Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Naïve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
Comprehensive Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Evaluation of Once-Daily Efavirenz 400 and 600 mg in Treatment-Na¨ıve HIV-Infected Patients at 96 Weeks: Results of the ENCORE1 Study
0 & Dianne Carey
1 & Laura Dickinson
2 On behalf of the ENCORE1 Study Group
3 Hospital Ramos Mej ́ıa , Buenos Aires , Argentina
4 HIV-NAT Thai Red Cross AIDS Research Center , Bangkok , Thailand
5 Desmond Tutu HIV Foundation , Cape Town , South Africa
6 St. Stephen's Centre, Chelsea and Westminster Foundation Trust , London , UK
7 The Kirby Institute, University of New South Wales Australia , Wallace Wurth Building, High Street, Kensington, Sydney, NSW 2052 , Australia
8 Department of Molecular and Clinical Pharmacology, University of Liverpool , Block H, First Floor, 70 Pembroke Place, Liverpool L69 3GF , UK
Background ENCORE1 demonstrated non-inferiority of daily efavirenz 400 mg (EFV400) versus 600 mg (EFV600) to 96 weeks in treatment-na¨ıve, HIV-
infected adults but concerns regarding lower EFV400
concentrations remained. Therefore, relationships
between EFV pharmacokinetics (PK) and key genetic
polymorphisms with 96-week efficacy and safety were
Methods Relationships between EFV PK parameters and
single nucleotide polymorphisms (SNP; CYP2B6, CYP2A6,
CYP3A4, NR1I3, NR1I2, ABCB1) with plasma HIV-RNA
(pVL)\200 copies/mL and EFV discontinuation and adverse
events at 96 weeks were explored. Receiver operating
characteristic curve analysis evaluated the predictability of
middose interval (C12) cutoffs and 96-week pVL.
Results A total of 606 patients (32 % female; 37 %
African, 33 % Asian; n = 311 EFV400, n = 295 EFV600)
were included. EFV PK parameters, including C12, were
not associated with pVL \200 copies/mL at 96 weeks
(odds ratio [OR] 5.25, 95 % confidence interval [CI]
0.41–67.90, p = 0.204). Lower risk of CNS-related adverse
events was associated with CYP2B6 983TC/CC (OR 0.35,
95 % CI 0.15–0.81, p = 0.015) and higher risk was
associated with CYP2B6 15582CT/TT and ABCB1 3435TT
(OR 1.46, 95 % CI 1.02–2.09, p = 0.040; OR 2.31, 95 %
CI 1.33–4.02, p = 0.003, respectively). Discontinuation
due to adverse events (clinician decision) was
independently associated with dose (OR 2.54, 95 % CI 1.19–5.43,
p = 0.016). C12 between 0.47 and 0.76 mg/L provided
sensitivity/specificity [90 % (100 %/92.3 to 98.9 %/
92.3 %) for achieving pVL \200 copies/mL at 96 weeks.
Conclusions A higher rate of EFV-related adverse events
and discontinuations due to these events for EFV600 were
not driven by polymorphisms assessed. Although a single
threshold concentration associated with HIV suppression
may be clinically useful, it was not viable for ENCORE1.
Implementation of EFV400 would improve toxicity
management whilst still maintaining good efficacy.
Despite concerns regarding lower plasma
concentrations obtained with efavirenz 400 mg
(EFV400) compared with 600 mg (EFV600) in
ENCORE1, virological efficacy was not
compromised at 96 weeks (HIV-RNA [pVL] \200
copies/mL: 97 vs. 99 %, p = 0.091). Achieving pVL
\200 copies/mL at 96 weeks was not associated
with the selection of single nucleotide
polymorphisms (SNP; CYP2B6, CYP2A6, CYP3A4,
NR1I3, NR1I2, ABCB1) assessed.
