Many physiologic differences between children and adults may result in age-related changes in pharmacokinetics and pharmacodynamics. Factors such as gastric pH and emptying time, intestinal transit time, immaturity of secretion and activity of bile and pancreatic fluid among other factors determine the oral bioavailability of pediatric and adult populations. Anatomical, physiological and biochemical characteristics in children also affect the bioavailability of other routes of administration.Key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein binding and total body water. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I and phase II metabolic enzymes. Immaturity of glomerular filtration, renal tubular secretion and tubular reabsorption at birth and their maturation determine the different excretion of drugs in the pediatric population compared to adults.

We explored the associations of the CD4/CD8 ratio with markers of immunoactivation, immunosenescence and T-cell subsets, in 37 vertically HIV-infected children and adolescents. CD4/CD8 ratio inversion was associated with higher frequencies of activated, senescent and activated/exhausted CD4+ and CD8+ T-cells, and a skewed T-cell phenotype from naive toward effector memory which persisted after the multivariate analysis. Thus, the CD4/CD8 ratio may identify patients with higher immunoactivation despite ART.

Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality.

The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/µL compared to those with a CD4 count of 750-999 cells/µL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/µL.

There have been few major advances in paediatric HIV management over the last 2 years. Decisions about starting antiretroviral therapy can now be based on a recent large meta-analysis of the predictive value of CD4 and HIV RNA viral load (VL) in nearly 4000 untreated children, which is discussed in these updated guidelines. Risk estimates for progression to AIDS and death using surrogate markers can now be broken down by age, allowing more accurate discussion with families. In addition, there is increasing recognition of the problems of long-term adherence, drug resistance and cumulative toxicity in adults and children. The controversy over whether to treat asymptomatic infants continues. For older children more data on the efficacy of ritonavir boosted protease inhibitor (PI) regimens suggests that these may be the PI option of first choice. There is still no adult or paediatric trial evidence on which to base decisions about whether to start with PI-or non-nucleoside reverse transcriptase inhbitor (NNRTI)-based regimens, but the PENPACT 1 trial, which is addressing this question, is ongoing. There are increasing moves to provide simpler antiretroviral therapy (ART) regimens, including once daily dosing, but these lag behind adult regimens because of the paucity of pharmacokinetic data. Resistance assays should now be performed in all HIV-infected infants exposed to ART in pregnancy. Therapeutic drug monitoring may be very important in children because of high between-and within-child variability in drug absorption and metabolism. A trial to evaluate this should start shortly in Europe (PENTA 14 trial). The value of resistance tests for choice of second-line and subsequent choices of ART regimens remain unproven (the PERA trial will report late in 2004), but resistance assays are increasingly being used. The issue of when to switch therapy also remains unanswered and is being addressed within the PENPACT 1 trial. Regular formal assessment of adherence is now the standard of care, and routine monitoring in the clinic for lipodystrophy syndrome (LDS) and other ART toxicities is increasingly important. These guidelines will be updated again in 2006.