ACTG PROTOCOL 152 Questions and Answers
1. WHAT WAS THE PURPOSE OF STUDY ACTG 152?
AIDS Clinical Trials Group (ACTG) 152 was a randomized, double-blind clinical trial designed to compare three different drug regimens to determine which is most effective for symptomatic children with HIV who received little or no prior antiretroviral therapy. The study also compared the toxicities or side effects of the three treatment arms.
2. WHAT DRUGS WERE USED IN THIS STUDY?
Two different drugs were used in this study. The drugs that were evaluated, either in combination or alone, were zidovudine (AZT) and didanosine (ddI). Patients enrolled in the study had an equal chance of receiving one of the following treatments:
A. AZT alone (180 mg/m2 every 6 hours) B. ddI alone (120 mg/m2 every 12 hours), C. combination AZT (120 mg/m2 every 6 hours) and ddI (90 mg/m2 every 12 hours)
3. WHO PARTICIPATED IN THE STUDY?
A total of 839 children ranging in age from months to 18 years enrolled in ACTG 152. Of the children enrolled in the trial, 54 percent were younger than 30 months at entry. Equal numbers of boys and girls enrolled, and 54 percent were black non-Hispanic, 30 percent were Hispanic, 14 percent were white non-Hispanic and 2 percent had another race/ethnicity. Only children who had no or little prior antiretroviral therapy (less than six weeks of prior AZT) and had AIDS were eligible for the study. Only 8 percent of the enrolled children received any prior AZT.
4. WHO SPONSORED THIS STUDY?
ACTG 152 is a collaborative effort conducted by the Pediatric ACTG and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Child Health and Human Development (NICHD). The study is co-chaired by Drs. Carol J. Baker and Janet Englund from the Baylor College of Medicine, Houston, Texas. Bristol-Myers Squibb provided the ddI and the Burroughs Wellcome Co. (now Glaxo-Wellcome) provided the AZT for the study.
5. HOW WAS THE EFFECTIVENESS OF THE TREATMENTS EVALUATED?
The study was designed to evaluate whether there were differences in the rate of development of primary clinical endpoints among the three treatment regimens. These endpoints included:
A. Impaired weight gain B. Neurologic deterioration C. Development of two or more new or recurrent opportunistic infections D. Death E. Development of a malignancy
The study was double-blind, meaning that neither physicians nor families knew into which treatment regimen a child enrolled. Patients who were randomly assigned to one of the two monotherapy treatment arms (AZT alone or ddI alone) and who developed a primary endpoint other than death were switched to the other monotherapy arm. Children on the combination arm (AZT and ddI) who met a primary endpoint went off the study and were offered the best available treatment.
6. WHEN AND WHERE WAS THE STUDY CONDUCTED?
Study enrollment began in August 1991 and the last patient enrolled in August 1993. The study was conducted at 78 sites in the United States funded by NIAID and NICHD. The AZT monotherapy arm of the study was closed by the Executive Committee of the Pediatric ACTG in February 1995. This was based on the evaluation of interim efficacy results by the Data Safety Monitoring Board in which they concluded that the AZT monotherapy arm was significantly less efficacious and had more toxicities than the best of the two remaining treatment arms. Patients on the AZT monotherapy arm were informed about their treatment and offered the best available therapy at that time. Follow up and final evaluations for the patients remaining on blinded study drugs took place between February 1995 and August 1995. Patients received study drugs through November 1995 at which time those patients and their physicians remaining on the ddI or combination treatment arms were told the patient's treatment assignment.
7. WHAT WERE THE FINAL RESULTS OF THE STUDY?
The final results of ACTG 152 showed that pediatric patients who had little or no prior antiretroviral experience, and were randomized to either ddI monotherapy or the combination of AZT plus ddI, had better clinical outcomes with less toxicity than did those on AZT monotherapy. These clinical outcomes included less physical growth impairment, neurologic deterioration, and development of two or more opportunistic infections, malignancy or death. No differences in efficacy were noted between the ddI monotherapy and combination AZT plus ddI treatment arms, but the ddI monotherapy arm had the least toxicity.
8. HOW CAN THE DIFFERENCE IN EFFICACY BETWEEN THE TREATMENT REGIMENS IN THIS TRIAL BE EXPLAINED?
Investigators do not yet know, but one explanation may be that over a period of time resistant strains of HIV emerge more rapidly in patients receiving AZT alone compared to patients taking the other therapies. The ACTG 152 investigators are addressing this difference by evaluation of resistance rates on the treatment arms of the study. It is possible, however, that other unknown mechanisms might be present.
9. WHAT SPECIFIC CLINICAL ENDPOINTS OCCURRED? WERE THERE ANY DEATHS?
The endpoints, including impaired weight gain, neurologic deterioration, new or recurrent opportunistic infections, malignancy and death, occurred in children enrolled in all three arms. These endpoints as a group occurred more frequently in the AZT monotherapy arm. Of the patients in the overall study, 12 percent died by the time of the final analyses. The deaths occurred in all three arms.
