Drug–drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose of RAL when administered with RIF to HIV and TB co-infected children.
P1101 is a phase I/II open-label dose-finding study of RAL with RIF for children 2 to less than 12 years of age beginning treatment for HIV and active TB.
Four sites in South Africa.
Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after antiretroviral therapy was initiated; a fourth antiretroviral agent was then added.
Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old) and cohort 2 (6 to <12 years old). Pharmacological targets [geometric mean (GM) AUC12 h of 14–45 μmol/l h and GM C12 h ≥75 nmol/l) were reached in both cohort 1 (28.8 μmol/l h and 229 nmol/l) and cohort 2 (38.8 μmol/l h and 228 nmol/l). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment because of grade 4 hepatitis that was possibly treatment-related. At week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml; 19 of 24 (79%) were below 50 copies/ml.
Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.
aDepartment of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
bHarvard T.H. Chan School of Public Health/Frontier Science Foundation, Boston, Massachusetts
cUniversity of Alabama at Birmingham, Birmingham, Alabama
dEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda
eColumbiaUSA Technologies at the National Institute of Allergy and Infectious Diseases, Rockville, Maryland
fFHI 360, Durham, North Carolina
gFrontier Science & Technology Research Foundation, Inc, Amherst, New York
hNational Institute of Allergy and Infectious Diseases, Rockville, Maryland
iMerck & Co, Inc, Palo Alto, California, USA
jPerinatal HIV Research Unit, University of the Witwatersrand
kWits Reproductive Health and HIV Institute, Johannesburg
lDesmond Tutu TB Centre, Western Cape
mDepartment of Paediatrics and Child Health, FAM-CRU, Stellenbosch University, Cape Town, South Africa
nDavid Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
Correspondence to Paul Krogstad, MD, Departments of Pediatrics and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA Los Angeles, CA 90095, USA. E-mail: email@example.com
Received 18 March, 2019
Revised 15 August, 2019
Accepted 16 August, 2019