EFV-related adverse events and discontinuations due
to these events were increased with dose but the
higher rate of EFV-related adverse events for
EFV600 was not associated with the SNPs
investigated. CNS adverse events were not driven by
EFV dose or concentrations; however, CYP2B6
15582CT/TT and ABCB1 3435TT carriers were at
higher risk (46 and 131 %, respectively) of
CNSrelated adverse events compared with 35 % lower
risk in CYP2B6 983TC/CC patients. Possession of
the CYP2B6 516GT and TT variants and
CYP2A6*9B CA/AA carriers was associated with a
higher risk of overall EFV discontinuation (80, 166
and 100 %, respectively), whereas NR1I2 63396TT
carriers were at decreased risk (22 %).
ENCORE1 questions the validity of the currently
accepted minimum effective concentration (MEC) of
1.0 mg/L. The proportions of patients with pVL
C200 copies/mL was not significantly different
between those with model-predicted EFV C12
(middosing interval concentration) above or below
1.0 mg/L (2 % [11/557] vs. 11 % [2/18], p = 0.059;
note that 2/20 patients with C12 \1.0 mg/L had
missing pVL at 96 weeks). Although a threshold
concentration is clinically useful, the
acceptable receiver operating characteristic criteria
associated with a range of C12 cutoffs
(0.47–0.76 mg/L) for pVL \200 copies/mL at
96 weeks suggests a single target value is not
Antiretroviral dose reduction is an ongoing area of debate,
focusing on advantages of reduced adverse events and
treatment costs versus the potential risk of higher rates of
Efavirenz (EFV; 600 mg once daily), the mainstay of
combination antiretroviral therapy in resource-limited
], was selected as a potential candidate for dose
reduction based on early clinical data that observed similar
short-term efficacy with lower EFV doses (200 and 400 mg
once daily [
]). These data and the principle that successful
antiretroviral dose reduction can cut medication costs and
allow greater treatment coverage, was the impetus behind
the design and implementation of the ENCORE1 trial.
ENCORE1, a multicentre, double-blind,
placebo-controlled trial, demonstrated non-inferiority of reduced-dose
EFV (400 mg once daily; EFV400) with the standard dose
(600 mg once daily; EFV600) in treatment-na¨ıve,
HIVinfected adults at 48 weeks [
] and was sustained to
96 weeks [
Important concerns regarding the impact of lower
concentrations with EFV400 and overall influence of key genetic
factors on pharmacokinetics (PK) were recently addressed for
the 48-week outcome data [
]. In this study, we present the
final EFV PK-pharmacodynamic (PD) and pharmacogenetic
cross-sectional analysis of ENCORE1 at 96 weeks.
The ENCORE1 study design (to 48 and 96 weeks) has
been previously described in detail [
]. ENCORE1 was a
randomised, double-blind, placebo-controlled trial in
treatment-na¨ıve, HIV-infected individuals C16 years of
age recruited from 38 study sites across Africa, Asia, South
America, Europe and Oceania. Patients were randomised to
EFV400 or EFV600 with tenofovir/emtricitabine
(Truvada , 300/200 mg) administered once daily. The study
was granted ethical and regulatory approval and written
informed consent was obtained from all participants.
