Review

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Potential effect of pharmacogenetics on maternal,

fetal and infant antiretroviral drug exposure during
pregnancy and breastfeeding
Mother-to-child-transmission rates of HIV in the absence of any intervention range between 20 and 45%.
However, the provision of antiretroviral drugs (ARVs) during pregnancy, delivery and breastfeeding can
reduce HIV transmission to less than 2%. Physiological changes during pregnancy can influence ARV
disposition. Associations between SNPs in genes coding for metabolizing enzymes, and/or transporters,
and ARVs disposition are well described; however, relatively little is known about the influence of these
SNPs on ARV pharmacokinetics during pregnancy and lactation as well as their effect on distribution into
the fetal compartment and breast milk excretion. Differences in maternal, fetal and infant ARV exposure
due to SNPs may affect the efficacy and safety of ARVs used to prevent mother-to-child-transmission. The
aim of this review is to provide an update on the effect of pregnancy-induced changes on the
pharmacokinetics of ARVs and highlight the potential role of pharmacogenetics.

KEYWORDS: antiretrovirals n drug transporters n highly active antiretroviral therapy
n HIV n pregnancy n prevention of mother-to-child transmission
Mother-to-child-transmission (MTCT) rates of
HIV without any intervention range between 20
and 45% [1] . An estimated 387,000 children were
infected with HIV through MTCT in 2008 [201] .
Approximately 80% of these children acquired
HIV infection during labor and in the peri-
partum period, with the remaining infections
occurring during breastfeeding [202] . A major
step forward in the fight to eliminate pediatric
HIV/AIDS has been the introduction of highly
efficacious, prophyl­actic, antiretroviral (ARV)
regimens to prevent MTCT of HIV.
The ACTG 076 trial was the first to demon­
strate the efficacy of maternal/infant ARV
prophyl­­axis in prevention of MTCT of HIV [2] .
Providing zidovudine (ZDV) monotherapy dur-
ing pregnancy (starting between 14 and 34 weeks
gestation), during delivery and to the newborn
for 6 weeks reduced HIV transmission rates from
25 to 8% in nonbreastfeeding infants. A single
maternal dose of nevirapine (NVP) at the onset
of labor and to the newborn at 48–72 h of life
was shown to reduce perinatal HIV transmission
[3] . Combining ZDV monotherapy prophyl­­axis
with single-dose maternal/infant NVP reduced
HIV transmission to less than 2% [4] . Owing to
the rapid scale-up of ARV treatment programs,
an increasing number of HIV-infected pregnant
women are receiving highly active antiretroviral
therapy (HAART) during pregnancy for HIV
treatment and/or the prevention of transmission
of HIV. HAART during pregnancy and delivery
can reduce HIV transmission rates to 1.3% in
Adeniyi Olagunju1,2,
Andrew Owen2
& Tim R Cressey*3,4,5
nonbreastfeeding infants [5] . Moreover, maternal 1
Faculty of Pharmacy, Obafemi
HAART or daily infant NVP can reduce HIV-1 Awolowo University, Nigeria
2
Department of Molecular & Clinical
transmission during breastfeeding [6,7] . Maternal Pharmacology, Institute of
HA ART during pregnancy, delivery and Translational Medicine, University of
Liverpool, Liverpool, UK
through planned weaning by 6 months postpar- 3
Program for HIV Prevention &
tum can reduce HIV transmission to less than Treatment, Department of Medical
2% [8] . The 2010 WHO guidelines for the use Technology, Faculty of Associated
Medical Sciences, Chiang Mai
of ARVs for treating pregnant women and pre- University, Thailand
venting HIV infection in infants recom­mends 4
Harvard School of Public Health,
Boston, MA, USA
triple-ARV treatment for pregnant women who 5
Institut de Recherche pour le
need therapy for their own health (i.e., CD4 Développement (IRD), UMI 174,
Marseille, France
cell count below 350 cells/ml). For women who *Author for correspondence:
are not eligible for ARV therapy, two options Tel.: +66 53 894 994
are proposed: either ZDV monotherapy from Fax: +66 53 894 220
tim.cressey@phpt.org
as early as 14-weeks gestation plus intrapar-
tum single-dose NVP; or maternal triple-ARV
prophyl­­axis [203] . Breastfeeding infants are rec-
ommended to receive daily NVP prophyl­­axis
from birth throughout breastfeeding.
Achieving optimal ARV exposure throughout
pregnancy is critical. Physiological changes dur-
ing pregnancy can influence drug disposition and
several studies have demonstrated reduced ARV
exposures during pregnancy [9] . Considerable
data have demonstrated that host genetic poly-
morphisms in drug-metabolizing enzymes and
drug transporters can contribute towards the
interpatient variability of ARV pharmaco­­kinetics
[10] . Associations between SNPs and drug con-
centrations for several ARVs in adults and chil-
dren are well described [11] . Accumulating data
also indicate that SNPs associated with drug
toxicities or pharmaco­­kinetics can help identify part of

10.2217/PGS.12.138 © 2012 Future Medicine Ltd Pharmacogenomics (2012) 13(13), 1501–1522 ISSN 1462-2416 1501
Review Olagunju, Owen & Cressey

individuals at risk of early treatment discontinu- pregnancy can decrease drug absorption of weak
ation [12,13] . The influence of host genetic poly- acids, while increasing the absorption of weak
morphisms on HAART during pregnancy has bases. Longer gastrointestinal emptying/transit
not been extensively studied. However, it is pos- times due to higher progesterone production
sible that SNPs associated with ARV pharmaco­­ during pregnancy can slow the rate of absorp-
kinetics could exacerbate or reduce the effect of tion but could potentially increase overall drug
pregnancy-induced changes. In addition, data absorption. Nausea and vomiting associated
describing the influence of pharmaco­genetics with pregnancy can contribute to lower drug
on ARV safety and efficacy during lactation are adherence and absorption. Increases in body
limited. water, plasma volume and fat stores can increase
The aim of this review is to provide an update the volume of distribution of a drug thereby
on the effect of pregnancy-induced changes on reducing maximum plasma drug concentra-
the pharmaco­k inetics of ARVs and to provide tions. Pregnancy has been associated with a 15%
an overview of the potential role of pharmaco­ decline in plasma albumin and a >50% decline
genetics. The implications of pharmaco­genetics in a-1-acid glycoprotein concentrations, there-
on the exposure of breastfed infants to maternal fore the clearance of highly protein-bound drugs
ARVs during lactation are also discussed. may be higher during pregnancy because of the
increased percentage of unbound drug avail-
ARVs & HIV treatment able for metabolism (hepatic extraction ratio).
There are currently 26 ARVs approved by the Furthermore, changes in glomerular filtration
US FDA [204] . ARVs are classified into differ- rate, active tubular secretion and/or absorp-
ent classes based on their mechanisms of action. tion can affect renal excretion of drugs. The
To date, there are six ARV drug classes: nucleo- glomerular filtration rate in healthy women was
side/nucleotide reverse transcriptase inhibitors shown to be at least 50% higher during preg-
(NRTIs/NtRTIs); non-nucleoside reverse tran- nancy [14] . Common membrane transporters
scriptase inhibitors (NNRTIs); protease inhibi- are involved in active tubular secretion and/or
tors (PIs); integrase strand transfer inhibitors absorption but the effect of pregnancy has not
(INSTIs); entry inhibitors; and fusion inhibitors. been studied. Alterations in the activities of
HAART is recommended for the treatment of several key hepatic drug-metabolizing enzymes
HIV, and generally this involves providing triple-­ during pregnancy have been reported. The
ARV combinations from at least two drug classes. expression and activities of CYP3A4, CYP2C9
For example, current first-line HAART regimens and CYP2C19 vary at different stages of preg-
combine two NRTIs plus either a NNRTI, PI nancy. Tracy et al. reported a 35–38% increase
or INSTI [205] . in CYP3A4, CYP3A5 and CYP3A7 activities
All approved ARVs are administered orally, at all stages of pregnancy compared with post-
except for the fusion inhibitor, which is injected partum [15] . Progesterone-mediated activation
under the skin using a needle-free injection of nuclear receptors involved in the regula-
device. The majority of NRTIs/NtRTIs are tion of drug-metabolizing enzymes has been
excreted as unchanged drugs, while the other suggested as one of the mechanisms for preg-
classes undergo Phase I and/or II metabolism nancy-induced increases in drug-­metabolizing
by the CYP450 enzymes and UGT. A summary enzyme expression [16] . CYP3A4 is known to
of the elimination pathways for each of the share transcriptional regulation and induction
approved ARVs is presented in Table 1. Several pathways (mainly through the PXR and the
ARVs are both inducers and inhibitors of various CAR [NR1I3]) with other drug-metabolizing
CYP enzymes and drug transporters, which can enzymes, including CYP2B6, CYP2C and
lead to complex drug–drug interactions. UGT [17–19] . UGT-mediated glucuronidation
of some drugs also has been shown to increase
Physiological changes during during pregnancy. For example, the clearance of
pregnancy & potential effect on drug dihydro­artemisinin (a UGT1A9/2B7 substrate),
disposition the active metabolite of the antimalaria drug
Drug absorption, distribution, metabolism and artesunate, increases by 42% during pregnancy
excretion can be influenced by physiological [20] . Finally, the activity of ADH was higher dur-
changes during pregnancy. Changes in drug ing pregnancy in rodents [21] . The functional
absorption during pregnancy are highly depend- consequences of SNPs on genes encoding com-
ent on the physiochemical properties of drugs. mon metabolizing enzymes are summarized
For example, increases in gastric pH during in Table 2 .

