MAJOR ARTICLE

Pharmacokinetics of Efavirenz and Treatment of

HIV-1 Among Pregnant Women With and
Without Tuberculosis Coinfection
Kelly E. Dooley,1 Paolo Denti,3 Neil Martinson,1,4 Silvia Cohn,1 Fildah Mashabela,4 Jennifer Hoffmann,1 David W. Haas,2
Jennifer Hull,5 Regina Msandiwa,4 Sandra Castel,3 Lubbe Wiesner,3 Richard E. Chaisson,1 and Helen McIlleron,3 for the
TSHEPISO Study Team
1
Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Vanderbilt University, Nashville, Tennessee; 3Division of Clinical Pharmacology,
Department of Medicine, University of Cape Town, 4Perinatal HIV Research Unit, University of the Witwatersrand, and 5Department of Obstetrics, Chris
Hani Baragwanath Hospital and University of the Witwatersrand, Soweto, South Africa

Background. Pregnancy and tuberculosis treatment or prophylaxis can affect efavirenz pharmacokinetics, ma-
ternal human immunodeciency virus type 1 (HIV-1) treatment outcomes, and mother-to-child transmission
(MTCT) risk.
Methods. We evaluated a prospective cohort of pregnant, HIV-infected women with and without tuberculosis in
Soweto, South Africa. Pharmacokinetic sampling was performed at gestation week 37 and during the postpartum
period. Efavirenz trough concentrations (Cmin) were predicted using population pharmacokinetic models. HIV-
viral load was measured at delivery for mothers and at 6 weeks of age for infants.
Results. Ninety-seven women participated; 44 had tuberculosis. Median efavirenz Cmin during pregnancy
was 1.35 g/mL (interquartile range [IQR], 0.902.07 g/mL; 27% had an efavirenz Cmin of < 1 g/mL), compared
with a median postpartum value of 2.00 g/mL (IQR, 1.403.59 g/mL; 13% had an efavirenz Cmin of < 1 g/mL).
A total of 72% of pregnant women with extensive CYP2B6 genotypes had an efavirenz Cmin of <1 g/mL. Rifampin
did not reduce the efavirenz Cmin. Isoniazid (for prophylaxis or treatment), though, reduced the rate of efavirenz
clearance. At delivery, median durations of ART were 13 weeks (IQR, 918 weeks) and 21 weeks (IQR, 1364
weeks) for women with and those without tuberculosis, respectively; 55% and 83%, respectively, had a viral load
of <20 copies/mL (P = .021). There was 1 case of MTCT.
Conclusions. Pregnancy increased the risk of low efavirenz concentrations, but MTCT was rare. A detectable
HIV-viral load at delivery was more common among pregnant women with tuberculosis, in whom ART was gen-
erally initiated later.
Keywords. pregnancy; efavirenz; population pharmacokinetics; HIV/tuberculosis co-infection; rifampin;
isoniazid preventive therapy; pharmacogenetics.

Human immunodeciency virus (HIV) and tuberculo-
sis are leading infectious causes of death among women
of reproductive age [15]. In South Africa, 40% of
Received 12 May 2014; accepted 23 July 2014; electronically published 31 July
2014.
Presented in part: XIXth International AIDS Conference, Washington, D. C., 23
July 2012.
Correspondence: Kelly E. Dooley, MD, PhD, Johns Hopkins University School of
Medicine, 600 N Wolfe St, Osler 527, Baltimore, MD 21287 (kdooley1@jhmi.edu).
The Journal of Infectious Diseases 2015;211:197205
The Author 2014. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/infdis/jiu429
maternal deaths are caused by HIV or HIV-related dis-
ease [6]. Pregnancy increases the risk of tuberculosis [7],
and in pregnant women with HIV infection, the risk for
active tuberculosis disease is high, ranging from 0.7% to
7.9% in high-burden countries [812].
Treatment of HIV infection in pregnant women re-
gardless of CD4+ T-cell count is recommended by the
World Health Organization [13]. Combination antire-
troviral treatment (ART) is safe and effective during
pregnancy and is associated with reduced infant mortal-
ity and mother-to-child transmission (MTCT) of HIV
[14]. First-line treatment for much of Africa includes te-
nofovir, emtricitabine or lamivudine, and efavirenz

