1. What was the purpose of ACTG 175?
ACTG 175 was designed to evaluate whether treatment of HIV infection with one drug (monotherapy) was the same, better than, or worse than treatment with two drugs (combination therapy) in patients with CD4+ T cells between 200 and 500/mm3. (CD4+ T cells play a crucial role in the immune response, signalling other cells in the immune system to perform their special functions. A healthy person usually has 800 to 1,200 CD4+ T cells/mm3.)
2. What drugs were used in this study?
Three different drugs were used to conduct this study. The drugs that were evaluated, either in combination or alone were: 1) zidovudine (AZT), 2) didanosine (ddI), and 3) zalcitabine (ddC). All three drugs are nucleoside analogues that act as reverse transcriptase inhibitors (RT-inhibitors). This class of drugs prevents the enzyme known as reverse transcriptase from functioning properly. The reverse transcriptase enzyme is needed by HIV in order to function.
3. Who sponsored the study?
ACTG 175 was conducted by the AIDS Clinical Trials Group (ACTG), which is supported by the National Institute of Allergy and Infectious Diseases (NIAID); a part of the National Institutes of Health. The drugs used in this study were provided by their manufacturers -- Glaxo-Wellcome Company (AZT), Bristol-Myers Squibb, Inc. (ddI), and Hoffmann-La Roche, Inc. (ddC).
4. Where and when was the study conducted?
ACTG 175 was conducted at 43 sites within both the adult and pediatric ACTG's and 9 sites of the National Hemophilia Foundation. Participants were enrolled into the study between December 1991 and October 1992, and received treatment through December 1994. Follow-up and final evaluations of participants took place between December 1994 and February 1995.
5. Who participated in this study?
The study was open to HIV-infected individuals who had CD4+ T cell counts between 200 and 500 cells/mm3 at the time of entering the study and no history of AIDS-related conditions other than minimal Kaposi's sarcoma.
A total of 2,467 people entered this study, approximately half of whom had never taken AZT before enrollment. All of the participants were between the ages of 12 years and 70 years, 82 percent were male and 18 percent were female. Seventy percent of study participants were white/non- Hispanic, 17 percent were Black, 12 percent were Hispanic and the remaining 2 percent were of other ethnic origins.
6. What was the design of the study?
ACTG 175 was a randomized, double-blind, phase II/III clinical trial. All participants enrolling in the study had and equal chance of receiving one of the following treatments:
A. AZT (600 mg/day) alone, or B. ddI (400 mg/day) alone, or C. AZT (600 mg/day) + ddI (400 mg/day), or D. AZT (600 mg/day) + ddC (2.25 mg/day)
7. How was the effectiveness of these treatments evaluated?
These treatments were first evaluated for their ability to prevent a 50 percent decline in the CD4+ T cell count, the development of AIDS, or death. Secondarily, the treatments were evaluated for their ability to prevent AIDS or death, without considering what happened to the CD4+ T cell count. In this study, AIDS was defined as the occurrence of one of the opportunistic infections or cancers associated with HIV infection. In addition, the safety of each of these treatments was closely monitored.
8. What were the results of the study?
The results of ACTG 175 showed that patients randomized to ddI monotherapy and the combinations of AZT + ddI and AZT + ddC had better outcomes than did those on AZT monotherapy based on a 50 percent decline in CD4+ T cell count, AIDS, or death. The regimens were comparable in these patients. When only considering the clinical endpoints for all patients, AZT + ddI or ddI alone were both more effective than AZT monotherapy in preventing AIDS-defining conditions and prolonged survival.
Specifically, the results of ACTG 175 can be summarized as follows:
A. For ACTG 175 participants who had never taken AZT before entering the trial, treatment with ddI alone, the combination of AZT + ddI, or the combination of AZT + ddC were each more effective than treatment with AZT alone in delaying a 50 percent decline in CD4 +T cells, AIDS, or death. With respect to the clinical endpoints (AIDS or death), AZT + ddC was of significantly greater benefit than AZT alone. Nonetheless, ddI, AZT + ddI, and AZT + ddC were generally comparable.
B. For ACTG 175 participants who had taken AZT before entering the study, treatment with ddI or AZT + ddI was better than continuing to take AZT alone. Investigators noted no clear differences between the ddI and AZT + ddI treatments - they both appeared to be equally effective in preventing HIV disease from progressing. Treatment with AZT + ddC provided no additional benefit to continued treatment with AZT when analyzed on the basis of clinical endpoints.
9. Were there any differences in toxicity among the different regimens?
The rates of drug-related adverse experiences in this trial were moderate and not unexpected. Investigators noted no significant differences in the safety of the four treatments.
10. What are the implications of these results?
The results of ACTG 175 together with the results from earlier studies demonstrate that antiretroviral therapy is beneficial to HIV-infected people who have less than 500 CD4+ T cells/mm3. This study also shows, for the first time, that an improvement in survival can be achieved in a population at an intermediate stage of the disease. It confirms the importance of careful planning in the use of antiretroviral regimens since prior antiretroviral experience may substantially influence the effectiveness of the treatment regimen.
11. Were any other studies conducted as part of ACTG 175?
A number of substudies were part of ACTG 175. These include a virology substudy, in which the amount of virus in the blood and resistance to the anti-HIV drugs are being studied. Other substudies are examining women's health problems and the participant's quality of life. This information is being analyzed and will be available in the near future.
12. Are other studies similar to ACTG 175 being conducted?
Two very large, on going trials are being conducted to address the questions similar to those addressed in ACTG 175, but in populations with later-stage disease. These trials are the Community Programs in Clinical Research on AIDS (CPCRA) 007 study (for HIV-infected people with less than 200 CD4+ T cells) and the DELTA trial, a European/Australian collaborative study, (for HIV-infected people with less than 350 CD4+ T cells). In both of these trials participants are randomized to receive either ddI or ddC in combination with AZT. Neither trial has a ddI monotherapy arm. Both trials will be completed in December 1995 or January 1996. Once these results are available, NIAID and the multinational DELTA trial sponsors will collaborate to analyze findings. In addition, the results of ACTG 175 will be examined in relation to data from earlier ACTG studies involving these treatments, such as ACTG 116A, ACTG 116B/117, and ACTG 155.
13. Where can I get more information about this and other clinical trials?
Further information about this trial is available from the AIDS Clinical Trials Information Services, 1-800-TRIALS-A.
General information about HIV disease, testing or treatment options may be obtained from your health care provider, your local and state health department, or by calling one of several national organizations. Some of these include:
o AIDS Treatment Information Service (1-800-448-0440) o National AIDS Information Hotline (1-800-342-AIDS)