Review

HIV treatment in pregnancy

Heather Bailey, Rebecca Zash, Virginia Rasi, Claire Thorne

Almost 25 years since antiretroviral therapy (ART) was first shown to prevent mother-to-child transmission of HIV, Lancet HIV 2018
76% of pregnant women living with HIV (over 1 million women) receive ART annually. This number is the result of Published Online
successes in universal ART scale-up in low-income and middle-income countries. Despite unprecedented ART- June 26, 2018
http://dx.doi.org/10.1016/
related benefits to maternal and child health, challenges remain related to ART adherence, retention in care, and
S2352-3018(18)30059-6
unequal access to ART. Implementation research is ongoing to understand and to address obstacles that lead to loss
Population, Policy and Practice
to follow-up. The biological mechanisms that underlie observed associations between antenatal ART and adverse Programme, UCL Great
outcomes in pregnancy and birth are not completely understood, with further research needed as well as strengthening Ormond Street Institute of
of the systems to assess safety of antiretroviral drugs for the mother and HIV-exposed child. In the treat-all era, as Child Health, University College
duration of treatment and options for ART expand, pregnant women will remain a priority population for treatment London, London, UK
(H Bailey PhD, V Rasi MD,
optimisation to promote their health and that of their ART-exposed children. C Thorne PhD); Beth Israel
Deaconess Medical Center,
Introduction and to neonates) in high-income countries after the ACTG Division of Infectious Diseases,
Boston, MA, USA (R Zash MD);
Of 34·5 million adults living with HIV globally in 2016, 076 trial,4 which found a 68% reduction in MTCT, was
Harvard TH Chan School of
15·3 million (44%) were women of reproductive age; followed by clinical trials in low-income and middle- Public Health, Boston, MA, USA
hence, nearly half of the population who are on or in income countries, initially assessing abbreviated, simple (R Zash); and Botswana
need of antiretroviral therapy (ART) might become antiretroviral regimens and then combination ART Harvard AIDS Institute
Partnership, Gaborone,
pregnant. Provision of ART to women before and during prophylaxis.9 Subsequent randomised and observational
Botswana (R Zash)
pregnancy and breastfeeding prevents mother-to-child data showed that zidovudine monotherapy was inferior
Correspondence to:
transmission (MTCT) and improves health and survival to combination ART in preventing MTCT.10,11 WHO Dr Claire Thorne, Population,
of mothers,1 which itself benefits the health of their guidelines for treatment of HIV in pregnant women have Policy and Practice Programme,
children.2 Treatment of pregnant women living with HIV evolved in the context of growing evidence on the UCL Great Ormond Street
Institute of Child Health,
is key to achievement of overall global health goals effectiveness and safety of ART, changing drug affordability,
University College London,
(including UN sustainable development goal 3 and and the need to simplify treatment programmes for London WC1N 1EH, UK
UNAIDS 90-90-90) as well as those relating specifically to programmatic scale-up.1 In the past 10 years, ART coverage claire.thorne@ucl.ac.uk
maternal and child health, notably the UNAIDS super in pregnancy has increased as treatment options and HIV For more information on
fast-track target of fewer than 20 000 new paediatric HIV treatment and prevention policies and options have worldwide HIV data
infections by 2020. evolved (figure). see http://aidsinfo.unaids.org/

Pregnant women are a special population from a
treatment perspective, largely because of the opportunity
to prevent MTCT with antiretroviral drugs and the need
to consider safety of the women themselves and their
exposed fetuses and children. Physiological changes in
pregnancy (eg, blood volume expansion and gastro-​
intestinal, enzymatic, and hormonal changes) might also
affect pharmacokinetic properties of antiretroviral drugs
and can lead to altered absorption, reduced protein
binding, and increased elimination.3 Pregnancy became
the first setting in which treatment as prevention was
applied programmatically, after publication of the
ACTG 076 randomised clinical trial4 results in 1994.
Thus, before WHO’s 2015 recommendation to treat all
people infected with HIV, pregnancy was a period in
which ART to prevent MTCT was given to women who
did not need treatment for their own health.
Preventing mother-to-child transmission of HIV-1
Maternal HIV RNA load is the most predictive risk factor
for MTCT of HIV; suppressive ART in pregnancy and
breastfeeding is, therefore, the principal intervention to
prevent transmission.5–7 Without any maternal ART,
15–30% of formula-fed babies and up to 45% of those who
are breastfed will become infected.8 Rapid adoption of
zidovudine monotherapy (given antenatally, intrapartum,
In high-income countries, the implementation of ART
has reduced MTCT rates to less than 1–2% since 2000,12,13
with extremely low rates being reported among women
who conceive while receiving ART (eg, 0·2% in France
from 2000 to 2010)14 and on a population level (eg, 0·27%
in the UK from 2012 to 2014).15 In low-income and
middle-income countries, MTCT rates of less than
5% have been achieved in clinical trials10,11,16 and in four
UNAIDS Global Plan priority countries where women
primarily breastfeed (Namibia, South Africa, Swaziland,
and Uganda); data available up to 2016).8 The expansion
of coverage of ART in pregnancy in low-income and
middle-income countries from 50% coverage in 2010 to
75% in 2016 led to a 47% reduction in new paediatric HIV
infections.
Services for the prevention of MTCT also play an
important role in primary prevention for pregnant
women who do not have HIV, particularly for those
identified as being at high risk for infection. For HIV-
negative women in serodiscordant couples, the
periconception period and pregnancy can be times of
heightened HIV acquisition risk because of reduced use
of barrier protection and biological factors.17 Because of
high HIV RNA viral loads in incident infection, the risk
of MTCT is increased.18 Pre-exposure prophylaxis (PrEP)19
is one of several strategies that can support safer

