Dosing of lopinavir/ritonavir in the CHIPS cohort
18 February 2009. Related: Conference reports, HIV 9th Glasgow 2008.
Polly Clayden, HIV i-Base
Sarah Walker from the Medical Research Council presented data from the UK/Irish Collaborative HIV Paediatric Study (CHIPS) cohort looking at paediatric dosing of lopinavir/ritonavir (LPV/r). [1]
Dr Walker explained that the licensed LPV/r paediatric daily dose is 460 mg/m2 without, and 600 mg/m2 with concomitant NNRTI therapy. The 460 mg/m2 dose without NNRTIs was chosen in preference to 600 mg/m2 in a post hoc drug-interaction analysis [2]. Following the completion of the phase II trial, this post hoc analysis revealed a significant interaction between NNRTI and LPV/r, leading to the lower dose being licensed for use without NNRTI. The phase II trial showed very good viral load data overall, with 79% of children <400 copies/mL at 48 weeks, but this was based on the higher 600 mg/m2 dose. Because of this uncertainty some paediatricians prefer to prescribe the higher dose of LPV/r irrespective of concomitant NNRTI therapy.
In the CHIPS study the investigators evaluated the LPV/r doses prescribed without NNRTIs in the cohort from 2000–2007.
They looked at predictors of current dose, including sex, VL and CD4, age, CDC stage, height/weight-for-age, calendar year, formulation, frequency and previous PI use, using mixed models allowing child and hospital effects.
They also evaluated the impact of the LPV/r dose on viral load suppression 6 months after starting it using logistic models and over longer follow up using binomial mixed models.
Dr Walker reported, 311/1,336 (25%) children in the cohort had received LPV/r without an NNRTI; for a total of 654 child-years. Of these children, 238 (77%) were still on LPV/r when they were seen last.
The median age of the children at initiation of LPV/r was 9 (IQR 5–12) years. The investigators recorded 684 doses in 299/311 children of which 52% were syrup, 38% capsules and 10% tablets. 662 (97%) doses were taken twice daily.
Overall the dose/m2 could be estimated 2,748 times in 278 children (the remaining children did not have height/weight recorded). They found few (7%) doses were >10% below the 460 mg/m2 target, and few (9%) >10% above the 600 mg/m2 target, with the majority >410–<530 mg/m2 (46%) or >530–<660 mg/m2 (39%).
In a multivariate analysis, the investigators found doses were: 17 mg/m2 [95%CI 0–34], higher in children who had prior CDC C event, p=0.05; 2 mg/m2 [0–3] higher for every log10 higher VL, p=0.02; 48 mg/m2 [38–58] higher with capsules/tablets vs syrups, p<0.001; 22 mg/m2 [4–40] higher with twice- vs once-daily dosing, p=0.02; 19 mg/m2 [15–24], p=0.001, and 10 mg/m2 [6–14], p<0.001 higher for every one unit lower current weight- and height-for-age, respectively; and 9 mg/m2 [5–14] higher for every year younger over 10, p<0.05.
Dr Walker noted that the mean dose for a 10 year old, without prior CDC event, average weight and age for height receiving capsules or tablets was 546mg/m2. She also noted that dosing varied greatly by centre with some using higher and some lower doses.
The investigators found no evidence that the initial LPV/r dose was associated with significantly improved viral load suppression at 6 months and reported: <400 copies/mL, AOR=1.06 per 50 mg/m2 (95%CI 0.87-1.28), p=0.58; <50 copies/mL, AOR=0.81 per 50mg/m2 (95%CI 0.65-1.01), p=0.06.
The investigators concluded: “Doses were higher with capsules/tablets, likely reflecting over- rather than under-dosing when solid formulations cannot achieve exact doses. However, we found no clear evidence that higher doses improved VL suppression.”
Dr Walker added: “Opinion seems to be split as to the most appropriate LPV/r dose in children.”
References:
- Walker AS et al. To overdose or underdose? The question of Kaletra in children in the UK/Irish Collaborative HIV Paediatric Study (CHIPS). 9th International Congress on Drug Therapy in HIV Infection , Glasgow. November 2008. Abstract O123.
http://www.jiasociety.org/content/11/S1/O8 - Saez-Llorens X, et al.: Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2003, 22:216-224.