1502 Pharmacogenomics (2012) 13(13) future science group

 Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding Review
Table 1. Summary of antiretroviral-metabolizing enzymes, transporters and protein binding.
Drug Metabolism Transporters Protein binding (%)
Nucleoside reverse transcriptase inhibitors
Abacavir ADH and UGT ABCB1 and ABCG2 50
Didanosine Excreted unchanged ABCC4, SLC28A2, SLC28A3, SLC29A1, <5
SLC29A2 and SLC29A3
Emtricitabine Excreted unchanged ABCC1 and ABCC4 <4
Lamivudine Excreted unchanged ABCG2, ABCC4, SLC22A1, SLC22A2, 36
SLC22A3, SLC28A1, SLC28A3 and SLC29A3
Stavudine Excreted unchanged ABCC4, SLC28A1, SLC28A3 and SLC29A3 <10
Tenofovir Excreted unchanged ABCB1, ABCC4, ABCC10, SLC22A6 and >7
SLC22A8
Zidovudine UGT2B7 ABCG2, ABCC4, SLC22A6, SLC22A7, SLC22A8 30–38
and SLC22A11
Non-nucleoside reverse transcriptase inhibitors
Delavirdine CYP3A4 NA 98
Efavirenz CYP2B6, CYP2A6, UGT2B7 and ABCG2, Abcb5 99
CYP3A4
Etravirine CYP2C19, CYP3A4 and CYP2C9 NA >99
Nevirapine CYP3A4 and CYP2B6 ABCC10 60
Rilpivirine CYP3A4 and CYP3A5 NA >99
Protease inhibitors
Amprenavir CYP3A4 ABCB1 90
Atazanavir CYP3A4 ABCB1, ABCC1 and ABCG2 86
Darunavir CYP3A4 ABCB1, SLCO1A2 and SLCO1B1 95
Fosamprenavir CYP 3A4 ABCB1 90
Indinavir CYP3A4 ABCB1 and ABCC2 60
Lopinavir CYP3A4 ABCB1, ABCC1, ABCC2, SLCO1A2 and 98
SLCO1B1
Nelfinavir CYP3A4 and CYP2C19 ABCB1 >98
Ritonavir CYP3A4 and CYP2D6 ABCB1 and ABCC2 98
Saquinavir CYP3A4 and CYP3A5 ABCB1, ABCC2, SLCO1A2, SLCO1B1 and 97
SLCO1B3
Tipranavir CYP3A4 ABCB1 >99
Integrase/fusion/entry inhibitors
Enfuvirtide Excreted unchanged NA 92
Maraviroc CYP3A4 ABCB1 and SLCO1B1 76
Raltegravir UGT1A1 ABCB1, SLC15A1 and OAT1c 83
NA: No available data.

Pregnancy & drug transporters the physiochemical properties, placental blood

ARV use during pregnancy can lead to fetal
exposure to the drugs. Maternal ARV pen-
etration into the fetal compartment may be a
factor contributing to towards their overall
prophyl­actic effect [22] . Conversely, fetal ARV
exposure has implications for toxicities that
have been documented [23,24] . In addition to
flow, plasma pH, protein binding and placen-
tal drug metabolism, fetal exposure is depend-
ent on the placental expression, subcellular
localization, activity and substrate specificity of
drug efflux and influx transporters [25] . At least
18 transporters known to be relevant to ARV
distribution are expressed on either the apical

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Review Olagunju, Owen & Cressey
Table 2. Influence of genetic polymorphisms in metabolizing
enzymes/nuclear receptors on antiretroviral drug exposure.
Protein/gene Functional SNPs (effect on plasma exposure)
CYP2A6 1836G>T and 1093G>A (↑ EFV) [113,114]
CYP2B6 516G>T and 983T>C (↑ EFV and ↑ NVP) [94,95]
CYP2C19 rs4244285 and rs12248560 (? ETR)
CYP3A5 CYP3A5*1 (↓ SQV, ↓ IDV and ↓ ATV) [95,143]
*3 (↓ NVP)
UGT1A1 UGT1A1*28 and 211G>A (↑ ATV-related hyperbilirubinemia) [148,149]
UGT2B7 735A>G (↔ EFV)
802C>T (↓ EFV)
CAR (NR1I3) 540CC (↑ discontinuation of EFV)
PXR (NR1I2) 63396 C>T (↓ ATV)
?: Effect unknown; ↑: Increased; ↓: Decreased; ↔: No difference; ATV: Atazanavir; EFV: Efavirenz;
ETR: Etravirine; IDV: Indinavir; NVP: Nevirapine; SQV: Saquinavir.
(maternal) and basolateral (fetal) membranes of
syncytiotrophoblasts as well as the endothelium
of fetal capillaries (Figure 1) . Members of the ATP-
dependent binding cassette efflux transporter
superfamily limit fetal exposure to maternal
ARVs [26] . Transporters in the ATP-independent
solute carrier superfamily, including organic
anion transporting polypepetides, organic anion
transporters, organic cation transporters (OCTs)
and equilibrative nucleoside transporters, are also
relevant for distribution of ARVs into the fetal
compartment. Recently, Iqbal et al. reviewed the
gestational changes in the expression and func-
tion of placental drug transporters as well as the
associated genetic polymorphisms [27] . The func-
tional consequences of genetic polymorphisms
in the encoding genes were also been recently
highlighted by Ieiri et al. [28] . The substrate spe-
cificities, placental and mammary gland expres-
sion, and effects of associated functional SNPs
are presented in Table 3. Their localization on the
basolateral or apical membranes of the placental
syncytiotrophoblast and the cord:maternal blood
(C:M) ratios for ARVs are shown in Figure  1.
Ultimately, the transfer of drug from mother
to infant will depend on the combined influ-
ence of influx and efflux transporters within the
placental barrier. Furthermore, the subcellular
localization of such transporters is also likely to
be important since an apical influx transporter
may exhibit a similar effect upon fetal exposure
(in terms of direction) as that of a basolateral
efflux transporter and vice versa. Therefore, it is
important to consider synergy and antagonism
between multiple transporters when examining
specific mechanisms. Although it is conceivable
that transport may occur from mother to infant
or from infant to mother, the key phenotype
1504 Pharmacogenomics (2012) 13(13)
is the net effect on exposure of the infant to
maternal xenobiotics.
Other factors such as drug–drug interactions,
Ref.
HIV infection and coinfections have been rec-
ognized to affect drug transporter function in
other tissues [29–33] . Drug–drug interactions at
[123] the human placenta can also affect fetal expo-
sure to maternal drugs [34] . Therefore, the effects
of such nongenetic factors are recognized to be
important but are understudied and beyond the
scope of this review.
[114]
NRTI/NtRTI pharmacokinetics during
[13] pregnancy & the potential role of
[144]
pharmacogenetics
There are currently eight NRTIs/NtRTIs
approved for HIV treatment. All NRTIs/NtRTIs
are administered as prodrugs and must
undergo intracellular metabolism by cellular
kinases to their active ‘triphosphate’ anabo-
lites. Routine measurement of intracellular
NRTI–triphosphate concentrations remains
challenging. Comprehensive NRTI pharmaco­
kinetic data available during pregnancy have
subsequently been restricted to plasma NRTI
concentrations; however, the relationship
between NRTI plasma concentrations and drug
efficacy/toxicity remains unclear [35] . Below is
a summary of the effect of pregnancy on indi-
vidual NRTI/NtRTI exposure and available
pharmaco­genetic data.
ZDV (also know as azidothymidine) is a thy-
midine analog and was the first ARV approved
for treatment of HIV infection in 1987 [204] . It
was also the first ARV administered to HIV-
infected pregnant women and continues to play
a major role in the currently recommended
ARV prophyl­actic regimens. ZDV is primarily
eliminated through hepatic metabolism by UGT
[36] . Several studies have reported that ZDV
pharmaco­k inetics during the third trimester
of pregnancy are similar to nonpregnant adults
[37–39] . However, lower ZDV exposure during
the third trimester versus the postpartum period
has been reported (Table  4) [40] . The standard
dose of ZDV is currently 300 mg twice daily,
and no adjustments are recommended during
pregnancy. A lower dose of ZDV, 200 mg twice
daily, has been studied in nonpregnant adults
with low bodyweights (<60 kg) owing to con-
cerns of higher rates of drug toxicity. Pharmaco­
kinetic [41] and efficacy data [42] suggest that
this lower dose may be preferable in this patient
group; however, this dose has not been studied
in pregnant women. ZDV readily crosses the
placenta to the fetal compartment with a C:M
future science group
 Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding
concentration ratio of 1.13–1.27 [40] . To date,
no data on the effect of UGT host genetic poly-
morphisms on plasma ZDV pharmaco­k inetics
have been reported. Association between ZDV-
triphosphate concentrations and a SNP in the
drug transporter ABCC4 (MRP4) in HIV-
infected nonpregnant adults has been reported
[43] . Median ZDV–triphosphate concentra-
tions were 49% higher in ABCC4 3724G>A
(rs11568695) carriers versus homozygotes for
the common allele (p = 0.03). Two SNPs within
ABCG2, 421C>A (rs2231142) and 34G>A
(rs2231137), were also assessed, but neither were
associated with ZDV–triphosphate concentra-
tions. ABCC4 has been shown to contribute to
ZDV uptake into conditionally immortalized
rat syncytiotrophoblasts [44] and the clinical
Review
implications of ABCC4 polymorphisms during
pregnancy therefore warrant further study.
Stavudine (d4T) is thymidine analog. The
WHO ARV treatment guidelines recommend
a 30-mg twice-daily dose for adults [206] . The
pharmaco­k inetics of d4T in pregnancy appear
to be similar to those in HIV-infected men and
no dose adjustment is recommended [45] . Mean
d4T C:M concentration ratio is 1.0 (95% CI:
0.63–1.37). This drug was included in the first
generic fixed-dose combinations developed and
has been widely used in resource-limited set-
tings. However, WHO now suggests that coun-
tries phase out d4T and develop plans to move
towards alternative firstline regimens, primar-
ily owing to d4T-associated lipodystrophy. No
data are available on the role of transporter or

