Once daily lopinavir/ritonavir not recommended for routine use in children and adolescents
A PENTA trial conducted in Europe, Thailand, Argentina and Brazil did not demonstrate non-inferiority of once-daily to twice-daily lopinavir/ritonavir in children and adolescents.
Lopinavir/ritonavir is approved for use in adults once- or twice-daily, but only for twice-daily in children.
KONCERT was a phase 1/2 randomised trial in which children and adolescents 18 years or less, weighing at least 15kg, on lopinavir/ritonavir based ART with suppressed viral load (<50 copies/mL) for 24 weeks or more, either continued twice-daily dosing or switched to once-daily. Dosing was according to FDA approved body weight-based recommendations.
Hermione Lyall from Imperial College London presented data from the trial at CROI 2014 on behalf of the KONCERT investigators.
Participants were followed for minimum of 48 weeks with visits at weeks 0, 4, 8, 12 then every 12 weeks. The primary outcome was the proportion with confirmed viral load >50 copies/mL at 48 weeks. The non-inferiority margin was 12%.
A subset (n=53) of participants in the once daily arm had lopinavir/ritonavir pharmacokinetic (PK) evaluations at baseline (while still on twice daily dosing) and at four weeks (n=26). PK analyses were per-protocol and all others intention-to-treat.
A total of 173 participants were randomised to lopinavir/ritonavir either once-daily (n=86) or twice-daily (n=87). They were a median age of 11 years old (range 3.8 to14.7); 18% were aged 3 to 7, 43% 8 to 12 and 39% 13 to 18 years. There was a broad ethnic mix: 25% white, 27% black, 35% Asian, 6% mixed and 6% other. Median CD4 percent was 33% overall but there were more participants in the twice daily arm with CD4 percent above 30% (67% vs 60%).
At randomisation there was viral rebound in five children in the once-daily arm (none in the twice-daily). Median viral load was 120 copies/mL (range 51 to 91201) vs 134.5 copies/mL (range 57 to 270) in the once- and twice-daily arms respectively.
Over 50% of participants had been exposed to three classes of drugs and only 20% were on their first antiretroviral regimen.
The investigators found the AUC 0-24 and C (last) were less for the subset in the PK study at four weeks (once daily) compared to baseline (twice daily), see Table 1.
|once-daily (95%CI)||twice-daily (95% CI)||once/twice daily GM ratio (90% CI)|
(138.4 to 187.0)
(194.8 to 257.4)
(0.61 to 0.85)
(0.61 to 1.75)
(4.58 to 7.07)
(0.11 to 0.29)
Dr Lyall noted that a C(last) level just above 1 mg/L is considered to be acceptable and 40% in the study were below that level. She added that only two participants who took part in the PK substudy had viral rebound and both had good trough levels: 6.4 mg/L and 2.1 mg/L in the twice- and once-daily arms respectively. This raises the question of whether viral rebound is associated with drug levels or with adherence, she said.
At 48 weeks 12 vs 7 participants in the once- vs twice-daily arms had confirmed viral load >50 copies/mL; the estimated difference was 6% (90% CI -14 to 2), p=0.196. Because the confidence interval crossed the 12% level the study did not demonstrate non-inferiority.
Of the 12 people who had viral rebound at any point in the once-daily arm 7/9 who remained on the same dosing schedule resuppressed.
Changes from baseline to week 48 in CD4 percent, CD4 count, biochemistry, hematology, lipids, resistance and adverse events were similar between arms.
There was a strong preference for once-daily dosing with 84% participants/carers saying they preferred this. There was no significant difference between arms in adherence.
Although the results can be partly explained by chance viral load and CD4 percentage imbalances at baseline, they do not support the routine use of once daily lopinavir/ritonavir in children and adolescents.
Although these results do not support the routine use of once daily lopinavir/r in children and adolescents, in settings with close monitoring this might still be an option for a minority.
As with adults, once-daily boosted darunavir and atazanavir are preferred.
Lyall H et al. Final results of Koncert: A randomised noninferiority trial of QD Vs BD LPV/r dosing in children. 21st CROI. 3-6 March 2014, Boston. Oral abstract 74LB.