Olagunju 2012

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 Adeniyi Olagunju1,2,
n HIV n pregnancy n prevention of mother-to-child transmission
Andrew Owen2
& Tim R Cressey*3,4,5
Mother-to-child-transmission (MTCT) rates of nonbreastfeeding infants [5] . Moreover, maternal 1
Faculty of Pharmacy, Obafemi
HIV without any intervention range between 20 HAART or daily infant NVP can reduce HIV-1 Awolowo University, Nigeria
2
Department of Molecular & Clinical
and 45% [1] . An estimated 387,000 children were transmission during breastfeeding [6,7] . Maternal Pharmacology, Institute of
infected with HIV through MTCT in 2008 [201] . HA ART during pregnancy, delivery and Translational Medicine, University of
Liverpool, Liverpool, UK
Approximately 80% of these children acquired through planned weaning by 6 months postpar- 3
Program for HIV Prevention &
HIV infection during labor and in the peri- tum can reduce HIV transmission to less than Treatment, Department of Medical
partum period, with the remaining infections 2% [8] . The 2010 WHO guidelines for the use Technology, Faculty of Associated
Medical Sciences, Chiang Mai
occurring during breastfeeding [202] . A major of ARVs for treating pregnant women and pre- University, Thailand
step forward in the fight to eliminate pediatric venting HIV infection in infants recommends 4
Harvard School of Public Health,
Boston, MA, USA
HIV/AIDS has been the introduction of highly triple-ARV treatment for pregnant women who 5
Institut de Recherche pour le
efficacious, prophylactic, antiretroviral (ARV) need therapy for their own health (i.e., CD4 Développement (IRD), UMI 174,
Marseille, France
regimens to prevent MTCT of HIV. cell count below 350 cells/ml). For women who *Author for correspondence:
The ACTG 076 trial was the first to demon are not eligible for ARV therapy, two options Tel.: +66 53 894 994
strate the efficacy of maternal/infant ARV are proposed: either ZDV monotherapy from Fax: +66 53 894 220
[email protected]
prophylaxis in prevention of MTCT of HIV [2] . as early as 14-weeks gestation plus intrapar-
Providing zidovudine (ZDV) monotherapy dur- tum single-dose NVP; or maternal triple-ARV
ing pregnancy (starting between 14 and 34 weeks prophylaxis [203] . Breastfeeding infants are rec-
gestation), during delivery and to the newborn ommended to receive daily NVP prophylaxis
for 6 weeks reduced HIV transmission rates from from birth throughout breastfeeding.
25 to 8% in nonbreastfeeding infants. A single Achieving optimal ARV exposure throughout
maternal dose of nevirapine (NVP) at the onset pregnancy is critical. Physiological changes dur-
of labor and to the newborn at 48–72 h of life ing pregnancy can influence drug disposition and
was shown to reduce perinatal HIV transmission several studies have demonstrated reduced ARV
[3] . Combining ZDV monotherapy prophylaxis exposures during pregnancy [9] . Considerable
with single-dose maternal/infant NVP reduced data have demonstrated that host genetic poly-
HIV transmission to less than 2% [4] . Owing to morphisms in drug-metabolizing enzymes and
the rapid scale-up of ARV treatment programs, drug transporters can contribute towards the
an increasing number of HIV-infected pregnant interpatient variability of ARV pharmacokinetics
women are receiving highly active antiretroviral [10] . Associations between SNPs and drug con-
therapy (HAART) during pregnancy for HIV centrations for several ARVs in adults and chil-
treatment and/or the prevention of transmission dren are well described [11] . Accumulating data
of HIV. HAART during pregnancy and delivery also indicate that SNPs associated with drug
can reduce HIV transmission rates to 1.3% in 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 flow, plasma pH, protein binding and placen-
exposure to the drugs. Maternal ARV pen- tal drug metabolism, fetal exposure is depend-
etration into the fetal compartment may be a ent on the placental expression, subcellular
factor contributing to towards their overall localization, activity and substrate specificity of
prophylactic effect [22] . Conversely, fetal ARV drug efflux and influx transporters [25] . At least
exposure has implications for toxicities that 18 transporters known to be relevant to ARV
have been documented [23,24] . In addition to distribution are expressed on either the apical
future science group www.futuremedicine.com 1503