TFV (0.26–1.95)
SQV (0.00–0.06) [170] ABCC1
[169]

TPV (0.41)‡ RAL (0.09–2.3)

ABCB1 [156]
CYP3A4 [161] SLCO1B3
RTV (0.00–0.03)
[169] NVP (0.37–0.93)
[171] SLCO1B1
NFV (0.07–0.43)
SLC29A1 [172] UGT2B7 SLC22A3
MVC† (0.03–0.05)
[173]
SLC22A2
CYP3A4
BCRP ETR (0.30–0.40)
[122]
ZDV (0.18–17.2)
[169]
T-20 (ND) DRV (0.15–0.31) SLC22A1
[174] [175]

ABCC5
SLC29A2
LPV (0.18–0.21) ABC (0.92–1.42)
[130] [169] SLCO1A2
CYP2B6
IDV (0.00–0.08) EFV (0.37–0.74)
[108] SLC22A11
[169] APV (0.24–0.45)
ABCC2 [169]
SLC22A7

ATV (0.10–0.16) ABCC10 3TC (0.21–4.03)

[140] [169]

Maternal 0% 25% 50% 75% 100% Infant

(apical) (basolateral)

Figure 1. Placental expression of antiretroviral transporters and metabolizing enzymes. Cord:maternal blood (C:M) ratios are
shown in parentheses after the drug name. SLCO1A2 and SLCO1B3 are predominantly localized to the vasculo–syncytial membrane, while
SLCO1B1 appears to be expressed only in the first trimester. ABCC10 is also expressed at the placenta barrier, but its location has not
been determined.
†
In rhesus macaques.
‡
A single case report.
3TC: Lamivudine; ABC: Abacavir; APV: Amprenavir; ATV: Atazanavir; DRV: Darunavir; EFV: Efavirenz; ETR: Etravirine; IDV: Indinavir;
LPV: Lopinavir; MVC: Maraviroc; NFV: Nelfinavir; NVP: Nevirapine; RAL: Raltegravir; RTV: Ritonavir; SQV: Saquinavir; T‑20: Enfuvirtide;
TFV: Tenofovir; TPV: Tipranavir; ZDV: Zidovudine.

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Review Olagunju, Owen & Cressey

Table 3. Placenta and mammary gland expression, localization and substrate specificity of known antiretroviral
drug transporters and effects of associated functional SNPs.
Transporter (gene) Tissue localization Substrates Effects of SNPs Ref.
MDR1 (ABCB1) Placenta †
PIs , RAL, MVC, TFV
‡
3435C>T (↓ protein expression and ↓ NVP ht) [30,33,
and ABC 2677G>T (↓ protein expression) 176,177]
-129T>C (↓ protein expression)
MDR5 (ABCB5) Mammary gland§ EFV¶ ND [178]

MRP1 (ABCC1) Placenta and mammary

#
ATV, RTV, LPV, SQV, ND [33,179]
gland # IDV and FTC
MRP2 (ABCC2) Placenta† PIs‡ 1249G>A (SQV ↑), -24C>T (↓ IDV and ↓ TFV [82,180]
ktd)
MRP5 (ABCC5) Placenta # and mammary gland d4T ND [177,181]

BCRP (ABCG2) Placenta† and mammary gland NRTIs and EFV (?) C421A (↓ exp/act) [177,182]
rs2231164 (?)
rs2622604 (?)
MRP7 (ABCC10) Placenta§ and mammary gland TFV and NVP rs9349256 and rs2125739 (↑ TFV ktd), [72,96]
c.2759T>C (↓ NVP)
OATP1A2 (SLCO1A2) Placenta #†† PIs‡ SLCO1A2 516A>C (↔ LPV) [137,183]
404A>T (?)
559G>A (?)
38T>C (?)
833A>del (?)
OATP1B1 (SLCO1B1) ‡‡ Placenta # PIs‡ SLCO1B1 521T>C (↑ MVC and ↑ LPV) [137,138]

OATP1B3 (SLCO1B3) Placenta # PIs‡ ND [137,183]

OAT1(SLC22A6) Mammary gland TFV, RAL and ZDV R50H (↑ affinity for substrates) [30,184,185]

OAT2 (SLC22A7) Placenta and mammary gland

#
ZDV ND [57]

OAT3 (SLC22A8) Mammary gland ZDV and TFV ND [57]

OAT4 (SLC22A11) Placenta # ZDV ND [57,186,187]

ENT1 (SLC29A1) Placenta and mammary gland

†
ddI ND [57,188]

ENT2 (SLC29A2) Placenta and mammary gland

†
ddI and ZDV ND [57,188]

OCT1 (SLC22A1)§§ Placenta† and mammary gland 3TC OCT1 Arg61Cys (↑ mRNA exp) [56,58,
P283L and -P341L (↓ 3TC uptake) 188,189]

OCT2 (SLC22A2) Placenta # 3TC T199I, -T201M and -A270S (↓ 3TC uptake) [56,58,190]

OCT3 (SLC22A3) Placenta # and mammary gland 3TC rs2292334, rs2048327, rs1810126 and [56,188,
rs3088442 (↑ mRNA exp) 189,191]
†
Apical.
‡
Most PIs are substrates and inhibitors of these transporters.
§
Unknown.
¶
Study in rat GI tract.
#
Basolateral.
††
SLCO1A2 mRNA expression increases during gestation.
‡‡
Only mRNA detected.
§§
OCT1 showed more than fourfold higher RNA levels in lactating mammalian epithelia cells compared with nonlactating.
(?): Effect unknown; ↑: Increased; ↓: Decrease; ↔: No difference; 3TC: Lamivudine; ABC: Abacavir; Act: Activity; ATV: Atazanavir; d4T: Stavudine; ddI: Didanosine;
Del: Deletion; EFV: Efavirenz; Exp: Expression; FTC: Emtricitabine; Ht: Hepatotoxicity; IDV: Indinavir; Ktd: Kidney tubular dysfunction; LPV: Lopinavir; MVC: Maraviroc;
ND: No data; NVP: Nevirapine; NRTI: Nucleoside reverse transcriptase inhibitor; PI: Protease inhibitor; RAL: Raltegravir; RTV: Ritonavir; SQV: Saquinavir; TFV:
Tenofovir; ZDV: Zidovudine.

metabolism polymorphisms of d4T, but an asso-
ciation between HLA‑B*4001 and d4T-associated
lipodystrophy has been reported in Thailand [46] .
Abacavir (ABC) is a guanosine analog
approved by the FDA in 1998 [204] . The recom-
mended dosage for adults is 300 mg twice daily.
Best et al. reported that the pharmaco­k inetics of
ABC were similar during the third trimester and
postpartum, and that it readily crosses the pla-
centa (C:M ratio of 1.06) [47] . ABC is metabo-
lized by ADH and UGT, but there are currently
no reports on the influence of ADH or UGT
genetic polymorphisms on ABC pharmaco­
kinetics. ABC-hypersensitivity reaction can