EFV in Pregnant Women With HIV/M. tuberculosis JID 2015:211 (15 January) 197
(EFV) [15]. This combination is increasingly used for pregnant
women, although there are limited data describing EFV phar-
macokinetics (PK), virologic outcomes, and MTCT in this pop-
ulation [16, 17].
Rifampin, an essential rst-line tuberculosis drug, is a pro-
miscuous inducer of drug metabolizing enzymes, including
cytochrome P450 (CYP) [18]. Initial drug interaction studies
suggested that rifampin coadministration reduced EFV con-
centrations [19]. However, HIV treatment outcomes do not
appear to be inuenced by rifampin-containing tuberculo-
sis treatment, and current guidelines suggest using EFV with
rifampin-containing tuberculosis treatment without dose ad-
justment [2023]. The effect of rifampin on EFV exposures var-
ies by CYP2B6 metabolizer status. Further, isoniazid inuences
EFV concentrations via inhibition of CYP2A6 [24, 25]. The
effect of pregnancy and isoniazid and/or rifampin (used for
prophylaxis against or treatment of tuberculosis) on EFV PK,
virologic suppression, and MTCT have never been studied.
METHODS
Study Population
TSHEPISO is a prospective cohort study evaluating the effects
of tuberculosis on maternal and infant outcomes in pregnant
women with HIV infection. HIV-infected pregnant women
with active tuberculosis (cases) or matched controls were re-
cruited from antenatal clinics and obstetrics wards at Chris
Hani Baragwanath Hospital (Soweto, South Africa) between
January 2011 and January 2013. Eligible participants were
18 years old and pregnant (gestational age, 13 weeks).
Cases had conrmed or probable tuberculosis, while controls
had no evidence of tuberculosis. In the parent study, 2 controls
were enrolled for each case, matched on gestational age (within
2 weeks), maternal age (within 5 years), date of enrollment
(within 8 weeks), and site of planned delivery but not on
ART use or regimen. Antiretroviral and tuberculosis treatment
regimens were determined by participants primary care physi-
cians, according to national treatment guidelines. As per na-
tional guidelines, EFV is given at a dose of 600 mg once daily
at bedtime; the isoniazid dose is 5 mg/kg (maximum, 300
mg), while the rifampin dose is 10 mg/kg (maximum, 600
mg). Patients receiving EFV-based ART for 10 days by gesta-
tion week 36 could participate in the EFV PK substudy. This
study was approved by the institutional review boards of
Johns Hopkins Medicine, the University of the Witwatersrand,
and the University of Cape Town. Participants provided written
informed consent.
Study Protocol
Women enrolled in the EFV PK substudy underwent PK sam-
pling at gestation week 37 or delivery, if it preceded the sched-
uled PK visit. Sampling was performed again 6 weeks after
198 JID 2015:211 (15 January) Dooley et al
delivery. Blood samples for PK analysis were collected at arrival
in the clinic in the morning and then 2, 4, and 68 hours later.
Samples were generally collected between 10 and 24 hours after
the previous EFV dose. For patients presenting in labor, PK
samples were collected at 3-hour intervals from presentation
until delivery (maximum of 4 samples). Timing of the last
3 doses of EFV was recorded. A cord blood PK sample was col-
lected. A PK sample was collected from the infant 1 week after
delivery. HIV-viral load was measured at delivery, for mothers,
and at 6 weeks of age, for infants. CYP2B6 and NAT2 genotyp-
ing was performed on maternal whole-blood specimens.
Drug Concentration Analysis
EFV plasma concentrations were determined by liquid chroma-
tographytandem mess spectrometry in the Division of Clinical
Pharmacology, University of Cape Town (Supplementary Mate-
rials). The method was linear over the range of 0.02 to 20 g/
mL. The lower limit of quantication was 0.02 g/mL. The in-
terassay coefcient of variation (CV) and residual error (RE)
