Newsline

Survival is unaffected, and neutropenia is reduced

Several years ago, a landmark study established the efficacy of what was then regarded as a half-dose of zidovudine (600 mg/day) in adults. That is now the standard dose, and the severe bone marrow suppression that was common among patients taking 1200 mg of ZDV per day is now a distant memory. A similar finding is now reported by the AIDS Clinical Trials Group (ACTG). Over 400 children, ranging in age from 3 months to 12 years, were randomized in a double-blinded fashion to high-dose ZDV (180 mg/m²) or low- dose ZDV (90 mg/m²). Patients, who were symptomatic but without a diagnosis of AIDS, were followed for a mean of 35 months. Investigators were particularly interested in tolerance and neurodevelopmental changes. In addition, they followed survival, clinical parameters, and surrogate markers of disease progression.

Overall, low-dose and high-dose recipients were remarkably similar by all assessments throughout the study period. Neuropsychological deterioration was found to be much more frequent in children under six years of age, but no differences were found between treatment groups. Neither dose showed an advantage in preventing progression to an AIDS-defining condition or overall clinical deterioration. CD4 measurements and viral load assays did not differ significantly between the study arms. Furthermore, there was no difference in survival, which was 89% in each group at four years. The only distinction regarding adverse events was a slightly lower incidence of neutropenia in low-dose recipients. Given the striking similarity between the two groups, investigators speculate that the optimal dose of ZDV for pediatric AIDS patients might even be lower than 90 mg/m². However, they caution that these findings should not be extrapolated to pediatric patients with important CNS disturbances.

Dr. Catherine M. Wilfert, a co-author of the ACTG 128 study and a member of the editorial advisory board of HIV Newsline, comments:

In children as in adults, low-dose ZDV is indistinguishable from high-dose ZDV in therapy-naïve, relatively asymptomatic patients. The potential advantages of low-dose therapy are a reduction in the side effects seen with chronic administration of high-dose ZDV and a reduction in the cost of therapy. At best, ZDV monotherapy -- at either dose -- reduces viral burden in children by roughly 0.5 log. As ACTG 152 has shown us, monotherapy with ddI and combination therapy with ddI-ZDV are better than ZDV monotherapy, as assessed by clinical endpoints. We would predict that more efficient reductions in viral burden, achieved by drugs other than nucleoside analogs, will achieve better therapeutic responses.