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Final results of KONCERT: a randomized non-inferioritytrial of QD vs BD LPV/r dosing in children
Hermione Lyall, KONCERT Trial Team *Imperial College London, London, United Kingdom
Background: Evidence for the efficacy of once daily (QD) ART for HIV-1 infected children/adolescents is limited. Lopinavir/ritonavir (LPV/r) is approved for use in adults once or twice daily, but twice daily (BID) in children. Methodology: KONCERT was a randomized, non-inferiority PENTA trial in Europe, Thailand, Argentina and Brazil. Children (<18 yrs, >15kg) on LPV/r-containing ART with HIV-RNA (VL)<50 c/mL for >24 weeks were randomized to continue LPV/r BID or switch to QD dosing, according to FDA approved body weight-based dosing. Children were followed for minimum 48 weeks, visits at weeks 0, 4, 8, 12 then 12 weekly. The primary outcome was the percentage with confirmed VL>50 c/mL by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin). 26 children (on LPV/r 100/25mg pediatric tablets) in the QD arm had LPV/r pharmacokinetic (PK) measurements at weeks 0 (BID) and 4 (QD). Within-subject ratios for QD versus BID of AUC0-24, Cmax and Cmin were calculated. PK analyses were per-protocol, all others intention-to-treat. Results: 173 children were randomized to QD (86) or BID (87): 46% male, median age 11 (IQR 9-14) years; 25% white, 27% black, 35% Asian; 29% CDC stage C, median time on ART 7.2 years. Median baseline CD4% was 32% (IQR: 27, 36) QD vs 34% (28, 40) BID. Although all children had VL<50c/mL at screening, 12 (14%) QD vs 4 (5%) BID had baseline VL>50 c/mL (IQR: 66, 239). By week 48 (1 QD child lost at week 4), 97% and 98% of time was spent on QD and BID respectively. 12 QD vs 7 BID children had confirmed VL>50 c/mL within 48 weeks; the estimated percentage with VL rebound was 14% QD vs 8% BID: difference 6% (90% CI -2, 14; p=0.2); reducing to 4% (-4, 11) after adjustment for baseline CD4% and VL in a post-hoc analysis. No child died or had a new CDC C event. Two children (BID) had a major PI mutation at VL rebound (L90M, M46I+V82A); 3 QD vs 2 BID children had M184V, 2 QD vs 2 BID developed TAMs. Changes from baseline to week 48 in CD4%, CD4 count, biochemistry, hematology and lipids were similar between arms, as were the number of children with grade 3/4 AEs (10 QD vs 7 BID, p=0.6). 14 (4%) QD vs 6 (2%) BID children/carers reported missing a dose within 3 days of any clinic visit (p=0.2). For the 26 QD children in the PK substudy, the geometric mean ratio (GMR) (90% CI) of AUC0-24 was 0.72 (0.61, 0.85) falling outside the 80-125% limits for bioequivalence. GMR for Cmax was 1.13 (0.99, 1.28) and for Cmin was 0.18 (0.11, 0.29). Conclusions: Non-inferiority for VL suppression on QD versus BID LPV/r dosing was not demonstrated in this trial and LPV daily drug exposure was lower with QD dosing. Resistance and safety data were similar in both arms. Although the results can be partly explained by chance VL imbalance at baseline, they do not support the routine use of LPV/r QD in children and adolescents.