Most children with human immunodeficiency virus (HIV) infection acquire the infection by perinatal exposure. Zidovudine has been the recommended treatment for symptomatic children. Englund and associates conducted a multicenter double-blind investigation of the use of zidovudine, didanosine or both in previously untreated children with HIV infection.

A total of 839 children were assigned to treatment with zidovudine alone, didanosine alone or a combination of both zidovudine and didanosine. Follow-up was performed for a minimum of 104 weeks. Eight children were excluded from analysis because of refusal to participate following randomization or because they had already received more than six weeks of zidovudine therapy. Ninety percent of the children completed the study. The primary end point was the length of time until the first progression of HIV disease or until death. Disease progression was defined as the development of cancer, evidence of growth failure, the occurrence of two or more opportunistic infections, or evidence of two or more abnormalities of the central nervous system.

At the time of entry into the study, 450 (54 percent) of the children were under 30 months of age. Over 90 percent had acquired HIV perinatally. Only 29 children were born to mothers who had received zidovudine therapy prenatally. After the study had been under way for 23 weeks, interim analysis showed that patients receiving zidovudine alone had a relative risk of 0.61 for progression of HIV disease or death, compared with children treated with didanosine alone or combination therapy. Primary end points had been reached by 27 percent of the children receiving zidovudine, compared with 19 percent of those receiving didanosine and 18 percent of those receiving combination therapy. Because of this finding, the study arm with zidovudine alone was discontinued.

At the end of the study, children treated with didanosine alone had outcomes similar to those treated with combination therapy. The median follow-up was 32 months. However, compared with patients who received didanosine alone, those who received combination therapy had a 0.66 relative risk of serious anemia or neutropenia. This difference was primarily due to a lower risk of hematologic toxicity in older children receiving didanosine. A significant difference was not found among younger patients. No laboratory or clinically significant adverse effects necessitated cessation of therapy after the interim analysis.

At four weeks, CD4⁺ counts had increased by a mean of 22 percent in the children receiving combination therapy, compared with an increase of 6 percent in those receiving didanosine alone. This improvement was not sustained, however. By week 96, the mean percentage of change in the CD4⁺ count was similar in the two treatment groups.

In patients who initially tested positive for p24 antigen, the p24 antigen level after four weeks of treatment was 52 percent lower in the combination therapy group than in the didanosine group, but this benefit was not maintained after 24 weeks. Among patients who tested negative for p24 at the time of entry into the study, the length of time until the test became positive was similar in both treatment groups.

The authors conclude that the superiority of didanosine alone or the combination of didanosine and zidovudine over zidovudine alone in symptomatic children with HIV infection is a new and clinically important finding. Although combination antiviral regimens, especially those that include a pro-tease inhibitor, may delay disease progression and prolong survival in adults with HIV infection, their efficacy has not previously been assessed in children. At the present time, the authors recommend didanosine alone as the initial therapy for HIV-infected children who have not previously received antiretroviral therapy.