were 5.72%8.01% and 0.09% to 3.18%, respectively, and the
intraassay CV and RE were 1.13% to 8.53% and 6.10% to
11.96%, respectively.
CYP2B6 and NAT2 Metabolizer Status
Genomic DNA was extracted from whole blood. Genotyping of
known functional polymorphisms CYP2B6 516GT (rs3745274,
CYP2B6*6) 983TC (rs28399499, CYP2B6*18), and 15582CT
(rs4803419, CYP2B6*15) was performed using MassARRAY
iPLEX Gold (Sequenom, Inc). Composite CYP2B6 genotypes
were assigned as follows: extensive metabolizer (no variant allele
at 516 or 983), intermediate metabolizer (single variant allele at
position 516 or 983), slow metabolizer (2 variant alleles (ie, 516
TT, 983 CC, or 516 GT plus 983 TC), or very slow metabolizer
(2 variants alleles at position 983) [26]. None were homozygous
for 15582 TT. Genotyping of known functional polymorphisms
NAT2 191GA (rs1801279, *14), 341 TC (rs1801280, *5),
590GA (rs1799930, *6), and 857GA (rs1799931, *7) was
performed using TaqMan assays and the ABI Prism 7900 HT
Sequence Detection System. The NAT2 genotypes were assigned
as rapid (no variant allele), intermediate (1 variant allele), or
slow (heterozygous for 2 different polymorphisms or homozy-
gous for 1 polymorphism). Intermediate and rapid metabolizers
were grouped together.
PK and Statistical Analyses
Sample Size
The sample size was based on determining the effect of rifampin
on EFV concentrations. Using pilot study and published data
[27], we estimated that 100 participants contributing 48 sam-
ples each (during the intrapartum and postpartum periods)
would be sufcient to detect a 35% difference in oral clearance
(CL/F) at a signicance level of 0.05 with a power of 85%.
Population Pharmacokinetic Analyses Table 1. Description of the Study Population Overall and by Case
A population PK model of steady-state EFV was developed and Control Status
using nonlinear mixed effects modeling with NONMEM soft-
ware [28], version 7.2. Perl Speaks NONMEM [29], Xpose, Controls
Characteristic Cases (n = 44) (n = 53) All (n = 97)
and Pirana were used for model diagnostics and to facilitate
modeling [30, 31]. For the structural model, besides the standard Maternal age, y 28 (2531) 29 (2531) 28 (2531)
Gestational age at 29 (2634) 31 (2634) 30 (2634)
1- and 2-compartment models with rst-order elimination and enrollment, wk
rst-order absorption ( possibly with inclusion of a delay), a CD4+ T-cell count 288 (144427) 330 (260414) 311 (217415)
semiphysiological model with hepatic extraction, as presented at enrollment,
cells/mm3
by Gordi et al [32], also was tested. This latter model was imple-
HIV RNA load at enrollment, copies/mL
mented, justied by the disposition of EFV, with the intention
<20 12 (28) 30 (58) 42 (44)
to capture hepatic clearance and rst-pass extraction with 1
20 31 (72) 22 (42) 53 (56)
parameter (hepatic intrinsic clearance [CLint]) and allow for ef- CYP2B6 metabolizer status
fects on this parameter, such as CYP2B6 genotype, to affect sys- Extensive 10 (23) 11 (21) 21 (22)
temic clearance and bioavailability. This model required the Intermediate 28 (64) 26 (49) 54 (56)
following assumptions: EFV protein binding of 99.5% [33]; a Slow 5 (11) 14 (26) 19 (19)
xed plasma liver ow of 50 L/h for a typical individual weigh- Very Slow 1 (2) 2 (4) 3 (3)
ing 70 kg [34]; and a xed liver volume of 1 L, as assumed by NAT2 metabolizer status
Gordi et al [32]. Inclusion of between-subject and between- Rapid 24 (55) 31 (60) 55 (57)
occasion random effects was tested on PK parameters, using a Slow 20 (45) 21 (40) 42 (43)
log-normal distribution, and the error model was assumed with Gestational age at 38 (3640) 39 (3840) 39 (3740)
delivery, wk
an additive and proportional component. Inclusion of allome- Duration of EFV 13 (918) 21 (1364) 16 (1124)
tric scaling to adjust clearance and volume parameters (and use at delivery,
liver ow and volume for the semiphysiological model) was wk