www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6 1

 Review

Key milestones • WHO guidelines: ART eligible if CD4
count ≤350 per μL
• Prevention of MTCT: option A or B
• HPTN052 trial: ART as
prevention: early initiation
decreases risk of
transmission by 96% among
serodiscordant couples
• Option B+ starts in Malawi
• FDA
approves
PreP
• UNAIDS reports 30% decline
in AIDS-related mortality
since the peak in 2005
• WHO Consolidated
Guidelines: ART
recommended if CD4 count
≤500 per μL or disease
progresses to clinical stage 3
or 4
• Prevention of MTCT: option
B or option B+
• UNAIDS launches
90-90-90 targets*
• WHO Guidelines: Treat all • 70% of low-income and
lifelong as soon as possible middle-income countries
after diagnosis; PrEP should adopt policy of treat all
be offered to all groups at • LATTE-2 trial published
significant risk (phase 2b of CAB+RPV
• Option B+ policy in 80% of long-acting intramuscular
low-income and injection)
middle-income countries • Generic TDF/3TC/DTG pricing
• PROMISE trial results agreement and tentative
presented FDA approval
• Thailand is the first • Enrolment
country with starts in
generalised VESTED trial
(ART
epidemic to validate
optimisation
elimination of
MTCT† study in
pregnancy)

2010 2011 2012 2013 2014 2015 2016 2017 2018

Coverage of pregnant
47% 55% 62% 66% 63% 74% 76%
women who received
(38–56) (44–64) (50–73) (53–77) (58–84) (59–86) (60–88)
ART for PMTCT

Adult
women living 15·4 million 15·8 million 16·2 million 16·6 million 17·0 million 17·4 million 17·8 million
with HIV

Figure: Key milestones in treatment of HIV and HIV globally

Numbers of adult women living with HIV and antiretroviral therapy coverage of pregnant women are UNAIDS estimates. ART=antiretroviral therapy.
MTCT=mother-to-child transmission. Option A=zidovudine monotherapy and single-dose nevirapine. Option B=triple ART prophylaxis during pregnancy and
breastfeeding period. Option B+=lifelong ART. CAB=cabotegravir. RPV=rilpivirine. TDF=tenofovir disoproxil fumarate. 3TC=lamivudine. DTG=dolutegravir.
FDA=US Food and Drug Administration. *90% of people living with HIV to be diagnosed, 90% of those to be accessing ART, and 90% of those on ART to achieve an
undetectable viral load by 2020. †<50 cases of MTCT per 100 000 births and MTCT rate <5% in breastfeeding populations and <2% in non-breastfeeding populations.

