BBA - Molecular Basis of Disease 1867 (2021) 166206

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BBA - Molecular Basis of Disease

journal homepage: www.elsevier.com/locate/bbadis

HIV in pregnancy: Mother-to-child transmission, pharmacotherapy,

and toxicity
Lukas Cerveny a, Padma Murthi b, c, d, Frantisek Staud a, *
a
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
b
Department of Medicine, School of Clinical Sciences, and Department of Pharmacology, Monash Biomedicine Discovery Institute Monash University, Clayton, Victoria,
Australia
c
Hudson Institute of Medical Research, The Ritchie Centre, Clayton, Victoria, Australia
d
Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, Victoria, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: An estimated 1.3 million pregnant women were living with HIV in 2018. HIV infection is associated with adverse
HIV pregnancy outcomes and all HIV-positive pregnant women, regardless of their clinical stage, should receive a
Antiretroviral therapy combination of antiretroviral drugs to suppress maternal viral load and prevent vertical fetal infection. Although
Mother-to-child transmission
antiretroviral treatment in pregnant women has undoubtedly minimized mother-to-child transmission of HIV,
Placental membrane transporters
several uncertainties remain. For example, while pregnancy is accompanied by changes in pharmacokinetic
Placental/fetal development
Fetal programming parameters, relevant data from clinical studies are lacking. Similarly, long-term adverse effects of exposure to
antiretrovirals on fetuses have not been studied in detail. Here, we review current knowledge on HIV effects on
the placenta and developing fetus, recommended antiretroviral regimens, and pharmacokinetic considerations
with particular focus on placental transport. We also discuss recent advances in antiretroviral research and
potential effects of antiretroviral treatment on placental/fetal development and programming.

1. Introduction
Human immunodeficiency virus-1 (HIV) infection remains a global
health challenge. It has been estimated that almost 700,000 people died
of HIV-related diseases and 1.7 million were newly infected in 2019, and
38 million people worldwide were living with HIV at the end of the year
[1]. Moreover, in 2018 an estimated 1.3 million pregnant women with
HIV were at risk of developing AIDS and perinatal transmission of the
virus to their fetus. Mother-to-child transmission (MTCT) accounts for
most childhood HIV infections and may occur during second and third
trimesters of pregnancy, labor and delivery, or breastfeeding. It has been
proposed that the risk of HIV MTCT in the absence of any intervention is
up to 49%; approximately 8% of children are infected during pregnancy,
15% during labor and delivery, and 12–26% during breast-feeding [2,3].
However, with the massive advent of antiretroviral drugs, 67% of people
with HIV receive antiretroviral therapy (ART) and almost 60% live
without clinical symptoms of AIDS nowadays. Similarly, thanks to effi­
cient use of pharmacotherapy and other measures, the incidence of
MTCT has been reduced to <1% over the last 25 years. In an example of
high-quality management of MTCT of HIV, the WHO and Pan American
Health Organization joined forces to reduce it in Cuba. The initiative
included HIV testing of all pregnant women, ART provision for those
who tested HIV-positive, implementation of birth by cesarean section,
and replacement of breastfeeding by other alternatives. Five years after
applying these measures, Cuba was officially pronounced a country that
had completely eradicated MTCT of HIV [4]. However, the Cuban model
is not feasible in some other regions, such as sub-Saharan Africa, where
countries need to primarily rely on timely and efficient use of ART [5–8].
Currently, >30 US Federal Food and Drug Administration (FDA)-
approved antiretroviral drugs are available, singly or in various com­
binations, to clinicians and their patients. However, most of these drugs’
pharmacokinetics, efficacy, maternal and fetal safety during pregnancy
have not been sufficiently investigated, hence they are used off-label [9].
Although the success of ART in reducing MTCT is indisputable, the
research community and clinicians should not ignore possible effects of
antiviral pharmacotherapy on placental development and fetal pro­
gramming, which might potentially result in diseases later in adulthood.
In this review we outline current knowledge of HIV in pregnancy and

* Corresponding author at: Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho
1203, Czech Republic.
E-mail address: frantisek.staud@faf.cuni.cz (F. Staud).

