Q: Besides differences in drug dosing, why are special antiretroviral guidelines needed for children? Why is treatment recommended for all infected children under age 12 months?

A: One of the most important differences between HIV infection in adults and children relates to the mode of HIV acquisition. Most children are infected through mother to child transmission. This means that infection is acquired at a time of immunologic immaturity, resulting in less ability to control HIV replication. As a consequence, HIV RNA copy number in children reach very high levels by one month of age, and these high levels persist for a prolonged period, until several years of age. HIV disease progresses more rapidly in children than adults, with ~20% of children developing AIDS or death by age 2 years. Because HIV infection in most children is acquired near to or during the time of birth, with early diagnosis of infection, it is possible to be able to initiate antiretroviral treatment during early primary infection. Initiation of aggressive antiretroviral therapy during this early period of viral replication could theoretically diminish viral dissemination, particularly to the thymus, which is of critical importance in the immune development of the neonate, thereby preserving immune function, lowering the viral set-point, and resulting in improved clinical outcome. This is why initiation of therapy is recommended for all children under age 12 months regardless of virologic, immunologic or clinical status.

Q: The benefits of early aggressive therapy in children were stated as theoretical. Are there any data now to show that such early initiation of therapy provides an actual benefit to the infant?

A: Two clinical trials, PACTG 356 and 345, are evaluating early initiation of protease-inhibitor-containing combination therapy with 3 or 4 drugs in young infants. Preliminary data from these studies indicate excellent virologic response in most infants, with drop in HIV RNA to levels below quantification and in some cases HIV antibody seroreversion to HIV-antibody negativity, although HIV DNA PCR remains positive. PACTG 356, is evaluating early initiation of protease-inhibitor-containing combination antiretroviral therapy with 3 or 4 drugs in HIV-infected children aged 15 days to 2 years. Regimens studied in over 50 infants include ZDV/3TC/nevirapine (17 children), ZDV/3TC/nevirapine/abacavir (18 children), and d4T/3TC/nevirapine/nelfinavir; approximately 25 initiated therapy at under age 3 months. All regimens have shown excellent antiretroviral activity. In 15 infants who started therapy at under age 3 months, HIV RNA levels have been maintained at levels <50 copies/mL for >48 weeks, with preservation or restoration of CD4 cell numbers, including naïve CD4 cells, and reduction in the CD8+/DR population. All but 3 infants became HIV seronegative, with negative cultures and labile episomal replication intermediates, and HIV-specific cellular immune responses have not been detected [Luzuriaga K et al. Early therapy of vertical HIV-1 infection: evidence for cessation of viral replication and absence of virus-specific immunity. 7th Conference on Retroviruses and Opportunistic Infections, Jan-Feb 2000, San Francisco, CA, Abstract 211]. These results are consistent with the notion that early combination antiretroviral therapy may lead to cessation of viral replication and thus impact on the establishment of infection.

Q: What about difficulties with the ability of caregivers to administer complicated regimens to very young infants?

A: The guidelines acknowledge the importance of adherence to the prescribed regimen to avoid development of resistance and treatment failure. This is especially important when initiating possible life-long therapy at a very young age. The guidelines recommend that a comprehensive assessment of adherence issues be completed before treatment is started, with education of the caregivers regarding the critical importance of adherence. This assessment needs to be individualized for each family, with identification of potential specific barriers to adherence for that family, and development of a multidisciplinary approach with support services to address these barriers. It is better to delay initiation of treatment until the provider feels that the caregiver is comfortable with providing the regimen than to initiate therapy, only to have resistance develop due to inconsistent drug administration.

Q: What about the availability of drugs for young infants?

A: Young infants require liquid formulations of drugs that are palatable and can be given without major adjustments in dosing related to meals. Additionally, the pharmacokinetics of drugs in infants differs significantly from older children and may rapidly change as they age, so specific studies in young infants are needed to determine drug dosage. Drugs available in liquid formulation appropriate for infants include the NRTIs AZT, ddI, 3TC, d4T, and abacavir; the NNRTI nevirapine; and the PIs nelfinavir, ritonavir, and amprenavir. Specific dosing adjustments must be made for administration to infants under age 3 months. However, phase I studies to provide definitive recommendations for dosing during the first few months of life are completed only for AZT and 3TC, although studies are ongoing on most of the other drugs. Specific guidelines for the individual drugs based on published data or ongoing clinical trials are provided in the appendix of the guidelines. Importantly, ongoing studies of the protease inhibitors nelfinavir and ritonavir in young infants have recently indicated that significantly higher doses may be required to achieve adequate drug levels. Because lower doses provided poor drug levels, PACTG 356 is now studying nelfinavir at a dose of 55-65 mg/kg twice daily for infants 15 days and older, and PACTG 345 is studying ritonavir at a dose of 450 mg/meter squared of body surface area every 12 hours. There is no pharmacokinetic data on amprenavir in young infants and the liquid formulation has a high concentration of vitamin E and propylene glycol, thus administration is not recommended in children under 3 years.

Q: What is considered virologic failure in children?

A: Perinatally-infected infants generally have higher HIV RNA levels that persist for longer periods of time than infected adults; as a consequence, achieving maximal virologic suppression may be more difficult among young children, and the time to maximal suppression may be longer than observed in adults. The available data suggest that HIV RNA levels over 100,000 copies/mL are significantly associated with high risk of disease progression and mortality, particularly when the CD4 count is very low (<15%). In children aged 30 months or older, the risk of disease progression appears to significantly increase when HIV RNA levels are >15,000 copies/mL, similar to studies from infected adults. The goal of therapy in children, as in adults, is to achieve viral suppression to levels below assay quantitation. However, it is recognized that clinical benefit may be observed with decrements in HIV RNA that does not reach undetectable levels. While change in treatment regimen may be considered if HIV RNA is not suppressed to undetectable levels after 4-6 months of treatment, the initial level of RNA at the start of therapy and the level achieved with therapy should be considered when contemplating drug changes, particularly because of the limited availability of alternative drugs for children. For example, some experts would not feel an immediate change in therapy was warranted for a child who had very HIV RNA levels and have a 1.5-2.0 log drop in RNA copy number as long as the RNA drop is sustained, even if the RNA levels remain detectable at low levels as long as the levels are <10,000 copies/ml. At least 2 RNA measurements obtained more than 1 week apart should be performed before considering a change in therapy.

Q: Should antiretroviral drug resistance testing be used in children?

A: The newly updated guidelines (August 8, 2001) now have a new section on resistance testing that describes the types of assays available and issues related to each assay. The value of using phenotypic or genotypic assays in guiding treatment in children has not been established, and it was felt that specific recommendations for use of resistance assays for directing antiretroviral drug choice cannot be made at this time, although pediatric studies to evaluate this are planned. If resistance testing is used to determine the contribution of resistance to drug failure, it is important that the assays be done while the child is still receiving the antiretroviral drugs, as in the absence of treatment, wild-type virus is likely to replace resistant strains and mask the presence of resistant virus. While the presence of resistance to a particular drug suggests the drug will be unlikely to suppress viral replication at normally achieved drug levels, the absence of resistance does not insure that its use will be successfully, as cross-resistance can occur. Consultation with an expert in HIV disease in children is recommended to assist in interpretation of these assays when they are used.