conception in serodiscordant couples, alongside several
behavioural and biomedical interventions, including
fully suppressive treatment of either partner’s HIV
infection.20 Existing evidence, albeit scarce, supports the
safety of PrEP in the periconception period and during
pregnancy.21,22
Temporal trends in ART coverage in pregnancy
In high-income countries, where antenatal HIV
prevalence is low compared with that in low-income
countries, most HIV-diagnosed pregnant women receive
ART. This reflects high coverage of antenatal HIV
screening alongside the increasing proportion of women
already on ART at conception.15,23 For example, in the UK
and Ireland, 85% of pregnant women who gave birth
in 2012–14 were diagnosed before conception and
60% conceived while on ART.15 Among the few women
starting ART during pregnancy, treatment generally now
begins in the second trimester, for example, at a median
of 22 weeks in a European pooled analysis24 of more than
7000 births in the period 2008–14.
Around 90% of the 1·4 million pregnancies per year in
HIV-positive women occur in sub-Saharan Africa, where
ART scale-up among pregnant women was initially slow
but has rapidly accelerated in recent years (figure).
However, progress has been uneven, with coverage of
89% in eastern and southern Africa, 50% in west and
central Africa, and 20% in north Africa and the Middle
East. The 2015 WHO recommendation of lifelong ART
for all those diagnosed with HIV, regardless of CD4 cell
count, was adopted by 83% of low-income and middle-
income countries and 94% of countries that are part of
the UNAIDS Fast-Track strategy by the end of 2017.25 This
recommendation has resulted in a rapid rise of women
receiving ART at conception in many low-income and
middle-income countries, such as Botswana, where 48%
of women were on ART at conception in 2014 compared
with only 19% in 2009.26
ART in pregnant women: challenges in uptake,
adherence, and engagement
Experience since the introduction of option B+ (ie,
lifelong ART) has highlighted the multiple challenges in
delivering and sustaining ART on an individual and
programmatic level for women during pregnancy and
postnatally.23,27–35 Multiple individual, community, health
system, and other structural factors might positively or
negatively influence access to HIV testing and treatment,
adherence to ART, and engagement in HIV care in
pregnant women (panel), some of which are context-
dependent and many of which are not unique to
pregnancy. Notably, some barriers might not prevent the
initiation of ART but might might delay the start or or
lead to gaps in treatment; these are of importance in
pregnancy, in which there is a limited time to achieve an
undetectable HIV RNA viral load before giving birth.
In 2011, Malawi was the first country to introduce option
B+,1 and, therefore, was the first to experience the related
challenges of adherence and retention; a recent analysis
showed that loss to follow-up was highest in the first year

