Advances in Pediatric HIV Research

Despite the recent advancements in perinatal transmission research, the HIV/AIDS epidemic in children is hardly over. Even the most optimistic experts in the field acknowledge that, because women are among the fastest groups of people becoming infected with HIV, trends in perinatal transmission rates are likely to increase once again over time. It is estimated that more than 20,000 children in the United States are infected with HIV. While these children can expect to live longer, healthier lives in the age of highly active antiretroviral therapy (HAART), their treatment options are fewer and much less understood than those available for adults.

Over the past few years, there have been important advances in the diagnosis of HIV infection in children and infants. Until recently, it was difficult to confirm a potentially-exposed infant's HIV serostatus during the first year of his or her life; all children born to HIV-infected women carry their mother's HIV antibodies, sometimes for as long as 18 months after birth. In turn, standard ELISA and Western Blot testing are useless during this crucial time. Considering that nearly 25% of all HIV-infected infants rapidly progress to AIDS during the first year of life, pediatricians for many years had no choice but to aggressively monitor and treat all potentially-exposed infants during this time frame and to simply hope for the best. Now, due to the the increasing availability of PCR technology and other virologic tests, it has become possible to confirm an HIV diagnosis in approximately 95% of all infants during the first month of life.

There has also been much progress made in understanding the natural course of HIV disease in children. HIV-infected children differ from HIV-infected adults in numerous ways. For starters, there is a much more rapid rate of disease progression in children; the average time to an AIDS diagnosis is 8 to 17 months in children, compared to 8 to 11 years in adults. Secondly, normal T-cell counts are significantly higher in children younger than 6 years of age and can fluctuate greatly. Thus, it is much harder to determine when opportunistic infections (OIs) might occur in HIV-infected children and to determine whether or not antiviral treatment or combinations of treatments are yielding the desired effect. Thirdly, HIV-infected children -- possibly due to their high T-cell counts -- have higher viral load levels than those typically seen in adults during the first several years of infection. Finally, HIV-infected children have an increased incidence of recurrent invasive bacterial infections. Moreover, OIs often represent primary disease with a more aggressive course, given lack of prior immunity. For example, an HIV positive child who has never been infected with the chicken pox virus may develop a severe case of chicken pox with initial (primary) infection. In contrast, many OIs in adults are reactivations of latent infections to which some level of immunity may exist. The chicken pox virus, which remains dormant inside of the body after the primary infection, may reactivate in an HIV positive adult or a child who has already had chicken pox, as shingles.

The number of treatments available to children has grown considerably over the last few years. The theory behind treating HIV-positive children is very similar to that of adults with HIV: HAART should be initiated promptly to slow HIV replication and disease progression. Yet, only a percentage of the total number of treatments approved for adults can be given to children, due to lack of pediatric safety data and formulation problems. Although some treatments are available in either a liquid or powder formulation for children, many other drugs are only available in adult-approved tablet or capsule formulas, which cannot be accurately broken down to meet pediatric dosing needs. While viral load has been shown to be an effective method of monitoring antiviral drug efficacy in pediatric patients, researchers have yet to determine exactly when children should start or switch antiretroviral therapy based on viral load results.

The antiviral treatments available in pediatric formulations include: AZT, ddI, d4T, 3TC, ritonavir, and nelfinavir. Glaxo-Wellcome's abacavir (1592) and Boehringer-Ingelheim's nevirapine are expected to be approved and available soon for children. Not surprisingly, many infants and children cannot tolerate many of these drugs (especially the protease inhibitors). Moreover, the majority of these treatments have only been tested in young children without prior antiretroviral experience. As a result, there is no way for antiretroviral-experienced children -- who now account for the majority of children alive with HIV today -- to know whether or not they will benefit from taking any of the other drugs approved or in development. As children get older, they also face dosing problems. For example, an eight or nine year-old child often requires a higher dose of a drug than recommended for infants, but still requires a dose less than that recommended for adults. This is especially true with the protease inhibitors, which require optimal dosing to delay resistance and prolong antiviral activity. Research looking at treatment options for antiretroviral-experienced children is still in its infancy. In turn, pediatricians do not yet have a solid standard-of-care to work from when treating older children with HIV.

Tim Horn is a member of the Pediatric AIDS Clinical Trial Group's Community Constituency Group.

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