tested at an early model development stage, as suggested in
the article by Anderson and Holford [35]. Other signicant co-
variate effects were then evaluated in the model, including age,
pregnancy, CYP2B6 genotype, and effect of concomitant tuber-
culosis treatment or prophylaxis (accounting for NAT2 acetylator
genotype). Model development was guided by the NONMEM
objective function value (OFV; assumed to be 2 distributed),
goodness-of-t plots, visual predictive checks (VPCs) [36], clin-
ical signicance, and biological plausibility. The population PK
model was used to generate individual post-hoc Bayesian esti-
mates of PK parameters, including model-predicted individual
trough concentrations (Cmin, or C24).
RESULTS
Participants
There were 97 HIV-infected pregnant women receiving EFV,
44 with tuberculosis and HIV infection and 53 with HIV infec-
tion alone, plus their infants. Demographic and laboratory
characteristics are presented in Table 1.
Population Pharmacokinetics of EFV During Pregnancy and
After Delivery
For the 97 participants, there were 176 PK visits (81 during
pregnancy or the intrapartum period and 95 during the post-
partum period); 73% of patients participated in both PK visits.
Seventeen patient visits were excluded from the population PK
models (and estimates of Cmin) because drug concentrations in
Data are median (interquartile range) or no. (%) of subjects.
all samples were below the limit of quantication. Three addi-
tional patient visits were excluded because timeconcentration
proles were inconsistent with recorded doses. The analyses in-
cluded 87 patients and 468 samples.
The model that provided the best t for the data was the
semiphysiological hepatic extraction model with rst-order ab-
sorption (Figure 1). Parameter estimates and their precision are
presented in Table 2; VPC is shown in Supplementary Figure 1.
The semimechanistic hepatic model provided a better t than a
traditional 1-compartment model, without needing the estima-
tion of extra parameters. This mechanistic model captures the ef-
fect of changes in liver metabolic activity (CLint) both on hepatic
clearance (CLH) and rst-pass hepatic extraction (EH). For ease of
interpretation, for each value of CLint, the corresponding typical
values of systemic apparent clearance (CL/F), and the hepatic
contribution to bioavailability (FH) are reported in Supplementa-
ry Table 1. Formulas are as follows: EH = [CLint fu]/[QH + (CLint
fu)], CLH = EH QH, and [CLH/FH] = [CLH/(1 EH)].
To capture variability in bioavailability from other factors,
such as reduced absorption or enteric metabolism, a random ef-
fect involving prehepatic bioavailability was included. The in-
clusion of allometric scaling to account for the effects of
weight on CL and volume improved the t and explained part
of the between-subject variability (OFV = 22 points). Trying
to include and estimate an effect of pregnancy on volume did

