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Interim Results: May , 2012

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

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Interim Results: May , 2012

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  1. 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

  2. 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” metabolismhigher EFV exposure • Variable expression of mutant genotypes in different populations

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. Dried Blood Spot Pharmacokinetics PIs and NNRTIs concentrations by DBS T Koal et al. Rapid Com Mass Spect. 2005; 19: 2995–300

  10. IMPAACT P1070

  11. IMPAACT P1070 24 hour PK

  12. IMPAACT P1070 EFV Plasma AUC’s

  13. EFV PK P1021 & P1070 Capparelli et al ICAAC 2010

  14. 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

  15. 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)

  16. 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

  17. 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

  18. 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

  19. 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)

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