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 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 EFV pharmacokinetic variability related to CYP 2B6 gene polymorphism –) or heterozygous) –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 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 24 week safety and tolerance of EFV Explore the influence of genetic polymorphisms on EFV clearance Explore the influence of genetic polymorphisms on EFV clearance

4. Secondary Objectives Correlate dried blood spot (DBS) and plasma EFV concentrations. 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. 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 Enrollment in TB-endemic countries only Inclusion criteria Inclusion criteria –HIV-infected infants ages 3 - <36 months –Initiating ART No minimum viral load or CD4 count required No minimum viral load or CD4 count required –HIV/TB co-infected Infants (Cohort II) Clinically diagnosed with TB Clinically diagnosed with TB Tolerating rifampin-containing ATT ≥ 2 weeks at entry Tolerating rifampin-containing ATT ≥ 2 weeks at entry Exclusion criteria Exclusion criteria Prior NVP or EFV exposure (including PMTCT), or born to mothers treated w/ NNRTIs for PMTCT 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: 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) Sample size: 25 evaluable subjects in each of age/cohort stratum at the accepted dose (n=100) Treatment regimen 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) CYP 2B6 genotype not analyzed in advance (Version 1.0) 24 weeks duration 24 weeks duration

7. PK Study Design Intensive 24 hour EFV PK at week 2 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 Dose selection algorithm determines appropriate dose for each age/cohort EFV clearance and exposure correlated with CYP 2B6 genotype after PK results available 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 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 completed study (24 wks) –14/14 undetected viral load 14 early discontinuation 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 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) (!) 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 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 HIV RNA <400 copies/ml at week 16 –ITT (off Rx=failure) 15/30 (50%) w/16 weeks FU 15/30 (50%) w/16 weeks FU –As Treated 15/16 (94%) treated through wk 16 15/16 (94%) treated through wk 16 14/14 (100%) treated through wk 24 14/14 (100%) treated through wk 24

17. Current status P1070 Enrollment on hold until late June Enrollment on hold until late June Version 2.0 Amendment 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 CRSPune, India BJMC CRSPune, India George ClinicLusaka, Zambia George ClinicLusaka, Zambia CAPRISA Umlazi Durban, SA CAPRISA Umlazi Durban, SA Soweto IMPAACTSoweto, SA Soweto IMPAACTSoweto, SA Harriet Shezi Clinic Soweto, SA Harriet Shezi Clinic Soweto, SA Stellenbosch UniversityTygerberg, SA Stellenbosch UniversityTygerberg, SA UZ – Parirenyatwa Harare, Zimbabwe UZ – Parirenyatwa Harare, Zimbabwe Makerere University-JHUKampala, Uganda Makerere University-JHUKampala, Uganda Molepolole, Botswana Molepolole PTT CRSMolepolole, Botswana Gabarone PTT CRSGabarone, Botswana Gabarone PTT CRSGabarone, Botswana KCMC Moshi, Tanzania KCMC Moshi, Tanzania

19. Thanks to the P1070 Study Team Carolyn Bolton/Mutsawashe Bwakura-Dangarembizi/ Ellen Chadwick, Co-chairs Carolyn Bolton/Mutsawashe Bwakura-Dangarembizi/ Ellen Chadwick, Co-chairs Edmund Capparelli, Vice Chair Edmund Capparelli, Vice Chair Patrick Jean-Philippe Patrick Jean-Philippe Carol Worrell Carol Worrell Kimberly Hudgens Kimberly Hudgens Pearl Samson Pearl Samson Barbara Heckman Barbara Heckman Lynette Purdue Lynette Purdue Stephen Spector Stephen Spector William Borkowsky William Borkowsky Amy Loftis James Amy Loftis James Chivon Jackson Chivon Jackson Dawn English Dawn English Alex Benns Alex Benns Kim Banks Kim Banks A.T. Bapuji (Aurobindo Pharma) A.T. Bapuji (Aurobindo Pharma)