Ann J Melvin
Infectious Diseases Specialist
University of Washington
In the same way as adults, children infected with HIV-1 have benefited significantly from the introduction of potent combination antiretroviral (ARV) therapy.(1,2) In countries with access to ARV therapy, there has been a dramatic decrease in the rate of hospitalisations, opportunistic infections and death among HIV-1-infected children.(3–6) In spite of this success, antiretroviral management in children remains challenging, and there are many barriers that need to be overcome in order to provide optimal long-term therapy for HIV-1-infected children.
The majority of studies of combination antiretroviral therapy in HIV-1-infected children published to date suggest that long-term control of viral replication is difficult to achieve in children treated with standard three-drug highly active antiretroviral therapy (HAART). In some studies, only 30–60% of children achieved suppression of plasma HIV-1 RNA levels to below the limits of detection after 24–48 weeks,(7–9) with young age(10,11) and prior treatment with antiretroviral agents(12,13) identified as risk factors for lack of sustainable virological response. Additional factors contributing to the poorer virological response in infants and children may include their higher viral burdens,(14,15) relatively immature immune systems,(16) unfavourable antiretroviral pharmacokinetics(17,18) and difficulties with medication adherence.
The pharmacokinetic characteristics of many of the ARVs are different in children, with the result that it is not always possible to extrapolate doses for children from adult studies.(18) Protease inhibitors in particular are less well absorbed and require higher dosages than would be predicted based on adult pharmacokinetic studies, particularly for younger children (eg, nelfinavir,(17,19) atazanavir(20)). Low drug levels resulting from insufficient dosing may partially explain the poor virological response to nelfinavir seen in some studies.(21) Increased oral clearance rates also result in the need for higher dosages in young children for some antiretrovirals (eg, nevirapine [NVP](22) and lamivudine(18)).
Therapeutic drug monitoring has been advocated as a useful tool to optimise antiretroviral drug levels in children.(23)
Strict adherence to the prescribed antiretroviral regimen, shown to be crucial to achieve sustained virological suppression in all populations,(24–26) is particularly challenging in young children. In addition to the usual barriers to adherence,(27–29) the volume and lack of palatability of the liquid formulations and the size and number of the capsules/tablets make actual administration of the medications difficult, thus increasing the potential for parent/child conflict. Liquids are also less portable, making it hard when families are not at home at the time of medication administration. Adherence may be improved by tailoring regimens to the families’ schedules, and providing adequate education about the medications, their side-effects and the risk for development of viral resistance when missed doses result in inadequate drug levels.
When administration of the medications is particularly problematic, gastrostomy tube placement for drug administration has been shown to be safe and effective.(30) Frequent contact with the family after initiation of a new regimen may provide encouragement to the family and an opportunity for timely intervention if problems are identified (see Resource).
Latest drugs in development
Many perinatally infected children were treated with sequential mono and dual nucleoside reverse transcriptase inhibitor (NRTI) therapy before the availability of the protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The resulting exposure to multiple ARVs, in addition to the difficulties with adherence, has led to the development of extensive viral resistance in many children.(31,32) A lack of access to new ARVs makes constructing effective salvage regimens for these children problematic. Frequently, licensing of new ARVs for children has lagged significantly behind adult licensing for the same agents, thereby limiting access for children to new, potentially effective ARVs. For example, tenofovir DF was licensed for adults in 2001, but due to concerns regarding potential effects on bone mineralisation the drug does not yet have a paediatric label. For other drugs, such as saquinavir, licensed for adults in 1995, development of a paediatric formulation has not been possible. New protease inhibitors such as tipranivir, although in phase III adult trials, are only now entering paediatric trials.
Overall, antiretrovirals appear to have similar safety profiles in children and adults. The major toxicities associated with each class of agents have been demonstrated in children with frequencies similar to that observed in adults.(33–35) Hyperlipidaemia is seen frequently in children, particularly those treated with protease inhibitors,(36) although the incidence of lipodystrophy may be lower.(37,38) Data are emerging to suggest that the development of lipodystrophy may be affected by pubertal status,(36,39) raising the possibility that the prevalence of lipodystrophy will increase as children age into adolescence. In addition, as HIV-infected children move into adolescence and adulthood, there is concern that long-term toxicities of ARVs will become more apparent, particularly the development of diabetes, cardiovascular disease and osteoporosis.(40)
Expanding access to ARVs to countries around the world has separate challenges for children. An increasing number of infected infants have been exposed to NVP for prevention of mother-to-child transmission (PMTCT). Although the data are limited, NVP resistance mutations have been found in more than 40% of infants HIV-infected in spite of perinatal NVP.(41) Since the NVP resistance mutations fade over time,(41) the significance of these mutations for future response to NVP treatment is not known. However, data in postpartum women suggest that the effectiveness of NVP in a subsequent treatment regimen may be decreased.(42) Lack of affordable paediatric formulations is a major barrier to expanding ARV therapy to children in developing countries. New generic fixed-dose combination tablets in usage worldwide are not appropriate for most children, and few companies marketing generic ARVs are providing liquid formulations.
Guidelines for antiretroviral treatment of HIV-1-infected children have been developed, in Europe by the Paediatric European Network for Treatment of AIDS (PENTA)(43) and in the USA by a working group established by the National Institutes of Health (NIH) and the Health Resources and Services Administration (HRSA).(30) General recommendations for the initiation of antiretroviral therapy are based on estimates of short-term risk of disease progression by age, immunological and clinical status.(44)
Special consideration should be taken for the decision regarding the initiation of treatment in infants. There are currently no parameters that reliably predict HIV-1 progression in infants, and infants are at risk of rapid HIV disease progression, particularly central nervous system decline.(45) Thus, many experts recommend initiating therapy in all HIV-1-infected infants less than 12 months of age. There are few trial data available in children to guide choice of initial antiretroviral drug regimen. PENPACT 1, a PENTA and Pediatric AIDS Clinical Trials Group joint trial addressing this question, is currently in progress.(46) A summary of all formulations currently available for children is given in Table 1.
HIV-1 infection in children has become a chronic yet manageable disease. The goal of ARV therapy in children is to maintain immunological and clinical health to allow children to grow into adulthood.
Addressing many of the issues discussed above will be necessary for the development of effective long-term ARV treatment strategies in children. Paediatric clinical trials investigating new antiretroviral agents and treatment strategies will be crucial to the continued virological success of antiretroviral therapy and ultimately to the health and wellbeing of HIV-infected children worldwide.
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Guidelines for the use of antiretroviral agents in pediatric HIV infection (HRSA, NIH)