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No Evidence of Virologic Benefit With Higher Lopinavir Dose for Children
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
A higher lopinavir/ritonavir dose, preferred by certain pediatricians because some evidence suggests a virologic benefit over a lower recommended dose, yielded no response advantage in an analysis of 160 children in the UK/Irish Collaborative HIV Paediatric Study (CHIPS) [1]. Guidelines call for a target total daily dose of 460 mg/m(2) of ritonavir-boosted lopinavir for children taking the protease inhibitors (PIs) without a nonnucleoside and 600 mg/m(2) for children taking the PIs with a nonnucleoside. But some pediatricians aim for the 600 mg/m(2) target even without a nonnucleoside because of a perceived antiviral advantage with the higher dose.
To determine how often British and Irish clinicians use which dose--and whether the higher dose truly yields a virologic edge--CHIPS investigators studied 311 children who took lopinavir/ritonavir without a nonnucleoside. Sixty-seven children (22%) started lopinavir/ritonavir as part of their first multidrug regimen, 37 (12%) as a substitution in a first-line regimen, 129 (41%) in a second-line regimen, and 78 (25%) after earlier single- or double-nucleoside therapy. Median age when children began lopinavir measured 9.0 years (interquartile range [IQR] 5.1 to 12.1), and 124 children (40%) had AIDS when starting lopinavir.
Clinicians recorded doses in 299 children, giving 52% of the doses as syrup, 38% as capsules, and 10% as tablets. Only 3% of doses were taken as a once-daily dose. The investigators could calculate lopinavir mg/m(2) in 278 of these 299 children. Only 6% of these doses fell more than 10% below the 460-mg/m(2) target and only 9% reached more than 10% above the 600-mg/m(2) target. The biggest proportion of doses, 46%, lay between 410 and 530 mg/m(2), while 39% lay between 530 and 660 mg/(2).
For a 10-year-old of average weight and height and without an AIDS diagnosis, the lopinavir target achieved with twice-daily capsules or tablets averaged 546 mg/m(2). Dosing varied widely from center to center, with some centers clearly favoring the lower target and others the higher. Gender, calendar year, prior PI use, or most recent CD4% did not correlate with current dose.
Of the 278 children whose lopinavir mg/m(2) could be figured, 160 (58%) had (1) a viral load above 1000 copies in the 6 months before starting lopinavir/ritonavir, (2) a lopinavir dose calculated in the first 3 months of lopinavir therapy, and (3) a recorded 6-month virologic response. In that subgroup, 28% had a 6-month load below 50 copies, 68% below 400 copies, and 73% below 1000 copies. The median dose for these 160 children stood at 524 mg/m(2) (IQR 468 to 599). While 7% lay more than 10% below the 460-mg/m(2) target, 11% lay more than 10% above the 600 mg/m(2) target.
An analysis factoring in pre-lopinavir viral load and age turned up no evidence that initial lopinavir dose correlated with an improved virologic response (below 50 or 400 copies) after 6 months of therapy. Nor did initial dose correlate with improved sub-400 copy response over longer follow-up in an analysis adjusting for age at viral load measurement, treatment center, and child-specific random effects. This model did find an 18% lower odds of attaining a sub-50-copy load with every 50 mg/m(2) higher dose (odds ratio 0.82, 95% CI 0.73 to 0.91, P < 0.01). But this result was driven by doses over 600 mg/m(2) , probably prescribed for children with more antiretroviral experience or with an actual or perceived risk of poor adherence.
The CHIPS team noted that "an unintended consequence" of uncertainty over appropriate lopinavir dosing "means that the vast majority of children were above minimum recommended dose," in contrast with most other antiretrovirals prescribed for children. The investigators are now analyzing how higher doses affect toxicity.
Reference
1. Walker AS, Boyd KL, Doerhold K, 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, November 9-13, 2008, Glasgow. Abstract O122.
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