2 www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6


of ART, with 77% of women retained in care at 12 months
after initiation, and that early signs of poor adherence
were markers of subsequent loss to follow-up. A
systematic review of studies investigating retention in
care during pregnancy and the postnatal period in Africa
in the option B+ era (that included 60 000 women)
reported a pooled estimate of 6 month retention of 73%;36
notably, half the studies were from Malawi and initiation
of ART on the same day that HIV diagnosis took place
was a risk factor for loss to follow-up.
Various delivery models for option B+ have been
assessed, alongside implementation research to
understand and address obstacles leading to loss to
follow-up;27,33 interventions include the use of mentor
mothers, lay counsellors, home visits, adherence groups,
mobile health reminders (eg, text messages), and quality
improvement strategies.37 The MoMent study38 in Nigeria
showed significant benefits of a mentor mother
intervention for retention in care (62% at 6 months post
partum vs 25% in controls) and viral load suppression
(nearly five times more common at 6 months post
partum in women with mentor mother support than
those without). In Malawi, the PURE study39 (a cluster
randomised controlled trial) showed that community-
based or facility-based expert peer support resulted in
significantly greater retention in care at 24 months after
ART initiation. In Mozambique, a stepped-wedge cluster
randomised controlled trial assessed the success of
workflow modifications and active tracking of patients
(including improved patient flow, continuous quality
improvement, enhanced counselling, and adherence
committees) to promote option B+ retention: 71% of
women were retained for 30 day refills in the intervention
period, versus 52% in the control period, but by 90 days
only around 40% of women were retained in both
groups.40
Adherence is also crucial in pregnancy, as missed ART
might lead to virological failure, increased risk of MTCT,
and potential transmission of drug resistant virus to
fetuses.41,42 Programmatic changes to address adherence
in pregnancy include a move to simplify ART with once-
daily and fixed-dose combination regimens, which have
been associated with improved adherence. However,
studies43,44 from Europe have reported that 14–20% of
pregnant women who conceive on ART have un-​
suppressed viral loads, with young women, those with
two or more children already, and those diagnosed for
longer periods at increased risk. A study from rural
South Africa reported that among pregnant women who
had been receiving ART for more than 6 months before
conception, 18% had detectable viral loads (>50 copies
per mL) at the time of conception,45 which is consistent
with findings from a previous Cape Town study,46 in
which 22% of women conceiving on ART had viral loads
greater than 50 copies per mL. Even with multiple
interventions, ART adherence (defined as ≥90%, based
on pharmacy refills) was only 23% for all women over a
www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6 3
Review
Panel: Barriers to initiation of and adherence to
antiretroviral therapy in pregnancy
Individual factors
• Poor knowledge or misconceptions of HIV, vertical
transmission or antiretroviral therapy
• Fears around side-effects and potential harms of
antiretroviral therapy for themselves and their fetuses or
infants
• Denial of HIV status
• Depression and other mental health problems;
emotional stress
• Substance misuse
• Conflicting priorities (eg, childcare, other care-taking
responsibilities, employment)
• Undisclosed HIV status or fear of disclosure of status
• Costs and perceived costs (including transport to clinic)
• Young age
• Low self-efficacy
• Pregnancy-related nausea and sickness
• Lack of or late presentation for antenatal care
• Cultural beliefs (eg, use of traditional medicines)
Community or partner factors
• Intimate partner violence
• Stigma
• Lack of support from partner, family, or community
Regimen factors
• Regimen with poor tolerability
• Complex regimen and scheduling requirements (pill
burden and frequency)
• Running out of pills
Health system and delivery model factors
• Under-resourced health system (eg, staffing, drug
availability, stock-outs, waiting times, delays in test
results)
• Centralised HIV services and poor coverage in rural or
remote settings
• Poor coverage and lack of integrated antenatal care or
services for the prevention of mother-to-child
transmission
• Insufficient adherence support
• Initiation of antiretroviral therapy on same day as HIV
diagnosis
Other structural factors
• Logistical challenges in accessing health services24,29–36
90 day period in cluster randomised controlled trial in
Mozambique.40 These findings emphasise the need for
optimised regimens as well as appropriate interventions
to maximise adherence before, during, and after
pregnancy, as well as scale-up of viral load monitoring in
pregnancy.1
In a systematic review and meta-analysis of more than
20 000 pregnant and postnatal women with HIV from
 Review
51 studies, no difference in adherence according to
setting (high-income vs low-income) was found, with a
pooled estimate of 74% of pregnant women having ART
adherence above 80% (deemed adequate adherence).31 In
a Swiss study,47 34% of women did not return for an HIV
care visit until 6–12 months after giving birth and 12%
were lost to follow-up for more than 12 months, and a
single-site study in the USA reported only 39% of women
engaged in care 1 year after giving birth48 Disengagement
from HIV care means interruption of ART, which has
important implications for maternal health, for MTCT,
and horizontal transmission, with similar problems
existing for those remaining in care postnatally but with
deteriorating ART adherence; among 523 women
starting ART during pregnancy in South Africa as option
B+ and achieving viral suppression during follow-up,
there was an 11% increased incidence of subsequent
viraemia for each additional month post partum.49
Optimised regimens and new antiretrovirals
WHO guidelines currently recommend fixed dose
combination tenofovir disoproxil fumarate with either
lamivudine or emtricitabine plus the non-nucleoside
reverse transcriptase inhibitor (NNRTI) efavirenz as
first-line therapy.1 In 2016, new alternative options for
ART for non-pregnant adults were included, with
dolutegravir (an integrase inhibitor) and 400 mg
efavirenz recommended for first-line therapy, and the
ritonavir boosted protease inhibitor darunavir and
raltegravir (an integrase inhibitor) recommended for
second-line or third-line therapy, so called optimised
antiretroviral regimens.1 The rationale for this transition
is to increase use of regimens that are highly effective,
have low toxicity, with a high genetic barrier to resistance,
and that have few drug interactions, while taking
into account key optimisation criteria, including
simplification, harmonisation, and cost, as well as safety
considerations for special populations, including
pregnant women.
WHO does not yet recommend dolutegravir within
preferred first-line regimens in pregnancy because of
sparse safety data and a concern about birth defects.50
Although more than 20 countries have updated their
national guidelines to include dolutegravir as a first-line
option, with many adopting a phased transition, most are
not recommending dolutegravir for pregnant women or
women planning to conceive. The exception is Botswana,
where dolutegravir-based ART has been rolled out to
all HIV-infected adults including pregnant women.
Nationwide implementation of tenofovir disoproxil
fumarate, emtricitabine, and dolutegravir for all new
initiations was completed rapidly over a few months in
2016 and the plan is to transition established regimens to
dolutegravir, pending further data on birth defects.
In high-income countries, recommended or preferred
options (particularly for third agents) for initial regimens
for ART-naive pregnant women vary somewhat and
4 www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6
guidelines are frequently updated. The European AIDS
Clinical Society (EACS) guidelines recommend ritonavir-
boosted atazanavir as a boosted protease inhibitor, and
the USA and UK guidelines also recommend ritonavir-
boosted darunavir . For integrase inhibitors, dolutegravir
is a recommended and preferred option in the UK and
EACS guidelines, but remains an alternative option in
the USA.51–53
Today, most pregnant women with HIV in high-income
countries are already receiving ART at conception;
guidelines recommend women review their ART
regimens, but it is generally recommended that pregnant
women remain on their existing regimens if there are no
tolerability issues and they have suppressed viral
loads.51–53
Four antiretroviral drugs have been authorised within
the past 7 years (table): rilpivirine, an NNRTI authorised
in 2011; cobicistat, a booster authorised in 2013;
dolutegravir, authorised in 2014, and tenofovir ala-​
fenamide, a nucleoside reverse transcriptase inhibitor
(NRTI) that was authorised in 2015. Notably, the
summaries of product characteristics regarding pregnancy
are mostly based on preclinical findings, with little data on
use in pregnancy, mainly recommending avoiding use in
pregnancy. However, real-world evidence shows increased
use of these drugs over time, largely reflecting initiation
before conception. For example, in the UK and Ireland
National Study of HIV in Pregnancy and Childhood,54
exposure to any combination containing rilpivirine
increased by more than ten times from 2013 to 2016 and
exposure to any combination containing dolutegravir
increased similarly from 2015 to 2016. Increasing real-
world use, therefore, provides not only the rationale but
also the means to address the gap between regulatory
recommendations and real-world experience.
Although dosing changes are rarely required for most
recommended drugs, data on rilpivirine has emphasised
the importance of studies of pharmacokinetics in the
context of pregnancy, with the area under the curve and
trough concentration of rilpivirine reduced in the second
half of pregnancy compared with post partum;55 concerns
regarding increased risk of virological failure have led to
regulatory recommendations advising close monitoring
of viral load or switching to another ART regimen in
pregnancy.
HIV treatment considerations in specific
populations
Late presenters
For women who are not on ART at conception, prompt
ART initiation is key to preventing MTCT, as the
probability of transmission is strongly associated with
duration of ART before giving birth and is particularly
important for women with high baseline viral loads.51,53
In the French Perinatal Cohort,14 the MTCT rate among
women starting ART in the third trimester was 2·2% in
2000–11, versus 0·7% in the entire cohort. In
 Review