Table 2. Influence of genetic polymorphisms in metabolizing is the net effect on exposure of the infant to
enzymes/nuclear receptors on antiretroviral drug exposure. maternal xenobiotics.
Other factors such as drug–drug interactions,
Protein/gene Functional SNPs (effect on plasma exposure) Ref.
HIV infection and coinfections have been rec-
CYP2A6 1836G>T and 1093G>A (↑ EFV) [113,114]
ognized to affect drug transporter function in
CYP2B6 516G>T and 983T>C (↑ EFV and ↑ NVP) [94,95] other tissues [29–33] . Drug–drug interactions at
CYP2C19 rs4244285 and rs12248560 (? ETR) [123] the human placenta can also affect fetal expo-
sure to maternal drugs [34] . Therefore, the effects
CYP3A5 CYP3A5*1 (↓ SQV, ↓ IDV and ↓ ATV) [95,143]
of such nongenetic factors are recognized to be
*3 (↓ NVP)
important but are understudied and beyond the
UGT1A1 UGT1A1*28 and 211G>A (↑ ATV-related hyperbilirubinemia) [148,149] scope of this review.
UGT2B7 735A>G (↔ EFV) [114]
802C>T (↓ EFV) NRTI/NtRTI pharmacokinetics during
CAR (NR1I3) 540CC (↑ discontinuation of EFV) [13] pregnancy & the potential role of
PXR (NR1I2) 63396 C>T (↓ ATV) [144]
pharmacogenetics
There are currently eight NRTIs/NtRTIs
?: Effect unknown; ↑: Increased; ↓: Decreased; ↔: No difference; ATV: Atazanavir; EFV: Efavirenz;
ETR: Etravirine; IDV: Indinavir; NVP: Nevirapine; SQV: Saquinavir. approved for HIV treatment. All NRTIs/NtRTIs
are administered as prodrugs and must
(maternal) and basolateral (fetal) membranes of undergo intracellular metabolism by cellular
syncytiotrophoblasts as well as the endothelium kinases to their active ‘triphosphate’ anabo-
of fetal capillaries (Figure 1) . Members of the ATP- lites. Routine measurement of intracellular
dependent binding cassette efflux transporter NRTI–triphosphate concentrations remains
superfamily limit fetal exposure to maternal challenging. Comprehensive NRTI pharmaco
ARVs [26] . Transporters in the ATP-independent kinetic data available during pregnancy have
solute carrier superfamily, including organic subsequently been restricted to plasma NRTI
anion transporting polypepetides, organic anion concentrations; however, the relationship
transporters, organic cation transporters (OCTs) between NRTI plasma concentrations and drug
and equilibrative nucleoside transporters, are also efficacy/toxicity remains unclear [35] . Below is
relevant for distribution of ARVs into the fetal a summary of the effect of pregnancy on indi-
compartment. Recently, Iqbal et al. reviewed the vidual NRTI/NtRTI exposure and available
gestational changes in the expression and func- pharmacogenetic data.
tion of placental drug transporters as well as the ZDV (also know as azidothymidine) is a thy-
associated genetic polymorphisms [27] . The func- midine analog and was the first ARV approved
tional consequences of genetic polymorphisms for treatment of HIV infection in 1987 [204] . It
in the encoding genes were also been recently was also the first ARV administered to HIV-
highlighted by Ieiri et al. [28] . The substrate spe- infected pregnant women and continues to play
cificities, placental and mammary gland expres- a major role in the currently recommended
sion, and effects of associated functional SNPs ARV prophylactic regimens. ZDV is primarily
are presented in Table 3. Their localization on the eliminated through hepatic metabolism by UGT
basolateral or apical membranes of the placental [36] . Several studies have reported that ZDV
syncytiotrophoblast and the cord:maternal blood pharmacok inetics during the third trimester
(C:M) ratios for ARVs are shown in Figure 1. of pregnancy are similar to nonpregnant adults
Ultimately, the transfer of drug from mother [37–39] . However, lower ZDV exposure during
to infant will depend on the combined influ- the third trimester versus the postpartum period
ence of influx and efflux transporters within the has been reported (Table 4) [40] . The standard
placental barrier. Furthermore, the subcellular dose of ZDV is currently 300 mg twice daily,
localization of such transporters is also likely to and no adjustments are recommended during
be important since an apical influx transporter pregnancy. A lower dose of ZDV, 200 mg twice
may exhibit a similar effect upon fetal exposure daily, has been studied in nonpregnant adults
(in terms of direction) as that of a basolateral with low bodyweights (<60 kg) owing to con-
efflux transporter and vice versa. Therefore, it is cerns of higher rates of drug toxicity. Pharmaco
important to consider synergy and antagonism kinetic [41] and efficacy data [42] suggest that
between multiple transporters when examining this lower dose may be preferable in this patient
specific mechanisms. Although it is conceivable group; however, this dose has not been studied
that transport may occur from mother to infant in pregnant women. ZDV readily crosses the
or from infant to mother, the key phenotype placenta to the fetal compartment with a C:M

concentration ratio of 1.13–1.27 [40] . To date, implications of ABCC4 polymorphisms during
no data on the effect of UGT host genetic poly- pregnancy therefore warrant further study.
morphisms on plasma ZDV pharmacok inetics Stavudine (d4T) is thymidine analog. The
have been reported. Association between ZDV- WHO ARV treatment guidelines recommend
triphosphate concentrations and a SNP in the a 30-mg twice-daily dose for adults [206] . The
drug transporter ABCC4 (MRP4) in HIV- pharmacok inetics of d4T in pregnancy appear
infected nonpregnant adults has been reported to be similar to those in HIV-infected men and
[43] . Median ZDV–triphosphate concentra- no dose adjustment is recommended [45] . Mean
tions were 49% higher in ABCC4 3724G>A d4T C:M concentration ratio is 1.0 (95% CI:
(rs11568695) carriers versus homozygotes for 0.63–1.37). This drug was included in the first
the common allele (p = 0.03). Two SNPs within generic fixed-dose combinations developed and
ABCG2, 421C>A (rs2231142) and 34G>A has been widely used in resource-limited set-
(rs2231137), were also assessed, but neither were tings. However, WHO now suggests that coun-
associated with ZDV–triphosphate concentra- tries phase out d4T and develop plans to move
tions. ABCC4 has been shown to contribute to towards alternative firstline regimens, primar-
ZDV uptake into conditionally immortalized ily owing to d4T-associated lipodystrophy. No
rat syncytiotrophoblasts [44] and the clinical 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.