2.2 Sampling and Pharmacokinetics (PK)
The ENCORE1 PK sampling scheme has been previously
]. Random, single blood samples were collected
at weeks 4 and 12 of therapy (between 8 and 16 h
postdose) and intensive sampling was also carried out in a
subgroup of patients (n = 46) between weeks 4 and 8
(predose [0 h], 2, 4, 8, 12, 16 and 24 h post-dose). EFV plasma
concentrations were quantified by a validated
high-performance liquid chromatography–tandem mass spectrometry
(HPLC–MS/MS) method [
] and non-linear mixed effects
modelling was applied to the data (NONMEM v. 7.2;
ICON Development Solutions, Ellicott City, MD, USA [
to determine EFV PK parameters in each patient at each
sampling occasion. The impact of patient demographics
and single nucleotide polymorphisms (SNPs; see below) on
EFV concentrations was evaluated as part of the modelling
]. Derived PK parameters, including area under
the concentration–time curve over the 24-h dosing interval
(AUC24), maximum concentration (Cmax), trough
concentration 24 h post-dose (C24) and concentration 12 h
postdose representing the mid-dose interval concentration (C12)
were determined for each sampling occasion, and the mean
for each patient was calculated. Standard modelling
practices were applied, with the procedures recently being
described in detail [
The SNPs CYP2B6 516 G[T (rs3745274), CYP2B6 983
T[C (rs28399499), CYP2B6 15582C[T (rs4803419),
CYP2A6*9B (rs8192726), CYP2A6*17 (rs28399454),
CYP3A4*22 (rs35599367), NR1I3 540C[T (rs2307424)
and NR1I3 1089T[C (rs3003596) were previously
]. Additionally, ABCB1 3435C[T (rs1045642),
NR1I2 63396C[T (rs2472677) and NR1I2 7635A[G
(rs6785049) were genotyped using real-time PCR allelic
discrimination assays for the present analysis
(C_7586657_20, C26079845_10 and C_29280426_10,
respectively; Applied Biosystems, Foster City, CA, USA),
as previously described [
2.4 Pharmacokinetic–Pharmacodynamic (PK–PD)
Analysis: Relationships with Virological and Safety Endpoints
The primary PD endpoint was the proportion of patients
with plasma HIV RNA (pVL)\200 copies/mL at 96 weeks
by randomised dose (Fisher’s exact test). Patients without a
viral load measurement at 96 weeks were excluded from
the analysis. Relationships between pVL \200 copies/mL
at 96 weeks and log-transformed model-predicted EFV
AUC24, Cmax, C24, and C12 were performed by logistic
Safety endpoints consisted of EFV discontinuation and
adverse events. Overall discontinuation was defined as
interruption in EFV treatment for more than 30 days.
Adverse events were categorised as EFV-related defined in
the Stocrin product information [
], and EFV-related
according to clinician decision. Additionally, CNS adverse
events (as a subset of adverse events) defined in the
Stocrin product information (including abnormal dreams,
anxiety, dizziness, headache, impaired concentration,
insomnia and somnolence [
]) and treatment cessation
due to EFV-related adverse events (clinician decision)
were also assessed.
Differences in proportions of each safety endpoint by
EFV dose were assessed using Pearson’s Chi-square test.
Geometric mean ratio (GMR; 90 % confidence interval
[CI]) was calculated to compare PK parameters between
those who did or did not stop therapy and/or experience
adverse events. Differences were considered significant if
the CI did not cross 1.
2.5 Pharmacogenetics: Relationships with Virological and Safety Endpoints
Differences in proportions of pVL \200 copies/mL at
96 weeks for each genetic polymorphism and pVL
C200 copies/mL at week 96 stratified for metaboliser
status (extensive, intermediate, slow; based on CYP2B6
516G[T/986T[C/CYP2A6*9B/*17 composite genotype as
previously reported [
]) and dose were assessed using
Fisher’s exact test.
Evaluation of relationships between overall
discontinuation with SNPs and EFV-related adverse events (Stocrin
product information) and dose and SNPs was performed
using Cox regression adjusted a priori for potential
confounders (e.g. age, sex). Post hoc exploratory analysis of
the crude association of dose and SNPs with CNS-related
adverse effects, EFV-related adverse events (clinician
decision) and treatment cessation due to EFV-related
adverse event (clinician decision) was undertaken using
logistic regression or Cox regression as appropriate.
2.6 Evaluation of the Recommended Minimum
Effective Concentration (MEC, 1.0 mg/L)
Differences in the proportions of patients with
model-predicted EFV C12 below and above the recommended
minimum effect concentration (MEC) of 1.0 mg/L [
stratified by pVL (\200 copies/mL vs. C200 copies/mL)
was determined using Fisher’s exact test. A receiver
operating characteristic (ROC) analysis was also performed
to investigate the predictability of mid-dose interval
concentration (C12) cutoffs and achieving pVL \200 copies/
mL at 96 weeks. Patients with pVL missing at 96 weeks
were excluded from the analysis.
Statistical analyses were performed using SPSS version
21 (IBM Corporation, Armonk, NY, USA).