1506 Pharmacogenomics (2012) 13(13) future science group

 Table 4. Summary of pharmacokinetic parameters of antiretroviral drugs during pregnancy and postpartum from selected publications.
Drug Dosage (mg) Third trimester of pregnancy Postpartum Ref.
(US FDA AUC (µg/h/ml) Cmax (µg/ml) Ctrough (µg/ml) AUC (µg/h/ml) Cmax (µg/ml) Ctrough (µg/ml)
category)
Nucleoside reverse transcriptase inhibitors

future science group

3TC (C), 150 b.i.d. 4.9 (4.0–6.1)† 1.3 (1.1–1.6) NR 5.1 (3.7–6.9) ‡ 1.20 (0.98–1.50) NR [39]
GM (95% CI)
ABC (C), 300 b.i.d. 5.9 (5.2–6.8) 1.9 (1.6–2.2) BQL (BQL–0.102) 5.4 (4.3–6.8) 2.1 (1.6–2.7) BQL (BQL–0.203) [47]
GM (95% CI)
FTC (B), 200 q.d. 8.0 (7.1–8.9) 1.4 (1.2–1.6) 0.06 (0.04–0.06) 9.7 (8.6–10.9) 1.4 (1.3–1.7) 0.09 (0.07–0.1) [63]
median (range)
TDF (B), 245 q.d. 2.4 (2.1–2.6) 0.27 (0.22–0.33) 0.05 (0.04–0.06) 3.2 (2.7–3.7) 0.35 (0.29–0.42) 0.08 (0.06–0.09) [68]
GM (95% CI)
ZDV (C), mean 200 every 4 h 1.2 (±0.27) 1.04 (±0.45) NR 1.8 (±0.13) 1.2 (±0.01) NR [40]
(±SD)
Non-nucleoside reverse transcriptase inhibitors
EFV (D), 600 q.d. 55.4 (13.5–220.3) 5.4 (1.9–12.2) 1.60 (0.23–8.13) 58.3 (22.7–214.4) 5.10 (1.96–11.42) 2.05 (0.31–8.43) [108]
median (range)
ETR (B), 200 q.d. 4.5 (3.0–8.9)§ 0.69 (0.45–1.20) 0.41 (0.15–0.90) NR NR NR [122]
median (range)
NVP (B), 200 b.i.d. 47.0 (41.5–58.9) 5.3 (4.7–6.3) 3.1 (2.7–4.1) 59.4 (53.6–69.6) 6.6 (5.9–7.7) 3.9 (3.5–4.9) [91]

www.futuremedicine.com
GM (90% CI)
Protease inhibitors
fAPV (C), 700/100 b.i.d. 32.4 (14.2–54.4) 5.93 (1.66–12.53) 1.70 (0.71–3.23) 50.7 (11.6–62.4) 5.7 (2.1–11.4) 2.43 (0.37–3.82) [153]
median (range)
ATV/RTV (B), 300/100 q.d. 41.9 (27.4–60.8) 3.6 (2.8–5.1) 0.7 (0.5–1.1) 57.9 (47.1–64.8) 4.1 (3.0–5.8) 1.2 (1.1–2.0) [141]
median (IQR)
ATV/RTV (B), 400/100 q.d. 46.6 (11.0–88.3) 4.70 (0.88–7.50) 0.74 (0.14–2.10) 55.1 (9.9–99.5) 4.52 (0.93–9.45) 0.88 (BQL–2.70) [142]
median (range)
DRV/RTV (B), 600/100 b.i.d. 50.8 (23.8–102.0) NR 3.10 (0.78–8.90) 70.0 (40.3–176.0) NR 2.8 (1.6–5.5) [152]
median (range)
DRV/RTV (B), 800/100 q.d. 67.7 (30.3–106.0) NR 1.60 (0.15–2.50) 87.9 (77.5–150.0) NR 2.83 (1.14–4.00) [152]
median (range)
IDV/RTV (C), 400/100 b.i.d. 16.1 (7.5–39.9) 3.5 (1.3–7.4) 0.13 (0.07–0.60) 27.1 (18.6–44.7) 5.5 (3.8–9.4) 0.28 (0.14–0.71) [192]
median (range)
Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding

†
Single dose.
‡
Steady state.
§
AUC 6 h reported for one patient and AUC 12 h for others.
3TC: Lamivudine; ABC: Abacavir; ATV: Atazanavir; AUC: Area under the curve; b.i.d.: Twice daily; BQL: Below quantification limit; DRV: Darunavir; EFV: Efavirenz; ETR: Etravirine; fAPV: Fosamprenavir; FTC: Emtricitabine;
GM: Geometric mean; IDV: Indinavir; IQR: Interquartile range; LPV: Lopinavir; MVC: Maraviroc; ND: No pregnancy vs postpartum pharmacokinetic data; NFV: Nelfinavir; NFV‑M8: Nelfinavir metabolite; NR: Not reported;
NVP: Nevirapine; q.d.: Once daily; RAL: Raltegravir; RTV: Ritonavir; SD: Standard deviation; SQV: Saquinavir; T‑20: Enfuvirtide; TDF: Tenofovir disoproxil fumarate; TPV: Tipranavir; ZDV: Zidovudine.
Review

1507
 Table 4. Summary of pharmacokinetic parameters of antiretroviral drugs during pregnancy and postpartum from selected publications (cont).

1508
Drug (US Dosage (mg) Third trimester of pregnancy Postpartum Ref.
FDA AUC (µg/h/ml) AUC (µg/h/ml)
Review
Cmax (µg/ml) Ctrough (µg/ml) Cmax (µg/ml) Ctrough (µg/ml)
category)
Protease inhibitors (cont.)
LPV/RTV (C), 400/100 b.i.d. 58.0 (50.4–70.7) 7.5 (6.7–8.7) 2.5 (2.0–3.5) 89.4 (74.0–107.9) 10.0 (8.4–11.8) 4.7 (3.1–6.8) [131]
GM (95% CI)
LPV/RTV (C), 400/100 b.i.d. 64.6 (59.7–69.8) 8.1 (7.5–8.7) 2.7 (2.4–3.1) NR NR NR [132]
median (range) (Thai women)
LPV/RTV (C), 600/100 b.i.d. 96 (43–198) 10.7 (5.8–19.1) 5.1 (1.5–12.2) 133 (66–237) 14.6 (9.8–22.8) 7.2 (2.8–21) [136]
median (range)
NFV (B), 1250 b.i.d. 18.9 (3.6–53.7) 3.2 (0.9–6.5) 0.900 30.8 (1.3–123.9) 4.6 (0.3–9.9) 1.100 (<0.039–4.800) [193]
median (range) (<0.039–4.400)
NFV-M8, NA 1.500 (<0.234–12.400) 0.3 (0.1–1.9) 0.100 (<0.039–0.900) 11.300 1.200 (<0.039–4.900) 0.300 (<0.039–3.900) [193]
Olagunju, Owen & Cressey

median (range) (<0.234–43.700)

SQV/RTV (B), 1000/100 b.i.d. 12.71 (8.96–26.93) 3.23 (2.68–6.03) 0.26 (0.23–1.01) 28.94 (14.55–58.49) 3.92 (2.96–5.66) 0.86 (0.25–2.21) [194]
GM (95% CI)
TPV (C), ND ND ND ND ND ND ND –
median (range)
Others
MVC (B) ND ND ND ND ND ND ND –
median (range)
RAL (C) 400 b.i.d. 8.3 (3.0–17.5) 1.80 (0.69–6.30) 0.090 (0.014–0.470) 7.5 (2.0–25.5) 2.80 (0.35–8.90) 0.500 (<0.010–0.770) [156]

Pharmacogenomics (2012) 13(13)

median (range)
T‑20 (B) ND
median (range)
†
Single dose.
‡
Steady state.
§
AUC 6 h reported for one patient and AUC 12 h for others.
3TC: Lamivudine; ABC: Abacavir; ATV: Atazanavir; AUC: Area under the curve; b.i.d.: Twice daily; BQL: Below quantification limit; DRV: Darunavir; EFV: Efavirenz; ETR: Etravirine; fAPV: Fosamprenavir; FTC: Emtricitabine;
GM: Geometric mean; IDV: Indinavir; IQR: Interquartile range; LPV: Lopinavir; MVC: Maraviroc; ND: No pregnancy vs postpartum pharmacokinetic data; NFV: Nelfinavir; NFV‑M8: Nelfinavir metabolite; NR: Not reported;
NVP: Nevirapine; q.d.: Once daily; RAL: Raltegravir; RTV: Ritonavir; SD: Standard deviation; SQV: Saquinavir; T‑20: Enfuvirtide; TDF: Tenofovir disoproxil fumarate; TPV: Tipranavir; ZDV: Zidovudine.