https://doi.org/10.1016/j.bbadis.2021.166206
Received 5 February 2021; Received in revised form 18 May 2021; Accepted 11 June 2021
Available online 29 June 2021
0925-4439/© 2021 Elsevier B.V. All rights reserved.
L. Cerveny et al.
Fig. 1. Measures to prevent HIV mother-to-child transmission. The first step
should be universal maternal HIV testing as early as possible during each preg­
nancy and prenatal counseling. If the results are positive women should imme­
diately start ART regardless of the gestation phase and clinical stage. When the
HIV load exceeds 1000 RNA copies/mL plasma or is unknown near the time of
delivery women should deliver by elective cesarean section and, if possible,
women should avoid breastfeeding. This package of preventive interventions can
reduce the overall risk of fetal infection to <1%.
the use of ART in it. In detail, we focus on mechanisms of HIV passage
through the placenta, changes in morphology and histology of the
placenta in HIV-positive women, and their pregnancy outcomes. Then
we summarize current knowledge on use of ART to prevent MTCT of the
virus, considering pharmacokinetic parameters in pregnancy and
mechanisms affecting placental transfer of antiretrovirals. We also
provide an overview of possible acute and chronic toxic effects of anti­
retrovirals on both fetal development and programming.
2. Mechanisms and risks of mother-to-child transmission of HIV
Several possible mechanisms of HIV transmission from mother to her
offspring have been described, including in utero transplacental HIV
transport, intrapartum transmission, and infection through breastfeed­
ing. High maternal viral load is the strongest risk factor for both in utero
and intrapartum MTCT. Risks for vertical HIV transmission are also
influenced by the viral phenotype and increased by host factors such as
advanced HIV-1-related illness/AIDS, maternal co-infections, prolonged
rupture of amniotic membranes, and polymorphism of genes affecting
virus entry or immune responses [10,11]. Moreover, there are some
indications that overall risks for in utero HIV transmission may be higher
if primary HIV infection occurs during pregnancy rather than before
conception [12,13].
The placenta provides a barrier that effectively reduces, but does not
completely prevent, HIV transmission and the most frequent window for
in utero transmission is the last 14 days before delivery [14]. Mecha­
nisms of HIV passage across the placenta are not well known [15]. The
virus infects syncytiotrophoblast, cytotrophoblast, and villous endo­
thelial cells [16], but placental cells produce various soluble factors and
2
BBA - Molecular Basis of Disease 1867 (2021) 166206
receptors including cytokines and chemokines that may reduce HIV
replication in trophoblasts [17,18]. In utero, single or multiple major
maternal HIV variants are transmitted [19]. HIV MTCT occurs mainly
via transcytosis of HIV-infected cells [16] while free virus can pass
through the placenta via injured villous surface [15]. Feto-placental
macrophages, called Hofbauer cells, may putatively facilitate placental
HIV transmission [20] and contribute to selection of HIV variants
infecting the developing fetus [16]. HIV-1 enters cells of the immune
system, including Hofbauer cells, via interaction of the surface envelope
glycoprotein gp120 with CD4 and chemokine co-receptors CCR5 or
CXCR4, and the transmembrane envelope protein gp41 promotes fusion
of the virus with the host cell’s plasma membrane (Fig. 3).
Possible mechanisms whereby the virus infects the fetus intrapartum
include microtransfusion during contractions, ascension through the
cervix and vagina during parturition, and absorption of the virus
through the infant’s digestive tract [14,21]. In contrast to in utero
transmission of HIV, minor HIV-1 variants with relatively high gene
diversity are most likely to cause intrapartum infections [19].
Transmission through breast-feeding can occur at any point during
lactation [22]. Cell-free and infected CD4+ cells can transmigrate across
fetal oral and intestinal epithelia, probably because their mucosal layers
are relatively narrow, have comparatively low stratification, and lack
expression of anti-HIV innate proteins [23]. The risk factors related to
HIV transmission through breastfeeding have been less studied but are
apparently associated with maternal viral load and subclinical mastitis
[24,25]. The risk is cumulative; the longer the HIV-infected mother
breastfeeds, the greater the additional risk of viral transmission to the
newborn. Where breastfeeding is common and prolonged this route of
transmission may account for up to half of HIV infections in infants and
young children [22].
3. Placenta as an HIV sanctuary site
By definition, a viral sanctuary site is an anatomical compartment
where a virus can replicate due to poor efficacy of ART and/or particular
biological properties [26]. HIV infects and replicates in trophoblasts
[15], however, with much lower efficacy when compared with CD4+
cells [27,28]. This is likely because none or minimal amounts of CD4,
CCR5 and CXCR4 are expressed in the membranes of trophoblasts
[28–30]. HIV thus enters the trophoblast cells by less effective CD4-
independent pathways, via receptor-mediated endocytosis [27,28,30]
and/or direct cell-cell contact [28,31]. Moreover, infection of tropho­
blasts can be reduced by soluble factors, including placental chemokine
(C-C motif) ligand 5, macrophage inflammatory protein-1β or leukemia
inhibitory factor, creating suppressive environment at the feto-placental
interface [32]. On the other hand, viral production in trophoblast cells
may be supported by exposure to tumor necrosis factor-α, interleukin-1,
and/or interleukin-8 produced by the placenta or released upon viral/
bacterial/protozoal infection, which was suggested to accelerate HIV
MTCT transmission [30,32]. Recently, syncytin, the envelope glyco­
protein of human endogenous retrovirus family W1 expressed in
placental trophoblasts, has been shown to contribute to viral replication
in the placenta [31].
HIV maintains a low level of infection in placentas despite ART and
can be reactivated after its discontinuation [31]. Placental sanctuary
sites likely develop through activities of placental membrane ABC efflux
transporters (see below) [33]. Moreover, HIV in trophoblasts (and
associated cell-to-cell infection) is less sensitive to ART than free-living
virus [31]. Nevertheless, the exact effects of HIV in sanctuary site on
total rate of MTCT remain to be elucidated.
4. Pathological effects of HIV on placental structure
Pioneering studies of third-trimester placentas of HIV-infected
pregnant women who received no antiretroviral treatment did not
identify any significant morphological abnormalities [34] and found
L. Cerveny et al.
them to be both heavier [34] and lighter [35,36] than those of controls.
Histologically, maternal HIV infection is reportedly associated with
higher incidences of chorioamnionitis [34,35,37], villous hyper­
cellularity [34], funisitis, placental membrane inflammation [38],
villous immaturity, allantois vasculopathy [39], and deciduitis [35]. It
has also been associated with inflammation of placental villi, which
frequently accompanies congenital viral infections [40], but more
controversially [34,35,37,41].
No significant differences in histological findings including cho­
rioamnionitis, villitis, villous stromal fibrosis, infarction, abnormal
villous maturation, and deciduitis in first- and second-trimester pla­
centas have been detected between groups of seropositive and sero­
negative women [34,42]. Studies on HIV in Africa have concluded that
chorioamnionitis is a risk factor for perinatal and early in utero trans­
mission of HIV-1 [42]. Another trial, however, suggested the opposite
correlation [35].
Maternal HIV infection is also associated with higher risk for
placental infection with human papilloma virus, which provokes sig­
nificant structural changes of the villi, potentially hampering normal
interchange of gases and nutrients at the maternal-fetal interface [43].
5. Effects of in utero HIV exposure on fetal development
Observational studies have indicated links between HIV infections
and adverse pregnancy outcomes, such as increased frequencies of
spontaneous abortion, stillbirth, perinatal and infant mortality, intra­
uterine growth restriction, and low birth weight [7,41,44]. This may
result from HIV-triggered shift to significantly activated, proin­
flammatory intrauterine immune environment and thus disrupted
immunological tolerance normally present during pregnancy [45,46].
The extent of maternal immune deficiency is positively correlated with
risks for prematurity [7,47]. Subsequently, preterm birth might result in
early infant morbidity, mortality, and/or chronic diseases later in life
[48]. Disease progression is also more rapid in infants infected perina­
tally than in those infected later by breastfeeding, with the accelerated
pathogenesis being attributed to differences in immunological maturity
at the time of infection, and/or detrimental effects of HIV infection upon
infant growth and development [49].
Neonates exposed to HIV perinatally, but uninfected are at increased
risk of prematurity, fetal hypotrophy, and mortality [7,44,45]. Higher
rates of MTCT of sexually transmitted infections (hepatitis C and
3
BBA - Molecular Basis of Disease 1867 (2021) 166206
hepatitis B viruses, Neisseria gonorrhea, syphilis, and others) have been
reported [7]. Due to decreased immune function, these neonates are also
at risk of lower respiratory tract infections of varied aetiology, gastro­
enteritis [45], and late-onset neonatal group B Streptococcus infection,
the leading cause of neonatal sepsis [45,50]. It is also hypothesized that
they reveal short-lived memory response to vaccination, increased risk
of autoimmune diseases and increased susceptibility to HIV infection
during adulthood [45,46].
In the postnatal period there are higher frequencies of undernutri­
tion, infection, and psychological consequences following neonatal
exposure [51]. However, these effects also seem to be linked to maternal
social vulnerability, poverty, and substance abuse [7].
6. Prevention of HIV mother-to-child transmission
It has been estimated that implementation of prevention of MTCT
(PMTCT) services prevented HIV infection of around 1.4 million chil­
dren between 2010 and 2018 [52], so PMTCT of HIV is one of the great
public health successes of the past two decades. This PMTCT has four
main elements. First, universal maternal testing and prenatal coun­
seling. Second, use of ART during pregnancy, labor and delivery, fol­
lowed by postnatal administration to the infant. Third, elective cesarean
delivery before amniotic membrane rupture (after 38 weeks of gesta­
tion) in cases where the HIV load exceeds 1000 RNA copies/mL plasma
or is unknown. Fourth, avoidance of breastfeeding. This package of
preventive interventions can reduce the risk for fetal infection to <1%
(Fig. 1) [8,53,54]. Introduction of these measures in Cuba resulted in
complete eradiation of HIV MTCT by 2015, five years after initiation [4].
In the USA, only 44 infants were born with HIV infection in 2016 and the
estimated incidence of perinatally acquired HIV infection was 1.1 out of
100,000 live births [8]. In less advantaged settings, however, there is an
ongoing epidemic of pediatric HIV infection; estimates indicate that
there were approximately 150,000 new pediatric infections globally in
2019 [55], mostly acquired through MTCT, and mostly in sub-Saharan
Africa. This is due to the fact that integration of programs aiming at
HIV PMTCT in this area are hampered by multiple factors including
bureaucracy, HIV stigma, shortage of training for medical staff, staff
turnover (frequently due to high workloads), insufficient infrastructure
and HIV testing, and site-to-site differences in HIV routine care [56,57].
Fig. 2. Schematic illustration of membrane
transporters involved in placental pharmaco­
kinetics of antiretrovirals. In the apical
(mother-facing) microvillous membrane
important protective efflux transporters, P-
glycoprotein (ABCB1) and breast cancer
resistance protein (ABCG2), are localized as
well as influx organic cation/carnitine trans­
porters (OCTNs) and equilibrative nucleoside
transporter 1 (ENT1) mediating facilitated
diffusion of nucleosides and nucleoside-
derived drugs [104,111,112,121,123,141].
Influx organic cation transporter 3 (OCT3) and
organic anion transporter 4 (OAT4) mediating
feto-maternal transport of their substrates
have been detected in the basal membrane
[132]. Equilibrative nucleoside transporter 2
(ENT2) is putatively expressed in both
trophoblast poles [121,122]. Data on func­
tional expression and localization of CNTs
remain controversial [104,105,123,126–128].
L. Cerveny et al. BBA - Molecular Basis of Disease 1867 (2021) 166206

