Preliminary results of the study, which was terminated early, indicate that combination antiretroviral therapy should be the preferred initial treatment for symptomatic HIV-infected children, particularly those under 3 years of age, who have never been treated with anti-HIV drugs. In many cities in the northeastern United States, HIV disease is the leading cause of death among children ages 2 to 5.
"These results provide new hope for young children who develop symptomatic HIV disease. The preliminary results of this study clearly demonstrate that combination therapy can significantly slow disease progression and reduce the risk of death in HIV-infected infants and children, as is the case in adults," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which supported the study along with the National Institute of Child Health and Human Development (NICHD).
On June 18, 1997, an independent Data and Safety Monitoring Board (DSMB) reviewed preliminary results of the study, known as AIDS Clinical Trials Group (ACTG) 300, and recommended that enrollment be stopped early and that the study be closed. The DSMB based this recommendation on the obvious improvement in clinical benefits conferred by the combination regimens over ddI monotherapy, which had been shown earlier to provide significant clinical benefits in a similar population of children. For example, the DSMB found that the AZT/3TC combination treatment decreased the risk of death by 80 percent relative to ddI treatment alone.
"The dramatic reduction in disease progression and death noted with the combination regimens was most evident in the group under age 3," says Ross McKinney, M.D., of Duke University Medical Center in Durham, N.C., protocol chair of ACTG 300. He adds, "The findings increase the urgency to explore the effects in young children of more intensive combinations that include protease inhibitors."
Two protease inhibitors, nelfinavir and ritonavir, were recently approved for treating HIV-infected children. Several studies using protease inhibitors in combination with other antiretrovirals are being conducted by the Pediatric AIDS Clinical Trials Group (PACTG). ACTG 300 was conducted at 87 centers in the United States: 65 sites and subsites of the PACTG, a clinical network jointly funded by NIAID and the NICHD, and 22 sites supported by Glaxo Wellcome.
A total of 615 infants and children participated in the study; data from 596 of them were included in the preliminary analysis. These included 236 patients on AZT/3TC, 235 on ddI monotherapy and 125 on AZT/ddI. Of the 596, 42 percent were male; 63 percent were black; 22 percent were Hispanic; 14 percent were white; and 1 percent were of other ethnic origin.
ACTG 300, a randomized, double-blind Phase 2/3 study, opened in July 1995. It was initially designed to determine the safety and efficacy of the three regimens of treatment in symptomatic HIV-infected infants and children up to 15 years of age who had received little or no prior antiretroviral therapy. However, in February 1996, another pediatric treatment trial, ACTG 152, found that AZT/ddI and ddI alone conferred similar clinical benefit. Based on these results, the ACTG 300 protocol team decided about a year ago to stop enrollment into the AZT/ddI treatment arm.
Therefore, most of the analyses done on ACTG 300 to date have compared data from the AZT/3TC and the ddI monotherapy groups only. For their analyses, the investigators stratified the participants by age at entry (less than 3 years or equal to or greater than 3 years) because younger children are at greater risk for developing a faster course of HIV disease. About 20 percent of HIV-infected children develop serious disease in the first year of life; most of these children die by age 4 years. Fifty-three percent of the ACTG 300 participants included in the data analyzed were younger than 3 years old.
At enrollment, the patients ranged in age from 42 days and 15 years old. They had symptomatic HIV disease based on criteria developed by the Centers for Disease Control and Prevention (CDC) and had received less than 56 days of prior antiretroviral therapy. The overall median CD4+ T cell count was 728 cells per cubic millimeter (mm3) of blood.
The primary clinical outcomes of the study were disease progression and survival. Disease progression was defined as worsening to CDC Category C classification (clinical AIDS-defining condition or abnormally low CD4+ T cell count), inadequate growth, or deterioration in neurologic and neuropsychologic function.
Initially, children were assigned at random to receive either AZT/3TC, AZT/ddI or ddI alone. Based on the results of ACTG 152, the protocol team stopped accruing patients into the AZT/ddI arm in May 1996, and new enrollees continued to be assigned to either of the other two treatment groups. However, children in all three arms remained on blinded therapy and were followed for study outcomes.
The analyses of the data from children concurrently randomized to all three treatment groups indicated that survival and delay in disease progression were significantly improved for the groups receiving either combination when compared with those in the ddI monotherapy arm.
The two-arm analyses found that AZT/3TC decreased the chance of disease progression, including death, by 70 percent relative to ddI monotherapy. Growth failures and central nervous system deterioration were the most common clinical endpoints reported. The differences between the two groups were primarily due to outcomes in the group of children under age 3 years, where most endpoints (83 percent) and all the deaths (three on AZT/3TC and 15 on ddI alone) occurred. Only nine cases of disease progression occurred in the older group of patients, limiting the conclusions that can be drawn from that study stratum.
The results also revealed differences in changes in CD4+ T cell counts between the AZT/3TC and ddI study arms from baseline to weeks 36-48. Children who received AZT/3TC had a significantly greater increase in absolute CD4+ T cell counts (median 73 cells/mm3) compared with the ddI treatment group (median 4 cells/mm3).
The investigators observed no major differences in the safety or toxicity of the three treatment regimens except for a slight increase in hepatic toxicity in the patients who received ddI. In general, patients tolerated the medications well.
Substudies of ACTG 300, including one evaluating HIV levels in the patients' blood and another monitoring the development of drug resistance, are currently being analyzed. Preliminary data suggest that all treatments reduced viral load below baseline levels but that the combination regimens did so more effectively.
The drugs used in the study were provided by their manufacturers, Glaxo Wellcome (AZT and 3TC) and Bristol-Meyers Squibb (ddI). Glaxo Wellcome also supported the viral load studies.
The findings from both ACTG 300 and ACTG 152 demonstrate that combination antiretroviral therapy significantly slows disease progression and decreases mortality among children with HIV disease. The studies differ, however, as to their conclusions regarding the relative clinical efficacy of ddI monotherapy compared with combination therapy. Reasons for the difference between these two studies are not readily apparent but may be due in part to an increased rate of early central nervous system (CNS) progression endpoints observed in the ddI monotherapy arm of ACTG 300. This might be related to somewhat more sensitive measures used in ACTG 300 to assess CNS progression. In addition, ACTG 300 had a shorter average length of follow-up compared with ACTG 152 (11 months versus 32 months). The protocol team has further analyses under way to better understand the differences between the two studies.
NIAID and NICHD are components of NIH. NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, asthma and allergies. NICHD conducts and supports laboratory, clinical and epidemiological research on the reproductive, neurobiologic, developmental, infectious, social and behavioral processes that determine and maintain the health of children, adults, families and populations. NIH is an agency of the U.S. Department of Health and Human Services.
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