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

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
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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]
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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

occur in 5–8% of patients within 6 weeks of 3TC for prevention of MTCT [60] . Recent studies
initiating treatment and in rare cases can be fatal have associated mtDNA halogroup T/L1c and
[48] . The HLA‑B*5701 allele is strongly associ- mtDNA 4917G (increased risk), HFE 845G>A
ated with ABC hypersensitivity and ABC is cur- (rs1800562) and IL-12B 3´-UTR*2 (rs3212227)
rently the only ARV for which pharmacogenetic (decreased risk), as well as TNF- variants 1031*2
testing is currently recommended [49,50] . (rs1799964) and 308*2 (rs1800629) (increased
Lamivudine (3TC) is a cytidine analog risk) with NRTI-associated adult neuropathy
excreted primarily unchanged via the kidneys. [61,62] . Their roles in infant mitochondrial toxic-
3TC was approved by the FDA in 1995 [204] . ity as a result of in utero exposure to maternal
The recommended dosage of 3TC for adults is drug need further investigation.
300 mg once daily or 150 mg twice daily. The Emtricitabine (FTC) was approved by the
pharmacokinetics of 3TC during pregnancy was FDA in 2003 [204] . Like 3TC, it is a cytidine
reported to be similar during the last trimester analog excreted primarily unchanged via the kid-
compared with nonpregnant adults (Table 4) [39] . neys. The approved dosing in adults is 200 mg
A recent population pharmacok inetic study once daily. Within-subject comparisons of FTC
reported the oral clearance of 3TC to be 22% pharmacokinetics during pregnancy and postpar-
higher in pregnant women. However, the authors tum revealed significantly higher apparent clear-
concluded that this increase was not clinically rel- ance during pregnancy [63] . Significantly lower
evant and did not warrant a dose adjustment [51] . area under the curve (AUC) and drug concentra-
It crosses the human placenta with a median C:M tion 24 h postdose also were found during the
concentration ratio of 1.06. However, amniotic third trimester of pregnancy (Table 4) . FTC was
fluid concentrations were five-times higher than well distributed to the fetal compartment with
in maternal plasma, suggesting passive diffusion mean C:M concentration ratio of 1.2 (1.0–1.5).
across the amnion, fetal uptake and fetal clear- FTC is excreted into human breast milk but the
ance [52] . Like ZDV, 3TC is a substrate for the concentrations attained would represent a dose
drug transporter ABCC4 and ABCC4 4131G>T approximately 2% of the proposed oral dose for
(rs3742106) carrier status has been associated neonates [64] . It is a substrate for ABCC1 [65] ,
with 20% higher 3TC–triphosphate intracellular which is expressed in both the placenta and
concentrations (p = 0.004) [43] . Furthermore, mammary gland [57] . However, no studies have
3TC breast milk concentrations were reported assessed the influence of genetic polymorphisms
to be approximately threefold higher than mater- and its disposition.
nal serum concentrations [53] . However, 3TC Tenofovir disoproxil fumarate (TDF) is a
ingested by breastfed infants appears to be poorly nucleotide analog of adenosine and was approved
absorbed with low plasma concentrations (<0.10 by the FDA in 2001 [204] . The recommended
µg/ml) detected [54] . 3TC is also a substrate for oral dose for adults is 300 mg once daily. TDF is
the organic cation transporters OCT1, OCT2 the oral prodrug of tenofovir (TFV). Following
and OCT3 [55,56] , all of which are expressed oral absorption, TDF rapidly undergoes esterase
in the kidney, placenta and mammary gland hydrolysis and is converted to TFV, a nucleo-
(exepct for OCT2 in the latter) [57] . In a recent tide (nucleoside monophosphate) analog that is
study Choi et al. observed reduced 3TC uptake taken up by cells. Intracellularly, TFV is rapidly
in oocytes expressing OCT1-P283L and OCT1- phosphorylated by cellular nucleotide kinase to
P341L as well as those expressing OCT2-T199I, its active anabolite TFV diphosphate. TFV is
OCT2-T201M and OCT2-A270S variants com- primarily excreted unchanged by the renal route
pared with with the reference sequences [58] . The through a combination of glomerular filtration
consequences of functional SNPs of OCTs on and active tubular secretion [66] . Burchett et al.
3TC pharmacok inetics have not been studied assessed the pharmacokinetics of TFV between
in vivo. Such SNPs may also influence the distri- 30 and 36 weeks gestation age and 6–12 weeks
bution of 3TC to the fetal compartment as well postpartum [67] . Median (range) TFV AUC
as its excretion into breast milk. was significantly lower during the third tri
Rare cases of lethal mitochondrial dysfunction mester, 2.5 (1.1–2.6) µg/h/ml during pregnancy
in infants exposed in utero to ZDV and 3TC were compared with 2.96 (1.62–7.2) postpartum
reported in the late 1990s [59] . These severe cases (p = 0.02). However, third trimester Cmin were
are clinically very similar to known genetically not different from postpartum values. A recent
induced mitochondrial defects. Evidence of study reported a 25% reduction in TFV exposure
mitochondrial damage has been demonstrated during the third trimester compared with post-
in HIV-uninfected infants exposed to ZDV and partum. The authors speculated that the decrease