Fig. 3. Scheme of HIV replication and mechanisms of action of FDA approved and investigational antiretroviral drugs. HIV contains several important molecules.
Glycoprotein 120 (gp120) is an envelope surface molecule, which has interactive effects with CD4 molecules and CCR5 and/or CXC4 co-receptors on CD4-expressing
cells (predominantly helper T-cells). It results in conformational changes of gp120 and transmembrane glycoprotein 41 (gp41) that trigger fusion of HIV with the host
cell membrane. Reverse transcriptase controls cellular synthesis of viral complementary DNA that is subsequently integrated as double-stranded DNA by the enzyme
integrase to the host cells’ genome. Newly synthesized polyproteins are cleaved by proteases, which is important for virion maturation. Cobicistat and ritonavir listed
in the figure are used only as pharmacokinetic boosters to increase the bioavailability and prolong plasma half-lives of PIs.
*, preferred first-line therapy; **, when started prior to conception the drug should be continued during pregnancy; ***, no data on pharmacokinetics and safety in
pregnancy available; #, alternative to the first-line therapy; ##, not recommended due to substantial decrease in plasma concentrations of antiretroviral drug in the
second and third trimesters; ###, obsolete due to unfavorable pharmacokinetics and/or potentially negative impact on maternal or fetal health; §, investiga­
tional drugs.

7. Antiretroviral therapy in pregnancy (NRTI) zidovudine could reduce the risk for vertical transmission by
67% [58]. Although zidovudine is no longer recommended for first line
In 1994, the first controlled study of antiretroviral prophylaxis in ART in adults, it is still considered an alternative first-line medication for
pregnancy revealed that the nucleoside reverse transcriptase inhibitor pregnant and breastfeeding women with HIV. ART decreases HIV viral

