Important note: Information in this article was accurate in April 1999. The state of the art may have changed since the publication date.Presentations on pediatric AIDS at the recent Retrovirus Conference focused on broadening treatment options. Highlighted were studies of anti-HIV therapies, particularly protease inhibitor (PI) containing regimens. While encouraging, studies elicited concerns of adherence and long-term side effects. Few studies dealt with these concerns, but one addressed the use of a surgically inserted feeding tube to improve adherence. Another indicated that children on PI regimens experience changes in cholesterol and other lab markers associated with body composition changes in adults.
Preliminary data from studies using indinavir (Crixivan®), nelfinavir (Viracept®) or ampren-avir (Agenerase®) with two nucleoside analogue reverse transcriptase inhibitors (NARTIs) all showed positive effects on viral load suppression and CD4+ cell count improvements, even among extensively treated children. The durability of the response, however, remains to be seen.
A study evaluating the dual PI regimen approach using saquinavir soft gel capsules (Fortovase®), nelfinavir and NARTIs also showed encouraging results. Seventeen children (median age of five) with a median CD4+ cell count of 600 and viral load of 10,000 HIV RNA copies/mL enrolled. Starting doses of saquinavir and nelfinavir were 33mg per kg of body weight given three times daily. While the short-term anti-HIV activity of the combination looked good, it wasn't much different from what has been seen with single PI regimens. After 24 weeks, 65% of the children had a viral load of less than 400 copies/mL, 47% had HIV levels below 50 copies/mL and CD4+ cell counts increased by about 159. While the regimen was generally well tolerated, the overall benefits compared to single PI regimens have not been demonstrated.
Hydroxyurea (HU, Hydrea®) has been shown to be a useful adjunct therapy to some nucleoside analogue drugs in the treatment of HIV infection. Studies in adults confirm that adding HU to some regimens, especially those containing ddI (didanosine, Videx®), enhances their anti-HIV activity. However, HU suppresses white blood cells in general and then sometimes blunts CD4+ cell increases usually observed with anti-HIV therapy. Therefore, in general it is probably unwise to use HU in people with very low CD4+ cell counts unless other alternatives are lacking. The negative effect HU may have on CD4+ cell counts is likely to be temporary and should stop once it is withdrawn.
A study evaluating HU in combination with ddI and/or d4T suggests that it has similar anti-HIV effects in children as in adults. Sixteen children (median age of 6.7) participated in the 48 week HU dose-escalating study. The initial dose was between 10-20 mg/kg daily, and the final dose was 30 mg/kg once daily. While results were only available through week 16, they suggest that short-term HU therapy is safe and generally well tolerated, with moderate anti-HIV activity and minimal effect on CD4+ cell percentages.
Compared to adults, children appear to have more rapid clearance of HU from their blood, which may mean that children will require higher doses relative to body weight. HU remains of interest to researchers because it offers another mechanism of action against HIV, one unaffected by the development of resistance to other classes of drugs. Another possible benefit shows HU readily penetrates a wide range of cell types, some not easily reached by other drugs.
While these studies point to expanding anti-HIV therapies, more information is needed to determine how to dose these new drugs, particularly in infants and pubescent children. More data are needed to determine the most appropriate time to start or change therapy in the pediatric population.
Adherence issues are important to consider when evaluating the effectiveness of anti-HIV therapy. Dosing schedules, dietary requirements, the amount and taste of medications and children's dependence on adults may influence adherence and present obstacles to effective viral suppression.
One study described a controversial approach to dealing with adherence in kids. Seventeen children (median age of 2.9) receiving anti-HIV therapy had feeding tubes inserted. They were generally well tolerated, with 23% of children experiencing tenderness at the site within the first two months and one case of infection requiring antibiotics. In addition to improved adherence and viral load reductions, there was a reduction in drug administration time and associated behavioral problems, such as resisting efforts to administer the medication.
Feeding tubes have been used in adults and children for nutritional support, but are not widely used because of risks associated with infections, like sepsis. This study suggests that they might be considered for some children to overcome adherence challenges. They may be very useful in situations where the parent or guardian is ill or unavailable, when the child is in school or daycare for long periods of time or in the overall absence of day-to-day stability. However, the increased risk for bacterial infections that can lead to serious, life-threatening complications remains a primary concern.
Protease Inhibitors
Nucleoside Analogue Reverse Transcriptase Inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors
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Changes in the way fat (lipids) is processed (i.e. metabolized) in adults have been noted with the use of PIs. A study examining the effect of PIs on cholesterol metabolism in children showed changes similar to those observed in adults. Pre- and post-treatment cholesterol levels from 82 HIV-infected pre-pubescent children showed a mean increase of 34mg after PI-containing therapy. Cholesterol levels were highest in those children on a combination of ritonavir and saquinavir. The study concluded that PI therapy is associated with significant increases in cholesterol levels.
As with adults, it is unknown if PI-induced increases in cholesterol levels are associated with complications related to cholesterol increases in the general population (e.g. heart disease). These changes in adults are believed to be associated with changes in overall body composition and fat distribution in the body—a syndrome known as lipodystrophy. Little is known or reported on the incidence of lipodystrophy in children. For more on lipodystrophy, see articles above.
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