Preclinical safety data from
animal studies
DTG No developmental toxic effects
ABC+3TC+DTG† or teratogenicity; in studies of
drugs in combination with 3TC
there was an increase in early
embryonic deaths in rabbits at
relatively low systemic
exposures; DTG, 3TC, ABC had no
effect on fertility in men or
women
RPV No reproductive toxic effects and
FTC+TDF+RPV† no teratogenicity in rats and
FTC+TAF+RPV† rabbits; no effect on fertility in
animals, but effect is unknown in
humans; RPV toxic effects on the
liver are associated with liver
enzyme induction in rodents
TAF No reproductive toxic effects in
FTC+TAF† rats or rabbits, no effect on
fertility, pregnancy, or fetal
parameters; bone and kidney are
main toxicity target with reduced
mineral density in dogs and rats
COBI No reproductive toxic effects and
ATV + COBI† no teratogenic effects in rats or
DRV + COBI† rabbits; ossification changes
EVG + FTC + TDF† observed (spinal column and
EVG + COBI + FTC+ TAF† sternebra) in foetuses at
maternal toxic doses in rats only;
in rats, elvitegravir, cobicistat,
emtricitabine, and tenofovir
disoproxil fumarate increased
post-implantation loss and
decreased fetal weights
DTG=dolutegravir. ABC=abacavir. 3TC=lamivudine; RPV=rilpivirine. FTC=emtricitabine. TDF=tenofovir disoproxil fumarate. TAF=tenofovir alafenamide. COBI=cobicistat. ATV=atanazavir. DRV=darunavir.
EVG=elvitegravir. *Placental transfer categories based on mean or median cord blood to maternal delivery plasma drug ratio: high is >0·6; moderate is 0·3–0·6; low is <0·3.†Fixed-dose combination. Data
sources: European Medicines Agency, AIDS info, US Department of Health and Human Services, i-base ; US National Institutes of Health.
Clinical data on toxic
effects on pregnancy:
statements from
summaries of product
characteristics
Data are scarce and effect
on human pregnancy
unknown; should be used
only if benefit outweighs
risk to fetuses
Data are scarce: as a Moderate to high
precautionary measure, placental transfer
preferable to avoid use in
pregnancy; for
emtricitabine, rilpivirine,
and tenofovir alafenamide,
effective contraceptives
must be used; there are no
adequate and well
controlled studies in
pregnant women
No adequate and well
controlled studies in
pregnancy: should be used
only if the benefit
outweighs the risk to the
fetus
No or scarce clinical data: Low placental
consider use only if benefit transfer
outweighs the risk; for
ATV/COBI, DRV/
COBI, FTC/TAF, there are
no data in pregnant
women; for
EVG+COBI+FTC+TDF and
EVG+COBI+FTC+TAF, no
effective contraceptives
should be used
Transplacental Pharmacokinetics Dosing Ongoing clinical studies
passage recommendations
(evidence from
animal studies)
High placental Area under the curve No change DolPHIN1 (NCT02245022): safety and
transfer* might decrease in indicated pharmacokinetics ; IMPAACT P1026s
third trimester (NCT00042289): DTG
compared with post pharmacokinetics in pregnancy vs
partum, but post partum and infants; ING200336
recipients in third (NCT02075593): ARIA sub-study for
trimester have good incident pregnancies; safety and
viral suppression pharmacokinetics of Triumeq;
DolPHIN-2 (NCT03249181): efficacy
of DTG-based vs EFV-based ART in
women presenting late in pregnancy
and their infants; VESTED/IMPAACT
2010 (NCT03048422): safety and
efficacy of DTG+FTC+TAF,
EFV+FTC+TDF, DTG+FTC+TDF in
ART-naive pregnant women and
infants
Highly variable, area RPV plasma TMC114HIV3015 (NCT00855335):
under the curve 30% concentration study of 19 pregnant women during
lower in pregnancy reduced but second and third trimesters and
than postpartum; insufficient data to postpartum; ten women completed
most pregnant recommend dosing the study with no MTCT; RPV was well
women exceed target change tolerated during pregnancy and post
exposure, but those partum; IMPAACT P1026s
with detectable viral (NCT00042289): large study on
load had lower RPV pharmacokinetics in pregnancy vs
troughs post partum and their infants,
including RPV
No data available No pharmacokinetics Dosing: insufficient VESTED/IMPAACT 2010
on placental studies in human data to make
transfer pregnancy dosing
recommendation
Exposure and Not yet studied; IMPAACT P1026s: EVG+COBI,
boosting effect when in combo DRV+COBI, ATV+COBI,
markedly reduced in with TDF and FTC pharmacokinetics in pregnancy vs
pregnancy no change in dose is post partum and their infants; PANNA
indicated (NCT00825929): large
pharmacokinetics study on ART
including EVG+COBI, DRV+COBI

