P1070: Dose Finding and P1070: Dose Finding and Pharmacogenetic study of Pharmacogenetic study of Efavirenz in HIV- Infected and Efavirenz in HIV- Infected and HIV/TB Co-Infected Infants & HIV/TB Co-Infected Infants & Children < 36 months of ageChildren < 36 months of age

Interim Results:Interim Results: MayMay, 2012, 2012

BackgroundBackground

EFV is one of few treatment options for EFV is one of few treatment options for HIV-infected infants w/ TB co-infection HIV-infected infants w/ TB co-infection – Dosing in infants <3 years not establishedDosing in infants <3 years not established

EFV pharmacokinetic variability related EFV pharmacokinetic variability related to CYP 2B6 gene polymorphismto CYP 2B6 gene polymorphism– CYP 2B6 GG (homozygous) or ) or GT

(heterozygous) heterozygous) “extensive” metabolism

– CYP 2B6 TT (mutant) genotype “poor” metabolism higher EFV exposure

Variable expression of mutant genotypes in different populations

Primary ObjectivesPrimary Objectives

Determine dose requirements of EFV Determine dose requirements of EFV administered as opened capsules to administered as opened capsules to HIV-infected OR HIV/TB co-infected HIV-infected OR HIV/TB co-infected infants [on Anti-TB Rx (ATT)] 3 - <36 infants [on Anti-TB Rx (ATT)] 3 - <36 m of agem of age

24 week safety and tolerance of EFV 24 week safety and tolerance of EFV Explore the influence of genetic Explore the influence of genetic

polymorphisms on EFV clearancepolymorphisms on EFV clearance

Secondary ObjectivesSecondary Objectives

Correlate dried blood spot (DBS) and Correlate dried blood spot (DBS) and plasma EFV concentrations.plasma EFV concentrations.

Assess the ability of 8-hydroxy/EFV Assess the ability of 8-hydroxy/EFV ratios in plasma and urine to predict ratios in plasma and urine to predict EFV clearance phenotype.EFV clearance phenotype.

Study DesignStudy Design

Enrollment in TB-endemic countries onlyEnrollment in TB-endemic countries only Inclusion criteriaInclusion criteria

– HIV-infected infants ages 3 - <36 monthsHIV-infected infants ages 3 - <36 months– Initiating ARTInitiating ART

No minimum viral load or CD4 count required No minimum viral load or CD4 count required

– HIV/TB co-infected Infants (Cohort II)HIV/TB co-infected Infants (Cohort II) Clinically diagnosed with TB Clinically diagnosed with TB Tolerating rifampin-containing ATT Tolerating rifampin-containing ATT ≥≥ 2 weeks at entry 2 weeks at entry

Exclusion criteriaExclusion criteria Prior NVP or EFV exposure (including PMTCT), or born Prior NVP or EFV exposure (including PMTCT), or born

to mothers treated w/ NNRTIs for PMTCTto mothers treated w/ NNRTIs for PMTCT

Study Design IIStudy Design II

Subjects stratified into age/cohort strata:Subjects stratified into age/cohort strata:– HIV vs. HIV/TB co-infectedHIV vs. HIV/TB co-infected– Age (3 - <24 m vs. 24 - <36 m)Age (3 - <24 m vs. 24 - <36 m)

Sample size: 25 evaluable subjects in each of Sample size: 25 evaluable subjects in each of age/cohort stratum at the accepted dose age/cohort stratum at the accepted dose (n=100)(n=100)

Treatment regimenTreatment regimen– EFV + 2 NRTI’s chosen by site investigatorEFV + 2 NRTI’s chosen by site investigator– Same EFV starting dose used for all subjects in each Same EFV starting dose used for all subjects in each

age stratum/cohort age stratum/cohort CYP 2B6 genotype not analyzed in advance (Version CYP 2B6 genotype not analyzed in advance (Version

1.0)1.0)