10. WERE THERE ANY DIFFERENCES IN TOXICITY AMONG THE DIFFERENT REGIMENS?
Yes. The fewest numbers of toxicities occurred in children on the ddI monotherapy treatment arm. This was particularly evident among children 30 months or older, in which rates of severe hematologic toxicities were significantly lower for those receiving ddI compared to those receiving combination AZT plus ddI. Among children younger than 30 months on entry, there were no differences in hematologic or chemistry toxicities among those receiving ddI or AZT plus ddI. In general, the toxicities of both AZT and ddI were manageable and reversible with normal clinical monitoring, or dose reduction or switching to other therapies.
11. WHAT ARE THE IMPLICATIONS OF THESE RESULTS?
The results of ACTG 152 indicate that treatment with either ddI monotherapy or the combination of AZT plus ddI results in slower disease progression than treatment with AZT monotherapy among children who have not received prior antiretroviral therapy. Because ACTG 152 evaluated only HIV-infected children with little or no prior antiretroviral therapy, these findings cannot not be generalized to children who have already received antiretroviral therapy. Further research is needed to evaluate the relative efficacy of monotherapy versus combination therapy among children with prior antiretroviral experience.
12. WHAT OTHER ANTIRETROVIRAL THERAPIES ARE AVAILABLE TO PEDIATRIC AIDS PATIENTS AT THIS TIME?
A number of possibilities exist, including monotherapy ddI or combinations of AZT, ddI, ddC and d4T. In addition, other clinical trials also are available for children with HIV through the Pediatric ACTG. These include a large trial comparing the efficacy of AZT plus 3TC to AZT plus ddI and to ddI alone. Protocols with other antiretrovirals including protease inhibitors are also in development.
13. WHAT IMPACT WILL THESE RESULTS HAVE ON GENERAL CARE OF CHILDREN WITH AIDS NOT ON STUDY PROTOCOLS?
Physicians caring for children with symptomatic HIV disease who have not received prior antiretroviral therapy should consider these findings from ACTG 152 as they make decisions regarding initial antiretroviral therapy taking into account the child's specific clinical condition and needs.
14. SHOULD CHILDREN ALREADY RECEIVING AZT THERAPY BE SWITCHED TO AN ALTERNATIVE REGIMEN?
Physicians will need to review the clinical course of individual patients. For those children who have not received antiretrovirals and who are similar to the symptomatic children in ACTG 152, the results of this study should be carefully considered in making treatment choices. The study results do not address the best treatment for symptomatic HIV-infected children who had prior antiretroviral experience. Consultation with a specialist in pediatric HIV disease may be indicated.
15. HOW DOES THIS INFORMATION RELATE TO FINDINGS FROM CLINICAL TRIALS IN ADULTS COMPARING AZT AS SINGLE AGENT THERAPY TO OTHER THERAPIES?
These findings are similar to the results of the adult clinical trial ACTG 175 that were reported in September 1995. Among adult participants of ACTG 175 who had never taken antiretrovirals before the trial, the results indicated that treatments with ddI alone, the combination of AZT plus ddI, or the combination of AZT plus ddC were each more effective than treatment with AZT alone with respect to immunologic decline, AIDS or death. When considering clinical endpoints for all patients in ACTG 175, ddI monotherapy or combination AZT plus ddI were both more effective than AZT monotherapy in preventing AIDS-defining conditions and prolonging survival.
16. HOW DO THESE RESULTS RELATE TO THE FINDINGS FROM ACTG 076 REGARDING THE USE OF AZT TO REDUCE PERINATAL TRANSMISSION OF HIV?
AZT, when administered according to the ACTG 076 regimen and as described in the PHS recommendations published in the Morbidity and Mortality Weekly Report (Aug. 5, 1994) or The New England Journal of Medicine (Nov. 2, 1994), substantially reduces the risk of perinatal transmission. AZT remains the treatment of choice for that situation. It is not possible to extrapolate from ACTG 152, which was designed to assess therapy for children with AIDS, to the perinatal setting. Furthermore, little evidence exists of the effectiveness of other regimens for the prevention of perinatal transmission.
17. HOW CAN INFORMATION BE OBTAINED ABOUT OTHER CLINICAL TRIALS FOR CHILDREN WITH HIV?
The AIDS Clinical Trials Information Service at 1-800-TRIALS-A has current information on available clinical trials for both children and adults. The service operates Monday through Friday, 9 a.m. to 7 p.m. E.T. A bilingual health specialist is available to talk to Spanish-speaking callers. The service also is available for hearing impaired callers at: TTY/TDD 1-800-243-7012.
NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.
Prepared By: Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892 U.S. Public Health Service U.S. Department of Health and Human Service