3.1 Patients and PK
Overall, 630 patients received at least one dose of EFV as
part of ENCORE1 [
]; 606 (32 % female) were included in
the previously described population PK model [
] and the
present analyses (Fig. 1a). Median (range) age, weight,
baseline (week 0) pVL and CD4 cell count were 35 years
quantification, ITT intention to treat, LC–MS/MS liquid
chromatography–tandem mass spectrometry, PCR polymerase chain reaction,
(18–69), 65 kg (39–148), 56,803 copies/mL
(162–10,000,000) and 270 cells/mm3, respectively.
Patients identified themselves as African (37 %), Asian
(33 %), Hispanic (17 %), Caucasian (13 %) and
Aboriginal/Torres Strait Islander (ATSI; 0.2 %), and 51 % and
49 % were randomised to EFV400 (n = 311) and EFV600
(n = 295), respectively.
Subsequent to PK model development [
additional SNPs were genotyped (ABCB1 3435C[T, NR1I2
63396C[T, NR1I2 7635A[G) to complete the panel
selected for ENCORE1. Upon assessment in the model as
covariates they were found not to have a significant impact
on EFV apparent oral clearance (CL/F). Therefore, the PK
parameters did not alter from the previous 48-week
analysis and were carried forward to the 96-week analysis. The
final model included baseline weight and CYP2B6
516G[T/983T[C/CYP2A6*9B/*17 composite genotype as
significant covariates [
]. Predicted EFV PK parameters
stratified by dose and by dose and metaboliser status
(extensive, intermediate, slow; based on CYP2B6 516G[T/
983T[C/CYP2A6*9B/*17 composite genotype), as
presented for the 48-week analysis, are summarised
(Online Resource 1 and 2, respectively).
Genotyping was possible in 595 patients, and of the 606
patients included in the analysis, 32 did not have a genotyping
sample (Fig. 1b). Amplification failed in three patients for
NR1I2 63396C[T and NR1I2 7635A[G. Depending on the
SNP, PK and genetic data were available for between 570 and
574 patients (Fig. 1b). Genotype frequencies summarised by
ethnicity are shown in Table 1 (Caucasian, Hispanic and
ATSI were combined for consistency with the 48-week
]); all were in Hardy–Weinberg equilibrium, with
the exception of NR1I2 7635A[G; however, this was rectified
when stratified by ethnicity.
3.3 PK–PD Analysis: Relationships with Virological and Safety Endpoints
At 96 weeks, 97 and 99 % of patients were \200 copies/
mL for EFV400 and EFV600, respectively (p = 0.091;
98 % pVL \200 copies/mL overall); 2 % (n = 13) had a
detectable pVL C200 copies/mL, and 5 % (n = 31) of pVL
Following univariable logistic regression, no
relationships were observed between achieving pVL \200 copies/
mL at 96 weeks and log-transformed EFV PK parameters
(logAUC24 odds ratio [OR] 4.20, 95 % CI 0.31–57.77,
p = 0.283; logCmax OR 1.87, 95 % CI 0.11–32.50,
p = 0.667; logC24 OR 4.17, 95 % CI 0.70–24.94,
p = 0.118; and logC12 OR 5.25, 95 % CI 0.41–67.90,
p = 0.204).
Eleven percent (n = 34) and 13 % (n = 39) of patients
discontinued EFV400 and EFV600, respectively
(p = 0.395; 73/606 [12 %]), and amongst those who
discontinued, median (range) time to discontinuation was
36 weeks (2–90). Significantly higher proportions of
EFV600 patients experienced EFV-related adverse events
than EFV400 (Stocrin product information: 73 vs. 66 %,
p = 0.043; clinician decision: 46 vs. 38 %, p = 0.048) and
more stopped therapy due to adverse events judged by a
clinician (8 vs. 3 %, p = 0.019). CNS adverse events were
similar between doses (42 % EFV400 vs. 46 % EFV600,
p = 0.287).
Model-derived AUC24, Cmax and C12 were significantly
lower in those who did not discontinue therapy or stop due
to EFV-related adverse events (clinician decision), and
EFV Cmax was significantly reduced in those who did not
experience EFV-related adverse events (Stocrin product
information or clinician decision). PK parameters were not
significantly different between those who did and did not
have CNS adverse events (Table 2).
