Tammy Meyers1, Pearl Samson, Edward P Acosta, Jack Moye, Ellen Townley, Sarah Bradford, Linda Marillo, Kayla Denson, Laura Hovind, Thucuma Sise, Hedy Teppler, Sisinyana Ruth Mathiba, Masebole Masenya, Anneke Hesseling, Mark F Cotton, Paul Krogstad. 1. 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.
Abstract
OBJECTIVES: 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. DESIGN: 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. SETTING: Four sites in South Africa. METHODS: 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. RESULTS: 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. CONCLUSION: Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.
OBJECTIVES: Drug-drug interactions limit current antiretroviral treatment options for HIV-infectedchildren 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-infectedchildren. DESIGN: 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. SETTING: Four sites in South Africa. METHODS: 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. RESULTS: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. CONCLUSION: Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infectedchildren receiving RIF for TB.
Authors: Paul Krogstad; Pearl Samson; Edward P Acosta; Jack Moye; Ellen Townley; Sarah Bradford; Emily Brown; Kayla Denson; Bobbie Graham; Laura Hovind; Thucuma Sise; Hedy Teppler; Sisinyana Ruth Mathiba; Lee Fairlie; Jana L Winckler; Gretchen Slade; Tammy Meyers Journal: J Pediatric Infect Dis Soc Date: 2021-03-26 Impact factor: 3.164
Authors: Tom G Jacobs; Elin M Svensson; Victor Musiime; Pablo Rojo; Kelly E Dooley; Helen McIlleron; Rob E Aarnoutse; David M Burger; Anna Turkova; Angela Colbers Journal: J Antimicrob Chemother Date: 2020-12-01 Impact factor: 5.790