Initial therapy with didanosine (ddI) alone slows disease progression in HIV-infected children as effectively as combination therapy with ddI and AZT, according to the final results of an NIH-funded clinical trial presented in February to the Food and Drug Administration. Prior interim data analyses from the trial, known as AIDS Clinical Trials Group (ACTG) 152, had shown that either of the ddI treatment regimens were superior to treatment with AZT alone.
These are important findings from the largest controlled pediatric HIV trial to date. The results add significantly to our knowledge of therapy for children with HIV disease," says Anthony S. Fauci, M.D., director of NIAID, which co-funded ACTG 152 with the National Institute of Child Health and Human Development.
Between August 1991 and August 1993, ACTG 152 enrolled 839 children ranging in age from 3 months to 18 years at 78 different study sites in the United States. Only children who had received little or no prior antiretroviral treatment were eligible to participate.
Each child was assigned at random to one of the three treatment groups; neither the doctors, the patients, nor the parents knew which therapy each child received.
The study's AZT-only treatment arm was discontinued last year after interim analyses indicated that AZT monotherapy was less effective than either of the ddI treatments and was associated with more side effects (see AIDS Agenda, Spring 1995). Patients in the AZT group were then offered the best available therapy at that time.
Final analyses of ACTG 152 assessed the relative efficacies and toxicities of the ddI regimens. Both ddI treatments were equally effective in preventing or delaying such clinical outcomes as poor weight gain, developmental and neurologic problems, new or recurrent opportunistic infections, malignancy and death.
Fewer toxicities occurred in children receiving ddI monotherapy among children 30 months or older, rates of such hematologic disorders as anemia and decreased white blood cells were significantly lower for those receiving ddI compared to those receiving ddI plus AZT. In general, however, detrimental side effects were easily managed for both AZT and ddI recipients.
The ACTG 152 findings are similar to the results of the adult clinical trial ACTG 175 that were reported last September. In that study, HIV-infected adults who had never taken antiretrovirals had better clinical outcomes when treated with ddI alone, ddI plus AZT, or AZT plus zalcitabine (ddC), than those who were treated with AZT monotherapy.
Although investigators are not certain why treatment regimens that include ddI are superior to AZT, they speculate that drug-resistant strains of HIV may develop more rapidly in patients receiving AZT monotherapy compared to other therapies. Whatever the reason, the results of ACTG 152 could have a significant impact on the care of children with AIDS.
Still, researchers are quick to caution that because the trial involved only HIV-infected children who had received little, if any, prior therapy, the findings cannot be generalized to children who have already received antiretroviral therapy.
In addition to the ddI regimens investigated in this trial, other AIDS antiretroviral therapies being studied for use in children include various combinations of ddC, d4T (stavudine), ddI and AZT. The NIAID Pediatric ACTG also supports a number of other clinical trials for children with HIV, including a large study comparing the efficacy of AZT plus 3TC (lamivudine) to AZT plus ddI, and to ddI alone. The Institute also is planning clinical trials of protease inhibitors in pediatric AIDS patients.
HIV disease is the fifth leading cause of death among children younger than 15 years in the United States, according to the National Center for Health Statistics. An estimated 12,000 children in this country are infected with HIV.
ACTG 152 was co-chaired by Carol J. Baker, M.D., and Janet Englund, M.D., both from the Baylor College of Medicine in Houston. Bristol-Myers Squibb provided the ddI and the Burroughs Wellcome Co. (now Glaxo-Wellcome) provided the AZT for the study.