Interim Results of Efavirenz Dose Finding and Pharmacogenetic Study in HIV-Infected Infants
This interim analysis from the IMPAACT P1070 study investigates the appropriate dosing and pharmacogenetics of Efavirenz (EFV) in HIV-infected and HIV/TB co-infected infants aged 3 to under 36 months. The study assesses safety, tolerance, and pharmacokinetics while exploring the impact of CYP 2B6 gene polymorphisms on EFV metabolism. Initial data indicates that dosing adjustments are necessary based on genotype to prevent excessive drug exposure in poor metabolizers. Enrollment continues in TB-endemic countries, aiming for effective ART in vulnerable populations.
Interim Results of Efavirenz Dose Finding and Pharmacogenetic Study in HIV-Infected Infants
E N D
Presentation Transcript
P1070: Dose Finding and Pharmacogenetic study of Efavirenz in HIV- Infected and HIV/TB Co-Infected Infants & Children < 36 months of age Interim Results:May, 2012
Background • EFV is one of few treatment options for HIV-infected infants w/ TB co-infection • Dosing in infants <3 years not established • EFV pharmacokinetic variability related to CYP 2B6 gene polymorphism • CYP 2B6 GG(homozygous) or GT (heterozygous) • “extensive” metabolism • CYP 2B6 TT (mutant) genotype • “poor” metabolismhigher EFV exposure • Variable expression of mutant genotypes in different populations
Primary Objectives • Determine dose requirements of EFV administered as opened capsules to HIV-infected OR HIV/TB co-infected infants [on Anti-TB Rx (ATT)] 3 - <36 m of age • 24 week safety and tolerance of EFV • Explore the influence of genetic polymorphisms on EFV clearance
Secondary Objectives • Correlate dried blood spot (DBS) and plasma EFV concentrations. • Assess the ability of 8-hydroxy/EFV ratios in plasma and urine to predict EFV clearance phenotype.
Study Design • Enrollment in TB-endemic countries only • Inclusion criteria • HIV-infected infants ages 3 - <36 months • Initiating ART • No minimum viral load or CD4 count required • HIV/TB co-infected Infants (Cohort II) • Clinically diagnosed with TB • Tolerating rifampin-containing ATT ≥ 2 weeks at entry • Exclusion criteria • Prior NVP or EFV exposure (including PMTCT), or born to mothers treated w/ NNRTIs for PMTCT
Study Design II • Subjects stratified into age/cohort strata: • HIV vs. HIV/TB co-infected • Age (3 - <24 m vs. 24 - <36 m) • Sample size: 25 evaluable subjects in each of age/cohort stratum at the accepted dose (n=100) • Treatment regimen • EFV + 2 NRTI’s chosen by site investigator • Same EFV starting dose used for all subjects in each age stratum/cohort • CYP 2B6 genotype not analyzed in advance (Version 1.0) • 24 weeks duration
PK Study Design • Intensive 24 hour EFV PK at week 2 • Individual dose adjustment as needed x1 to ensure appropriate exposure • Dose selection algorithm determines appropriate dose for each age/cohort • EFV clearance and exposure correlated with CYP 2B6 genotype after PK results available
Progress as of May 2011 • 34 patients enrolled; 6 currently on study • 26 Cohort I, 8 Cohort II (TB) • 26 GG/GT, 8 TT genotypes • 14 completed study (24 wks) • 14/14 undetected viral load • 14 early discontinuation • 3 toxicity endpoints (non-life threatening) • 6 withdrew (moved away, adherence etc) • 5 PK endpoints • 4/5 TT genotype with high EFV levels • 50% dose reduction (per protocol) still higher than target exposure
Dried Blood Spot Pharmacokinetics PIs and NNRTIs concentrations by DBS T Koal et al. Rapid Com Mass Spect. 2005; 19: 2995–300
EFV PK P1021 & P1070 Capparelli et al ICAAC 2010
PK Interim Summary • EFV dose has been selected for both age groups of extensive metabolizers (CYP 2B6 GG/GT) (!) • This dose produces excessive EFV levels in poor metabolizers (CYP 2B6 TT), even after 50% dose adjustment • CYP 2B6 genotype will be performed at screening and used to determine starting dose of EFV • Assay will be done in Johannesburg with rapid turnaround • LOA & full amendment in progress
Probably/Possibly Treatment-related Toxicity by CYP 2B6 Genotype • GG/GT subjects (n=26) • Gr 4 ANC (n=1) • TT subjects (n=8) • Gr 4 ANC (n=1), Gr 3 Hgb (n=1) • Central nervous system • Gr 1 irritability (n=2) • Gr 2 change in level of consciousness (n=1)
P1070 Virology Results • HIV RNA <400 copies/ml at week 16 • ITT (off Rx=failure) • 15/30 (50%) w/16 weeks FU • As Treated • 15/16 (94%) treated through wk 16 • 14/14 (100%) treated through wk 24
Current status P1070 Enrollment on hold until late June Version 2.0 Amendment Infants >24 months who received sdNVP for PMTCT or born to mothers treated with NVP or EFV for PMTCT will be allowed to enroll Infants with severe malnutrition (WAZ below -3) will be allowed to enroll into Cohort II (TB) Infants in Cohort I who develop TB or TB-IRIS will be allowed to receive anti-TB therapy by rolling over into Cohort I, Step 2. CYP 2B6 genotyping will be run at screening and used to determine starting dose of EFV
P1070 Sites • BJMC CRS Pune, India • George Clinic Lusaka, Zambia • CAPRISA Umlazi Durban, SA • Soweto IMPAACT Soweto, SA • Harriet Shezi Clinic Soweto, SA • Stellenbosch University Tygerberg, SA • UZ – Parirenyatwa Harare, Zimbabwe • Makerere University-JHU Kampala, Uganda • MolepololePTT CRSMolepolole, Botswana • Gabarone PTT CRS Gabarone, Botswana • KCMC Moshi, Tanzania
Thanks to the P1070 Study Team • Carolyn Bolton/MutsawasheBwakura-Dangarembizi/ Ellen Chadwick, Co-chairs • Edmund Capparelli, Vice Chair • Patrick Jean-Philippe • Carol Worrell • Kimberly Hudgens • Pearl Samson • Barbara Heckman • Lynette Purdue • Stephen Spector • William Borkowsky • Amy Loftis James • Chivon Jackson • Dawn English • Alex Benns • Kim Banks • A.T. Bapuji (AurobindoPharma)