4
L. Cerveny et al.
loads in maternal blood and genital secretions and antiretrovirals with
high transplacental passage provide pre-exposure prophylaxis for in­
fants, thereby protecting maternal health and powerfully reducing both
in utero and perinatal MTCT of HIV [1]. Global efforts have resulted in up
to 85% of HIV-positive pregnant and breastfeeding women receiving
ART [1]. Currently, >30 antiretroviral drugs are approved by the FDA,
nine of which are used in first-line regimens for ART-naïve pregnant
women with HIV (see Fig. 3). In the following text we describe phar­
macokinetic aspects of ART in pregnant women, including placental
transport of antiretrovirals.
7.1. Pharmacokinetic considerations and antiretroviral therapy
Antiretrovirals are used during pregnancy and lactation in off-label
regimens due to exclusion of pregnant and lactating women from clin­
ical trials. Their use in pregnancy is dependent on toxicity, pharmaco­
kinetics, and fetal/neonatal exposure data collected during phase IV
clinical tests and/or opportunistic studies on women who become
pregnant while receiving ART [9]. This is unfortunate as pregnancy is a
dynamic state in which physiological (and hence pharmacokinetic pa­
rameters) constantly change [59]. Thus, changes in pregnancy, espe­
cially in the second and third trimesters, may result in altered exposure
[60–67]. For example, absorption of drugs from the gastrointestinal
tract and oral bioavailability vary due to changes in gastric secretion and
motility of the small intestine. Similarly, changes in other physiological
variables, such as increases in cardiac output or blood volume, will
affect drug disposition. In addition, changes in biotransformation ac­
tivities and rates of liver and kidney blood perfusion, as well as
glomerular filtration, will modify drugs’’ metabolism, excretion and
elimination half-lives. Notably, increases in activities of CYP3A4 and
CYP2D6, the most important cytochrome P450 isoforms, have been re­
ported in pregnant women, including up to 35 and 48% increases in the
third trimester [68,69].
Possible effects of pregnancy on pharmacokinetics of drugs
frequently and chronically prescribed during gestation have been thor­
oughly and systematically reviewed by Pariente et al. [65]. They illus­
trated that pregnancy affects the pharmacokinetics of most
antiretrovirals, thereby significantly raising their elimination/clearance
and reducing their exposure parameters (Cmax, AUC). Therefore,
pregnant women administered ART may require adjusted dosing
schedules to obtain comparable antiretroviral exposure to that of non-
pregnant women. However, routine dose adjustment of combination
ART during gestation is not recommended and should be evidence-based
using appropriate pharmacokinetic models [9,59,70–73].
For preferred protease inhibitors (PIs: atazanavir, darunavir or
lopinavir) all in combination with low-dose ritonavir, a pharmacoki­
netic booster that inhibits CYP3A and P-glycoprotein (ABCB1), signifi­
cant decreases in exposures in pregnancy have been reported [74–77].
The darunavir dose has to be doubled to maintain sufficient exposure
[75,78]. Increased dosing of lopinavir is not recommend for all pregnant
women [62,79], but may be considered in a personalized manner, e.g.
for PI-experienced pregnant women [80]. Similarly, atazanavir plasma
concentrations equivalent to those postpartum can be achieved by
increased dosing [81], but some experts recommend an increased dose
of atazanavir only for treatment-experienced pregnant women who are
also receiving tenofovir disoproxil fumarate [8]. Because these PIs are
highly bound to plasma proteins [61,62], decreased AUC in the second
and third trimester are likely due to overall decrease in total plasma
protein concentrations and consequent acceleration of excretion
[70,71,82]. However, the effectiveness of HIV suppression with normal
adult dosing of these PIs is usually preserved as concentrations of un­
bound fraction are unaffected [61,62]. Thus, other mechanisms are also
presumably involved. Darunavir, lopinavir, and atazanavir are almost
exclusively metabolized by CYP3A4 [83,84] and darunavir and ataza­
navir are substrates of ABCB1 [83,85] so increases in CYP3A4 and
ABCB1 activities towards term of pregnancy may contribute to
5
BBA - Molecular Basis of Disease 1867 (2021) 166206
reductions in their exposure [59]. Currently, effects of combinations of
the pharmacokinetic booster cobicistat (an inhibitor of CYP3A and
ABCB1 [86]), with atazanavir, darunavir, or the integrase strand
transfer inhibitor (INSTI) elvitegravir, in pregnancy are being investi­
gated. However, plasma concentrations have been substantially
(50–90%) lower than those of postpartum counterparts. This reduced
exposure does not guarantee anti-HIV efficacy of these regimens in
pregnancy [74,87,88] and these combinations should be avoided [8].
Interestingly, doses of the non-nucleoside reverse transcription in­
hibitor (NNRTI) efavirenz should be reduced in pregnancy, despite ob­
servations of lower exposure with normal adult dosing. This is because
free circulating active efavirenz concentrations are only moderately
lower than those in non-pregnant women and remain sufficiently
effective against HIV, while side effects are less frequent [89,90]. On the
other hand, there is also evidence for increased exposure in the third
trimester than postpartum, as also reported for the NNRTI etravirine,
which can be associated with increased risks for toxicity [66].
Exposure to the NRTIs emtricitabine, abacavir, zidovudine, and
lamivudine is not changed during the third trimester, so no dosing ad­
justments in pregnancy are required [91–93]. Physiological changes
during pregnancy may amplify effects of drug-drug interactions,
resulting in more profound reductions in absolute drug exposure and
thus hampering treatment efficacy [94]. Optimization of antiretroviral
dosing based on therapeutic monitoring [61,95–97] and/or physiology-
based pharmacokinetic modeling [98–100] may be helpful for assurance
of the safety and effectiveness of maternal and fetal therapy.
Since information on dosage adjustment in pregnancy is constantly
evolving, the reader is referred to the FDA’s “HIV Treatment Information
for Pregnant Patients” for the most recent information [101].
7.2. Passage of antiretrovirals across the placenta; role of membrane
transporters
Antiretrovirals are primarily used to suppress maternal viral loads,
thereby diminishing the progression of HIV infection to AIDS, and
decreasing risk of horizontal as well as vertical HIV transmission. At
least one of the compounds must cross the placenta to provide pre-
exposure prophylaxis for the fetus [8]. On the other hand, deleterious
effects of antiretrovirals on the fetus and/or placenta have been
described (see below). Therefore, transport of drugs across the placenta
and their subsequent effects on the fetus are of great concern [9]. A
pragmatic balance needs to be established between fetal protection
against HIV and drug toxicity. Therefore, transplacental kinetics of
antiretrovirals and all influential factors need to be understood for
balanced selection of effective but safe ART in pregnancy [9,59].
The placenta is a barrier that separates maternal and fetal circula­
tions. For a drug to travel from maternal to fetal blood it must cross the
syncytiotrophoblast layer, interstitium, and endothelial cells in fetal
capillaries. Transport of drugs across the placenta occurs mainly via
passive diffusion along the concentration gradient [102]. However, the
placenta is equipped with a battery of efflux and influx transporters that
to some extent control mother-to-fetus transport of drugs [102–106].
Empirical evaluation of placental transport of drugs in clinical settings is
limited to measurement of umbilical cord and maternal plasma drug
concentrations at delivery, and ratios of these concentrations provide
little information about the time-dependent pharmacokinetics involved.
Therefore, current research relies on alternative experimental ap­
proaches, such as use of in vitro cell-based (BeWo, JEG-3, JAR) models,
placental fragments and explants or dually perfused human or rodent
placenta. All these models have pros and cons [9,107], and thus should
be used in combination to obtain as comprehensive understanding of the
real in utero phenomena as possible. Collected data can then help
development of robust pregnancy physiology-based pharmacokinetic
models that can be potentially used to predict prenatal exposure to
maternally administered drugs [108–110].
We and other teams have used various experimental approaches to
L. Cerveny et al. BBA - Molecular Basis of Disease 1867 (2021) 166206

