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P1101: PHASEI/II STUDY OF RALTEGRAVIR CONTAINING REGIMEN IN HIV-TB COTREATED CHILDREN
Tammy Meyers1, Paul Krogstad2, Pearl Samson3, Edward P. Acosta4, Jack Moye5, Ellen Townley6, Sarah Bradford7, Linda Marillo8, Laura Hovind8, Thucuma Sise6, Hedy Teppler9, Sylvia Dittmer10, Lee Fairlie11, Anneke Hesseling12, Mark Cotton13
1The Chinese University of Hong Kong, Hong Kong, Hong Kong,2University of California Los Angeles, Los Angeles, CA, USA,3Harvard University, Cambridge, MA, USA,4University of Alabama at Birmingham, Birmingham, AL, USA,5National Institute of Child Health and Human Development, Bethesda, MD, USA,6NIAID, Rockville, MD, USA,7FHI 360, Durham, NC, USA,8Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA,9Merck & Co, Inc, Palo Alto, CA, USA,10Chris Hani Baragwanath Hospital, Johannesburg, South Africa,11Wits Reproductive Health and HIV Institute, Johannesburg, South Africa,12Desmond Tutu TB Centre, Western Cape, South Africa,13Stellenbosch University, Cape Town, South Africa
Current antiretroviral (ARV) treatment options for children co-infected with TB and HIV-infection are limited. RIF induces UDP-glucuronosyltransferase activity accelerating the clearance of raltegravir (RAL). In adults, doubling the RAL dose partially overcame this PK interaction with no safety concerns. We sought to determine the optimal and safe dose of RAL when administered with RIF-containing anti-TB therapy in HIV-infected children.
P1101 is a dose finding study for RAL for HIV-infected children receiving RIF-containing TB therapy for at least one week, with three age cohorts: Cohort 1: 2 to <6 years (closed), Cohort 2: 6 to <12 years of age and Cohort 3: 4 weeks to <2 years, aiming to enroll 12 evaluable children for PK and safety in each cohort. At enrollment children start 3 ARVs, including chewable RAL formulation at 12 mg/kg/dose twice daily (twice the recommended pediatric dose). Intensive RAL PK sampling is done 1 week after ARV therapy is initiated and then a 4th ARV is added. Clinical and lab assessments are routinely completed. RAL is stopped at TB treatment completion and children are followed for additional 3 mos. PK targets are a geometric mean (GM) AUC12h of 14-45 (µM-h) and GM C12h ≥75 nM. Here we report the results from Cohort 1.
Among 12 children, 7 (58%) were male, median age 3 years (IQR 2-5), baseline Log10 RNA median 4.91 (IQR 4.42-5.42), median CD4 count 559 cells/mL (IQR 390-1185), median CD4 percent 15% (IQR 9-24). PK at Week 1 showed GM AUC12h (%CV) of 28.8 mMxh (50%); the GM C12h was 229 nM (76%). 1/12 (8% with 95% CI [0%,34%]) had a grade 3 elevation of ALT at Week 4 deemed possibly related to RAL. RAL/ART were temporarily withheld for 21 days and then restarted, with no subsequent recurrence. While RAL was held temporarily, this child did not achieve virologic success (>1 log10 drop from baseline at Week 8 or HIV RNA ≤400 copies/mL). 11/12 (92%), were virologically suppressed by Week 8, with 95% CI (62%, 100%). For n=12 at Week 8, median log10RNA change from baseline was -3.16 (IQR -3.79, -2.55), median CD4 change from baseline was 101 cells/mL (IQR -70 to 230], median CD4 percent change from baseline was 6.1% (IQR 1.9-9.7).
A 12mg/kg dose twice daily of the oral chewable formulation of RAL safely achieved PK targets in HIV-infected children 2 to <6 years with TB.