Table: Summary of pregnancy-related characteristics (preclinical, published product characteristics, pharmacokinetic, dosing, and clinical studies) of selected authorised antiretrovirals

high-income countries, a substantial proportion of In Thailand, raltegravir intensification for high-risk For more on European
women who are diagnosed with HIV antenatally are pregnant women is now in national guidelines. A Medicines Agency see
http://www.ema.europa.eu/ema/
diagnosed late; for example, 32% in a European pooled pilot study showed the operational feasibility of adding
For more on AIDS info see
analysis were diagnosed at 20 weeks’ gestation or later,56 raltegravir to standard ART in women presenting late
https://aidsinfo.nih.gov/
largely because of late presentation. Raltegravir is (starting ART after 32 gestational weeks) or with viral guidelines/htmltables/3/5947
recommended in late presentation to antenatal care or load of more than 1000 copies per mL at 34–38 gestational For more on i-base see http://i-
high viral loads in late pregnancy in several guidelines weeks; viral load declined by a median 1·6 log10 copies base.info/htb/33406
(within a three-drug regimen or with raltegravir inten-​ per mL during a median of 3 weeks’ intensification, with Fore more on US National
sification to an existing three-drug regimen) because of a 3·9% MTCT rate reported.57 Institutes of Health see https://
its transplacental transfer efficiency and rapid reduction Once safety data on dolutegravir accumulates, it might clinicaltrials.gov