was due to reduced absorption and/or increased which is expressed in the human placenta [57] , and
volume of distribution as no change in the termi- its possible role, including the effect of genetic
nal elimination half-life was observed (Table 4) [68] . polymorphisms, in the uptake of TFV into the
Benaboud et al. studied the effects of pregnancy fetal compartment should be studied. TFV is also
on TFV pharmacok inetics using a population excreted into human breast milk but at low con-
pharmacokinetic analysis involving 46 pregnant centrations – equivalent to a median dose of 4.2
and 156 nonpregnant HIV-infected women [69] . µg/day for a 3‑kg neonate, or 0.03% of the oral
The apparent oral clearance was 39% higher in dose proposed for neonates [64] .
pregnant women. These authors suggested that
a TFV dose increase should be considered for Pharmacokinetics during pregnancy
women from the second trimester until deliv- & the potential role of
ery in order to achieve comparable exposure to pharmacogenetics
nonpregnant adults. Non-nucleoside reverse transcriptase
It is of interest to note that, while TFV readily inhibitors
crosses the human placenta with C:M concen- Four NNRTIs are currently available for the
tration ratio of 1.04 (0.6–1.7) [67] , the transfer treatment of HIV. NNRTIs are primarily metab-
into cerebrospinal fluid has been reported to olized by CYP enzymes and, with the excep-
be an order of magnitude lower with cerebro- tion of NVP, are highly protein bound (Table 1) .
spinal fluid:plasma ratio of 0.057 (0.03–0.1) Therefore, drugs in this class are expected to
[70] . This difference may be indicative of sub- be susceptible to temporal changes in hepatic
stantial differences in the expression profile of enzyme activities and plasma protein fluctuations
transporters between these barriers. TFV is a during pregnancy. NNRTIs plasma drug con-
substrate for ABCC4, OAT1, OAT3 [71] and centrations also have been associated with SNPs
MRP7 (ABCC10) [72] . Interestingly, OAT1, in genes encoding the enzymes involved in their
OAT3 and ABCC4 are expressed in choroid metabolism, transport and nuclear receptor type
plexus epithelial cells but not in the placenta transcription factors.
[73–75] , while ABCC10 is expressed in both the NVP was the first NNRTI receiving FDA
placenta and CNS [57] . OATs are involved in the approval in 1996 [204] . It is initiated at a lower dose
efflux of their substrates out of the CNS [76,77] . (or ‘lead-in’ dose) for the first 2 weeks to allow
The mechanisms behind this observed differ- for the autoinduction of metabolizing enzymes,
ence have not been studied in detail. Carriers of which increases its clearance. Initiating NVP
ABCC4 3463A>G (rs1751034) were reported to in this stepwise fashion reduces the frequency
have 35% higher intracellular TDF diphosphate of drug-associated rashes. One 200 mg tablet is
concentrations than noncarriers (p = 0.04) [78] . administered once daily for the first 14 days and
TFV is transported into proximal tubular cells by if there are no clinical signs of rash the dose is
OAT1 and to a lesser extent OAT3 [79] , which is increased to 200 mg twice daily [84] . Single and
located on the basolateral membrane. It remains chronic NVP dosing has been used during preg-
unknown if a change in OAT1 expression/activ- nancy to prevent MTCT of HIV. A single mater-
ity plays a role in increased TFV clearance dur- nal dose of NVP at the onset of labor and to the
ing pregnancy, and if such changes are driven by newborn at 48–72 h of life is still recommended
genetic polymorphisms. as an option in the WHO prevention of MTCT
The luminal efflux system(s) involved in guidelines. Concerns have been raised over the
the transport of TFV out of proximal tubular use of single-dose NVP [203] . Due to its long half-
cells and into the urine is not well described. life, NVP can persist in the plasma for up to 4
Three transporters, ABCC2 [80] , ABCC4 [81] weeks postpartum following a single intrapartum
and ABCC10 [72] have been reported to play a dose [85] . This prolonged period of monotherapy,
role in the active renal tubular efflux of TFV. A in the presence of replicating viruses, can increase
genetic variant of ABCC2 (rs717620) [82] , and the risk of selecting NNRTI resistance mutations.
two ABCC10 SNPs (rs9349256 and rs2125739) NNRTI mutations detected in the postpartum
were identified as predictors of TFV-induced period have been shown to affect the efficacy of
nephrotoxicity [72] . Higher plasma TFV concen- future NNRTI based-HAART regimens [86] .
trations in patients with kidney tubular dysfunc- However, short-course ARV treatments post
tion have also been reported [83] . The implica- partum (7–30 days) can reduce the risk of select-
tions of these SNPs on TFV pharmacokinetics ing NNRTI resistance mutations postpartum
during pregnancy and risk of tubular dysfunction following intrapartum NVP [87,88] . The associa-
are unknown. TFV is a substrate for ABCC10, tion of SNPs in metabolizing enzymes with NVP