investigate the role of drug transporters in placental kinetics of anti­
retrovirals. Placenta strongly expresses ATP-binding cassette (ABC) drug
efflux transporters, such as ABCB1 and breast cancer resistance protein
(ABCG2) [111,112]. These proteins are localized in the apical mem­
brane of syncytiotrophoblast (Fig. 2), where they actively transport their
substrates from the placenta to the maternal circulation, thus providing
fetal protection against potentially hazardous compounds. They recog­
nize hundreds of structurally divergent substrates [113] including
clinically used antiretrovirals (Tables 1 and 2) [85,114–120]. There is
also growing evidence that solute carrier (SLC) transporters contribute
to placental transfer of antiretrovirals. NRTIs, the foundations of com­
bination ART, are nucleoside-derived drugs. Therefore, we addressed
the possibility that equilibrative nucleoside transporters (ENTs) that are
localized on both poles of the syncytiotrophoblast [104,121–123] (see
Fig. 2) and known to facilitate diffusion of nucleosides and nucleoside-
derived drugs [124] contribute to placental transfer of abacavir,
emtricitabine, or zidovudine [104,125]. We found that placental pas­
sage of abacavir, but not zidovudine and emtricitabine, is facilitated by
ENT1 [104]. However, interaction between emtricitabine and placental
ENT1 has been recently reported [126]. Concentrative nucleoside
transporters (CNTs) may also putatively contribute to placental transfer
of antiretrovirals [126]. However, conflicting data have been published
on CNTs’ gene expression, protein levels, and localization. We detected
significant amounts of CNT2 and CNT3 transcripts in first and term
placentas and showed that CNT2 in the placenta is likely regulated by
protein kinase A [105]. Govindarajan et al. only detected CNT2 mRNA
[123], and no significant CNT activity was observed in microvillous
membrane vesicles prepared from term placentas [104,121], but
another group detected expression of genes encoding all CNT variants
(CNT1, CNT2, and CNT3) in term placentas, and showed that CNT3 can

Table 1
Preferred first-line antiretroviral drugs and alternative drugs to first-line ART used in ART-naive pregnant women with HIV.
Pharmacodynamic Drug Abbrev. Physical-chemical Plasma Placental Range of C/M Ref.
group properties protein transporter concentrations ratios
Lipid solubility; pKa binding (substrate/ at delivery
inhibitor)

Nucleoside reverse Abacavir ABC logP = 1.20; apKa 50% ABCB1, ABCG2, 1.03–1.06 [92,104,116,143,205,206]
transcriptase (most acidic) = 15.41; ENT1, OCT3
a
inhibitors pKa (most basic) = 5.8
(NRTI) Emtricitabine FTC logP = − 0.43; pKa = <4% ENT1, CNT1, 0.95–1.82 [91,126,145,206–209]
2.65 MATE1, OCT3,
OCTN1
Lamivudine 3TC logP = − 1.4; apKa <36% MATE1, OCT3 0.93–1.22 [92,117,189,205,206,210,211]
(most acidic) = 14.29;
a
pKa (most basic) =
− 0.16
b
Tenofovir TDF logP = 1.25; pKa = 3.75 <0.7%c ABCB1, ABCG2, 0.62–6.0 [145,206,207,209,211]
disoproxil OCT3
fumarate
Zidovudine AZT logP = 0.05; apKa 30–38% ABCB1, ABCG2, 0.81–1.6 [115,212–214]
(most acidic) = 9.96; OAT4, CNT1
a
pKa (most basic) = − 3
Non-nucleoside reverse Efavirenz EFV logP = 4.6; apKa (most >99% ABCB1, ABCG2, 0.49–0.67 [212,215–218]
transcriptase acidic) = 12.52; apKa MATE1
inhibitors (most basic) = − 1.5
(NNRTI) Rilpivirine RPV logP = 4.86; pKa = 5.6 >99% ABCB1, ABCG2, 0.50–0.74 [129,150,151,219,220]
OCTN
Protease inhibitors Atazanavir ATV logP = 4.5; apKa 86% ABCB1, ABCG2, 0.12–0.21 [77,81,85,221–224]
(PIs) (strongest acidic) = OCTN
11.92; apKa (strongest
basic) = 4.42
Darunavir DRV logP = 1.89; apKa 95% ABCB1 0.11–0.24 [119,225,226]
(strongest acidic) =
13.59; apKa (strongest
basic) = 2.39
a
Lopinavir LPV logP = 3.91–4.69; >98% ABCB1, ABCG2, 0–0.57 [129,211,212,221]
a
pKa (strongest acidic) OCTN
= 13.39; apKa
(strongest basic) =
− 1.5
d
Ritonavir RTV logP = 3.9; apKa 98–99% ABCB1, ABCG2, 0–0.55 [129,212,221]
(strongest acidic) = OCTN
13.68; apKa (strongest
basic) = 2.84
Integrase strand transfer Dolutegravir DLV logP = 2.2; pKa = 8.2 98.9% ABCB1, ABCG2, 1.06–1.25 [129,190,209,227,228]
inhibitors OCTN
a a
(INSTIs) Raltegravir RLV logP = − 0.39; pKa 83% ABCB1, eABCG2, 1.21–1.5 [120,229–234]
e
(strongest acidic) = MATE1
5.62; apKa (strongest
basic) = − 1.5
a
Predicted value, experimental value not known.
b
Tenofovir disoproxil fumarate is rapidly hydrolyzed to tenofovir after oral administration, therefore the plasma protein binding of tenofovir is provided; tenofovir
disoproxil fumarate (but not tenofovir) is a substrate of placental ABCB1 and ABCG2 [114].
c
In vitro value.
d
Ritonavir is used as a CYP3A4 and ABCB1 inhibitor to increase bioavailability and plasma half-lives of co-administered PIs [95].
e
Weak interaction with low propensity to cause drug-drug interactions.
C/M ratio, cord to maternal plasma concentrations ratio; logP, pKA, and plasma protein values were taken from DrugBank Online|Detailed Drug and Drug Target
Information, www.drugbank.com