of viral load.51,53 replace raltegravir for late presenters, as it should have

www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6 5

 Review
similar effectiveness but only needs to be taken once
daily (raltegravir is taken twice daily). The DolPHIN-2
trial (NCT03249181) is investigating in Uganda and
South Africa whether a dolutegravir-based regimen is
superior to efavirenz-based regimens in preventing
MTCT for women initiating ART in the third trimester of
pregnancy, with results expected in 2021.
Hepatitis B virus co-infection
Part of WHO’s rationale for choosing lamivudine or
emtricitabine plus tenofovir disoproxil fumarate as the
NRTI component in first-line ART was its activity against
HBV. In sub-Saharan Africa, prevalence of HBV
co-infection in pregnant women with HIV ranges from
2–16%, with up to 30% being positive for the hepatitis
B e antigen and thus at high risk of vertical HBV
transmission;58 meanwhile, only around 40% of the
world’s infants receive HBV vaccine at birth.59 Treating
pregnant women who are co-infected with HIV and HBV
with a regimen based on lamivudine or emtricitabine
plus tenofovir disoproxil fumarate, has potential to reduce
vertical transmission of both infections, regardless of
whether maternal HBV has been diagnosed.59 This public
health aspect, alongside the HBV therapeutic benefit,
requires consideration in future policy decisions
regarding NRTIs, including recycling them in second-
line therapies.
Pregnant women who inject drugs
There are an estimated 3·5 million women who inject
drugs worldwide, with a higher HIV prevalence than
seen among men who inject drugs.60 WHO guidelines
present the key principles of HIV treatment and care for
women who inject drugs, namely access to essential
harm reduction (ie, needle and syringe exchange
programmes and opioid substitution therapy) and the
same access to ART as other populations.1 Pregnancy can
be a strong motivator for reducing drug use, but
discrimination, stigma, punitive drug policies, and lack
of targeted or tailored services are major barriers for
pregnant women accessing services for women who
inject drugs.60 Increased risk of receiving no antenatal
ART has been described among women who inject drugs
in an eastern European setting,61 and late presentation
to antenatal care and high preterm birth rates might
contribute to reduced duration of antenatal ART in
pregnant women who inject drugs accessing care. In
terms of therapeutic management, interactions between
methadone and some antiretrovirals (eg, efavirenz and
boosted protease inhibitors) might require adjustment of
the methadone dose.
Safety
There remain some large gaps in knowledge about the
safe use of ART in pregnancy for new antiretroviral
drugs.26,62 A major factor has been the exclusion of
pregnant women or women planning a pregnancy from
6 www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6
registrational and strategic trials of ART. Furthermore,
data relating to use in non-pregnant women is also
limited, because of the predominance of male
participants in clinical trials of new antiretroviral drugs
and regimens, with only a quarter of patients in such
trials being female.63 In the WAVE trial,64 women who
became pregnant were allowed to continue on the drug
studied, with appropriate follow-up of pregnancy and
infant outcomes. Although this is a welcome trend,
pregnancy-specific safety data are very slow to accumulate
for new drugs, given the dependence on observational
data (table).
Teratogenicity
As increasing proportions of women are conceiving on
ART, attention continues to be focused on the potential
teratogenicity of ART, particularly for new drugs. Before
2018, studies of antenatal HIV treatment showed an
overall similar prevalence of birth defects in ART-exposed
infants compared with the general population, with
studies also showing no association between first
trimester exposure to any ART and major birth defects.65,66
To provide evidence on the development of the first
harmonised WHO guidelines, and in response to case
reports of neurological birth defects associated with the
use of efavirenz, a series of systematic reviews were
conducted. The most recent review67 to date assessed first
trimester exposure, finding no increased risk of birth
defects in efavirenz-exposed infants.
The Antiretroviral Pregnancy Registry (APR) collects
prospective data when ART exposure is assessed before
birth outcomes are reported, predominantly through
voluntary reports from mainly US-based health-care
providers. The APR68 has sufficient statistical power to
rule out an increased risk of 1·5 times or greater in
overall birth defects in infants exposed to zidovudine,
lamivudine, tenofovir disoproxil fumarate, abacavir,
emtricitabine, nevirapine, ritonavir, lopinavir, and
zidovudine, and an increase of two times in those
exposed to darunavir, rilpivirine, efavirenz, and
raltegravir compared with the general US population.
Some studies have identified potential safety signals,
which require continued monitoring. For example, a US
study reported a significantly increased risk of congenital
abnormalities associated with zidovudine exposure in
the first trimester, and an increase in skin and
musculoskeletal defects,66 while the French Perinatal
Cohort69 reported a two-times increased risk of congenital
heart defects associated with first trimester zidovudine
exposure (although this increase was not found in the
APR).70
In May 2018, four infants with neural tube defects
were reported among 426 births to women who started
dolutegravir-based ART before conception in Botswana,50
nearly ten-times higher than the expected prevalence.
These results are based on a small number of events and
further studies are needed to confirm or refute the