concentrations following an intrapartum single An association between HLA‑B*3505 and
dose have been reported, but the modest effects NVP-induced skin rash has been reported [99] .
may not be clinically significant [89] . Furthermore, a genome-wide association study
Chronic NVP dosing is increasingly used, in revealed that variations in the CCHCR1 gene
part owing to the availability of generic triple- were strongly associated with NVP-induced skin
drug fixed-dose combinations in resource- rash [100] . Incorporating genetic and clinical risk
limited settings. The geometric mean third factors may therefore have utility in reducing the
trimester:postpartum ratio for NVP AUC has incidence of NVP related-toxicities in women
been reported to be 0.90 (90% CI: 0.80–1.02) initiating NVP during pregnancy.
[90] and 0.79 (90% CI: 0.70–0.90) [91] . A 30% There are currently no data on NVP
decrease in NVP AUC between pregnant and pharmacok inetics during lactation. However,
nonpregnant women has been reported [92] , but its excretion into human breast milk has been
no dose adjustment is currently recommended. reported with milk:plasma ratios of 0.67 [53]
CYP2B6 516G>T (rs3745274) and CYP2B6 and 0.75 [54] , resulting in 0.97 and 0.73–1.03
983T>C (rs28399499) SNPs have been asso- µg/ml, respectively, in breastfed infants’ plasma.
ciated with higher NVP plasma concentra- Interestingly, this is higher than the >0.10 µg/ml
tions. Penzak et al. reported NVP median target on which current postexposure prophyl
plasma concentration of 7.61 µg/ml in indi- axis dosing guidelines are based [203] , but less
viduals with CYP2B6 516TT genotype versus than the target trough concentration of >3.0
4.18 and 5.56 µg/ml in those with 516GG and µg/ml in HIV-infected children [101] . However,
516GT genotypes, respectively [93] . These find- breast milk ingestion of NVP has been associ-
ings were confirmed in a larger study where ated with increased risk of cutaneous adverse
median (range) NVP plasma concentrations drug reactions in breastfed infants compared
were 5.18 (1.89–11.16), 6.13 (0.15–11.69) and with nelfinavir [102] . The new WHO guidelines
6.69 (4.16–21.03) µg/ml for carriers of CYP2B6 recommend NVP for postexposure prophyla xis
516GG, GT and TT genotypes, respectively [94] . in breastfeeding populations, which may mean
This latter study was also the first to demon- that the exposure in infants in developing coun-
strate that carriers of CYP2B6 983 TT and TC tries whose mothers also take NVP may be higher
genotypes had significantly higher NVP plasma than anticipated. This may conceivably impact
concentrations. Both CYP2B6 516G>T and upon NVP-associated adverse drug reactions in
CYP3A5*3 (rs776746) were associated with NVP these infants but this has not been studied in
pharmacok inetics in a recent study in Malawi. detail.
The CYP2B6 516 T allele increased NVP AUC Efavirenz (EFV) was approved by the FDA
by 92% and CYP3A5*3 decreased NVP AUC by in 1998 [204] and early reports of congenital neu-
31% in a multivariable model [95] . The inclusion ral tube defects resulting from first-trimester
of host genetic polymorphisms in pharmaco exposure have limited its use during pregnancy
kinetic studies of NVP during pregnancy may [103] . Although emerging data on the safety of
help identity subpopulations of women who are EFV use in pregnancy provide some reassurance
at higher risk of subtherapeutic concentrations. [104–107] , the number of cases monitored and the
To date, relatively little data have emerged relative rarity of neural tube defects and facial
on efflux or influx transporters capable of NVP clefts cannot yet rule out some degree of risk.
transport. However, NVP was recently shown to In 2010, WHO updated their prevention of
be a substrate for ABCC10 and SNPs within the MTCT guidelines and recommended EFV use
gene encoding this efflux pump were shown to be as part of combination ARV therapy after the
associated with plasma concentrations of NVP first trimester [203] .
[96] . This is an area where further mechanistic Recently the first pharmacokinetic data evalu-
investigation is warranted since the identification ating the standard dose (600 mg once daily) of
of placental or mammary gland transporters may EFV during the third trimester of pregnancy and
underpin studies to identify pharmacogenetic postpartum were published [108] . There was no sig-
correlates of exposure of the fetus or infant, nificant difference in EFV AUC and Cmax during
respectively. pregnancy compared with postpartum (Table 4) ;
Higher incidences of NVP-related rash and geometric mean ratios were 0.97 (90% CI:
hepatotoxicity have been reported in HIV- 0.83–1.13) and 1.11 (90% CI: 0.99–1.24),
infected pregnant women with CD4 counts respectively. However, EFV oral clearance was
of >250 cells/mm3 [97,98] and NVP-containing significantly higher during the third trimes-
HAART is not preferred in these patients. ter and the drug concentration 24 h postdose