6
L. Cerveny et al. BBA - Molecular Basis of Disease 1867 (2021) 166206

Table 2
Antiretroviral drugs that can be continued during pregnancy when they are started before conception.
Pharmacodynamic group Drug Abbrev. Physical-chemical Plasma Placental Range of C/M Ref.
properties protein transporter concentrations ratios
Lipid solubility; pKa binding (substrate/ at delivery
inhibitor)
c e
Nucleoside reverse Tenofovir TAF logP = 1.6, pKa = 3.96 80% ABCB1, ABCG2 0.97 [154,235]
transcriptase inhibitors alafenamide
(NRTIs) fumarate
a
Non-nucleoside reverse Etravirine ETV logP = 3.67, alogP = d
99.9% ABCB1, ABCG2 0.32–0.52 [66,212,236–240]
transcriptase inhibitors 5.54
a
(NNRTIs) pKa (strongest acidic) =
12.49; apKa (strongest
basic) = 4.13
Nevirapine NVP logP = 2.5; apKa 60% ABCB1, ABCG2 0.59–1.0 [212,215,216]
(strongest acidic) =
10.37; apKa (strongest
basic) = 5.06
a
Entry and fusion Maraviroc MVC logP = 4.3, alogP = 3.63 76% ABCB1, OAT4, 0.33–0.37 [129,155,212,241,242]
a
inhibitors pKa (strongest acidic) = OCTN
13.98; apKa (strongest
basic) = 9.65
b
Enfuvirtide T-20 – 92% – Undetectable in cord [212]
plasma
a
Predicted value.
b
Biomimetic peptide.
c
Ex vivo value.
d
In vitro value.
e
Analysis was performed in cohort (n = 1) treated with tenofovir alafenamide fumarate in combination with cobicistat.
logP, pKA, and plasma protein values were taken from DrugBank Online|Detailed Drug and Drug Target Information, www.drugbank.com.

participate in nucleoside-derived drug uptake [127]. Moreover, Errasti-
Murugarren et al. detected significant levels of CNT1 protein (but no
other CNT proteins), despite negligible transcript-level expression,
localized in both syncytiotrophoblast poles [128]. Clearly, more
research is needed to fully elucidate functional expression of nucleoside
transporters in the placenta and their role in materno-fetal transport of
antiretrovirals.
Organic cation/carnitine transporters (OCTNs) and multidrug and
toxin compound extrusion transporter 1 (MATE1) are localized in the
apical membrane of the syncytiotrophoblast (Fig. 2). OCTN transporters
primarily govern uptake of L-carnitine from maternal circulation [129],
but may also putatively transport emtricitabine into syncytiotrophoblast
[126]. On the other hand, MATE1 contributes to fetal protection against
xenobiotics and affects placental kinetics of lamivudine [117,130,131].
Organic anion transporter 4 (OAT4) [132] and organic cation trans­
porter (OCT3) [103,130] have been found in the syncytiotrophoblast’s
basal membrane (Fig. 2) where they mediate uptake of negatively and
positively charged compounds, respectively, from the fetal circulation
[103,130,131,133]. An overview of antiretrovirals used in pregnancy
with their basic physico-chemical characteristics, protein binding pa­
rameters, and interactions with membrane transporters localized in the
placenta is provided in Tables 1 and 2.
The expression and transport activity of transport proteins are not
uniform, frequently differ among individuals, and vary during gestation
[104,105,107]. In addition, the expression of genes encoding placental
transporters can be modulated (up or down) by drug exposure, patho­
logical conditions, genetic variants, and/or drug-drug interactions
[134–140]. Therefore, rates of antiretrovirals’ placental transfer may
differ among individuals and stages of pregnancy.
7.3. Current guidelines for pharmacotherapy of pregnant women
Based on recent safety and efficacy evidence, the current US Peri­
natal Guidelines [8] recommend as first-line therapy NRTIs, abacavir
plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine or
lamivudine [143–146], in combination with either a PI (ritonavir
boosted atazanavir [76] or ritonavir boosted darunavir [147]) or INSTI
(dolutegravir [148] or raltegravir [149]). The NNRTIs efavirenz or ril­
pivirine can serve as alternatives to the first-line PIs or INSTIs
[150,151]. On the other hand, European guidelines recommend initia­
tion of ART containing dolutegravir after 8 weeks of pregnancy due to
potential of higher risks for neural tube defects if used periconception
[152,153]. Women who are already on suppressive ART at the time of
conception should continue without changes, unless drugs with un­
proven efficacy and reportedly inferior safety in pregnancy are being
used (if so, they should be substituted by drugs with more favorable risk-
benefit ratios [8]).
All women with HIV who have not received antepartum ART should
start therapy immediately to prevent perinatal transmission of HIV.
Although intrapartum/neonatal antiretroviral medications will not
prevent perinatal transmission that occurs before labor, most trans­
mission occurs near to or during labor and delivery [8].
NNRTIs (nevirapine and etravirine), the NRTI tenofovir alafenamide
fumarate [154], and entry and fusion inhibitors (maraviroc and enfu­
virtide) should be continued if started before conception [8,155].
Cobicistat-boosted regimens (with atazanavir, darunavir, or the INSTI
elvitegravir) [9], or dual combination of dolutegravir and lamivudine
should be avoided due to risk for insufficient viral suppression [67]. For
recently approved drugs such as the INSTI bictegravir and NNRTI dor­
avirine, or the CD4 antagonist ibalizumab, there are no data on their
efficiency and safety in pregnancy, and thus should also be avoided
[8,67,142]. An overview of currently approved and investigational
antiretrovirals and their action mechanisms is provided in Fig. 3.

Official guidelines for use of antiretroviral drugs in pregnancy
distinguish between pharmacotherapy of ART-naïve pregnant women
and pregnant women already on ART. Currently, ART should be initi­
ated for antiretroviral-naïve pregnant women with HIV as early as
possible regardless of their clinical stage and continued throughout
gestation [8,142].
8. Toxicity of antiretroviral therapy in the fetoplacental unit
Since antiretrovirals are used chronically, often throughout gesta­
tion, they can potentially affect fetal development and/or programming.
In addition, placental maturation and functions may be disturbed by
chronic exposure to antiretrovirals. The most frequently reported (and