3.4 Pharmacogenetics: Relationships with Virological and Safety Endpoints
None of the SNPs assessed were associated with achieving
pVL \200 copies/mL (Table 3). Proportions of patients
with pVL C200 copies/mL at 96 weeks stratified by
GMRs geometric mean ratios, PI product information, CI confidence interval, AUC24 area under the curve over 24 h, Cmax maximum
concentration, C24 trough concentration 24 h post-dose, C12 concentration 12 h post-dose representing the mid-dose interval concentration
a n = one patient excluded; received efavirenz 800 mg during pharmacokinetic sampling
b No event/event
metaboliser status were similar between doses (EFV400 vs.
EFV600 extensive: 3 vs. 1 %, p = 0.624; intermediate: 4
vs. 2 %, p = 0.281; slow: 5 vs. 0 %, p = 0.504).
Following adjustment for age, sex and dose, and
stratifying by country, CYP2B6 516GT, TT and CYP2A6*9B
heterozygote or homozygous variant (CA or AA) patients
had an 80, 166 and 100 % increased risk of overall
discontinuation, respectively, whereas NR1I2 63396TT
carriers had a 22 % reduced risk (Table 4). Upon
multivariable Cox regression analysis, dose or SNPs were not
associated with EFV-related adverse events (Stocrin
product information or clinician decision) following
adjustment; however, a greater risk of stopping due to
EFV-related adverse events by clinician decision was
observed with EFV600 compared with EFV400 (OR 2.54,
95 % CI 1.19–5.43, p = 0.016). A decreased risk of CNS
CI confidence interval, HR hazard ratio
a Forwards likelihood ratio
b Adjusted for dose, age, sex; stratified by country
adverse events (Stocrin product information) was
associated with CYP2B6 983TC or CC carriers (OR 0.30, 95 %
CI 0.12–0.75, p = 0.010) but an increased risk in patients
with CYP2B6 15582CT or TT and ABCB1 3435TT carriers
was observed (OR 1.59, 95 % CI 1.11–2.27, p = 0.011;
and OR 2.14, 95 % CI 1.25–3.67, p = 0.006, respectively).
3.5 Evaluation of the Recommended MEC (1.0 mg/ L)
The proportions of patients with pVL C200 copies/mL was
not significantly different between those with
model-predicted EFV C12 above or below 1.0 mg/L (2 vs. 11 %,
p = 0.059). Fourteen and six patients had predicted C12
below the recommended MEC for EFV400 and EFV600,
respectively, but only one patient in each randomised arm
was not suppressed below 200 copies/mL at 96 weeks. In
these two patients, EFV C12 and metaboliser status were
0.77 mg/L and extensive metaboliser (EFV400), and
0.38 mg/L and intermediate metaboliser (EFV600; two
viral load measurements were unavailable) [Online
Resource 3]. The ranges of predicted C12 stratified by
metaboliser status of the ten (EFV400) and three patients
(EFV600) with pVL C200 copies/mL at 96 weeks (n = 13
total) were 0.77–3.65 mg/L (extensive, n = 3),
1.45–3.38 mg/L (intermediate, n = 5), 3.0 mg/L and
6.10 mg/L (slow, n = 2) for EFV400; and 2.19 mg/L
(extensive, n = 1), 0.38 mg/L and 3.02 mg/L
(intermediate, n = 2) for EFV600.
Generally, the ROC curve lay along the line of unity
between sensitivity and 1-specificity, suggesting the
analysis was informative to an extent. The
sensitivity/specificity of using C12 of 1.0 mg/L (currently recommended
MEC) for achieving pVL \200 copies/mL at 96 weeks
was 97.1 %/84.6 %, with a likelihood ratio (LR) of 6.
Acceptable ROC criteria were generated for a number of
C12 values, suggesting a range of potential cutoffs; for
example, C12 between 0.47 and 0.76 mg/L provided
sensitivity/specificity [90 % (100 %/92.3 % to 98.9 %/
92.3 %) with an LR of 13.
