This study demonstrates that 94% of infants <6 months of age initiating combination antiretroviral therapy with a high dose of LPV/r (300/75 mg/m2
per dose twice daily) were able to achieve HIV-RNA <400 copies/ml and 66% maintained viral suppression for a median of 123 weeks on cART. This occurred despite low LPV levels at 2 weeks of therapy, with the lowest exposures in infants <6 weeks of age, in whom the median AUC was approximately half of that seen in children >6 months [8
]. However, by 12 months of age, the younger cohort caught up with the older cohort, with comparable median LPV AUCs and similar to the mean (±standard deviation) values for children 6 months to 12 years of age taking 300/75 mg/m2
/dose of LPV/r (116.4±57.1 μg h/ml) and adults taking 400/100 mg/dose LPV/r (92.6±36.7 μg h/ml) [12
]. Longitudinal median predose LPV levels, which were also initially low, increased throughout the study, meeting or exceeding levels similar to mean values reported for older children (6.53±4.57) and adults (7.1±2.9 μg/ml) [12
]. It should be noted, however, that = the LPV dose of 300 mg/m2
used for the duration of the study is higher than the currently recommended dose for children over 6 months of age.
Despite the initially low LPV exposure, the overall virologic efficacy was good with 71% (by ITT analysis) of the combined cohorts having HIV-1 RNA <400 copies/ml at 48 weeks; of note, 80% of the younger cohort achieved virologic suppression during the time when the LPV concentrations were lowest [8
]. This compares favorably with other cohorts of early initiated cART regimens: The Italian Register for HIV Infection in Children reported that 22 of 30 (73%) infants treated under 6 months of age had virologic suppression with a variety of cART regimens, five of whom received LPV/r [14
]. Prendergast and colleagues initiated treatment of 49 South African infants at a median of 42 days of age (range 7–397) with a nelfinavir-based cART regimen and found that approximately 90% had achieved a viral load <400 copies/ml by 24 weeks [15
]. In contrast, more than half of our enrolled patients did not achieve viral loads <400 copies/ml until after 24 weeks. This delay may be due in part to the high median baseline viral load of 5.8 log10
copies/ml, but the slow viral load decline may also be related to initially low LPV concentrations, leaving the two NRTI’s responsible for most of the antiviral activity. This concept may be supported by the observation that patients with a higher percentage of predose concentrations over the target level of 1 μg/ml throughout the study were more likely to have durable suppression, but this correlation could also be explained purely by better medication adherence. Almost all infants in this trial were naive to protease inhibitors and 21 of 21 with baseline genotypes performed had LPV-sensitive HIV strains [11
]. It is unknown whether similar virologic efficacy will be achieved in infants born to heavily pretreated mothers who transmit resistant virus.
Among patients treated for longer than 8 weeks, all achieved HIV-RNA <400 copies/ml and 66% maintained viral suppression for the duration of the study; however, several other infants had periods of confirmed poor adherence with viral rebound to >400 copies/ml. This is consistent with an observational study of 112 HIV-infected children by Giannattasio et al.
] who noted that adherence to antiretroviral therapy is a dynamic phenomenon with individual children gaining and losing adherence over time. In addition, patients taking LPV/r therapy had a significantly higher rate of nonadherence in their cohort than patients taking other agents. Notably, even with periods of poor adherence, our patients’ ability to re-suppress the viral load when adherence improved is encouraging and suggests that LPV/r has a high barrier to resistance.
The median CD4+
T-lymphocyte percentage was stable throughout the study, spanning an age range during which infants generally experience a natural decline in both CD4 percentage and number. Among patients still on therapy, 96% had CD4 >25% at 48 weeks, similar to the Italian cohort of infants treated before 6 months of age, in which 97.5% of patients had >25% CD4+
T-lymphocytes at a median follow-up of 5.96 years [17
]. Furthermore, the median CD8+
T-lymphocyte percentage in our patients remained stably low throughout the study; this finding has been reported in other infants treated before 6 months of age, in contrast to elevated CD8 percentages in patients whose therapy was deferred [14
LPV/r was generally well tolerated with only one patient discontinuing treatment due to complaints of mild vomiting and loose stools [9
]. Patients’ linear growth improved during the course of the study whereas weight Z
scores remained relatively stable. None of the infants in our study reported symptoms of immune reconstitution. In contrast, one-third of a South African cohort of 48 infants initiating therapy <6 months of age developed the immune reconstitution inflammatory syndrome (IRIS); however, all had WHO stage III or IV disease or CD4 <25%, thereby representing a more severely affected group of patients [18
Our patients had a significant increase in nonfasting total cholesterol by 8 weeks which persisted through 96 weeks; these nonfasting values fall into the 75–90 percentiles of fasting serum total cholesterols in US children between 0 and 4 years of age reported in the Lipid Research Clinics Prevalence Study [19
]. Data from normal infants show that cholesterol levels rapidly rise from approximately 70 mg/dl at birth to between 100 and 150 mg/dl during the first weeks of life; thereafter, levels slowly increase to an average of 160–165 mg/dl at 2 years of age [19
]. Our patients progressed through this age range during the course of the study, making it difficult to differentiate the expected rise in cholesterol and the effect of antiretroviral therapy. The National Cholesterol Education Program of the National Heart, Lung, and Blood Institute established abnormal cut-points of total cholesterol for children 2–18 years of age in 1992 which have been adopted by the American Academy of Pediatrics; a total cholesterol level at the 75–95% (170–199 mg/dl) is considered borderline, whereas cholesterol at the 95%, or >200 mg/dl, is considered elevated and should be treated. Although it is widely accepted that atherosclerotic cardiovascular disease (CVD) begins early in life and has both genetic and environmental factors which determine the disease course, data do not exist which correlate a particular level of childhood cholesterol that predicts adult CVD [20
]. The long-term implications of nonfasting cholesterol levels in the range of 170-200 mg/dl in young infants will require more study and focused follow-up. It is interesting that there was no elevation in triglycerides throughout the study, in contrast to that observed in adults treated with LPV/r [21
Recent publications substantiating the benefit of early initiation of antiviral therapy including protease inhibitors combined with superior efficacy among infants exposed to nevirapine for prevention of mother to child transmission suggests that LPV/r will be used more commonly in very young infants [3
]. In many countries, LPV/r is now the standard protease inhibitor used as the initial antiretroviral regimen for infants with a previous exposure to nevirapine [5
]. As the largest database of pharmacokinetics and efficacy among infants treated within the first 6 months of life, this study will help guide dosing and use of LPV/r in this age group. Our study found that the high dose of 300/75 mg/m2
/dose of LPV/r seems appropriate for most infants <6 months of age, especially those who are treatment-naive, however, the lower LPV concentrations observed in the first months of life suggest that studying a higher dose of LPV/r in very young infants should be considered. Although improved drug exposure cannot be guaranteed with higher dosing, especially if there is limited absorption of LPV/r in very young infants, this could also allow investigation of whether more rapid decay of virus could be achieved and have an impact on longevity of viral suppression. Frequent monitoring of young infants receiving LPV/r is advisable, to provide both guidance to the family on successful drug administration techniques and to adjust the dose for weight gain to maintain maximal drug exposure during periods of rapid growth. Careful attention to these details should optimize the early efficacy of LPV/r-based antiretroviral therapy for young infants and build the foundation for prolonged virologic suppression.