future science group

 Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding
occur in 5–8% of patients within 6 weeks of
initiating treatment and in rare cases can be fatal
[48] . The HLA‑B*5701 allele is strongly associ-
ated with ABC hypersensitivity and ABC is cur-
rently the only ARV for which pharmaco­genetic
testing is currently recommended [49,50] .
Lamivudine (3TC) is a cytidine analog
excreted primarily unchanged via the kidneys.
3TC was approved by the FDA in 1995 [204] .
The recommended dosage of 3TC for adults is
300 mg once daily or 150 mg twice daily. The
pharmaco­kinetics of 3TC during pregnancy was
reported to be similar during the last trimester
compared with nonpregnant adults (Table 4) [39] .
A recent population pharmaco­k inetic study
reported the oral clearance of 3TC to be 22%
higher in pregnant women. However, the authors
concluded that this increase was not clinically rel-
evant and did not warrant a dose adjustment [51] .
It crosses the human placenta with a median C:M
concentration ratio of 1.06. However, amniotic
fluid concentrations were five-times higher than
in maternal plasma, suggesting passive diffusion
across the amnion, fetal uptake and fetal clear-
ance [52] . Like ZDV, 3TC is a substrate for the
drug transporter ABCC4 and ABCC4 4131G>T
(rs3742106) carrier status has been associated
with 20% higher 3TC–triphosphate intra­cellular
concentrations (p  =  0.004) [43] . Furthermore,
3TC breast milk concentrations were reported
to be approximately threefold higher than mater-
nal serum concentrations [53] . However, 3TC
ingested by breastfed infants appears to be poorly
absorbed with low plasma concentrations (<0.10
µg/ml) detected [54] . 3TC is also a substrate for
the organic cation transporters OCT1, OCT2
and OCT3 [55,56] , all of which are expressed
in the kidney, placenta and mammary gland
(exepct for OCT2 in the latter) [57] . In a recent
study Choi et al. observed reduced 3TC uptake
in oocytes expressing OCT1-P283L and OCT1-
P341L as well as those expressing OCT2-T199I,
OCT2-T201M and OCT2-A270S variants com-
pared with with the reference sequences [58] . The
consequences of functional SNPs of OCTs on
3TC pharmaco­k inetics have not been studied
in vivo. Such SNPs may also influence the distri-
bution of 3TC to the fetal compartment as well
as its excretion into breast milk.
Rare cases of lethal mitochondrial dys­function
in infants exposed in utero to ZDV and 3TC were
reported in the late 1990s [59] . These severe cases
are clinically very similar to known genetically
induced mitochondrial defects. Evidence of
mitochondrial damage has been demonstrated
in HIV-uninfected infants exposed to ZDV and
future science group
Review
3TC for prevention of MTCT [60] . Recent studies
have associated mtDNA halogroup T/L1c and
mtDNA 4917G (increased risk), HFE 845G>A
(rs1800562) and IL-12B 3´-UTR*2 (rs3212227)
(decreased risk), as well as TNF- variants 1031*2
(rs1799964) and 308*2 (rs1800629) (increased
risk) with NRTI-associated adult neuropathy
[61,62] . Their roles in infant mitochondrial toxic-
ity as a result of in utero exposure to maternal
drug need further investigation.
Emtricitabine (FTC) was approved by the
FDA in 2003 [204] . Like 3TC, it is a cytidine
analog excreted primarily unchanged via the kid-
neys. The approved dosing in adults is 200 mg
once daily. Within-subject comparisons of FTC
pharmaco­kinetics during pregnancy and postpar-
tum revealed significantly higher apparent clear-
ance during pregnancy [63] . Significantly lower
area under the curve (AUC) and drug concentra-
tion 24 h postdose also were found during the
third trimester of pregnancy (Table 4) . FTC was
well distributed to the fetal compartment with
mean C:M concentration ratio of 1.2 (1.0–1.5).
FTC is excreted into human breast milk but the
concentrations attained would represent a dose
approximately 2% of the proposed oral dose for
neonates [64] . It is a substrate for ABCC1 [65] ,
which is expressed in both the placenta and
mammary gland [57] . However, no studies have
assessed the influence of genetic polymorphisms
and its disposition.
Tenofovir disoproxil fumarate (TDF) is a
nucleotide analog of adenosine and was approved
by the FDA in 2001 [204] . The recommended
oral dose for adults is 300 mg once daily. TDF is
the oral prodrug of tenofovir (TFV). Following
oral absorption, TDF rapidly undergoes esterase
hydrolysis and is converted to TFV, a nucleo-
tide (nucleoside monophosphate) analog that is
taken up by cells. Intracellularly, TFV is rapidly
phosphorylated by cellular nucleotide kinase to
its active anabolite TFV diphosphate. TFV is
primarily excreted unchanged by the renal route
through a combination of glomerular filtration
and active tubular secretion [66] . Burchett et al.
assessed the pharmaco­kinetics of TFV between
30 and 36 weeks gestation age and 6–12 weeks
postpartum [67] . Median (range) TFV AUC
was significantly lower during the third tri­
mester, 2.5 (1.1–2.6) µg/h/ml during pregnancy
compared with 2.96 (1.62–7.2) postpartum
(p = 0.02). However, third trimester Cmin were
not different from postpartum values. A recent
study reported a 25% reduction in TFV exposure
during the third trimester compared with post-
partum. The authors speculated that the decrease
www.futuremedicine.com 1509
Review Olagunju, Owen & Cressey
was due to reduced absorption and/or increased
volume of distribution as no change in the termi-
nal elimination half-life was observed (Table 4) [68] .
Benaboud et al. studied the effects of pregnancy
on TFV pharmaco­k inetics using a population
pharmaco­kinetic ana­lysis involving 46 pregnant
and 156 nonpregnant HIV-infected women [69] .
The apparent oral clearance was 39% higher in
pregnant women. These authors suggested that
a TFV dose increase should be considered for
women from the second trimester until deliv-
ery in order to achieve comparable exposure to
nonpregnant adults.
It is of interest to note that, while TFV readily
crosses the human placenta with C:M concen-
tration ratio of 1.04 (0.6–1.7) [67] , the transfer
into cerebrospinal fluid has been reported to
be an order of magnitude lower with cerebro-
spinal fluid:plasma ratio of 0.057 (0.03–0.1)
[70] . This difference may be indicative of sub-
stantial differences in the expression profile of
transporters between these barriers. TFV is a
substrate for ABCC4, OAT1, OAT3 [71] and
MRP7 (ABCC10) [72] . Interestingly, OAT1,
OAT3 and ABCC4 are expressed in choroid
plexus epithelial cells but not in the placenta
[73–75] , while ABCC10 is expressed in both the
placenta and CNS [57] . OATs are involved in the
efflux of their substrates out of the CNS [76,77] .
The mechanisms behind this observed differ-
ence have not been studied in detail. Carriers of
ABCC4 3463A>G (rs1751034) were reported to
have 35% higher intracellular TDF diphosphate
concentrations than noncarriers (p = 0.04) [78] .
TFV is transported into proximal tubular cells by
OAT1 and to a lesser extent OAT3 [79] , which is
located on the basolateral membrane. It remains
unknown if a change in OAT1 expression/activ-
ity plays a role in increased TFV clearance dur-
ing pregnancy, and if such changes are driven by
genetic polymorphisms.
The luminal efflux system(s) involved in
the transport of TFV out of proximal tubular
cells and into the urine is not well described.
Three transporters, ABCC2 [80] , ABCC4 [81]
and ABCC10 [72] have been reported to play a
role in the active renal tubular efflux of TFV. A
genetic variant of ABCC2 (rs717620) [82] , and
two ABCC10 SNPs (rs9349256 and rs2125739)
were identified as predictors of TFV-induced
nephrotoxicity [72] . Higher plasma TFV concen-
trations in patients with kidney tubular dysfunc-
tion have also been reported [83] . The implica-
tions of these SNPs on TFV pharmaco­kinetics
during pregnancy and risk of tubular dysfunction
are unknown. TFV is a substrate for ABCC10,
1510 Pharmacogenomics (2012) 13(13)
which is expressed in the human placenta [57] , and
its possible role, including the effect of genetic
polymorphisms, in the uptake of TFV into the
fetal compartment should be studied. TFV is also
excreted into human breast milk but at low con-
centrations – equivalent to a median dose of 4.2
µg/day for a 3‑kg neonate, or 0.03% of the oral
dose proposed for neonates [64] .
Pharmacokinetics during pregnancy
& the potential role of
pharmacogenetics
„„ Non-nucleoside reverse transcriptase
inhibitors
Four NNRTIs are currently available for the
treatment of HIV. NNRTIs are primarily metab-
olized by CYP enzymes and, with the excep-
tion of NVP, are highly protein bound (Table 1) .
Therefore, drugs in this class are expected to
be susceptible to temporal changes in hepatic
enzyme activities and plasma protein fluctuations
during pregnancy. NNRTIs plasma drug con-
centrations also have been associated with SNPs
in genes encoding the enzymes involved in their
metabolism, transport and nuclear receptor type
transcription factors.
NVP was the first NNRTI receiving FDA
approval in 1996 [204] . It is initiated at a lower dose
(or ‘lead-in’ dose) for the first 2 weeks to allow
for the autoinduction of metabolizing enzymes,
which increases its clearance. Initiating NVP
in this stepwise fashion reduces the frequency
of drug-associated rashes. One 200 mg tablet is
administered once daily for the first 14 days and
if there are no clinical signs of rash the dose is
increased to 200 mg twice daily [84] . Single and
chronic NVP dosing has been used during preg-
nancy to prevent MTCT of HIV. A single mater-
nal dose of NVP at the onset of labor and to the
newborn at 48–72 h of life is still recommended
as an option in the WHO prevention of MTCT
guidelines. Concerns have been raised over the
use of single-dose NVP [203] . Due to its long half-
life, NVP can persist in the plasma for up to 4
weeks postpartum following a single intrapartum
dose [85] . This prolonged period of monotherapy,
in the presence of replicating viruses, can increase
the risk of selecting NNRTI resistance mutations.
NNRTI mutations detected in the post­partum
period have been shown to affect the efficacy of
future NNRTI based-HAART regimens [86] .
However, short-course ARV treatments post­
partum (7–30 days) can reduce the risk of select-
ing NNRTI resistance mutations postpartum
following intrapartum NVP [87,88] . The associa-
tion of SNPs in metabolizing enzymes with NVP
future science group
 Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding
concentrations following an intra­partum single
dose have been reported, but the modest effects
may not be clinically significant [89] .
Chronic NVP dosing is increasingly used, in
part owing to the availability of generic triple-­
drug fixed-dose combinations in resource-
limited settings. The geometric mean third
trimester:postpartum ratio for NVP AUC has
been reported to be 0.90 (90% CI: 0.80–1.02)
[90] and 0.79 (90% CI: 0.70–0.90) [91] . A 30%
decrease in NVP AUC between pregnant and
nonpregnant women has been reported [92] , but
no dose adjustment is currently recommended.
CYP2B6 516G>T (rs3745274) and CYP2B6
983T>C (rs28399499) SNPs have been asso-
ciated with higher NVP plasma concentra-
tions. Penzak et  al. reported NVP median
plasma concentration of 7.61 µg/ml in indi-
viduals with CYP2B6 516TT genotype versus
4.18 and 5.56 µg/ml in those with 516GG and
516GT genotypes, respectively [93] . These find-
ings were confirmed in a larger study where
median (range) NVP plasma concentrations
were 5.18 (1.89–11.16), 6.13 (0.15–11.69) and
6.69 (4.16–21.03) µg/ml for carriers of CYP2B6
516GG, GT and TT genotypes, respectively [94] .
This latter study was also the first to demon-
strate that carriers of CYP2B6 983 TT and TC
genotypes had significantly higher NVP plasma
concentrations. Both CYP2B6 516G>T and
CYP3A5*3 (rs776746) were associated with NVP
pharmaco­k inetics in a recent study in Malawi.
The CYP2B6 516 T allele increased NVP AUC
