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Background:  Children failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART need new second-line treatment options. Appropriate dosing and efficacy of dual-boosted protease inhibitor (PI), saquinavir (SQV)/lopinavir (LPV)/ritonavir (RTV) in RTI-pretreated children is unknown. This is the first dual-boosted PI study in children.

Methods:  We planned interim analysis at 24 weeks of an ongoing, prospective, single-arm, open-label study at 2 Thai sites with 20 children with prior virologic failure on NRTI/NNRTI combinations. Children were treated with twice-daily saquinavir (SQV) hard gel capsule 50 mg/kg and lopinavir (LPV)/ritonavir (RTV) 230/57.5 mg/m². Lamivudine (3TC) was added for 10 patients with no M184V. After 10 days to 4 weeks, 12-hour pharmacokinetic assessment by HPLC was performed. Children were then assessed to week 24. Intent-to-treat analysis was used except for pharmacokinetic/pharmacodynamics analysis in which 1 child who was using of rifampicin was excluded.

Results:  Baseline data were median age 8.5 years, 6 male and 14 female, percentage CDC A:B:C 5%:85%:10% and median CD4 percentage (count) 6.5% (129 cells/mm³), HIV RNA 4.9 log₁₀, triglycerides 111 mg/dL, total cholesterol 150 mg/dL. At week 24, 80% and 60% of children had HIV RNA < 400 and < 50 copies/mL. CD4 percentage (count) rose by 6% (216 cells/mm³) (p < 0.01) and HIV RNA fell by –2.5 log₁₀ (p < 0.001). At week 24, more children in site 1 had RNA < 50 than site 2 (7 of 8 vs 5 of 12) due to differences in adherence; use of 3TC did not correlate with RNA reductions. There were significant weight and height gains of 1.5 kg and 2 cm (p < 0.01). Significant rises of triglycerides and total cholesterol were seen with median changes of 56 and 36.5 mg/dL, respectively (p = 0.01); 60% had triglyceride levels ³ 150 and 30% had total cholesterol levels ³ 200. One child had grade 3 gastrointestinal symptoms related to all study drugs. Two children had HIV-related illnesses early in the study. Pharmacokinetic/pharmacodynamics analysis showed LPV C_min > 1 and SQV > 0.28 mg/L to correlate with HIV RNA suppression and LPV C_max > 15 mg/L to correlate with total cholesterol rises > 200 mg/dL.

Conclusions: Dual-boosted PI with SQV LPV/RTV was well tolerated and had good efficacy at 24 weeks. The pharmacokinetic parameters were acceptable. Hyperlipidemia was common and associated with high LPV C_max.

Keywords: Pediatrics; Salvage therapy; Pharmacokinetics