EFV in Pregnant Women With HIV/M. tuberculosis JID 2015:211 (15 January) 199

Figure 1. Structural model. Efavirenz is absorbed from the absorption
compartment into the liver with a rst-order process (ka). During the
rst-pass through the liver, a fraction EH of the amount is extracted,
while the rest reaches the systemic circulation. The drug then recirculates
in the system with a ow equivalent to liver plasma ow (QH), and at each
pass the liver extracts a further fraction EH.
coadministration on EFV exposure is shown in Figure 2. For
one of the subjects, CYP2B6 metabolizer status was not avail-
able, so the value was imputed using a mixture model, which
allows a multimodal distribution of the individual parameter
across the population, taking into account the relative frequency
of each genotype in the study population and that subjects EFV
concentrations, as in the report by Keizer et al [37].
After including these covariates in the model, pregnancy in-
creased CLint by 20% (OFV = 11). This was in addition to ef-
fects of allometric scaling. Treatment with isoniazid (either with
rifampicin for treatment or alone for prophylaxis) among pa-
tients with a slow NAT2 acetylator status reduced the EFV
CLint by 20%; including this improved model t modestly
(OFV = 5).

not provide any improvement in model t. The main determi-
nant of CLint was CYP2B6 genotype; CLint varied signicantly
depending on whether the participant had an extensive, inter-
mediate, slow, or very slow CYP2B6 metabolizer status
(OFV = 52). The effect of CYP2B6 genotype and isoniazid
Table 2. Final Population Pharmacokinetic Model Parameter
Estimates
Effect of Pregnancy on Concentrations of EFV
The median model-estimated EFV Cmin during pregnancy or the
intrapartum period was 1.35 g/mL (interquartile range [IQR],
0.902.07 g/mL), compared with 2.00 g/mL (IQR, 1.403.59
g/mL) during the postpartum period (Tables 3 and 4). The pro-
portion of women with a Cmin of < 1 g/mL was 27% during
pregnancy and the intrapartum period and 13% during the

Variability,b % CV
Parameter Typical Value (90% CIa) (90% CIa)
CLint, L/hc
Extensive 3710 (30804330) Between subject:
33.0 (18.241.3)
Intermediate 2200 (19702440) ...
Slow 957 (7361310)
Very slow 312 (246568)
Vd, Lc 354 (284433)
Prehepatic relative 1d Between
bioavailability occasion: 32.7
(21.643.3)
ka, 1/h 0.471 (.2861.14) ...
Proportional error, % 9.31 (7.2610.9) ...
Additive error, mg/L 0.0846 (0.128) ...
Pregnancy on CLint, % 19.0 (9.6229.1) ...
Isoniazid and slow 20.8 (32.5 to 6.62) ...
NAT2 on CLint, %
VH, Lc 1d ...
QH, L/hc 50d ...
Fu, % 0.5d ... Figure 2. Efavirenz exposure, by CYP2B6 genotype and isoniazid inhibi-
Abbreviations: CLint, clearance intrinsic (for the separate categories of CYP2B6 tion. The box plot summarizes the percentiles in each CYP2B6 category
genotype); fu, unbound fraction of efavirenz in plasma; ka, first-order absorption (extensive [EXT], intermediate [INT], slow [SLW], and very slow [VSL]), sepa-
rate constant; QH, plasma liver flow; Vd, volume of distribution; VH, volume of rating visits in which a patient with slow NAT2 acetylator status was receiv-
the liver compartment. ing isoniazid (sufx -I). Dots represent individual visits, with hollow dots
a
90% confidence intervals (CIs) were obtained with a 200-sample being the visits with isoniazid co-administration. There were no visits for in-
nonparametric bootstrap.
b
dividuals with very slow CYP2B6 genotype and slow NAT2 acetylator status
Random effects have been modeled with a log-normal distribution, and the
values of variability are reported as approximate percentage CV.
receiving isoniazid. Area under the concentrationtime curve (AUC024) values
c
Scaled with allometric scaling based on weight. The typical value is reported
were determined using the formula for linear kinetics, re-adapted using the
for a 70-kg woman. parameters from the hepatic extraction model, as follows: AUC024_SS = [BIO
d
Fixed. DOSE]/[fu CLint], where BIO is the prehepatic bioavailability.

