Efavirenz (EFV) Concentrations in Pregnant Women Taking EFV-Based Antiretroviral Therapy (ART) with and without

Rifampin-Containing Tuberculosis (TB) Treatment

Helen McIlleron, Neil Martinson, Paolo Denti, Fildah Mashabela, Jennifer Hunt, Saba Shembe, Jennifer Hull, David W. Haas, Regina Msandiwa, Silvia Cohn, Sandra Meredith, Lubbe Wiesner,

Richard Chaisson, Kelly E. Dooley, and the TSHEPISO Study Team

Background• In South Africa, the current standard of care for pregnant women with

HIV infection and < 350 CD4 cells/mm3 is combination ART

• There are limited data on efavirenz (EFV) pharmacokinetics (PK) in pregnant women, though its use is increasing (Cressey et al., 2012)

• In Soweto, an estimated 0.8-2.2% of pregnant women with HIV also have active TB (Gounder et al. 2011; Kali et al. 2006)

• Rifampin, a key component of first-line TB treatment, reduces concentrations of many antiretroviral (ARV) drugs

• The combined effect of pregnancy and rifampin-containing TB treatment on EFV PK, virologic suppression and prevention of maternal-to-child transmission of HIV-1 (PMTCT) has not been studied

Study design• TSHEPISO is a prospective cohort study among HIV-infected pregnant

women with TB (n=250 CASES) and without TB (n=500 CONTROLS), currently enrolling in Soweto, South Africa

• Antenatal clinics and obstetrics ward at Chris Hani Baragwanath Hospital, women at 13-34 weeks gestation

• Impact of TB/HIV co-infection in pregnancy on maternal and infant outcomes being evaluated

• Women (n=150) with and without TB, on EFV-containing ART (600 mg QD) will enroll in an EFV PK/PD substudy, along with their infants

• We report preliminary results from 76 women and 70 infants in the TSHEPISO EFV PK substudy to date

Methods: EFV PK Substudy• Blood samples for EFV PK analysis were collected:

– Maternal: 37 weeks gestation or delivery, then 6 weeks post-partum; up to 4 samples per occasion

– Cord blood at delivery, infant sample at 7 days

• Plasma concentrations determined by LCMS/MS†

• CYP2B6 genotyping of maternal DNA§– Extensive = 516GG and 983TT– Intermediate = 516GT or 983CT– Slow = 516TT or (516GT and 983CT) or 983CC– Very Slow = 983CC

• Post-hoc Bayesian estimates of PK parameters from NLME modeling with allometric scaling, using NONMEM

• HIV-1 viral load collected at delivery for mothers, at 6 weeks for infants†Clinical Pharmacology Analytical Laboratory, University of Cape Town; §Pharmacogenomics

Laboratory, Vanderbilt University, Nashville and University of the Witwatersrand, Johannesburg

Results: Study participantsCases (n=33) Controls (n=43)

Age in years, median (IQR) 29 (26-34) 30 (26-32)

Gestational age at enroll, median (IQR) 29 (26-32) 31 (24-33)

CD4 cells/mm3 at enroll, median (IQR) 288 (137-427) 330 (260-382)

HIV RNA copies/mL at enroll, N (%)*<20>=20

9 (28%)23 (72%)

25 (58%)18 (42%)

CYP2B6 metabolizer status, N (%)ExtensiveIntermediateSlowVery Slow

8 (26%)20 (59%)4 (15%)1 (3%)

10 (24%)19 (45%)13 (31%)

1 (2%)

Gestational age at delivery, median (IQR) 38 (36-40) 39 (38-40)

Weeks on EFV at delivery, median (IQR) 12 (5-18) 21 (12-68)

*p<0.05 in univariate analysis

EFV Population PK Model

Central Compartment

TV Ka=0.417 h-1

TV V/F=469 L

AbsorptionCompartment

TV CL/F, by genotype:

Extensive: 19.7 L/hIntermediate: 12.1 L/h Slow: 7.99 L/h Very Slow: 2.19 L/h

BSV 35.6%

F=1 (FIXED)

BOV 32.2%Dose

TV CL/F=11.7 L/h

BSV 65.5%BOV 33.9%

For Slower metabolizers:

CL/F -59% when on RIF co-

treatment

EFV Population PK model features

• 1-compartment model• Visits excluded if all EFV samples BLQ (13 PK

samples in 10 participants)• Allometric scaling with body weight applied to

CL/F and V/F• CL/F strongly influenced by CYP2B6 genotype• Did not detect significant longitudinal variations in

EFV PK (pre/post partum)• Rifampicin co-treatment decreased EFV CL/F in

slower metabolizers

*1 Very Slow has EFV value > upper limit of assay

CYP2B6 and EFV PK estimates

*

Maternal EFV PK estimates, by pregnancy status and rifampin co-treatment

Pre/intrapartum(n=59)

6 weeks Post-partum(n=50)

Cmin (mg/L)* 1.4 (0.99, 1.89) 1.68 (1.22, 2.78)% with Cmin<1 mg/L 25.4% 20.0%

*Median (IQR)

The population PK model post-hoc estimates were used to predict individual Cmin,

reported here with the BLQ values that could not be included in the model

Taking rifampin for TB treatment

(n=30)Not taking rifampin

(n=46)

Cmin (mg/L)* 1.76 (0.89, 3.13) 1.52 (1.14, 2.02)

% with Cmin<1 mg/L 29.6% 17.1%

Maternal EFV PK estimates, effect of weight and RIF

*Median (IQR)

<60 kg(n=15 RIF,10 no RIF)

>=60kg(n=22 RIF,41 no RIF)

Weight/RIF

Cmin (mg/L)* 1.91 (1.23, 3.71)

1.91 (0.86, 3.13) RIF

treatment% with Cmin<1 mg/L 20.0% 31.6%

Cmin (mg/L)* 1.33 (1.12, 1.64)

1.55 (1.13, 2.07) No RIF

treatment% with Cmin<1 mg/L 11.1% 16.7%

Cord blood and infant PK results

• Cord blood (n=45)– Median EFV concentration 1.15 (0.628 – 1.91) mg/L– Below the limit of quantification in 4/45 (8.9%) samples • Infant blood (7 days) (n=57)– Median EFV concentration BLQ (BLQ - 0.079) mg/L– Below the limit of quantification in 35/57 (61.4%) samples• Cord and maternal pre-partum concentrations were

highly correlated (r=0.93)• Infant 7-days blood concentrations were BLQ in most

cases, but quantifiable values were related to larger cord blood concentrations.

Virologic outcomes

• Maternal viral load at delivery – 70% of cases and 83% of controls had VL<20

copies/mL at delivery (p=0.24)– Of those taking EFV for at least 12 weeks at delivery,

82% of cases and 93% of controls had VL<20 copies/mL (p=0.26)

• PMTCT – No transmission from women taking EFV at delivery

Limitations

• Single site• Sparse sampling• Not all participants presented for all sampling

visits• Observational study in complex setting, no

DOT-ART• Small sample size for subgroup comparisons

Summary• Rich dataset including 76 women, 70 infants, PK and

VL data from high burden HIV/TB setting

• Estimated Cmin among women pre/intrapartum and post-partum were not significantly different

• In a model that accounts for weight and CYP2B6 genotype, unable to show significant effect of rifampin on EFV PK (except among slow EFV metabolizers)

• Despite about 30% with Cmin <1 mg/L, VL suppressed in most women taking EFV for 3 months or more at the time of delivery, and no MTCT

AcknowledgementsPerinatal HIV Research UnitLala MasekoJoyce NetshivhaleAbram MaubaneAgnes ShilubaneMatabogo LetutuGlenda Gray

Chris Hani Baragwanath HospitalJennifer HullEckhart BuchmanSthe VelaphiSanjay LalaKhakhu Mathivha

University of the WitwatersrandWendy StevensSergio Carmona

A special thanks to all study participants

University of Cape TownDivision of Clinical Pharmacology laboratory Marilyn Solomons

Johns Hopkins UniversityChris Hoffmann

Vanderbilt UniversityDanielle RichardsonPaul LegerCara Sutcliffe

FundingNIH/NICHD R01HD064354 (Chaisson)NIH K23 (Dooley)NIH/NIAID R01 AI-077505, NCATS UL1 TR-000011 (Haas)

Thank you