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Optimal Use of Efavirenz in HIV+/ TB+ Coinfected Children Aged 3 to 24 months
Carolyn Moore1; Pearl Samson2; Edmund Capparelli3; Mutsawashe Bwakura-Dangarembizi4; Patrick Jean-Philippe5; Nahida Chakhtoura6; Alex Benns7; Bonnie Zimmer7; Chivon McMullen-Jackson8; Ellen G. Chadwick9
1Cntr for Infectious Disease Rsr in Zambia, Lusaka, Zambia;2Harvard Sch of PH, Boston, MA, USA;3Univ of California San Diego, San Diego, CA, USA;4Univ of Zimbabwe, Harare, Zimbabwe;5Henry M. Jackson Fndn for the Advancement of Military Med, Bethesda, MD, USA;6Eunice Kennedy Shriver NICHD, Bethesda, MD, USA;7Frontier Sci & Tech Rsr Fndn, Amherst, NY, USA;8Baylor Coll of Med, Houston, TX, USA;9Northwestern Univ, Chicago, IL, USA
Poor tolerability and interactions between ARVs and rifampin-containing anti-TB therapy (ATT) limit treatment options for HIV+/TB+ children. EFV has minimal interactions with rifampin, making it a good option for HIV/TB co-infection but PK variability and formulation issues have precluded dosing guidelines for young children. We sought to determine an EFV dose and study its safety and efficacy in HIV+ children from TB-endemic countries. Here we present the data for HIV+/TB+ infants 3 months to two years.
IMPAACT P1070 is a prospective, Phase I/II open-label 24 wk trial of EFV in HIV+ children 3-<36 months with or without TB. Using CYP2B6 genotype-directed, weight-band dosing subjects initiated EFV & 2 NRTIs at EFV doses of ~65mg/kg as opened capsules once-daily. These dosages are ~ 30% greater than those used in TB-uninfected infants (results not shown). CYP2B6 genotype was drawn at baseline and intensive PK was performed at wk 2. Doses were adjusted if outside the target AUC (35 -180 mcg*hr/mL). HIV-1 RNA and toxicity labs were drawn every 4-8 wks.
8 subjects 3 to <24 months receiving ATT (5 males, med age 13 months (10-17.5 IQR)) enrolled with median follow up of 24wk (18-25 IQR). All 8 were CYP2B6 GG/GT and initiated EFV at a median dose of 64.9 mg/kg (57.7-67.7 IQR). The median EFV AUC was 92.87 mcg*h/mL ( 40.9-160.14 IQR). 6/8 subjects met the wk 2 AUC target, 1 was below (due to non-adherence) and 1 above (achieved the target range after dose reduction). Possibly treatment-related toxicities ≥ gr 3 occurred in 1 subject (gr 4 SGPT/SGOT) at wk24. This resolved after discontinuing EFV, TMP/SMX and ATT and did not recur when EFV was restarted. 2 subjects discontinued EFV before wk24; 1 due to difficulty administering EFV and 1 for poor adherence. Baseline median RNA was 5.9 log10 copies(cps) /ml (5.5-6.1 IQR) and 8/8 (100% ITT; 95%CI 63-100%) achieved either ≥1 log10 drop from baseline RNA or <400 cps/ml by week 8; 5/6 subjects who completed 24 wks had RNA <400 cps/ml and 1/6 had 404 cps/ml.
Amplified dosing (~65.9 mg/kg) in co-infected HIV+/TB+ children with CYP2B6 GG/GT genotype produced therapeutic EFV concentrations in most children <2 yrs with excellent safety and virological outcomes. However, a lower dose is likely to be needed in this age group taking ATT with slow CYP2B6 metabolism, as is required in young children without ATT. Optimal exposure of EFV can be achieved in HIV+/TB+ children <2yrs but requires pretreatment genotyping.