ENCORE1 included a genetically and geographically
diverse population of patients, thus providing an important
dataset for thorough investigation of EFV PK–PD and
pharmacogenetic relationships with clinical outcome and
adverse events. EFV concentrations have previously been
associated with virus suppression [
]; however, this was
not confirmed in ENCORE1. Relationships between
modelderived PK parameters and achieving pVL\200 copies/mL
at 96 weeks (cross-sectional assessment) were not
significant. Although significant associations were observed
with pVL \200 copies/mL at the 48-week cross-sectional
analysis (but CIs were wide) , both analyses should be
interpreted cautiously, given only 16/593 (3 %) and 13/575
(2 %) patients had pVL C200 copies/mL at 48 and 96 weeks,
respectively. Furthermore, the PK was performed between 4
and 12 weeks, and the association may have been lost for the
more distal assessment at 96 weeks. Moreover, similar to the
48-week analysis [
], none of the SNPs assessed showed a
significant association with virological control at 96 weeks.
This is in agreement with previous studies in which CYP2B6
polymorphisms in particular did not predict virological
failure in HIV patients with differential or self-reported poor
]. Given the low proportion of failures in
ENCORE1, the study lacked adequate power to fully
evaluate the impact of selected SNPs on HIV suppression.
However, a genome-wide association study conducted by
Lehmann and colleagues was able to detect a genotypic
relative risk of approximately 80 % power for
polymorphisms with strong individual effects, but no associations
with failure were observed even when adherence subgroups
were considered .
Possession of homozygous wild-type CYP2B6
15582C[T/516G[T/983T[C (CC/GG/TT) is predictive of
EFV C24 in the lowest concentration stratum [
concerns have grown as to whether this population of
individuals would be at increased risk of virological failure,
particularly when receiving EFV400. This genotype was
not predictive of failure in patients receiving the standard
EFV dose [
] and 47 ENCORE1 patients randomised to
EFV400 with this genotype; only one had a detectable pVL
C200 copies/mL at 96 weeks. Individual mean predicted
EFV C24 was 2.79 mg/L in this patient and well above the
median of 0.82 mg/L for this genotype group.
A previously defined MEC of 1.0 mg/L is often quoted
as a therapeutic cutoff for EFV mid-dosing interval
]; however, this value was obtained in an
era of less potent antiretroviral therapy, with lamivudine,
zidovudine, nelfinavir and amprenavir most commonly
coadministered with EFV [
]. The validity of a
threshold concentration for virological failure has also been
disputed due to low sensitivity of the predictive value,
particularly in adherent patients [
]. ENCORE1 provided
an opportunity to investigate the plausibility of the widely
implemented MEC. We chose to evaluate the threshold
using the final 96-week pVL data rather than 48 weeks as
this may be more representative of patients receiving
longterm therapy. Assessment of the MEC was based on C12
(representing mid-dose interval concentrations) instead of
C24 in order to remain consistent with the original
publication by Marzolini et al [
]. However, it is important to
note that with only 2 % of patients with pVL C200 copies/
mL at 96 weeks, a robust interrogation of the MEC is
limited and care must be taken not to infer too much from
the analysis. A range of C12 cutoffs (representing
middosing interval concentration) with acceptable sensitivity
and specificity criteria were obtained by ROC analysis,
suggesting a single threshold value is not statistically valid.
Also, the proportion of patients with detectable viral load
C200 copies/mL at 96 weeks was not significantly
different between patients with predicted C12 below or above
1.0 mg/L with a similar lack of association for C24 (data
not shown). However, this analysis should be interpreted
cautiously given the limited failures and that PK data
obtained following 4–12 weeks of therapy may not reflect
concentrations at 96 weeks. Nonetheless, EFV
concentrations below the currently accepted MEC had better
sensitivity/specificity for achieving 96-week pVL \200 copies/
mL, suggesting adherence is an important driver of
virological suppression at 96 weeks in ENCORE1 patients.
