Preliminary results of the two studies, known as ACTG 175 and CPCRA 007, were first announced by NIAID in 1995, and have played an important role in helping define the standard of care for HIV-infected people and shaping subsequent clinical studies of antiretroviral medications.
"ACTG 175 was noteworthy because it was the first trial to provide conclusive evidence that antiretroviral therapy could reduce the risk of death in people with intermediate-stage HIV disease and no symptoms, and CPCRA 007 provided important information on combination therapy for HIV-infected people with more advanced disease," says Anthony S. Fauci, M.D., NIAID director. "Both ACTG 175 and CPCRA 007, in addition to other recent studies, underscore the importance of careful planning in the use of antiretroviral drugs since prior antiretroviral experience can profoundly influence the effectiveness of some treatments."
"Subsequent to these two studies, results from other trials, especially those that have assessed protease inhibitors in combination with other drugs, have provided impressive results, giving hope for a level of control of HIV disease that has thus far eluded patients and physicians," he adds.
ACTG 175 was conducted at 43 sites of the AIDS Clinical Trials Group and nine sites of the National Hemophilia Foundation. The study investigators analyzed data from 2,467 patients with initial CD4+ T cell counts between 200 and 500 per cubic millimeter (mm³) of blood. Fifty-seven percent of these patients had previously received anti-HIV therapy; most had no HIV-related symptoms at study entry.
Patients in ACTG 175 received one of four anti-HIV treatment regimens: zidovudine (AZT) alone; AZT plus didanosine (ddI); AZT plus zalcitabine (ddC); or ddI alone. They were followed for a median of 143 weeks.
In their analyses of the study results, ACTG 175 investigators found that ddI alone, the AZT+ddI combination, and the AZT+ddC combination were each superior to AZT alone in preventing one or more of the serious consequences of HIV infection: significantly declining CD4+ T cell counts, a new AIDS-defining condition (e.g., Pneumocystis carinii pneumonia) or death.
When the investigators looked only at the clinical endpoints of a new AIDS-defining condition or death, treatment with either AZT+ddI or ddI alone was more effective than AZT alone. In the analysis of clinical endpoints, the benefit of AZT+ddC over AZT alone appeared to be limited to volunteers without prior antiretroviral treatment.
In the study, there were no major differences in the toxicities associated with the four treatments.
In a second report from ACTG 175, the investigators found that reducing the levels of HIV in patients' blood with therapy lowered their risk of developing AIDS or dying. The degree to which HIV levels were suppressed was greater and more sustained with the AZT+ddI and the AZT+ddC combinations, and with ddI alone, than with AZT alone.
CPCRA 007 was conducted at sites that are part of the Terry Beirn Community Programs for Clinical Research on AIDS; it is also known as the "NuCombo" study.
This trial assessed the safety and efficacy of combination therapy -- AZT+ddI or AZT+ddC -- as compared to AZT alone in 1,102 HIV-infected people who had fewer than 200 CD4+ T cells/mm³ of blood at study entry or who previously had suffered an AIDS-defining condition. Seventy-seven percent of the patients who enrolled in CPCRA 007 had received prior antiretroviral therapy.
Over a median follow-up time of 35 months, combination therapy (AZT+ddI or AZT+ddC) provided only marginal benefits, which were not statistically significant, in slowing progression of clinical disease and reducing the rate of death as compared to AZT alone. In addition, toxicities were more frequent in the two combination groups than among patients taking AZT alone.
However, in subgroup analyses of patients with little or no prior AZT use, combination therapy was more effective than AZT alone in terms of slowing disease progression to AIDS or death. Use of combination therapy provided no additional benefit to patients who had previously used AZT for more than 12 months.
The ACTG is a nationwide multicenter clinical trials network, based at major research institutions, that tests new drugs for adults infected with HIV. The CPCRA is a network of primary care physicians and nurses who work with NIAID staff to design and conduct community-based clinical trials in patients with HIV disease and AIDS.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the Public Health Service, U.S. Department of Health and Human Services.