200 JID 2015:211 (15 January) Dooley et al

Table 3. Effect of Patient Characteristics, Cotreatments, and Drug Metabolizing Genotypes on Efavirenz Trough Concentrations (Cmin)
During Pregnancy and Postpartum

Efavirenz Cmin

Group Pregnancy/Intrapartum Period (n = 73) Postpartum Period (n = 75) All (n = 148)a

All 1.35 (0.902.07) 2.00 (1.403.59) 1.65 (1.112.86)
Weight, kg
>60 1.35 (0.882.07) 2.07 (1.353.27) 1.58 (1.012.64)
n = 62 n = 42 n = 104
60 1.31 (0.902.26) 2.00 (1.494.33) 1.88 (1.333.96)
n = 11 n = 33 n = 44
Tuberculosis drugs
None 1.28 (1.041.92) 1.84 (1.393.07) 1.58 (1.122.47)
n = 40 n = 40 n = 80
Isoniazid only 1.57 (1.561.83) 1.79 (1.492.41) 1.68 (1.522.12)
n=5 n=3 n=8
Isoniazid and rifampin 1.33 (0.832.22) 2.29 (1.354.41) 1.86 (0.893.09)
n = 28 n = 32 n = 60
CYP2B6 metabolizer
Extensive 0.79 (0.671.02) 1.33 (0.741.57) 0.88 (0.671.39)
n = 18 n = 16 n = 34
Intermediate 1.38 (1.091.81) 2.03 (1.472.81) 1.71 (1.282.33)
n = 43 n = 42 n = 85
Slow 4.09 (3.526.54) 6.11 (3.597.24) 5.26 (3.557.15)
n = 10 n = 14 n = 24
Very Slow 19.22 (18.2420.21) 17.42 (7.3720.5) 18.24 (17.420.2)
n=2 n=3 n=5
Isoniazid usersb
NAT2 genotype, rapid 1.48 (0.912.04) 2.03 (1.264.22) 1.80 (1.073.2)
n = 16 n = 20 n = 36
NAT2 genotype, slow 1.35 (0.852.19) 2.88 (1.514.33) 1.87 (0.893.0)
n = 17 n = 15 n = 32
Data are median (interquartile range).
a
Includes all individual observations during pregnancy, the intrapartum period, and the postpartum period.
b
Includes only the 68 observations during which the participant was receiving isoniazid.

postpartum period; 72% of women with extensive CYP2B6 me-
tabolizer status had a Cmin of < 1 g/mL during pregnancy.
Effects of Tuberculosis Treatment or Prophylaxis on
Concentrations of EFV
During pregnancy and the intrapartum period, the median
estimated EFV Cmin for women receiving EFV-based ART
and concurrent rifampin- and isoniazid-containing tuberculo-
sis treatment was 1.33 g/mL (IQR, 0.832.22 g/mL), com-
pared with 1.57 g/mL (IQR, 1.561.83 g/mL) for isoniazid
alone for tuberculosis prophylaxis and 1.28 g/mL (IQR,
1.041.92 g/mL) when no tuberculosis drugs were given (Ta-
bles 3 and 4). Among pregnant/intrapartum women, 36% had
an EFV Cmin of < 1 g/mL while receiving rifampin and isoni-
azid, compared with 20% among women receiving only isonia-
zid and 23% receiving no antituberculosis drugs. Among slow
CYP2B6 metabolizers, use of isoniazid (with or without rifam-
pin) was associated with higher EFV Cmin values, especially
among individuals with slow NAT2 genotypes.
Cord Blood and Neonatal Concentrations of EFV Among Infants
Born to Women Receiving EFV-Based ART
The median EFV concentration in cord blood (n = 50) was 1.30
g/mL (IQR, 0.752.33 g/mL) and was below the limit of
quantication in 5 of 50 samples (10%). Cord and maternal pre-
partum concentrations were highly correlated (r = 0.95). EFV
concentrations in plasma specimens from 7-day-old infants
were below the limit of quantication (0.02 g/mL) for 44 of
67 (66%). The presence of quantiable EFV in infant plasma
correlated with higher cord blood concentrations (r = 0.75).
Virologic Suppression Among Pregnant Women
Receiving EFV as Part of ART
At delivery, the median duration of EFV ART was 13 weeks
(IQR, 918 weeks) for cases and 21 weeks (IQR, 1364
weeks) for controls. Among 57 women with viral load measured
at the time of delivery, 55% of cases (12/22) and 83% of controls
(29/35) had an HIV-1 load of <20 copies/mL (P = .021). Viral
resistance testing was not routinely performed at delivery, but

