June 1999
CHICAGO - In children younger than 2 years of age with HIV, potent antiretroviral therapy should be initiated as close as possible to the time of acquisition of infection to control viral replication for the long term. While recent studies show this course of action may be effective to slow down viral replication, there are some drawbacks to be considered, including a reduction of HIV-specific immune response.
"Recent trials of antiretroviral combination therapy in infants and children have provided an improved understanding of the pathogenesis of pediatric HIV-1 infection," said Katherine Luzuriaga, MD, at the 6th Conference on Retroviruses and Opportunistic Infections here.
Luzuriaga, associate professor of pediatrics, University of Massachusetts Medical Center at Worcester Pediatrics and Molecular Medicine, Worcester, Mass., reviewed state-of-the-art pediatric antiretroviral therapy.
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As of this year, 11 antiretroviral agents have been extensively evaluated in children. Of these, nine agents are available in liquid formulations and are approved for pediatric administration.
The availability of these antiretroviral agents, along with recent improvements in molecular techniques to measure viral load, has allowed the design of clinical trials to further probe the pathogenesis of HIV infection, she noted.
The current understanding of pediatric HIV infection suggests that the long-term suppression of viral replication is essential to allow long-term survival, prevention and reversal of clinical symptoms, and the preservation and restoration of immune functions.
The effective suppression of viral replication during the acquisition of infection in early infancy has been associated with normal growth, maintenance of normal peripheral blood CD4 T-lymphocyte counts for age, lack of expansion of activated T-lymphocyte populations, and maintenance of the naive peripheral blood CD4 T-lymphocyte pool, according to Luzuriaga.
"Over the past year and a half several groups have worked to examine the kinetics of viral replication and the source of replicating viruses," she explained. "These studies have been primarily carried out in the context of early therapy protocols - that is protocols that have administered potent combinations of antiretroviral regimens to infants and children younger than 2 years of age."
These regimens have consisted of regimens of combinations that targeted reverse transriptase, such as zidovudine (AZT, Retovir, Glaxo Wellcome) lamivudine (3TC, Epivir, Glaxo Wellcome) and nevirapine (Viramune, Roxane Laboratories), AZT/3TC/nevirapine and 1592 Revapavir, and other regimens that have mixed transcriptase inhibitors such as AZT or stavudine (d4T, Zerit, Bristol-Myers Squibb) with 3TC and ritonavir (Norvir, Abbott Laboratories) or nelfinavir (Viracept, Agouron Pharmaceuticals).
"All together these data, from a small number of children, suggest that using several different regimens, good short-term control of viral replication can be achieved," Luzuriaga said.
These data also suggest that at least the short-term ability to clear the virus following the initiation of one regimen that targets just reverse transcriptase and another regimen, that included a protease inhibitor is approximately similar, she added.
While the majority of these data were obtained in infants and children younger than 2 years of age, some data are available for older children. The data in older children suggests the kinetics of replication of older children are similar to the kinetics in young babies.
While collectively the data suggests that following the initiation of potent antiretroviral therapy researchers were successful in controlling viral replication, the success is not without ramifications. "By controlling viral replication we appear to have removed the stimulus for the development of HIV specific immune response," Luzuriaga explained.
In a study of 19 infants who initiated potent antiretroviral combinations prior to 3 months of age and who received therapy for a minimum of 48 weeks, 12 children or 63%, experienced an apparent control of viral replications.
"An examination of their immune systems has also provided further evidence for control of viral replication. All 12 infants had high titers to HIV specific antibodies prior to the initiation of therapy. They all began to lose antibodies over the first year of life. This is in contrast to the continued detection of HIV specific antibodies in babies in whom viral replication was not suppressed on the identical regimen," she reported.
The lack of HIV specific response is a concern because the antiretroviral therapies do not eradicate the virus.
Combination antiretroviral therapy has changed the natural history of HIV infection in children. "However, whether we are truly going to be able to shift the paradigm of pediatric infection from a rapidly progressive, uniformly fatal infection to that of a controllable chronic infection remains to be seen," Luzuriaga said.
To better understand the potential for long-term success more research to understand the pathogenesis of pediatric infection is needed. New studies are currently underway to further investigate potential reservoirs and cellular sources of viral replication.
Researchers expect these studies to further clarify findings regarding viral replication and HIV specific immune response as early as next year, she said.
For more information:
- Luzuriaga K. State-of-the-art lecture pediatric antiretroviral Therapy. 6th Conference on Retroviruses and Opportunistic Infections. Jan. 31-Feb 4. Chicago.
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