by 92% and CYP3A5*3 decreased NVP AUC by
31% in a multivariable model [95] . The inclusion
of host genetic polymorphisms in pharmaco­
kinetic studies of NVP during pregnancy may
help identity subpopulations of women who are
at higher risk of subtherapeutic concentrations.
To date, relatively little data have emerged
on efflux or influx transporters capable of NVP
transport. However, NVP was recently shown to
be a substrate for ABCC10 and SNPs within the
gene encoding this efflux pump were shown to be
associated with plasma concentrations of NVP
[96] . This is an area where further mechanistic
investigation is warranted since the identification
of placental or mammary gland transporters may
underpin studies to identify pharmaco­genetic
correlates of exposure of the fetus or infant,
respectively.
Higher incidences of NVP-related rash and
hepatotoxicity have been reported in HIV-
infected pregnant women with CD4 counts
of >250 cells/mm3 [97,98] and NVP-containing
HAART is not preferred in these patients.
future science group
Review
An association between HLA‑B*3505 and
NVP-induced skin rash has been reported [99] .
Furthermore, a genome-wide association study
revealed that variations in the CCHCR1 gene
were strongly associated with NVP-induced skin
rash [100] . Incorporating genetic and clinical risk
factors may therefore have utility in reducing the
incidence of NVP related-toxicities in women
initiating NVP during pregnancy.
There are currently no data on NVP
pharmaco­k inetics during lactation. However,
its excretion into human breast milk has been
reported with milk:plasma ratios of 0.67 [53]
and 0.75 [54] , resulting in 0.97 and 0.73–1.03
µg/ml, respectively, in breastfed infants’ plasma.
Interestingly, this is higher than the >0.10 µg/ml
target on which current postexposure prophyl­
axis dosing guidelines are based [203] , but less
than the target trough concentration of >3.0
µg/ml in HIV-infected children [101] . However,
breast milk ingestion of NVP has been associ-
ated with increased risk of cutaneous adverse
drug reactions in breastfed infants compared
with nelfinavir [102] . The new WHO guidelines
recommend NVP for post­exposure prophyl­a xis
in breastfeeding populations, which may mean
that the exposure in infants in developing coun-
tries whose mothers also take NVP may be higher
than anticipated. This may conceivably impact
upon NVP-associated adverse drug reactions in
these infants but this has not been studied in
detail.
Efavirenz (EFV) was approved by the FDA
in 1998 [204] and early reports of congenital neu-
ral tube defects resulting from first-trimester
exposure have limited its use during pregnancy
[103] . Although emerging data on the safety of
EFV use in pregnancy provide some reassurance
[104–107] , the number of cases monitored and the
relative rarity of neural tube defects and facial
clefts cannot yet rule out some degree of risk.
In 2010, WHO updated their prevention of
MTCT guidelines and recommended EFV use
as part of combination ARV therapy after the
first trimester [203] .
Recently the first pharmaco­kinetic data evalu-
ating the standard dose (600 mg once daily) of
EFV during the third trimester of pregnancy and
postpartum were published [108] . There was no sig-
nificant difference in EFV AUC and Cmax during
pregnancy compared with postpartum (Table 4) ;
geometric mean ratios were 0.97 (90%  CI:
0.83–1.13) and 1.11 (90%  CI: 0.99–1.24),
respectively. However, EFV oral clearance was
significantly higher during the third trimes-
ter and the drug concentration 24 h postdose
www.futuremedicine.com 1511
Review Olagunju, Owen & Cressey
significantly lower compared with postpartum.
The C:M concentration ratio of EFV was 0.49
(90% CI: 0.37–0.74). Based on these data, no
dose adjustment is required during pregnancy.
Considerable data are available on the effect of
host genetic polymorphisms on EFV pharmaco­
kinetics and it is possible that dose adjustments
are applicable for genetically defined subgroups
of women. Interestingly, two women included
in the study above experienced extremely high
drug exposure during pregnancy [108] . This may
be explained by genetic polymorphisms, but the
consequences of such high exposures remain
unknown.
EFV is primarily metabolized by CYP2B6 [109]
with a minor contribution from CYP2A6 [110,111]
and glucuronidation of the 8-hydroxy metabo-
lite by UGT2B7 [112] . Genetic polymorphisms in
genes encoding these enzymes and the transcrip-
tional regulator, CAR, have been associated with
interindividual variability in EFV plasma drug
concentrations. The SNPs CYP2B6 516G>T
(rs3745274), CYP2B6 983T>C (rs28399499),
CYP2A6 1836G>T (rs8192726), UGT2B7
735A>G (rs28365062), UGT2B7 802C>T
(rs7439366) and CAR 540C>T (rs2307424)
have been investigated. In studies conducted in
HIV-positive Ghanaian patients, Kwara et al.
identified CYP2B6 516G>T, CYP2A6 1836G>T
and/or CYP2A6 1093G>A (rs28399454) and
UGT2B7*1a carrier status as predictors of EFV
plasma concentrations, accounting for 45.2,
10.1 and 8.6% of the total variance, respectively
[113,114] . Rotger et al. also reported significantly
higher plasma and intracellular EFV concentra-
tions and AUC in Caucasians with the CYP2B6
516TT genotype than in those with CYP2B6
516GG genotype [115] . CYP2B6 516TT was
also associated with higher incidences of EFV
neuropsychiatric side effects. The 983T>C poly-
morphism was also significantly associated with
higher EFV concentrations [94] . Recently, the
CYP2B6 516TT and CAR 540C>T genotypes
were associated with early treatment discontinu-
ation, with CNS toxicity accounting for 94.7%
of cases of discontinuation [13] . The effect of the
well defined SNPs that influence EFV plasma
concentrations and risk of CNS toxicity in
nonpregnant adults should be studied during
pregnancy.
EFV is excreted into breast milk. Schneider
et  al. reported a median infant plasma EFV
concentration of 0.87 µg/ml (range: 0.31–1.51
µg/ml) following breast milk ingestion from
mothers receiving EFV for prevention of MTCT
[116] . The recommended therapeutic range is
1512 Pharmacogenomics (2012) 13(13)
1.0–4.0 µg/ml [117] . Maternal EFV concentra-
tions, which depend on various host genotypes,
will be a major determinant of infant exposure.
However, EFV transport across the placenta and
into breast milk is also likely to be important but
is, as yet, largely unstudied. Peroni et al. recently
reported that EFV is a substrate of rat ABCG2
and inhibits its own intestinal permeability by
promoting overexpression of ABCG2 in the rat
GI tract [118] . ABCG2, which is highly polymor-
phic, has been shown to be highly expressed in the
apical membrane of human placenta syncytiotro-
phoblast [119] and human mammary gland during
lactation [120] . It has been suggested to play a role
in protecting the fetus against exposure to poten-
tially toxic compounds in maternal blood [121] .
SNPs in EFV transporters are expected to play
an important role in determining the exposure of
the fetus and breastfed infant-to-maternal EFV.
Etravirine (ETR) was approved by the FDA
in 2008 [204] . Data on ETR pharmaco­k inetics
during pregnancy are limited; only a small study
involving four HIV-infected pregnant women
treated with ETR (with darunavir [DRV] and
ritonavir [RTV]) describes the pharmaco­kinetics
of ETR during pregnancy [122] . ETR pharmaco­
kinetics during the third trimester was similar
to those of nonpregnant adults (Table  4) . C:M
concentration ratio in one woman was 0.33.
More data are clearly required and several ongo-
ing studies are assessing the pharmaco­k inetics
of ETR during pregnancy. ETR is primarily
metabolized by CYP2C19 [123] , whose expres-
sion and activity declines during pregnancy
[124] . It is also known to be highly polymorphic.
The CYP2C19*2 (rs4244285; high frequency
in Asians) and CYP2C19*17 (rs12248560; high
frequency in Africans) alleles have been associ-
ated with poor and ultrarapid metabolism of
CYP2C19 substrates, respectively [125,126] and
their effect on ETR pharmaco­kinetics is clearly
worthy of study. Furthermore, how these fac-
tors affect ETR pharmaco­kinetics during preg-
nancy remain uncharacterized but the presence
of CYP2C19*17 and known upregulation of
CYP3A4 activity during pregnancy may lead to
subtherapeutic concentrations.
Rilpivirine (RPV) is the newest NNRTI
approved by the FDA in 2011 [204] . It is metabo-
lized by CYP3A enzymes and 99.7% bound to
plasma proteins (mainly albumin) [207] . No data
on RPV pharmaco­k inetics during pregnancy
in humans are available. However, pregnancy-
induced increases in CYP3A enzyme activity
and decrease in albumin concentrations may be
expected to increase RPV clearance.
future science group
 Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding
„„ Protease inhibitors
There are currently ten PIs available for the treat-
ment of HIV. The PIs are primarily metabolized
by CYP enzymes and are highly protein bound
(Table 1) . Similar to the NNRTIs, these drugs are
expected to be susceptible to pregnancy-induced
changes in CYP enzymes and plasma protein
fluctuations.
Lopinavir/RTV (LPV/RTV) is one of the
most widely studied ARVs during pregnancy.
LPV is administered in combination with low-
dose RTV to ‘boost’ its pharmaco­k inetics. The
standard dose of LPV/RTV in nonpregnant
adults is 400/100 mg twice daily. LPV is primar-
ily metabolized by CYP3A4 and CYP3A5 iso-
enzymes. RTV is a potent inhibitor of CYP3A4
activity and concomitant administration of
LPV with RTV results in markedly higher LPV
concentrations. RTV is also a substrate for both
CYP3A4 and CYP2D6 [127] . Both LPV and
RTV are also ABCB1 and ABCC1 substrates
[128,129] and are highly bound (98%) to plasma
proteins. LPV/RTV is the preferred PI regimen
for ART-naive pregnant women.
Stek et al. assessed standard LPV/RTV dos-
ing during the third trimester and LPV expo-
sure was approximately 50% lower compared
with nonpregnant adults [130] . Mean (±standard
deviation) LPV C:M concentration ratio was
0.2 (±0.13). Changes in RTV pharmaco­k inetic
parameters were not statistically significant.
The soft-gel capsule formulation used in this
study has been replaced with a tablet formula-
tion, which has been shown to have improved
bio­availability (Table 4) [131] . LPV exposure dur-
ing the third trimester of pregnancy follow-
ing standard dosing in Thai women with the
tablet formulation was reduced by 22% [132] .
Similar findings have been reported by Calza
et al. [133] , Ramautarsing et al. [134] and Lambert
et al. [135] . In American women, a higher dose of
the tablet formulation, 600/125 mg, provided
comparable exposure to that observed in non-
pregnant adults [136] . Debate remains on the
optimal dose of LPV/RTV during pregnancy
and may differ between populations. Higher
LPV plasma concentrations have been associated
with the 521T>C (rs4149056) polymorphism in
SLCO1B1 [137] ; within a population pharmaco­
kinetic model homozygosity for the C allele was
associated with a 37% lower clearance [138] . The
influence of SLCO1B1 polymorphisms on LPV
exposure during pregnancy should be investi-
gated as the presence of this SNP may help com-
pensate for the pregnancy-induced changes in
some women. The possible influence of SNPs in
future science group
Review
SLCO1B1, ABCB1 and ABCC1 on transplacental
transfer of LPV and RTV also warrants further
study. However, LPV and RTV are undetectable
in human breast milk [139] .
Atazanavir (ATV) is the only PI that can be
administered with or without low-dose RTV.
The standard dose alone is 400 mg for ARV-naive
patients or, for ATV/RTV, 300/100 mg once
daily. ATV is metabolized by CYP3A enzymes
and is not recommended for administration
without RTV during pregnancy. Conflicting
data on ATV/RTV pharmaco­k inetics dur-
ing pregnancy have been reported. Ripamonti
et al. reported no significant differences in ATV
AUC, Cmax and Cmin antepartum compared with
postpartum [140] . By contrast, Mirochnick et al.