Self-reported adherence was documented at weeks 4, 48
and 96, and was [90 % in both treatment arms, which is
generally consistent with findings observing optimal
treatment response with adherence C95 % by pill count
]. Unfortunately, the adherence data collected as part of
ENCORE1 were not sensitive enough to determine impact
on clinical outcome.
Rates of overall discontinuation increased from 7 % at
48 weeks [
] to 12 % at 96 weeks, but were similar for
both EFV doses and comparable with previous reports [
]. EFV concentrations influenced by metabolic and
nuclear receptor polymorphisms but not dose were
significantly associated with discontinuation. In contrast to the
48-week analysis, carriers of both CYP2B6 516GT or TT
variants were at increased risk due to higher EFV
concentrations, along with CYP2A6*9B CA/AA. For the
48-week analysis, CYP2B6 516GT was not associated with
]; however, at 96 weeks,
discontinuations had increased, potentially altering the statistical
association. Possession of NR1I2 63396TT lowered the risk
of discontinuation by 22 % but was not assessed at
48 weeks, and inclusion in the multivariable model at
96 weeks may also speak to the disparity in relationships
observed with overall discontinuation at 48 and 96 weeks.
Pregnane X receptor (PXR, NR1I2) regulates basal
CYP3A4 expression, and NR1I2 63396C[T has been
linked to altered expression of PXR and activity of
]. Homozygosity for the NR1I2 63396C[T
variant has been associated with increased oral clearance
and subtherapeutic trough concentrations of unboosted
], and although CYP3A4 is a minor route
of EFV metabolism, decreased risk of discontinuation in
NR1I2 63396TT patients may be a consequence of lower
concentrations resulting from increased metabolism.
CNS adverse events at 96 weeks (as outlined in the
Stocrin product information) were not associated with
EFV dose or plasma concentrations. The primary
metabolite produced by CYP2B6 metabolism,
8-hydroxyefavirenz (8OH-EFV) [
], has been identified in vitro as a
contributing factor to toxicity in rat neuronal cultures [
and potentially 8OH-EFV, rather than the parent
compound, is a causative agent of CNS adverse events. Indeed,
in ENCORE1 patients a lower risk of CNS adverse events
at 96 weeks (and similarly at 48 weeks [
]) was observed
in CYP2B6 983TC/CC carriers, in which CYP2B6
metabolism is impeded, generating less 8OH-EFV and thus
providing a protective effect. Conversely, ABCB1 3435TT
markedly increased the risk of experiencing CNS adverse
events by 131 % compared with wild-type (CC). This is in
general consensus with a previous AIDS Clinical Trials
Group (ACTG) study that reported a relationship between
ABCB1 3435TT (with ABCB1 2677G[T) and failure of
EFV-containing regimens due to toxicity [
encodes the multidrug efflux transporter P-glycoprotein,
which is present at various physiological sites, including
the blood–brain barrier [
], where it limits entry of
compounds, including drugs, into the CNS. Furthermore,
ABCB1 3435TT has been associated with decreased
P-glycoprotein expression . EFV is not transported by
], but it is currently unknown
whether EFV metabolites, such as 8OH-EFV, are substrates.
We hypothesise that if 8OH-EFV is a substrate, patients
possessing the ABCB1 3435TT variant would be at greater
risk of CNS toxicity as a result of reduced efflux at the
Concerns regarding EFV-induced toxicities and
discontinuations due to these toxicities have recently led to
alterations in HIV treatment guidelines in the UK and US,
replacing EFV with integrase inhibitor-based (raltegravir,
dolutegravir, elvitegravir–cobicistat) regimens, or boosted
darunavir- or atazanavir-containing regimens as the
preferred first-line treatment for therapy-na¨ıve adults [
Although recommended as an alternative agent in
developed countries, EFV remains the first-line option for
treatment-na¨ıve patients in resource-limited settings due to
the lack of availability of newer compounds . Lower
rates of EFV-related adverse events (Stocrin product
information and clinician decision) were experienced with
EFV400 compared with EFV600. Moreover, EFV600 was
independently associated with a 154 % higher risk of
stopping due to EFV-related adverse events (clinician
decision). Improved tolerability of EFV400 would
therefore prove beneficial, lowering discontinuations and
preserving future treatment options for longer.
