In this study, we found that doses of 300/75 LPV/r mg/m2
twice daily were safe and effective in HIV-infected infants initiating ART before 6 weeks of age. It is particularly important to understand antiretroviral treatment options for this age group given accumulating evidence that early therapy is associated with superior outcomes. Violari and colleagues4
showed that initiation of ART by 12 weeks of age is associated with significantly improved survival when compared with deferred therapy. The European Collaborative Study found that both initiation of therapy at <5 months of age and use of ART as a first regimen were strongly associated with a more rapid improvement in CD4 count, independent of immunologic and clinical status at initiation.14
Although early testing of newborns has not been readily available in many resource-limited settings, the urgency to start treatment will drive the demand for early diagnosis, increasing the proportion of infants who are initiating ART at a very young age. Furthermore, as late gestational prevention ART regimens increase in potency, the majority of infants who fail perinatal prevention will have been infected in utero
, making their diagnosis possible within the first month of life.3
Thus, if the WHO objective of universal access to ART by 2010 is achieved in the setting of widespread early infant diagnostic capability, thousands of infants in this age group will soon be initiating treatment.15
Due to concerns about NNRTI resistance, protease inhibitors increasingly will be part of the preferred initial regimen in countries where single dose NVP is used for prevention of HIV transmission.5
LPV/r will be one of the first line agent choices in these settings, as it is one of the few protease inhibitors with a liquid formulation currently available.
Young infants in this trial exhibited lower LPV exposure than has been reported in older infants and children. () Several mechanisms may be responsible for this finding including low ritonavir serum concentrations, altered protein binding and poor absorption in young infants. The RTV component of LPV/r is essential for inhibiting LPV metabolism and increasing LPV exposure. The RTV AUC was about half that of older infants and may have led to less inhibition of LPV metabolism.6
However, the half-life of LPV was similar in both age groups, suggesting that enhanced metabolism was not the primary cause for the lower concentrations.
Comparative Pharmacokinetic Data for Lopinavir
Reduced LPV bioavailability (F) is likely the primary cause for the lower LPV exposure in this population. While lower RTV concentrations may have had some impact on LPV metabolism, they could also be a marker for reduced absorption of protease inhibitors rather than the primary cause. Similar increases in CL/F and V/F (80–102%) and the strong correlation between these two measures (Spearman Correlation r=0.72, P=0.02) is consistent with reduced LPV absorption and suggests that bioavailibility is the primary source for intersubject variability. The later LPV peak time in the younger cohort and larger age-related differences in Cmax (4.8 vs. 8.1mcg/mL) compared with Cpre (2.2 vs. 2.4 mcg/mL) also suggests altered absorption processes.6
Bioavailability of many protease inhibitors, including LPV, is increased with food. This characteristic may lead to reduced absorption in infants as has been observed with nelfinavir, which also requires food for optimal absorption.8
During the intensive PK evaluation, the infants in this study were receiving formula as their sole form of nutrition, which may not be optimal for LPV absorption. There was no correlation between volume or timing of formula administration and LPV/r exposure (data not shown). It is likely that the older cohort in this study received cereal and other foods in addition to formula which may have enhanced LPV bioavailability for that age group.
The LPV pharmacokinetic measures in this study were determined from total (bound and unbound) concentrations. Lopinavir is 98–99% protein bound, thus its free fraction is sensitive to changes in plasma binding protein concentrations. Low albumin and alpha-1 acid glycoprotein levels present during the first few weeks of life may have maintained normal, or near-normal, unbound active LPV concentrations despite reduced total LPV concentrations, Reduced LPV plasma binding would increase both CL/F and V/F in parallel as was observed in this study, but it would not have had a differential effect between Cmax and Cpre. While drug binding protein concentrations are expected to be lower in younger infants than older infants, this difference is small and cannot by itself explain the observed differences in the two age groups in LPV AUC.
Another factor contributing to variable drug exposure is suboptimal adherence. Some caregivers found it challenging to administer medications to infants and required time to learn the best technique. Although poor adherence was encountered at the initiation of therapy in a few subjects, the intensive pharmacokinetic evaluation was repeated in these subjects at a time when they exhibited good overall adherence. The LPV concentration profiles in indicate similar C0 and C12 values as would be expected with good adherence.
Despite the lower peak and average LPV exposure in these young infants, the LPV trough was similar to that of older infants and sub-therapeutic troughs (<1 mg/mL) were not frequently encountered. () A plasma concentration of 1 µg/mL still affords a 15-fold margin above the estimated IC50 for LPV, which has been used as a correlate of efficacy in treatment-naïve adults.16
Indeed, virologic response to LPV-based therapy was excellent, with only one of ten infants reaching a virologic endpoint at week 16 and a second experiencing virologic rebound at 24 weeks secondary to poor adherence. This short term efficacy is higher than seen in the older cohort of infants in this study in which only half of the infants had virologic suppression to <400 copies/ml at 24 weeks.6
In addition, entry CD4 percentages were high and remained stable throughout the study, although a normal decline would be expected in the first 6 months of life.17
It is difficult to determine whether the dosage studied in this trial is optimal for all infants less than 6 weeks of age. The 24-week virologic responses with LPV/r 300/75 mg/m2 were promising even in the subjects with lowest LPV concentrations. However, the number of subjects in this study was small, and the long term consequences of low LPV exposure (AUC) are unknown. There was great variability in LPV exposure, with approximately half of the infants in the range found in older infants. A higher LPV/r dose might put these young infants at risk for added toxicity. The one subject in this trial who had the dosage increased based on PK results subsequently required dosage reduction for excessive drug concentrations in serum and possible drug related toxicity. While it may be reasonable to consider initiating therapy with a dosage greater than 300 mg/m2, it would require careful monitoring of serum drug concentrations and toxicity in the setting of a study. Because dosage adjustments were delayed until after PK evaluations were completed in this study, the median doses at the time of the PK studies were >10% below the intended 300/75 mg/m2. One important way to optimize the likelihood of therapeutic LPV dosing is to adjust the dosage for incremental growth at more frequent intervals in the first months of life, during which time the infant experiences rapid weight gain. Long-term follow-up will be important to determine changes in pharmacokinetic profiles over time and longer-term efficacy in this vulnerable population.