observed significant differences between ante-
and post-partum pharmaco­k inetics with AUC,
Cmax and Cmin antepartum:postpartum ratios of
0.72, 0.47 and 0.58, respectively, without TFV,
and 0.73, 0.61 and 0.67, respectively, with TFV
(Table 4) [141] . Subsequently, an ATV/RTV dose
of 400/100 mg was assessed during pregnancy
and provided comparable exposure to non­
pregnant adults [142] . C:M ATV concentration
ratio of approximately 0.15 was observed in these
studies.
The CYP3A5*1B (rs28365095) allele has
been associated with increased ATV clearance
[143] . No significant differences in ATV AUC or
Cmax were observed in CYP3A5 expressors versus
nonexpressors in the presence of RTV, although
in a subgroup of non-African–American males
the faster CL/F persisted in CYP3A5 expressors
versus nonexpressors. Also, subjects with one or
two copies of the wild-type CGC haplotype for
ABCB1 (1236C, 2677G and 3435C; rs1128503,
rs2032582 and rs1045642, respectively) had
slower ATV clearance.
A polymorphism (63396C>T; rs2472677)
within the transcriptional regulator, PXR
(NR1I2) has also been shown to be associated
with unboosted ATV plasma concentrations [144]
and a 17% increase in unboosted ATV clear-
ance [145] . Furthermore, interaction between
CYP3A5 expressor status and PXR 63396C>T
(rs2472677) were also recently reported by Kile
et  al. [146] . ATV clearance was 37% lower in
nonexpressors of CYP3A5 with PXR 63396CC
genotype than those with CT or TT genotypes
and 63% lower in CYP3A5 expressors with PXR
63396CC genotype than those with CT or TT
genotypes  [146] . Based on available data, the
effect of the CYP3A5-expressor status on RTV
boosted ATV during pregnancy may be limited.
However, the ABCB1 3435C>T (rs1045642)
www.futuremedicine.com 1513
Review Olagunju, Owen & Cressey
polymorphism may influence ATV plasma con-
centrations in the presence of RTV [147] , and this
has not been investigated in pregnant women.
AT V use is associated with hyper­
bilirubinemia and an association between the
UGT1A1*28 (rs8175347) and hyperbilirubine-
mia has been observed [148] . Neonatal UGT1A1
211G>A (rs4148323) and SLCO1B1 388G>A
(rs2306283) polymorphisms, breastfeeding [149]
and, more recently, ATV use during pregnancy
[150] have all been identified as risk factors for
neonatal hyperbilirubinemia. Breast milk excre-
tion of ATV (unboosted) has also been reported
with a milk:plasma ratio of 0.13 [151] . Studies on
the role of these functional SNPs in neonatal
hyperbilirubinemia associated with ATV use
during pregnancy and lactation are needed.
DRV was approved in 2006 and is used in
combination with low-dose RTV at 600/100 mg
twice daily or 800/100 mg once daily in naive
patients. Little is known about the pharmaco­
kinetics of DRV during pregnancy. Capparelli
et al. assessed DRV/RTV once and twice daily
pharmaco­k inetics during the third trimester
and postpartum (Table 4) [152] . DRV clearance
was increased during the third trimester com-
pared with postpartum for both once and twice
daily dosing. The authors suggested that twice
daily dosing may be preferable during preg-
nancy to reduce the risk of low trough con-
centrations and higher doses of DRV/RTV are
currently under study. No functional SNPs have
been associated with DRV but the mechanisms
that regulate its pharmaco­k inetics are similar to
other PIs and many of the issues may therefore
be similar to those for LPV and ATV.
There are no data on the use of amprena-
vir during pregnancy. However, its prodrug
fosamprenavir boosted with low-dose RTV has
been assessed at a dose of 700/100 mg twice
daily and the AUC and C12 during the third
trimester were lower than postpartum (Table 4)
[153] . Fosamprenavir had a C:M concentration
ratio of 0.27 (95% CI: 0.24–0.45). No associa-
tion between SNPs and amprenavir pharmaco­
kinetics have been reported. NFV, saquinavir
and indinavir are among the older PIs and are
now used less frequently for HIV treatment
and during pregnancy, and therefore will not
included in this review, but lower NFV and
indinavir/RTV exposure during pregnancy has
been observed (Table 4) .
„„Integrase strand transfer inhibitors
Raltegravir (RAL) is the only approved INSTI
and the recommended dose is 400 mg twice daily.
1514 Pharmacogenomics (2012) 13(13)
A number of reports have emerged on its use in
late pregnancy. Taylor et al. [154] and McKeown
et al. have authored case reports of RAL dur-
ing pregnancy and observed rapid viral-load
reductions in women within days of initiating
a RAL-containing regimens [155] . Preliminary
results from an intensive pharmaco­kinetic study
of RAL ante- and post-partum showed that it
exhibited wide interindividual variability, con-
sistent with data in nonpregnant adults, and that
the exposure was not consistently altered during
pregnancy compared with postpartum (Table 4)
[156] . C:M RAL concentration ratio at delivery
was 1.20 (95% CI: 0.09–2.3) suggesting signifi-
cant transfer into the fetal compartment. RAL
is a substrate for ABCB1 [30] . The role of SNPs
associated with changes in its expression and
activity in RAL transport across the placenta has
not been studied. While elevated RAL levels may
protect against peri­natal HIV infection, the con-
sequences for exposed infants need to be clarified.
Interestingly, higher RAL concentrations have
been reported in Thai adults with an approxi-
mately twofold increase in AUC compared with
Caucasians at the standard dose [157] .
RAL is metabolized by UGT1A1, which is
highly polymorphic. Coadministration with
ATV (a known UGT1A1 inhibitor) resulted in
elevated RAL plasma levels (median [25th–75th
percentiles]: 0.52 [0.31–2.71] vs 0.22 [0.95–0.55]
µg/ml; p = 0.02). This study also reported the
lack of an association between elevated RAL
plasma concentrations and UGT1A1*28/*28
(rs8175347) reduced function genotype in Italian
patients [158] . An earlier study in Japanese patients
also reported no significant difference between
heterozygote *6 (rs4148323) and *28 allele car-
riers and homozygotes of the common allele [159] .
In a recent comprehensive population pharmaco­
kinetic/pharmaco­genetic analysis of RAL in
healthy and HIV positive individuals, Arab-
Alameddine et al. reported no association with
UGT1A1 SNPs. However, although extremely
rare, UGT1A9*3 (rs72551330) was identified as
possibly influencing RAL pharmaco­kinetics [160] .
Other factors influencing the wide interpatient
variability, fetal exposure, and infant exposure
through breast milk remain to be determined.
„„ Entry inhibitors/fusion inhibitors
Very limited information is available on enfu-
virtide during pregnancy. Its use in late preg-
nancy for prevention of MTCT in women pre-
senting with virological failure and multiclass
viral resistance mutations have been reported.
Enfuvirtidedoes not cross the placenta [161–165]
future science group
 Pharmacogenetics & antiretroviral drug exposure during pregnancy & breastfeeding Review
and has been associated with a case of MTCT NVP pharmaco­k inetics to identify pharmaco­
despite adequate maternal virological suppression genetic predictors of NVP exposure following
[166] . Only a single case report has described the
breast milk ingestion would be useful.
use of maraviroc during pregnancy with C:M To date, TFV has not been extensively used
ratio of 0.30 [167] . Maraviroc has been shown to during pregnancy. The inclusion of TFV in sev-
be a substrate for OATP1B1 and the 521T>C eral generic fixed-dose combination tablets will
(rs4149056) SNP in SLCO1B1 is associated with lead to a significant increase in its use during
plasma concentrations [168] . pregnancy and breastfeeding over the next few
years. Recent data suggest that its exposure is
Conclusion & future perspective reduced during the third trimester of pregnancy.
Highly efficacious regimens to prevent MTCT The necessity for a dose adjustment during
of HIV are now available. The rationale to use pregnancy is unclear, but studies investigating
pharmaco­genetics to help optimize ARV treat- the expression/activity of TFV drug transport-
ment for pregnant women is the same as in ers (e.g., ABCC4, OAT1, OAT3 and ABCC10)
adults. However, addition considerations apply during pregnancy could help determine if the
given that the maternal ARV exposure can lead reductions observed are driven by genetic poly-
to significant exposure to the fetus, or to new- morphisms. However, such studies should be
borns through breastfeeding. In addition, the interpreted with caution because it is intra­cellular
short duration of ARV use during pregnancy concentrations of the active metabolite that drive
emphasizes the need to rapidly achieve optimal efficacy and not the plasma concentrations of the
drug exposure. While we have shown that there parent drug. LPV/RTV is the preferred PI during
are numerous potential candidates for pharmaco­ pregnancy and has been assessed in diverse popu-
genomics investigation, the very low perinatal lations. LPV exposure is reduced during preg-
transmission rates observed using HAART or nancy, but the higher bioavailability of the new
ZDV plus single-dose NVP makes it unlikely tablet formulation helps to compensate for a por-
that further reductions could be gained through tion of the pregnancy-induced changes observed.
the use of pharmaco­genomics. Nevertheless, the However, the presence of the SLCO1B1 poly-
number of ARVs being used during pregnancy morphisms may also help to compensate for the
and breastfeeding is rapidly increasingly and pregnancy-induced changes in some women and
gaps remain regarding whether the maternal, should be investigated. Limited pharmaco­kinetic
fetal and infant drug exposures within geneti- data during pregnancy is available among the
cally defined subgroups of women are appropri- newer ARVs (RPV, ETR, RAL and maraviroc),
ate. For example, the CYP2B6 516G>T poly- and a better knowledge of the affinity of these
morphism is a major determinant of fetal and drugs for placental and mammary transporters
infant (during breastfeeding) EFV exposure. The is needed. To help answer these questions, there
short- and longer-term tolerability and toxicity is a need for large cohorts to allow for pharmaco­
of higher exposure of EFV within this subgroup genetic analysis as the fetal/infant exposure is
should be considered and dose adjustments may likely to be dependent on multiple mechanisms
be appropriate. in addition to those that regulate exposure in the
Generic fixed-dose tablets containing NVP mother. Overall, pharmaco­genetic studies can
will continue to be widely used in resource-­ contribute to our understanding of ARV expo-
limited settings in the coming years. Preliminary sure during pregnancy and breastfeeding, and
data suggest that incorporating genetic and may be able to help optimize maternal, fetal and
clinical risk factors may have utility in reduc- infant drug exposures within genetically defined
ing the incidence of NVP-related toxicities in subgroups of women.
women initiating NVP during pregnancy and
this model should be assessed prospectively. In Financial & competing interests disclosure
addition, some studies have shown that approxi- The authors have no relevant affiliations or financial involve‑
mately 30% of women receiving NVP during ment with any organization or entity with a financial interest
pregnancy have subtherapeutic trough concentra- in or financial conflict with the subject matter or materials
tions, so it remains important to try and deter- discussed in the manuscript. This includes employment, con‑
mine if host genetic polymorphisms could help sultancies, honoraria, stock ownership or options, expert
identity these women. The number of infants testimony, grants or patents received or pending, or
breastfeeding from mothers receiving NVP- royalties.
based HAART will also continue to increase, No writing assistance was utilized in the production of
and studies of functional SNPs associated with this manuscript.