significantly lower compared with postpartum. 1.0–4.0 µg/ml [117] . Maternal EFV concentra-
The C:M concentration ratio of EFV was 0.49 tions, which depend on various host genotypes,
(90% CI: 0.37–0.74). Based on these data, no will be a major determinant of infant exposure.
dose adjustment is required during pregnancy. However, EFV transport across the placenta and
Considerable data are available on the effect of into breast milk is also likely to be important but
host genetic polymorphisms on EFV pharmaco is, as yet, largely unstudied. Peroni et al. recently
kinetics and it is possible that dose adjustments reported that EFV is a substrate of rat ABCG2
are applicable for genetically defined subgroups and inhibits its own intestinal permeability by
of women. Interestingly, two women included promoting overexpression of ABCG2 in the rat
in the study above experienced extremely high GI tract [118] . ABCG2, which is highly polymor-
drug exposure during pregnancy [108] . This may phic, has been shown to be highly expressed in the
be explained by genetic polymorphisms, but the apical membrane of human placenta syncytiotro-
consequences of such high exposures remain phoblast [119] and human mammary gland during
unknown. lactation [120] . It has been suggested to play a role
EFV is primarily metabolized by CYP2B6 [109] in protecting the fetus against exposure to poten-
with a minor contribution from CYP2A6 [110,111] tially toxic compounds in maternal blood [121] .
and glucuronidation of the 8-hydroxy metabo- SNPs in EFV transporters are expected to play
lite by UGT2B7 [112] . Genetic polymorphisms in an important role in determining the exposure of
genes encoding these enzymes and the transcrip- the fetus and breastfed infant-to-maternal EFV.
tional regulator, CAR, have been associated with Etravirine (ETR) was approved by the FDA
interindividual variability in EFV plasma drug in 2008 [204] . Data on ETR pharmacok inetics
concentrations. The SNPs CYP2B6 516G>T during pregnancy are limited; only a small study
(rs3745274), CYP2B6 983T>C (rs28399499), involving four HIV-infected pregnant women
CYP2A6 1836G>T (rs8192726), UGT2B7 treated with ETR (with darunavir [DRV] and
735A>G (rs28365062), UGT2B7 802C>T ritonavir [RTV]) describes the pharmacokinetics
(rs7439366) and CAR 540C>T (rs2307424) of ETR during pregnancy [122] . ETR pharmaco
have been investigated. In studies conducted in kinetics during the third trimester was similar
HIV-positive Ghanaian patients, Kwara et al. to those of nonpregnant adults (Table 4) . C:M
identified CYP2B6 516G>T, CYP2A6 1836G>T concentration ratio in one woman was 0.33.
and/or CYP2A6 1093G>A (rs28399454) and More data are clearly required and several ongo-
UGT2B7*1a carrier status as predictors of EFV ing studies are assessing the pharmacok inetics
plasma concentrations, accounting for 45.2, of ETR during pregnancy. ETR is primarily
10.1 and 8.6% of the total variance, respectively metabolized by CYP2C19 [123] , whose expres-
[113,114] . Rotger et al. also reported significantly sion and activity declines during pregnancy
higher plasma and intracellular EFV concentra- [124] . It is also known to be highly polymorphic.
tions and AUC in Caucasians with the CYP2B6 The CYP2C19*2 (rs4244285; high frequency
516TT genotype than in those with CYP2B6 in Asians) and CYP2C19*17 (rs12248560; high
516GG genotype [115] . CYP2B6 516TT was frequency in Africans) alleles have been associ-
also associated with higher incidences of EFV ated with poor and ultrarapid metabolism of
neuropsychiatric side effects. The 983T>C poly- CYP2C19 substrates, respectively [125,126] and
morphism was also significantly associated with their effect on ETR pharmacokinetics is clearly
higher EFV concentrations [94] . Recently, the worthy of study. Furthermore, how these fac-
CYP2B6 516TT and CAR 540C>T genotypes tors affect ETR pharmacokinetics during preg-
were associated with early treatment discontinu- nancy remain uncharacterized but the presence
ation, with CNS toxicity accounting for 94.7% of CYP2C19*17 and known upregulation of
of cases of discontinuation [13] . The effect of the CYP3A4 activity during pregnancy may lead to
well defined SNPs that influence EFV plasma subtherapeutic concentrations.
concentrations and risk of CNS toxicity in Rilpivirine (RPV) is the newest NNRTI
nonpregnant adults should be studied during approved by the FDA in 2011 [204] . It is metabo-
pregnancy. lized by CYP3A enzymes and 99.7% bound to
EFV is excreted into breast milk. Schneider plasma proteins (mainly albumin) [207] . No data
et al. reported a median infant plasma EFV on RPV pharmacok inetics during pregnancy
concentration of 0.87 µg/ml (range: 0.31–1.51 in humans are available. However, pregnancy-
µg/ml) following breast milk ingestion from induced increases in CYP3A enzyme activity
mothers receiving EFV for prevention of MTCT and decrease in albumin concentrations may be
[116] . The recommended therapeutic range is expected to increase RPV clearance.