7
L. Cerveny et al.
comprehensively reviewed [8]) adverse pregnancy outcomes are low
birth weight, preterm birth (with relative risks/odds ratios ranging from
1.2 to 3.4), still birth, and fetal growth restriction. For some anti­
retrovirals there is also evidence of increased risks for congenital mal­
formations [153,156–159]; other adverse outcomes cannot be
recognized immediately after delivery and may remain unnoticed until
later stages of life such as poor neurodevelopment [160–162]. However,
there is a paucity of data and it is difficult if not impossible to draw clear
conclusions from current information. Mechanisms of antiretroviral
toxicity in pregnancy are also poorly understood and require systematic
investigation.
8.1. Acute toxicity; teratogenicity
The critical window for teratogenic effects of drugs is the first
trimester of pregnancy. Most published research on ART during this
period indicates a generally low association with teratogenicity
[159,163], but some specific antiretroviral agents seem to increase risks
[153]. The most frequently investigated drugs are efavirenz, zidovudine
and dolutegravir [153,156–159]. Until recently, dolutegravir was not
recommended for use at conception and in very early pregnancy due to
suspected neural tube defects [153]. However, this recommendation
was amended by US Perinatal Guidelines in August 2019 and dolute­
gravir is now a “Preferred antiretroviral drug throughout pregnancy and
an alternative antiretroviral drug for women who are trying to conceive”
[8]. Data from animal experiments [164] and retrospective studies
[153] suggest efavirenz may be a teratogen causing abnormalities in
neural tube and CNS development [165]. However, according to the
WHO, efavirenz-associated risks are outweighed by its benefits [159]
and current guidelines suggest efavirenz in triple therapy with preferred
NRTIs for pregnant women [8,142]. Clearly, clinicians must follow
frequent updates and implement them in their routines.
8.2. Long-term toxicity; fetal programming
Although risks for gross teratogenicity seem to be minimal, research
on long-term risks is needed to identify possible effects of perinatal
antiretroviral exposure on fetal programming and diseases occurring in
adulthood. In the latest literature, the most frequently discussed prob­
lems seem to be mitochondrial and neurodevelopmental toxicity.
Various studies have indicated changes in mitochondrial structure and
function in infants exposed to ART, especially NRTIs [166]. These
mitochondrial alterations may putatively lead to various clinical mani­
festations, such as seizures, cognitive and motor delay, abnormal neu­
roimaging, hyperlactatemia, and cardiac dysfunction [167,168].
Possible effects of antiretrovirals on neurodevelopmental outcomes have
been investigated in large-scale epidemiological studies. The heteroge­
neity of study populations and study designs may complicate interpre­
tation of cumulative data, but both acute effects of ART on
neurodevelopment and developmental delay have been discussed in
recent literature [160,162,169]. Long-term behavioral effects of pre­
natal exposure to ART have also been detected and studied in detail in
animal models, including alteration in social interactions, cognitive
functions, sensorimotor processing, and exploratory behaviors at later
stages in life [164,170].
Other types of long-term effects have also been reported. For
instance, a Danish study found that HIV-exposed but uninfected children
aged 0–5 years exposed to antiretrovirals were smaller at birth than
unexposed controls, but this difference decreased with time [171].
Obese HIV-exposed but uninfected youths seem to have an increased risk
of hypertension [172]. Prenatal ART exposure is also suggested to have
mild direct cardiac effects [173], and may reportedly be associated with
higher frequencies of tumor development [174,175]. However,
increased odds of cancer in children exposed in utero to ART have not
been confirmed [176], and further studies are needed to elucidate as­
sociations between long-term metabolic effects or cancer later in life and
8
BBA - Molecular Basis of Disease 1867 (2021) 166206
in utero exposure to antiretrovirals.
8.3. Placental toxicity
Since the placenta plays a fundamental role in fetal programming
[177], any detrimental effect of antiretrovirals on placental structure or
function seems likely to result in sub-optimal in utero conditions. Such
possible effects have been largely neglected and only a handful of papers
describe the potential toxicity of antiretrovirals on placental develop­
ment and function. However, recent studies on placentas collected from
women on ART have suggested that effects may include restricted
placental growth [41,178–180], increases in numbers of marginal in­
farcts [41,180], maternal vascular malperfusion and thrombosis
[179,180], membrane infection, hypervascularity, and reductions in
both the surface and perimeter of the terminal villi [180]. These
anatomical and histological changes may be associated with reported
increases in risk for preterm delivery [180]. Altered placental and fetus
growth resulting in increased placenta-to-birthweight ratio, a strong
indicator of various diseases occurring later in life, were also observed in
animal models [181,182].
Kala et al. (2020) investigated possible effects of PIs-based combi­
nation ART initiated at periconception on decidualization and spiral
artery remodeling in early pregnancy [183]. Using a set of mouse and
human placenta-based experiments, they concluded that lopinavir but
not darunavir-based treatment impaired uterine decidualization and
spiral artery remodeling in both human ex vivo and mouse in vivo
experimental models. They attributed lopinavir-associated deciduali­
zation defects to a decrease in expression of transcription factor STAT3,
which is known to regulate decidualization.
Efavirenz interacts with several serotonin receptors and blocks se­
rotonin transporter (SERT/SLC6A4). Since both fetal brain and the
placenta express these receptors and transporters, efavirenz exposure
during pregnancy might disturb serotonin homeostasis in the fetopla­
cental unit. Importantly, serotonin is a crucial neurotrophic factor for
fetal neurodevelopment and pharmacological insult can affect fetal
development/programming – similar to observed effects of prenatal use
of selective serotonin reuptake inhibitors [184,185]. Possible interfer­
ence of zidovudine with the development of the GABAergic system has
been recently reported in mice [186]. Nevertheless, more research is
required to fully understand the effects of prenatal antiretroviral expo­
sure on neurodevelopment.
9. Recent advances in antiretroviral research; long-acting
formulations, drugs in the pipeline
ART is constantly being developed and refined with an ultimate goal
to find effective regimens that can be prescribed in personalized fashion
with high efficacy and minimal acute and long-term side effects. Since
2015 several new drugs and regimens have been approved and imple­
mented in therapy of adults with HIV, but due to lack of safety, outcome,
and pharmacokinetic data they are not recommended for use in preg­
nancy. For instance, tenofovir alafenamide fumarate has been shown to
have more favorable pharmacokinetics (associated with lower renal and
bone toxicity) than tenofovir disoproxil fumarate [187,188]. Recently
published data on tenofovir alafenamide fumarate show that exposure to
this drug is lower in the third trimester than postpartum, whereas no
differences in exposure were observed between pregnancy and post­
partum in women taking tenofovir alafenamide fumarate with cobicistat
[154]. Tenofovir alafenamide fumarate is not recommended for use in