future science group www.futuremedicine.com 1515

Review Olagunju, Owen & Cressey

Executive summary
Mother-to-child transmission of HIV
ƒƒ Mother-to-child-transmission rates of HIV without any intervention range between 20 and 45%.
ƒƒ Antiretroviral drugs (ARVs) during pregnancy, delivery and through planned weaning by 6 months postpartum can reduce HIV
transmission to less than 2%.
Antiretroviral therapy during pregnancy
ƒƒ Physiological changes during pregnancy can influence drug disposition and several studies have demonstrated reduced ARV exposure
during pregnancy.
ƒƒ Associations between SNPs in genes coding for metabolizing enzymes and/or transporters and ARV disposition are well described;
however, relatively little is known about the influence of these SNPs on ARV pharmacokinetics during pregnancy and lactation, as well
as their effect on distribution into the fetal compartment and on breast milk excretion.
Influence of SNPs on ARVs during pregnancy & breastfeeding
ƒƒ Numerous potential candidates for pharmacogenomic investigation exist.
ƒƒ Preliminary data suggest that incorporating genetic and clinical risk factors may have utility in reducing the incidence of nevirapine
(NVP)-related toxicities in women initiating NVP during pregnancy.
ƒƒ Including studies of functional SNPs associated with NVP pharmacokinetics to identify pharmacogenetic predictors of NVP exposure
following breast milk ingestion would be useful.
ƒƒ The short- and longer-term tolerability and toxicity of higher exposure of efavirenz to the mother, fetus and infant within the CYP2B6
516G>T polymorphism should be considered; dose adjustments may be appropriate.
ƒƒ Studies investigating the expression/activity of tenofovir drug transporters (e.g., ABCC4, OAT1, OAT3 and ABCC10) during pregnancy
could help determine if the reductions observed are driven by genetic polymorphisms.
Conclusion & future perspective
ƒƒ The number of ARVs being used during pregnancy and breastfeeding is rapidly increasingly, and gaps remain regarding whether
maternal, fetal and infant drug exposures within genetically defined subgroups of women are appropriate.
ƒƒ Pharmacogenetic studies can contribute to our understanding of antiretroviral exposure during pregnancy and breastfeeding – it is
important to include genetic analysis within cohort studies and clinical trials of ARVs during pregnancy.

nn Short-course zidovudine plus single-dose pregnant women. Clin. Pharmacokinet.

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