EFV in Pregnant Women With HIV/M. tuberculosis JID 2015:211 (15 January) 201
Table 4. Percentage of Patients With Trough Efavirenz DISCUSSION
Concentrations of <1 g/mL During Pregnancy and the
Postpartum Period Our study is the rst to evaluate the combined effects of preg-
nancy and antituberculosis drugs on EFV PK and is the largest
Pregnant/ Postpartum PK study among pregnant women with HIV infection receiving
Intrapartum Period All
Group Period (n = 73) (n = 75) (n = 148)a
EFV-based ART. Pregnancy increased EFV clearance, and
women were at increased risk of low EFV Cmin (ie, < 1 g/mL)
All 20 (27) 10 (13) 30 (20)
during pregnancy, compared with the postpartum period.
Weight, kg
>60 17 (27) 8 (19) 25 (24)
Women with extensive CYP2B6 metabolizer status appeared
60 3 (27) 2 (6) 5 (11) to be at particularly high risk: the majority had a C min
Tuberculosis drugs of < 1 g/mL during pregnancy. Rifampin had little effect on
None 9 (23) 4 (10) 13 (16) median EFV concentrations but increased variability. Use of
Isoniazid only 1 (20) 0 (0) 1 (13) isoniazid (either as part of combination therapy for tuberculo-
Isoniazid and 10 (36) 6 (19) 16 (27) sis or alone for prophylaxis) increased EFV exposures. This
rifampin
effect was most apparent in patients with slow NAT2 metabo-
CYP2B6 metabolizer
lizer genotypes, a marker of high isoniazid concentrations. The
Extensive 13 (72) 7 (44) 20 (59)
proportion of women with an undetectable HIV-1 load at de-
Intermediate 6 (14) 1 (2) 7 (8)
Slow 1 (10) 2 (14) 3 (13)
livery was lower among women with tuberculosis, compared
Very slow 0 (0) 0 (0) 0 (0) with those without tuberculosis; of note, ART was started
Isoniazid usersb later in these women. MTCT was rare, and the 1 case that
NAT2 genotype, 4 (25) 4 (20) 8 (22) did occur was likely related to breast-feeding, coupled with
rapid poor maternal treatment adherence.
NAT2 genotype, 7 (41) 2 (13) 9 (28) Pregnancy-induced physiological changes can affect the PK
slow
of many drugs, including antiretrovirals [38, 39]. Until recently,
Data are no. (%) of subjects.
a
there were no data describing the PK of EFV during pregnancy,
Includes all individual observations during pregnancy, the intrapartum period,
and the postpartum period. likely because of concerns about teratogenicity. In one study, in-
b
Includes only the 68 observations during which the participant was receiving tensive PK sampling was performed during pregnancy and the
isoniazid.
postpartum period for 25 women receiving EFV-based ART
[16]. While overall exposures (measured by calculating the
area under the concentrationtime curve from 0 to 24 hours)
among 5 women who had testing for clinical reasons, there were and maximum concentrations were not signicantly different
no M184V, K65R, or K103N and thymidine analog mutations. during pregnancy, Cmin values were modestly reduced; however,
the proportion of women with a target Cmin of >1 g/mL was
Prevention of MTCT Among Women Receiving 88% during pregnancy and 92% for the same women during
EFV-Based ART at Delivery the postpartum period. Results of PK studies of EFV in preg-
Ninety-one of 93 live-born infants of 95 women receiving EFV- nancy may be expected to differ across settings, though, because
based ART at delivery underwent polymerase chain reaction of geographic differences in metabolizer genotype mix. Since
analysis for HIV-1 at 6 weeks. There was 1 case of MTCT. All weight affects oral clearance of EFV, it is possible that modest
infants received nevirapine daily for at least the rst 6 weeks of increases in CL/F are related to higher weights during pregnan-
life. In the case of MTCT, the mother enrolled as a case in the cy. In our study, we used allometric scaling to adjust CL by body
study at gestation week 37. At that time, she had received EFV- weight and detected a further increase in CL beyond the effect of
based ART for 8 weeks; her viral load was 185 copies/mL, and weight alone during pregnancy. While pregnancy may not alter
her CD4+ T-cell count was 148 cells/mm3. At delivery, during EFV PK signicantly enough to warrant dose adjustment
gestation week 39, she had received EFV-based ART for 67 broadly in pregnant women, patients with extensive CYP2B6
days and tuberculosis treatment for 51 days. The infant was metabolizer status who already have rapid clearance of EFV
breastfed exclusively and received nevirapine prophylaxis after may be at particular risk of low EFV concentrations. In the re-
birth. At 22 days, the infant tested negative for HIV DNA by cent ENCORE-1 study involving nonpregnant adults, doses of
PCR and had a CD4+ T-cell percentage of 38%. At 48 days, 400 mg and 600 mg of EFV had similar efcacy over 48 weeks
the infant tested positive for HIV DNA by PCR and had a of treatment [40]. The target Cmin for EFV, though, remains un-
CD4+ T-cell percentage of 32%. At the same visit, the infants clear, both in general and during pregnancy. Pregnant women
mother had an HIV-1 load of 218 672 copies/mL and reported with extensive CYP2B6 metabolizer status merit special atten-
breast-feeding. tion if a dose of 400 mg is to be considered.