ART-naïve pregnant women with HIV, but current guidelines already
suggest continuation of its use for women taking this medication prior to
conception, despite a lack of clinical data from sufficiently large
numbers of women [8]. In 2019 a very promising first ever fixed-dose
dual combination of dolutegravir and lamivudine was approved.
Although pharmacokinetics and antiviral efficacy of lamivudine and
dolutegravir in pregnancy have been investigated [93,189,190],
L. Cerveny et al.
dolutegravir and lamivudine is not recommended as a complete regimen
in pregnancy because data on antiviral efficacy are lacking [8,67]. Other
antiretrovirals that can be potentially used in pregnancy are doravirine
and bictegravir. Doravirine is active against HIV resistant to efavirenz
and nevirapine, less susceptible to development of resistance than ril­
pivirine and efavirenz, and expected to show lower propensity to drug-
drug interactions. Therefore, it can be prospectively considered as an
alternative to INSTIs [67]. Bictegravir has also shown high efficacy and
tolerability in non-pregnant adults in clinical trials [191,192].
Regarding bictegravir’s effects on the developing fetus, first signals from
clinical trials with a cohort of 25 pregnant women indicate that bicte­
gravir does not cause neural tube defects [193].
It should be stressed that not all adult patients with HIV fully profit
from ART. More than 25% of ART-naive patients initiating pharmaco­
therapy reportedly have episodes of non-adherence that potentially
threaten individuals’ prognosis and increase risks for horizontal and/or
vertical HIV transmission [194–196]. Therefore, there have been recent
efforts to develop and evaluate long-acting regimens [67,196] that could
substitute daily administration of antiretrovirals. This could help
improve problematic patients’ adherence to ART. Moreover, recent
surveys have demonstrated that long-acting regimens would be a
welcomed option for youths living with HIV [197,198]. The first and
only once-monthly, complete long-acting regimen that might replace the
current antiretroviral regimen for adult patients who are stably viro­
logically suppressed [199] is a combination of cabotegravir and rilpi­
virine. At the time of writing this is being reviewed by the FDA, but the
European Medicines Agency has already recommended marketing au­
thorizations. Cabotegravir was primarily developed as an injectable
formulation and both cabotegravir and rilpivirine are used as a nano­
suspension [200]. Another long-acting antiretroviral drug is ibalizumab,
a humanized anti-CD4 IgG4 monoclonal antibody. Ibalizumab blocks
entry of HIV-1 into CD4-positive cells and must be administered once
every 14 days via intravenous infusion. However, due to high treatment
costs and the need of administration by trained medical professionals,
ibalizumab is used only in treatment-experienced patients with multi-
drug resistant HIV strains [201,202].
There are at least two more promising investigational antiretrovirals
in the pipeline: islatravir (the first nucleoside reverse transcriptase
translocation inhibitor) and an NNRTI, dapivirine. Both of these drugs
are very potent against HIV-1, including multidrug-resistant strains, and
their pharmacokinetic and physico-chemical properties allow produc­
tion of long-acting antiretroviral formulations. Whereas islatravir has
been tested in oral, vaginal microbicide film, and subdermal drug-
eluting polymer implant formulations, dapivirine has been trialed as a
component of a one-month vaginal ring [67], which is currently under
review by the European Medicines Agency.
10. Conclusions and personal opinion
Since the first use of antiretroviral drug in gestation in 1994, there
has been tremendous progress in treatment of HIV-positive pregnant
women. Nowadays, up to 85% of HIV-positive pregnant women have
access to ART. In addition, dramatic reduction in the incidence of HIV
MTCT is one of the biggest healthcare achievements in the modern era.
However, these accomplishments should not stop efforts to make further
improvements or prevent us from seeing possible harmful effects.
• Pregnant women are generally excluded from clinical studies, so
prescription of ART is based on information obtained from non-
pregnant populations, largely ignoring possible differences in ef­
fects associated with gestation. Strictly controlled clinical studies
with drugs well tolerated in phase IV should be considered by reg­
ulatory agencies to rationalize dosing regimens. As previously rec­
ommended, a “formalized step-wise approach to including pregnant
women in antiretroviral drug research should become the new norm”
9
BBA - Molecular Basis of Disease 1867 (2021) 166206
[203] to acquire and employ more accurate data on dosing, safety
and efficacy of ART for pregnant women.
• Data on transport of antiretrovirals across the placenta is typically
derived from post-birth comparison of umbilical and maternal drug
concentrations. However, this approach provides little information
on their placental transport kinetics and fetal exposure earlier in
pregnancy. In addition, they are often structurally related to nucle­
osides, so they are potential substrates or inhibitors of nucleoside
transporters (ENT and/or CNT). Nevertheless, these transporters’
expression and function in the syncytiotrophoblast apical or basal
membrane have not been satisfactorily elucidated. Thus, their role in
transplacental passage of antiretrovirals is not known, and further
research on their transplacental transport must continue, employing
all possible methods, so both broader and more detailed knowledge
can be incorporated into clinical reasoning before ART is initiated.
• The enormous prophylactic efficacy of antiretrovirals in prevention
of MTCT might have obscured their long-term toxicity. However,
possible delayed adverse effects require much longer afterbirth
monitoring because they become observable later in life. Many
antiretrovirals interact with various biological targets in the
placenta, such as transporters or enzymes (others will be revealed in
the future) that might affect placental functions and fetal program­
ming. For example, inhibitory effects of antiretrovirals on mono­
amine transporters have been observed [204]. If administered in
pregnancy, they might significantly perturb homeostasis of seroto­
nin, dopamine, or norepinephrine in the fetoplacental unit and affect
programming of the fetal brain [185]. Several cases of impaired
neurodevelopment have been reported in the literature, but without
causative mechanisms. It is thus essential to monitor and document
long-term/delayed toxicity that antiretroviral drugs might trigger.
• Novel drugs and drug formulations in the pipelines of pharmaceu­
tical research hold promise of more effective and less toxic therapy.
Long-acting antiretrovirals, such as monoclonal antibodies or nano­
suspensions of small molecules, are being designed for once or twice
monthly administrations. This approach might replace daily ART in
individuals with low adherence.
A clear overall conclusion is that continuous research, both basic and
translational, in the ART of pregnant women is crucial to ensure well-
balanced, efficient, and safe treatment of both the mothers and their
children.
Declaration of competing interest
None.
Acknowledgements
The authors are thankful to Dr. Rona Karahoda for drawing Fig. 2.
The work of F.S. and L.C. on transplacental pharmacokinetics of
antivirals was supported by the Czech Science Foundation (grant no.
GACR 17-16169S) and the EFSA-CDN project [No. CZ.02.1.01/0.0/0.0/
16_019/0000841], which is co-funded by the ERDF.
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