CHICAGO - Long the forgotten victims of the AIDS epidemic, HIV-infected children have witnessed steadily improving pediatric antiretroviral therapies. The regimens have cut the number of neonatal and newborn HIV patients in half and controlled virus replication in those already infected.
Combination antiretroviral therapies, just one year ago thought to be out of the question for young children because of potential adverse events, have not only been found to be tolerable in clinical studies but have been adopted into guidelines by the Department of Health and Human Services. Several clinical pediatric studies were presented here at the 5th Annual Conference of Retroviruses and Opportunistic Infections.
Trying to determine the reverse transcriptase inhibitor (RTI) combination therapy that would most effectively suppress HIV viral loads, doctors at the Baylor College of Medicine and the University of Minnesota took 14 HIV-positive children between the ages of 3 and 13 years and gave them saquinavir soft-gel capsules (Invirase, Roche) along with two nucleoside reverse transcriptase inhibitors (NRTI) - stavudine (d4T, Zerit, Bristol-Myers Squibb) and lamivudine (3TC, Epivir, Glaxo Wellcome); stavudine and didanosine (ddI, Videx, Bristol-Myers Squibb); or zidovudine (ZDV, Retrovir, Glaxo Wellcome) and lamivudine.
Dosages were 33 mg three times a day with the children's progress being monitored by researchers for six months. Twelve of the 14 patients had prior NRTI therapy while two never had treatment, said Mark W. Kline, MD, associate professor of pediatric medicine at Baylor College of Medicine.
Overall, the dosages were found to be well tolerated in the young patients. One child with a pre-existing thrombocytopenia was found to have a marked decrease in his platelet count in the fourth week of treatment. But in the other patients, baseline CD4 cell counts and plasma HIV/RNA concentrations were 446 cells/mL and 4.6 log10 copies/mL, respectively. Mean CD4 count increased by 94 cells/mL and mean HIV/RNA concentration decreased by 2.8 log10 copies/mL, with seven of the 14 patient plasma samples below the limit of virus qualification (less than 400 copies/mL) by the eighth week.
"Combination therapy with saquinavir's soft gel formulation really showed excellent results in short-term tolerance and safety in HIV-infected children," said Kline. "Changes in CD4 counts and plasma HIV/RNA concentrations suggested potent short-term antiviral activity."
Doctors at the National Institute of Allergy and Infectious Disease (NIAID) studied 400 children 6 months to 6 years of age with advanced HIV disease who were failing their current antiretroviral therapies. The children received either AZT and ddI, nevirapine (Viramune, Roxane) and ddI or a triple combination of AZT, ddI and nevirapine. Researchers followed them for 48 weeks for laboratory and clinical evidence of disease progression. The drugs were found to be well tolerated with a lower-than-predicted mortality rate based on entry criteria; 5.6% of the patients died during the study, but none of the deaths were attributed to the study drugs, said researchers.
Maximal declines in plasma HIV/RNA levels were seen at the fourth week and were greatest for the three-drug regimen. As in adults, more aggressive antiretroviral therapy was associated with greater reductions in plasma HIV/RNA and presumably clinical benefit. Doctors noted maximal viral load reduction to less than 400 copies/mL was seen in the fourth week of the study.
Combination therapy regimens of AZT, 3TC and nevirapine were introduced over a 16-week period to determine the kinetics of viral replication in 16 treatment-naive, HIV-positive infants and children. Researchers from the Harvard School of Public Health and the University of Massachusetts Medical School found the children's baseline plasma HIV/RNA levels ranged from 10.4 copies/mL to 10.6 copies/mL. Plasma HIV levels fell to less than 400 copies/mL in nine of the 14 infants. Rapid reduction of plasma HIV-1 RNA levels was observed during the first week of therapy, followed by a slower second phase decay.
At the time of the conference, analysis had been completed for only nine of the infants. Analysis of the additional patients is ongoing. Using non-linear regression analysis, the first phase viral decay half-life ranged from 0.34 to 2.24 days and was shorter in infants older than 3 months. The second phase of viral decay appeared to be similar in the two age groups and similar to the second phase in adolescents and adults. The Harvard and University of Massachusetts teams concluded that control of HIV replication was not as rapid for younger children as for older children, a finding they are still exploring.
"We observed potent antiretroviral therapy following our initiation of a triple reverse transcriptase inhibitor regimen," said Katherine Luzuriaga, MD, of the University of Massachusetts Medical School. "We are planning long-term follow-ups to determine the durability of antiretroviral therapy in this group."
One study that could have heavy implications for AIDS treatment in infants is from the University of Alabama-Birmingham, suggesting that zidovudine could actually prevent other AIDS therapies from being fully effective against the virus. Jean-Pierre Sommadossi, MD, professor of clinical medicine at the university said when patients with AIDS were treated with AZT then switched to another NRTI their virus levels were reduced by about half on average. But when other drugs of the same class, like 3TC, were introduced to patients without previous AZT therapy, reductions were to levels at which no virus could be detected.
"There is still much that needs to be asked before we can say for certain that zidovudine limits the effects of other drugs," said Sommadossi. "We'll have to determine what role zidovudine plays in [AIDS treatment]."
For more information:
- Luzuriaga K, McManus M. Early combination therapy of vertical HIV-1 infection: viral kinetics and control of viral replication. Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Feb. 1-5. Chicago.
- Burchett SK, Carey V. Virologic activity of didanosine, zidovudine and nevirapine combinations in pediatric subjects with advanced HIV disease (ACTG 245). Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Feb. 1-5. Chicago.
- Kline MW, Blanchard SA. Phase 1 study of 1592U89 in HIV-infected children. Presented at the 5th Conference on Retroviruses and Opportunistic Infections. Feb. 1-5. Chicago.
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