24 weeks duration24 weeks duration

PK Study Design 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 Individual dose adjustment as needed x1

to ensure appropriate exposureto ensure appropriate exposure Dose selection algorithm determines Dose selection algorithm determines

appropriate dose for each age/cohort appropriate dose for each age/cohort EFV clearance and exposure correlated EFV clearance and exposure correlated

with CYP 2B6 genotype after PK results with CYP 2B6 genotype after PK results available available

Progress as of May 2011Progress as of May 2011

34 patients enrolled; 6 currently on study34 patients enrolled; 6 currently on study– 26 Cohort I, 8 Cohort II (TB) 26 Cohort I, 8 Cohort II (TB) – 26 GG/GT, 8 TT genotypes26 GG/GT, 8 TT genotypes

14 completed study (24 wks) 14 completed study (24 wks) – 14/14 undetected viral load14/14 undetected viral load

14 early discontinuation14 early discontinuation– 3 toxicity endpoints (non-life threatening)3 toxicity endpoints (non-life threatening)– 6 withdrew (moved away, adherence etc)6 withdrew (moved away, adherence etc)– 5 PK endpoints5 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 50% dose reduction (per protocol) still higher

than target exposurethan target exposure

Dried Blood Spot PharmacokineticsDried Blood Spot Pharmacokinetics

PIs and NNRTIs concentrations by DBS

T Koal et al. Rapid Com Mass Spect. 2005; 19: 2995–300

IMPAACT P1070IMPAACT P1070

0 4 8 12 16 20 24

Time After Dose

0

4

8

12

16

20

Ave

rag

e E

FV D

BS

Conc

(mcg

/mL)

EFV Cohorts (MAY 11)Impact of TB/Rifampin

CYP 2B6 EM

Cohort 1

CYP 2B6 EM

Cohort 2

IMPAACT P1070 24 hour PKIMPAACT P1070 24 hour PK

0 4 8 12 16 20 24

Time After Dose

0

6

12

18

24

30

Med

ian E

FV D

BS

Conc

(mcg

/mL)

EFV Cohort 1 (MAY 11)Impact of CYP 2B6 Genotype

CYP 2B6 EM CYP 2B6 PM

IMPAACT P1070 EFV Plasma AUC’sIMPAACT P1070 EFV Plasma AUC’s

Cohort 1GG/GT

Cohort 1TT

Cohort 2GG/GT

Cohort 2TT

10

100

1000

2000

Est

imate

d E

FV p

lasm

a A

UC

(m

cg*h

/mL)

P1070 Week 2 PK Evaluations

EFV PK P1021 & P1070EFV PK P1021 & P1070

Capparelli et al ICAAC 2010

0 2 4 6 8 10 12 14 16 18 20 22

Age (y)

0.00

0.20

0.40

0.60

0.80

1.00

P1021 P1070

GG/GT

P1070

TT

2.00

2.50

3.00

Est

imate

d E

FV

CL/F

(L/h

/kg

)

EFV Oral Clearance

PK Interim SummaryPK Interim Summary

EFV dose has been selected for both age groups of EFV dose has been selected for both age groups of extensive metabolizers (CYP 2B6 GG/GT) (!)extensive metabolizers (CYP 2B6 GG/GT) (!)– This dose produces excessive EFV levels in poor This dose produces excessive EFV levels in poor

metabolizers (CYP 2B6 TT), even after 50% dose metabolizers (CYP 2B6 TT), even after 50% dose adjustmentadjustment

CYP 2B6 genotype will be performed at screening CYP 2B6 genotype will be performed at screening and used to determine starting dose of EFVand used to determine starting dose of EFV– Assay will be done in Johannesburg with rapid turnaroundAssay will be done in Johannesburg with rapid turnaround– LOA & full amendment in progress LOA & full amendment in progress

Probably/Possibly Treatment-Probably/Possibly Treatment-related Toxicity by CYP 2B6 related Toxicity by CYP 2B6 GenotypeGenotype

GG/GT subjects (n=26)GG/GT subjects (n=26) Gr 4 ANC (n=1)Gr 4 ANC (n=1)

