two ongoing NIAID studies. ACTG 175 is comparing two drug combinations -- AZT/didanosine (ddI) and AZT/ddC -- with single drug therapy with AZT or ddI in 2,491 patients at earlier stages of HIV disease. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) network is enrolling people into a trial to compare two combination regimens, AZT/ddC and AZT/ddI, with AZT alone in participants with CD4+ T cell counts of 200/mm3 or fewer or with a diagnosis of AIDS. The CPCRA is a NIAID-supported, nationwide group of community-based AIDS research programs. Several other smaller studies are also underway.
NIAID, a component of the National Institutes of Health, supports research on allergies, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
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