202 JID 2015:211 (15 January) Dooley et al

 Cotreatment of tuberculosis and HIV infection is complicat-
ed by drug-drug interactions; while most attention has been fo-
cused on rifampin, patients treated for tuberculosis also receive
isoniazid, a CYP2A6 inhibitor. EFV is metabolized by CYP2B6
and CYP2A6. Drug interaction studies in healthy volunteers
evaluating the effects of rifampin on EFV PK showed reductions
in EFV concentrations, and based on modeling work [19, 41],
the Food and Drug Administration recommended that the
dose of EFV be increased among patients receiving rifampin
who weigh >50 kg [42]. However, the need for a dose increase
is hotly debated [2022, 43, 44]. EFV is largely metabolized by
CYP2B6, and concentrations are highly variable, with variabil-
ity largely explained by CYP2B6 metabolizer genotype. CYP2A6
is a minor metabolic pathway for EFV but plays a major role in
biotransformation of EFV among individuals with a slow
CYP2B6 metabolizer genotype. Isoniazid is always given with
rifampin for tuberculosis treatment and inhibits CYP2A6.
Drug interaction studies involving just rifampin may produce
signicantly different results than studies involving full tubercu-
losis treatment, particularly among patients with slow CYP2B6
metabolizer genotype [25]. Although the numbers were small,
patients with a slow EFV metabolizer genotype who were re-
ceiving tuberculosis treatment in our study had a median
EFV Cmin during pregnancy of 6.54 g/mL, which was much
higher than that for patients who were not receiving tuberculo-
sis treatment (3.86 g/mL). If EFV-related side effects are con-
centration dependent, this may be of particular concern in
populations where M. tuberculosis and HIV coinfection is com-
mon and 516T or 983C single-nucleotide polymorphisms are
prevalent. In addition, while median EFV concentrations are
similar among patients who are and those who are not receiving
tuberculosis treatment, the variability is higher with antituber-
culosis treatment, and more patients have a Cmin of <1 g/mL.
Our participants overall had good virologic responses to EFV-
based ART, whether or not they were receiving tuberculosis
treatment, and vertical transmission was rare. However, it is
possible that individuals with an extensive CYP2B6 metaboliz-
er status represent a subpopulation at particularly high risk of
treatment failure when EFV is given with rifampin-containing
tuberculosis treatment. In our study, although the number of
observations is limited, 77% of 13 patients receiving tubercu-
losis treatment with this genotype had a Cmin of < 1 g/mL at
their PK visit, compared with only 47% of 19 participants who
were not receiving tuberculosis treatment at the time of their
PK visit. A rapid CYP2B6 genotyping test to identify sub-
groups of patients at particular risk for low EFV concentra-
tions (ie, pregnant women, children, and individuals for
whom tuberculosis treatment has been coadministered)
would be useful.
For patients with HIV and M. tuberculosis coinfection, the
current standard of care is to initiate tuberculosis treatment
and then ART 28 weeks later [45, 46]. The optimal timing
EFV in Pregnant Women With HIV/M. tuberculosis
for initiation of ART for pregnant women with HIV infection
and tuberculosis is less clear. In our study, women with tuber-
culosis started ART about 2 months later than women without
tuberculosis and were much more likely to have a detectable
viral load at delivery than women without tuberculosis. The
risks and benets of earlier initiation of ART in this population
should be examined on a population level, taking into account
the potential impact on the health of the mother and her child.
Median EFV concentrations in cord blood were >1 g/mL
and were highly correlated with maternal concentrations. The
target concentration required to prevent transmission is un-
known. Since all infants born to participants in this study re-
ceived nevirapine daily for at least 6 weeks after birth, we
cannot determine the contribution of EFV-based ART to the
prevention of transmission. EFV concentrations were below
the limits of quantication in the majority of infants at 7 days
of life, indicating that even if therapeutic concentrations are
achieved at birth, they are short-lived.
This study had limitations. It was conducted at a single site;
however, genetic diversity was evident in the patient population,
as evidenced by the variability in CYP2B6 genotypes. We used a
sparse PK sampling strategy beginning several hours after the
evening dose of EFV. Although this sampling scheme limited
our ability to evaluate pregnancy-associated differences in ab-
sorption, we could readily estimate other PK parameters of
interest, such as CL/F and Cmin. Despite including multiple
covariate effects, the model still detected between-subject vari-
ability of 30% in CLint, and between-observation variability of
30% in bioavailability. This likely reects genuine physiological
factors that inuence variability in EFV PK and other factors,
such as imprecision in the reported dosing, skipping of some
doses, and intake of food, and other varying conditions that
were not controlled for in this observational study. For all as-
sumptions in the population PK model, such as xed hepatic
volume and plasma ow, sensitivity analyses were performed
that showed that these assumptions did not signicantly alter
model results.
In conclusion, pregnancy increased EFV clearance, and the
proportion of women with EFV Cmin < 1 g/mL was higher in
pregnancy than after delivery; women with extensive CYP2B6
metabolizer status may be at particularly high risk of low EFV
Cmin. Treatment for tuberculosis that includes isoniazid and ri-
fampin does not reduce overall EFV concentrations, but popu-
lation PK analyses suggest that EFV exposures are increased
among patients with a slow NAT2 genotype who are receiving
isoniazid. Women with tuberculosis and HIV infection were
more likely to have a detectable HIV-1 load at delivery than
women with HIV infection alone, likely because HIV treatment
was started later in pregnancy in coinfected patients. EFV con-
centrations in the majority of infants at 7 days of life were below
the limits of quantication, so a prolonged protective effect of
EFV in these infants is unlikely.
JID 2015:211 (15 January) 203
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases
online (http://jid.oxfordjournals.org). Supplementary materials consist of
data provided by the author that are published to benet the reader. The
posted materials are not copyedited. The contents of all supplementary
data are the sole responsibility of the authors. Questions or messages
regarding errors should be addressed to the author.
Notes
Acknowledgments. We thank the women who participated in this study
and the following individuals for their contributions to the success of this
study: Saba Shembe, Lala Maseko, Joyce Netshivhale, Abram Maubane,
Agnes Shilubane, Matabogo Letutu, Yudesh Baliram, and Glenda Gray,
from the Perinatal HIV Research Unit; Eckhart Buchman, Sthe Velaphi,
Sanjay Lala, and Khakhu Mathivha, from Chris Hani Baragwanath Hospital;
Wendy Stevens and Sergio Carmona, from the University of the Witwaters-
rand; Gary Maartens, Jennifer Norman, and Marilyn Solomons, from Uni-
versity of Cape Town; Christopher Hoffmann, from Johns Hopkins
University; Celine Gounder (for early assistance with this project); and
Danielle Richardson, Paul Leger, and Cara Sutcliffe, from Vanderbilt
University.
Financial support. This work was supported by the National Institute
of Child Health and Human Development, National Institutes of Health
(NIH; grant R01HD064354 to R. E. C., grants R01 AI077505 and UL1
TR000445 to D. W. H.); the NIH (grant K23AI080842 to K. E. D.); and
the Johns Hopkins Center for AIDS Research (NIH grant P30AI094189
to R. E. C.) and National Research Foundation of South Africa (grant
90729 to H. M.).
Potential conicts of interest. All authors: No reported conicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the con-
tent of the manuscript have been disclosed.
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