EFV plays a key role in the treatment of
HIV/tuberculosis (TB) co-infection [
] and is a recommended option
for HIV-infected pregnant women [
]. Rifampicin and
isoniazid, essential components of TB therapy, are known
to alter the EFV metabolic pathway through potent
induction of CYP2B6 and CYP3A4, and inhibition of
CYP2A6, respectively [
]. However, adequate HIV
suppression has been observed in HIV/TB patients
receiving EFV600 in the presence of TB medications [
Differential effects of rifampicin on CYP2B6 induction
according to genotype have been reported with greater
effects observed in those with fully functional CYP2B6,
leading to lower EFV concentrations in the presence of
rifampicin compared with EFV alone [
] and potentially
placing these patients at higher risk of failure. The impact
of TB therapy on EFV400 has not been studied and PK–PD
data are necessary before considering EFV dose reduction
in this patient population.
EFV PK–PD data during pregnancy and post-partum are
increasing. Some studies suggest little clinical impact of
pregnancy on EFV PK [
], however others have
reported increased CL/F, particularly in extensive
], but cases of mother-to-child
transmission were rare [
]. In the absence of clinical evidence,
EFV dose reduction in this distinct population is not
recommended; however, a clinical study to investigate the PK
of EFV400 during pregnancy is planned in
virologicallysuppressed (pVL \50 copies/mL), HIV-infected women
stable on EFV600 [
ENCORE1 has demonstrated successful antiretroviral dose
reduction, striking a balance between sustained virological
responses with fewer adverse events. Although a threshold
concentration may be clinically valuable, it was not
associated with HIV suppression in ENCORE1 patients and
may be of questionable use in resource-limited settings
where routine drug measurement is not performed.
Implementation of EFV dose reduction to 400 mg once
daily would improve toxicity management whilst
maintaining durable efficacy and would reduce drug costs,
allowing greater treatment coverage. Potentially, the
savings made could also aid funding of other public health
initiatives such as HIV prevention and education strategies.
Compliance with Ethical Standards
The authors would like to thank all the patients who volunteered to
participate in this study.
ENCORE1 substudies were funded through a project grant from the
Australian Government National Health and Medical Research
Council (NHMRC; APP1048402). The Kirby Institute is funded in
part by the Australian Government Department of Health and Ageing.
Gilead Sciences, Inc. donated TruvadaTM, and Mylan Inc. provided
EfamatTM and donated matched placebo.
All authors had full access to the study data and agreed to submit for
publication. The corresponding author had final responsibility for the
decision to submit for publication. No medical writers were used and
no agency made any payments for writing. Neither the funding
agency nor pharmaceutical companies supporting the trial played any
role in the collection, analysis, interpretation or reporting of these
Laura Dickinson is supported by Pre-DiCT-TB and has received a
travel bursary from Gilead Sciences, Inc.; David Back, Saye Khoo,
Andrew Owen and Laura Else have received research grants and/or
travel bursaries from Merck, Bristol–Myers Squibb,
GlaxoSmithKline, Pfizer, Abbott, ViiV Healthcare, Boehringer Ingelheim and
Janssen Pharmaceuticals; Marta Boffito has received travel and
research grants from, and has been an adviser for, Janssen, Roche,
Pfizer, ViiV Healthcare, Bristol–Myers Squibb, Merck Sharp &
Dohme and Gilead; Catherine Orrell has received a travel bursary
from Tibotec (2013) and an honorarium from Abbott (2011); Marcelo
Losso has received research grant support from Abbott, Merck
Research Laboratories and Pfizer; David A. Cooper has received
honoraria and research grant support from Gilead Sciences, Merck
Research Laboratories and Bristol–Myers Squibb; and Sean Emery
has received research grant support from Abbvie, Gilead Sciences,
Merck Research Laboratories, Pfizer and ViiV Healthcare. Rebekah
Puls, Janaki Amin, Deirdre Egan, Amanda Clarke, Dianne Carey and
Praphan Phanuphak report no conflicts of interest.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
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