TT subjects (n=8)TT subjects (n=8) Gr 4 ANC (n=1), Gr 3 Hgb (n=1)Gr 4 ANC (n=1), Gr 3 Hgb (n=1) Central nervous systemCentral nervous system

Gr 1 irritability (n=2)Gr 1 irritability (n=2) Gr 2 change in level of consciousness (n=1)Gr 2 change in level of consciousness (n=1)

P1070 Virology ResultsP1070 Virology Results

HIV RNA <400 copies/ml at week HIV RNA <400 copies/ml at week 1616– ITT (off Rx=failure) ITT (off Rx=failure)

15/30 (50%) w/16 weeks FU 15/30 (50%) w/16 weeks FU

– As TreatedAs Treated 15/16 (94%) treated through wk 1615/16 (94%) treated through wk 16 14/14 (100%) treated through wk 2414/14 (100%) treated through wk 24

Current status P1070Current status P1070

Enrollment on hold until late JuneEnrollment on hold until late June Version 2.0 Amendment Version 2.0 Amendment

– Infants Infants >24 months>24 months who received sdNVP for who received sdNVP for PMTCT or born to mothers treated with NVP or EFV PMTCT or born to mothers treated with NVP or EFV for PMTCT will be allowed to enrollfor PMTCT will be allowed to enroll

– Infants with Infants with severe malnutrition (WAZ below -3) severe malnutrition (WAZ below -3) will be allowed to enroll into Cohort II (TB)will be allowed to enroll into Cohort II (TB)

– Infants in Infants in Cohort I who develop TB or TB-IRIS will Cohort I who develop TB or TB-IRIS will be allowed to receive anti-TB therapybe allowed to receive anti-TB therapy by rolling by rolling over into Cohort I, Step 2. over into Cohort I, Step 2.

– CYP 2B6 genotyping will be run at CYP 2B6 genotyping will be run at screeningscreening and and used to determine starting dose of EFVused to determine starting dose of EFV

P1070 Sites P1070 Sites

BJMC CRSBJMC CRS Pune, IndiaPune, India George ClinicGeorge Clinic Lusaka, ZambiaLusaka, Zambia CAPRISA Umlazi CAPRISA Umlazi Durban, SADurban, SA Soweto IMPAACTSoweto IMPAACT Soweto, SASoweto, SA Harriet Shezi Clinic Harriet Shezi Clinic Soweto, SASoweto, SA Stellenbosch UniversityStellenbosch University Tygerberg, SATygerberg, SA UZ – Parirenyatwa UZ – Parirenyatwa Harare, ZimbabweHarare, Zimbabwe Makerere University-JHUMakerere University-JHU Kampala, UgandaKampala, Uganda Molepolole PTT CRS Molepolole, BotswanaMolepolole, Botswana Gabarone PTT CRSGabarone PTT CRS Gabarone, BotswanaGabarone, Botswana KCMC KCMC Moshi, TanzaniaMoshi, Tanzania

Thanks to the P1070 Study Thanks to the P1070 Study TeamTeam

Carolyn Bolton/Mutsawashe Bwakura-Dangarembizi/ Ellen Carolyn Bolton/Mutsawashe Bwakura-Dangarembizi/ Ellen Chadwick, Co-chairsChadwick, Co-chairs

Edmund Capparelli, Vice Chair Edmund Capparelli, Vice Chair Patrick Jean-PhilippePatrick Jean-Philippe Carol WorrellCarol Worrell Kimberly HudgensKimberly Hudgens Pearl SamsonPearl Samson Barbara HeckmanBarbara Heckman Lynette PurdueLynette Purdue Stephen SpectorStephen Spector William BorkowskyWilliam Borkowsky Amy Loftis JamesAmy Loftis James Chivon JacksonChivon Jackson Dawn EnglishDawn English Alex BennsAlex Benns Kim BanksKim Banks A.T. Bapuji (Aurobindo Pharma)A.T. Bapuji (Aurobindo Pharma)