Research supported by the National Institute of Allergy and Infectious Diseases (NIAID) has demonstrated that anti-HIV treatment of individuals with intermediate-stage HIV disease can lower their risk of developing AIDS and, in certain patients, can reduce the risk of death.
In a study of nearly 2,500 HIV-infected volunteers, with initial CD4+ T cell counts between 200 and 500/mm3, the drug didanosine (ddI), the combination of ddI plus zidovudine (AZT), and the combination of zalcitabine (ddC) plus AZT were each superior to the widely used first-line therapy, AZT alone, in preventing one or more serious consequences of HIV infection--significantly declining CD4+ T cell counts, developing an AIDS-defining condition or dying. Importantly, when investigators looked only at disease progression or survival in the overall study group, treatment with either ddI+AZT or ddI alone was more effective than AZT monotherapy.
The results of ACTG 175 build upon previous studies that suggested that antiretroviral therapy could clinically benefit patients with CD4+ T cell counts less than 500/mm3," says Anthony S. Fauci, M.D., NIAID director. "Significantly, the current study also has provided the first conclusive evidence that antiretroviral therapy can reduce the risk of death in asymptomatic people with intermediate-stage HIV disease. Other ongoing clinical trials with the medications in this study, as well as newer antiretroviral agents, promise to help further define the optimal care of all HIV-infected patients."
The preliminary results of the trial, known as AIDS Clinical Trials Group 175 (ACTG 175), will be presented at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) on September 18 by study co-chairmen Scott Hammer, M.D., of Harvard Medical School and David Katzenstein, M.D., of the Stanford University School of Medicine.
The overall finding of the study was that ddI alone, ddI+AZT and ddC+AZT were each superior to AZT alone in preventing one or more serious consequences of HIV infection, including CD4+ T cell decline. This result was observed whether or not participants had been previously treated with AZT. The three treatments were similar to one another in effectiveness.
Investigators also noted benefits when they looked only at the clinical events of disease progression or death without considering changes in CD4+ T cell counts. Those patients who had never taken AZT benefitted most from the combination of ddC+AZT. Those who had been previously treated with AZT benefitted most from either ddI or ddI+AZT.
ACTG 175 confirms the importance of careful planning in the use of antiretroviral regimens since prior antiretroviral experience may influence the effectiveness of some treatment regimens," Dr. Fauci says.
A total of 2,467 HIV-infected volunteers participated in ACTG 175, most of whom had no HIV-related symptoms at study entry. Patients were enrolled at 43 sites of the NIAID-supported AIDS Clinical Trials Group, and at nine sites of the National Hemophilia Foundation. All study participants had CD4+ T cell counts between 200 and 500 per cubic millimeter (mm3) of blood at study entry. A healthy individual without HIV infection usually has a CD4+ T cell count of 800 to 1200/mm3. The volunteers, 82 percent of whom had no HIV-related symptoms at study entry, were followed for a median of 143 weeks.
~1,067 patients (43 percent of total) had never taken any anti-HIV drugs, including AZT.The mean CD4+ T cell count at study entry was 372/mm3 in this "AZT-naive" group.
~1,400 patients (57 percent) had previously taken AZT for weeks to many months prior to enrollment in the study; the mean CD4+ T cell count at study entry was 338/mm3 in this "AZT-experienced" group.
Participants in ACTG 175 were randomly assigned to receive one of the following treatments:
1. AZT (600 mg/day) alone; 2. ddI (400 mg/day) alone; 3. AZT (600 mg/day) + ddI (400 mg/day); 4. AZT (600 mg/day) + ddC (2.25 mg/day).
The drugs used in the study were provided by their manufacturers -- Glaxo-Wellcome Company (AZT), Bristol-Myers Squibb Inc. (ddI), and Hoffmann-La Roche Inc. (ddC). All three drugs are nucleoside analogues that act as inhibitors of reverse transcriptase, an enzyme used by HIV to replicate.
The effectiveness of each treatment was evaluated in several ways. First, the investigators assessed the ability of each treatment to prevent the study's primary endpoints in aggregate: AIDS, death or a 50 percent decline in CD4+ T cell count. Additional study analyses evaluated the effectiveness of the treatments in preventing progression to AIDS or death ("clinical endpoints"), irrespective of changes in CD4+ T cell counts. Patients in the study who had a 50 percent decline in their CD4+ T cell counts or progressed to AIDS were re-assigned in a blinded, randomized fashion to a combination therapy (or a new combination therapy).
In addition, the safety of each treatment regimen was closely monitored. In the study, there were no major differences in the safety of the four treatments. A total of 461 subjects (18 percent) reported severe or life-threatening signs and symptoms while receiving the study treatment that was initially assigned, although these were not necessarily related to the drug.
The results of ACTG 175 will be submitted shortly to a peer- reviewed journal for publication. In addition, sub-studies of ACTG 175 are currently being analyzed, including studies of how the various treatments affected the amount of virus in patients' blood, the pharmacology of study drugs, HIV- or drug-related muscle disease, the development of HIV resistance to the drugs, women's health and the quality of life of study participants.
Two other large studies will provide further data related to some of the drug regimens used in ACTG 175 when used in different populations:
~An NIAID-supported trial known as CPCRA 007, which includes patients with CD4+ T cell counts of 200/mm3 or fewer.
~The DELTA trial, a European/Australian collaborative study, which includes patients with CD4+ T cell counts less than 350/mm3.
Results of these trials are expected in early 1996. Once those results are available, DELTA trial sponsors and NIAID investigators will collaborate to analyze the data from all three studies in order to better understand the implications of all the findings. In addition, the results of ACTG 175 will be examined in relation to data from earlier ACTG studies.
NIAID, a component of the National Institutes of Health, supports scientists and scientific studies at universities, medical schools and research institutions in the United States and abroad. As part of its efforts to improve the quality and duration of life of HIV-infected individuals, the institute supports four diverse AIDS clinical trials programs: the AIDS Clinical Trials Group, the Terry Beirn Community Programs for Clinical Research on AIDS, the Division of AIDS Treatment Research Initiative and the Division of Intramural Research clinical trials program on the NIH campus.
NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.