Protease inhibitors SLCO1B1, ABCB1 and ABCC1 on transplacental
There are currently ten PIs available for the treat- transfer of LPV and RTV also warrants further
ment of HIV. The PIs are primarily metabolized study. However, LPV and RTV are undetectable
by CYP enzymes and are highly protein bound in human breast milk [139] .
(Table 1) . Similar to the NNRTIs, these drugs are Atazanavir (ATV) is the only PI that can be
expected to be susceptible to pregnancy-induced administered with or without low-dose RTV.
changes in CYP enzymes and plasma protein The standard dose alone is 400 mg for ARV-naive
fluctuations. patients or, for ATV/RTV, 300/100 mg once
Lopinavir/RTV (LPV/RTV) is one of the daily. ATV is metabolized by CYP3A enzymes
most widely studied ARVs during pregnancy. and is not recommended for administration
LPV is administered in combination with low- without RTV during pregnancy. Conflicting
dose RTV to ‘boost’ its pharmacok inetics. The data on ATV/RTV pharmacok inetics dur-
standard dose of LPV/RTV in nonpregnant ing pregnancy have been reported. Ripamonti
adults is 400/100 mg twice daily. LPV is primar- et al. reported no significant differences in ATV
ily metabolized by CYP3A4 and CYP3A5 iso- AUC, Cmax and Cmin antepartum compared with
enzymes. RTV is a potent inhibitor of CYP3A4 postpartum [140] . By contrast, Mirochnick et al.
activity and concomitant administration of observed significant differences between ante-
LPV with RTV results in markedly higher LPV and post-partum pharmacok inetics with AUC,
concentrations. RTV is also a substrate for both Cmax and Cmin antepartum:postpartum ratios of
CYP3A4 and CYP2D6 [127] . Both LPV and 0.72, 0.47 and 0.58, respectively, without TFV,
RTV are also ABCB1 and ABCC1 substrates and 0.73, 0.61 and 0.67, respectively, with TFV
[128,129] and are highly bound (98%) to plasma (Table 4) [141] . Subsequently, an ATV/RTV dose
proteins. LPV/RTV is the preferred PI regimen of 400/100 mg was assessed during pregnancy
for ART-naive pregnant women. and provided comparable exposure to non
Stek et al. assessed standard LPV/RTV dos- pregnant adults [142] . C:M ATV concentration
ing during the third trimester and LPV expo- ratio of approximately 0.15 was observed in these
sure was approximately 50% lower compared studies.
with nonpregnant adults [130] . Mean (±standard The CYP3A5*1B (rs28365095) allele has
deviation) LPV C:M concentration ratio was been associated with increased ATV clearance
0.2 (±0.13). Changes in RTV pharmacok inetic [143] . No significant differences in ATV AUC or
parameters were not statistically significant. Cmax were observed in CYP3A5 expressors versus
The soft-gel capsule formulation used in this nonexpressors in the presence of RTV, although
study has been replaced with a tablet formula- in a subgroup of non-African–American males
tion, which has been shown to have improved the faster CL/F persisted in CYP3A5 expressors
bioavailability (Table 4) [131] . LPV exposure dur- versus nonexpressors. Also, subjects with one or
ing the third trimester of pregnancy follow- two copies of the wild-type CGC haplotype for
ing standard dosing in Thai women with the ABCB1 (1236C, 2677G and 3435C; rs1128503,
tablet formulation was reduced by 22% [132] . rs2032582 and rs1045642, respectively) had
Similar findings have been reported by Calza slower ATV clearance.
et al. [133] , Ramautarsing et al. [134] and Lambert A polymorphism (63396C>T; rs2472677)
et al. [135] . In American women, a higher dose of within the transcriptional regulator, PXR
the tablet formulation, 600/125 mg, provided (NR1I2) has also been shown to be associated
comparable exposure to that observed in non- with unboosted ATV plasma concentrations [144]
pregnant adults [136] . Debate remains on the and a 17% increase in unboosted ATV clear-
optimal dose of LPV/RTV during pregnancy ance [145] . Furthermore, interaction between
and may differ between populations. Higher CYP3A5 expressor status and PXR 63396C>T
LPV plasma concentrations have been associated (rs2472677) were also recently reported by Kile
with the 521T>C (rs4149056) polymorphism in et al. [146] . ATV clearance was 37% lower in
SLCO1B1 [137] ; within a population pharmaco nonexpressors of CYP3A5 with PXR 63396CC
kinetic model homozygosity for the C allele was genotype than those with CT or TT genotypes
associated with a 37% lower clearance [138] . The and 63% lower in CYP3A5 expressors with PXR
influence of SLCO1B1 polymorphisms on LPV 63396CC genotype than those with CT or TT
exposure during pregnancy should be investi- genotypes [146] . Based on available data, the
gated as the presence of this SNP may help com- effect of the CYP3A5-expressor status on RTV
pensate for the pregnancy-induced changes in boosted ATV during pregnancy may be limited.
some women. The possible influence of SNPs in However, the ABCB1 3435C>T (rs1045642)

