Doubling raltegravir dose could overcome interaction with rifampicin in children aged 2 to 6

Doubling the dose of raltegravir for children aged two to six years with TB and HIV co-infection who were taking rifampicin achieved adequate concentrations and was found to be safe. Results from IMPAACT P1101 were presented at CROI 2018.

A dose of 12 mg/kg of raltegravir (RAL) can be used for TB-HIV co-infected children taking rifampicin in this age group.

IMPAACT P1101 is a phase 1/2 dose finding study of RAL for HIV positive children receiving rifampicin (RIF)-containing TB treatment for at least one week. The study has three age cohorts: cohort 1: 2 to <6 years (results shown here), cohort 2: 6 to <12 years of age and cohort 3: 4 weeks to <2 years. Each cohort needs 12 participants for pharmacokinetic (PK) and safety evaluations.

Participants start a three-drug ART regimen at enrolment, including chewable RAL formulation at 12 mg/kg/dose twice daily (twice the recommended paediatric dose).

Intensive RAL PK sampling is performed one week after ART is started and then a forth ARV is added to the regimen – standard of care with TB treatment, usually efavirenz or lopinavir/ritonavir.

RAL is stopped when TB treatment is completed and participants followed for a further three months. PK targets are a geometric mean (GM) AUC12h of 6–20 mgxh/L (14–45 uMxh) and GM C12h > 33 ng/mL (>75 nM). The study defines virologic success as at least 1 log10 copies/mL reduction from baseline or viral load <400 copies/mL at week 8.

The 12 participants were 7 (58%) male, 100% black and median age of 3 years (IQR: 2 to 5). Median baseline viral load 4.91 log10 copies/mL (IQR: 4.42 to 5.42), CD4 count 559 cells/mL (IQR: 390 to 1185) and CD4 per cent 15% (IQR 9–24). Median follow up was 33 weeks (IQR: 28 to 37). The majority of participants (11/12) received efavirenz as the forth drug and one participant received lopinavir/ritonavir.

At week 1 GM AUC12h was 12.8 mgxh/L (28.8 uMxh; CV 50%) and GM C12h was 102 ng/mL (230 nM; CV 76%).

One participant had grade 3 AST and grade 3 ALT elevations at week 4 judged possibly related to RAL. RAL/ART was temporarily stopped for 21 days and then restarted, with no recurrence.

At week 8 11/12 (92%) participants achieved virologic success and 9/12 (75%) viral load <50 copies/mL; 10/11 remained <400 copies/mL through week 24. The participant who did not achieve virologic success was the same one that stopped ART temporarily.

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These data are welcome as options for treating coinfected children are scarce.

Results from cohorts 2 and 3 are needed before the double dose of RAL can be recommended for all TB-HIV co-infected infants and children treated with rifampicin.