The results of this study show that doses of LPV/r higher than those currently approved by the FDA are safe and well tolerated for up to 48 weeks in children and adolescents with HIV infection. There were no significant GI problems except in subjects with preexisting diarrhea. There was no significant increase in plasma triglycerides, and while there was an initial statistically significant increase in cholesterol, this was of modest size and did not worsen over the course of the study. There was no evidence of hepatic or cardiac toxicity with these higher doses. For those subjects who moved to step 2, there was no added toxicity with SQV in the regimen.
These higher doses of LPV/r resulted in drug exposures only slightly lower than those in adults treated with 667/167 mg of the LPV capsule twice daily (Kaletra product label; 15
). That LPV dose directly scaled for BSA (adult dose in mg/adult BSA, or 667 mg/1.73 m2
) would have been 385 mg/m2
for subjects not concurrently treated with an NNRTI. Our target dose was somewhat higher (400 mg/m2
) since the directly scaled pediatric dose has previously been shown to result in drug exposures lower than those in adults (36
). The target dose for subjects concurrently treated with NNRTIs was 480 mg/m2
, chosen to compensate for the higher LPV CL induced by NNRTI (3
). The actual administered doses were as high as 433 mg/m2
(14.8 mg/kg) and 487 mg/m2
(17.4 mg/kg) in group 1 and group 2, respectively, which were well tolerated by study subjects. While we found an NNRTI effect on LPV CL similar to that suggested by prior studies (17
), our study did not show the age and gender difference in CL identified by those investigators, perhaps because of the small size of this cohort.
We found diurnal variation in the LPV plasma concentration, with higher concentrations in the morning than in the evening. This pattern of diurnal variation has been identified by other investigators for RTV (14
) and other protease inhibitors (19
) and is postulated to result from reduced hepatic blood flow during sleep or changes in the plasma lipid concentration during the overnight fast which may alter the rate of drug absorption or CL. It is possible that the diurnal variation found in this study is accentuated by the use of higher doses of LPV.
The dose of SQV chosen for this study is higher than the directly scaled adult dose (1,000 mg/1.73 m2
= 578 mg/m2
) but was chosen because prior studies of SQV in children had suggested high oral CL (1
). Our subjects had higher SQV exposures than adults treated with SQV and standard doses of LPV/r, which is perhaps from the higher doses of LPV/r used in this study. Based on predetermined PK criteria, the SQV dose was decreased in three subjects and increased in one. The three subjects with higher SQV exposures had no evidence of drug-related toxicity.
While this study showed a trend toward improved virus load response in subjects with higher IQs (Table ), the enrolled subjects had failed many prior ARV regimens and had such a large change in their level of resistance to LPV prior to study entry (Table ) that the achievable IQ was quite low for most enrollees despite higher LPV concentrations. Even so, the CD4 cell count rose for the first 32 weeks of the study (Fig. ), and the virus load was statistically significantly lower than baseline through study week 16.
LPV/r was useful in other studies of ARV therapy for children who failed many prior regimens (7
), and the results of the current study suggest that higher doses might be helpful for some patients in that setting. The addition of SQV might further enhance the efficacy of salvage therapy for patients who had previously failed multiple ARV regimens (1
). In this study, subjects treated with NNRTI in addition to LPV/r and SQV had better virologic (Fig. ) and immunologic (Fig. ) responses to therapy, arguing that in the presence of a large change in the level of resistance, the addition of active drugs to a regimen may have a bigger impact on outcome than intensifying a regimen by using higher drug doses. Other new drugs (e.g., darunavir, tipranavir, maraviroc, raltegravir, etravirine, and enfuvirtide) might also offer appropriate options for salvage therapy when there is adequate PK information on dosing in children.
Adherence was difficult, as the regimen included a high pill burden. There were early dropouts for nonadherence, and there was difficulty with adherence for subjects staying on the study. In addition, the lack of a liquid formulation of SQV further enhanced the complexity of the regimen. These factors may have contributed to the poor viral load response seen in this study, although the high baseline resistance is an important consideration in explaining the persistence of detectable viremia (7
LPV/r was initially developed in capsule and liquid formulations. The liquid is still available, but the capsule has been discontinued and replaced with a tablet produced with a proprietary melt extrusion technology (21
). Absorption of the tablet is less dependent on meal conditions, and drug exposures are more uniform with the tablet than the capsule formulation (21
). This study was performed using the liquid or the capsule formulation of LPV/r. Drug exposures using the tablet formulation might be somewhat less variable than those found in this study.
This study was initially designed to enroll 48 subjects and have the statistical power to show improvement in virus load over 48 weeks of treatment. However, enrollees had very high levels of resistance to LPV, and therefore, the changes in virus load were less robust than anticipated. Study enrollment was therefore stopped early, when we had accumulated enough data to report accurate data on the PK and safety of high-dose LPV and SQV.
This study shows the safety of LPV/r when used at doses as high as 400/100 mg/m2/dose orally (p.o.) q12h and 480/120 mg/m2 p.o. q12h when combined with an NNRTI and also shows the safe addition of SQV to these high doses of LPV/r. This offers useful options for salvage ARV regimens for the treatment of children and adolescents who may have failed prior therapy, but the limited virologic response and the challenge of adherence to a regimen with a high pill burden may limit its usefulness since other ARVs are available for use. In addition, these higher doses identify a clearly safe “upper bound” to weight band dosing algorithms, an important consideration as LPV/r is used more widely in second-line regimens around the world.