polymorphism may influence ATV plasma con- A number of reports have emerged on its use in
centrations in the presence of RTV [147] , and this late pregnancy. Taylor et al. [154] and McKeown
has not been investigated in pregnant women. et al. have authored case reports of RAL dur-
AT V use is associated with hyper ing pregnancy and observed rapid viral-load
bilirubinemia and an association between the reductions in women within days of initiating
UGT1A1*28 (rs8175347) and hyperbilirubine- a RAL-containing regimens [155] . Preliminary
mia has been observed [148] . Neonatal UGT1A1 results from an intensive pharmacokinetic study
211G>A (rs4148323) and SLCO1B1 388G>A of RAL ante- and post-partum showed that it
(rs2306283) polymorphisms, breastfeeding [149] exhibited wide interindividual variability, con-
and, more recently, ATV use during pregnancy sistent with data in nonpregnant adults, and that
[150] have all been identified as risk factors for the exposure was not consistently altered during
neonatal hyperbilirubinemia. Breast milk excre- pregnancy compared with postpartum (Table 4)
tion of ATV (unboosted) has also been reported [156] . C:M RAL concentration ratio at delivery
with a milk:plasma ratio of 0.13 [151] . Studies on was 1.20 (95% CI: 0.09–2.3) suggesting signifi-
the role of these functional SNPs in neonatal cant transfer into the fetal compartment. RAL
hyperbilirubinemia associated with ATV use is a substrate for ABCB1 [30] . The role of SNPs
during pregnancy and lactation are needed. associated with changes in its expression and
DRV was approved in 2006 and is used in activity in RAL transport across the placenta has
combination with low-dose RTV at 600/100 mg not been studied. While elevated RAL levels may
twice daily or 800/100 mg once daily in naive protect against perinatal HIV infection, the con-
patients. Little is known about the pharmaco sequences for exposed infants need to be clarified.
kinetics of DRV during pregnancy. Capparelli Interestingly, higher RAL concentrations have
et al. assessed DRV/RTV once and twice daily been reported in Thai adults with an approxi-
pharmacok inetics during the third trimester mately twofold increase in AUC compared with
and postpartum (Table 4) [152] . DRV clearance Caucasians at the standard dose [157] .
was increased during the third trimester com- RAL is metabolized by UGT1A1, which is
pared with postpartum for both once and twice highly polymorphic. Coadministration with
daily dosing. The authors suggested that twice ATV (a known UGT1A1 inhibitor) resulted in
daily dosing may be preferable during preg- elevated RAL plasma levels (median [25th–75th
nancy to reduce the risk of low trough con- percentiles]: 0.52 [0.31–2.71] vs 0.22 [0.95–0.55]
centrations and higher doses of DRV/RTV are µg/ml; p = 0.02). This study also reported the
currently under study. No functional SNPs have lack of an association between elevated RAL
been associated with DRV but the mechanisms plasma concentrations and UGT1A1*28/*28
that regulate its pharmacok inetics are similar to (rs8175347) reduced function genotype in Italian
other PIs and many of the issues may therefore patients [158] . An earlier study in Japanese patients
be similar to those for LPV and ATV. also reported no significant difference between
There are no data on the use of amprena- heterozygote *6 (rs4148323) and *28 allele car-
vir during pregnancy. However, its prodrug riers and homozygotes of the common allele [159] .
fosamprenavir boosted with low-dose RTV has In a recent comprehensive population pharmaco
been assessed at a dose of 700/100 mg twice kinetic/pharmacogenetic analysis of RAL in
daily and the AUC and C12 during the third healthy and HIV positive individuals, Arab-
trimester were lower than postpartum (Table 4) Alameddine et al. reported no association with
[153] . Fosamprenavir had a C:M concentration UGT1A1 SNPs. However, although extremely
ratio of 0.27 (95% CI: 0.24–0.45). No associa- rare, UGT1A9*3 (rs72551330) was identified as
tion between SNPs and amprenavir pharmaco possibly influencing RAL pharmacokinetics [160] .
kinetics have been reported. NFV, saquinavir Other factors influencing the wide interpatient
and indinavir are among the older PIs and are variability, fetal exposure, and infant exposure
now used less frequently for HIV treatment through breast milk remain to be determined.
and during pregnancy, and therefore will not
included in this review, but lower NFV and Entry inhibitors/fusion inhibitors
indinavir/RTV exposure during pregnancy has Very limited information is available on enfu-
been observed (Table 4) . virtide during pregnancy. Its use in late preg-
nancy for prevention of MTCT in women pre-
Integrase strand transfer inhibitors senting with virological failure and multiclass
Raltegravir (RAL) is the only approved INSTI viral resistance mutations have been reported.
and the recommended dose is 400 mg twice daily. Enfuvirtidedoes not cross the placenta [161–165]

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.

Executive summary
Mother-to-child transmission of HIV
Mother-to-child-transmission rates of HIV without any intervention range between 20 and 45%.
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
Physiological changes during pregnancy can influence drug disposition and several studies have demonstrated reduced ARV exposure
during pregnancy.
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
Numerous potential candidates for pharmacogenomic investigation exist.
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.
Including studies of functional SNPs associated with NVP pharmacokinetics to identify pharmacogenetic predictors of NVP exposure
following breast milk ingestion would be useful.
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.
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
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.
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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Potential effect of pharmacogenetics on maternal,

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

Pregnancy & drug transporters the physiochemical properties, placental blood

future science group www.futuremedicine.com 1503

1504 Pharmacogenomics (2012) 13(13) future science group

TPV (0.41)‡ RAL (0.09–2.3)

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

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

future science group www.futuremedicine.com 1505

MRP1 (ABCC1) Placenta and mammary

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

OAT2 (SLC22A7) Placenta and mammary gland

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

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

ENT1 (SLC29A1) Placenta and mammary gland

ENT2 (SLC29A2) Placenta and mammary gland

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

future science group

median (range) (<0.234–43.700)

Pharmacogenomics (2012) 13(13)

future science group

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

1516 Pharmacogenomics (2012) 13(13) future science group

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