findings (eg, the Tsepamo Study in Botswana and
others). There are few published studies assessing
congenital defects in dolutegravir-exposed pregnancies.
In the APR, among 133 livebirths reported (77 with first
trimester exposure to dolutegravir), 3·0% had a birth
defect71 (with a prevalence of 2·7% among infants with
first trimester exposure and 2·8% among infants with
second and third trimester exposure in the APR
overall).68 In the European Pregnancy and Paediatric
HIV Cohort Collaboration, there were four children with
at least one birth defect recorded among 81 live births
(prevalence 4·9%; 95% CI 1·4–12·2%), of which 42 had
first trimester exposure to dolutegravir.72 National data
from HIV-exposed pregnancies in the UK indicate a
prevalence of birth defects of 2·9% among all births
exposed to ART.73
One of the challenges of obtaining sufficient data on
the risk of birth defects by ART regimen is that most of
these exposures occur in low-income and middle-income
countries, where there has been a lack of systematic
surveillance of drug safety in pregnancy. In these
settings, surveillance can be difficult because of concerns
about the reliability and coverage of medical and
pharmacy records, prevalence of home births, and
insufficient training to recognise birth defects. However,
recent efforts by several African countries to implement
birth surveillance has shown early success and WHO is
coordinating a system to pool this data to improve
efficiency and reach.27
Adverse birth outcomes
Untreated HIV infection in pregnancy is associated with
increased risk of various adverse birth outcomes,
including preterm birth, low birthweight, babies born
small for gestational age, and stillbirth, with highest risk
among women with advanced HIV disease or
immunosuppression.74 Although ART reduces the risk of
adverse birth outcomes associated with poor maternal
health or infant HIV infection, combination ART can
simultaneously increase the risk, particularly of preterm
birth, via other mechanisms that are not completely
understood, with greater risk of adverse pregnancy
outcome observed than with NRTI monotherapy or dual
therapy in low-income, middle-income, and high-income
countries.11,75 Proposed potential mechanisms include
ART-induced disruption or reversal of the shift from
T-helper type 1 to T-helper type 2 cells that is a normal
feature of pregnancy, resulting in predisposition to early
labour, and an increase in the inflammatory response
following ART initiation, as a result of immune
reconstitution syndrome.76
Combination ART was first associated with preterm
birth in Europe in 1998, with subsequent studies showing
the presence and magnitude of association to differ
according to ART regimen, timing of initiation, and
setting. Protease inhibitors (particularly when boosted
with ritonavir) have been widely implicated in observational
www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6 7
Review
studies77–80 and in the Mma Bana trial81 in Botswana, which
showed a preterm birth rate of 21·4% among women
randomised to receive zidovudine, lamivudine, ritonavir-
boosted lopinavir at 26–34 weeks’ gestation, versus
11·8% among those randomised to receive zidovudine,
lamivudine, and abacavir. Progesterone amounts might be
reduced by protease inhibitors, resulting in growth
restriction82 and providing a potential mechanistic link
between protease inhibitors and increased risk of preterm
birth (spontaneous or iatrogenic), with progesterone
supplementation for women on protease inhibitors being
explored.83 Data from the PROMOTE trial84 also show the
effect of ART on oestradiol levels, with lopinavir
and ritonavir-based ART associated with an increase
and efavirenz-based ART with a decrease in oestradiol and
correlations with risk of babies who are born small for
gestational age in both directions.
The PROMISE trial11 found an increased risk of babies
being born very preterm (<34 weeks) and neonatal death
at less than 14 days in women randomised to receive
ritonavir-boosted lopinavir plus tenofovir disoproxil
fumarate, and emtricitabine compared with those who
received ritonavir-boosted lopinavir, zidovudine, and
lamivudine, but not compared with zidovudine mono-​
therapy, resulting in a focus on the safety of regimens
containing tenofovir disoproxil fumarate. However, a
meta-analysis of 17 studies found that tenofovir disoproxil
fumarate was associated with a reduced risk of preterm
birth (relative risk [RR] 0·90, 95% CI 0·81–0·99) and
stillbirth (RR 0·60, 95% CI 0·43–0·84), with increased
risk of neonatal death at less than 14 days old found only
in the PROMISE study.85 These results might indicate an
issue with tenofovir disoproxil fumarate and emtricitabine
relating to increased tenofovir concentrations when
given with, for example, ritonavir-boosted lopinavir, or
they might reflect a low rate of adverse outcomes in the
zidovudine and lamivudine group of the PROMISE study
rather than an increased rate in the tenofovir disoproxil
fumarate and emtricitabine group.1
National surveillance data on safety of tenofovir
disoproxil fumarate from Botswana are also reassuring,
showing a significantly reduced number of babies born
small for gestational age among women initiating
tenofovir disoproxil fumarate, emtricitabine, and
efavirenz in pregnancy and among women on tenofovir
disoproxil fumarate, emtricitabine, and efavirenz from
conception compared with other ART regimens,
including zidovudine, lamivudine and nevirapine
and zidovudine, lamivudine, and ritonavir-boosted
lopinavir.80,86 Women on tenofovir disoproxil fumarate,
emtricitabine, and efavirenz at conception also had a
lower risk of giving birth to babies who are small for
gestational age compared with those on tenofovir
disoproxil fumarate, emtricitabine, nevirapine, or
tenofovir disoproxil fumarate, emtricitabine, lopinavir,
and ritonavir at conception, suggesting that it is difficult
to isolate the fetal effect of individual antiretrovirals
 Review
Search strategy and selection criteria
We searched PubMed using the following search terms:
pregnan*, HIV, human immunodeficiency virus,
antiretroviral, mother-to-child transmission, vertical
transmission, treat*, fet*, foet*, birth defect, preterm,
adverse birth outcome, adherence, loss-to-follow-up, option
B+, and retention. We screened reference lists of identified
studies and searched HIV conference abstracts published
since Jan 1, 2016, and the grey literature including WHO and
UNAIDS publications. We selected articles published in
English from 1994 to 2017 that we judged to be the most
relevant, prioritising systematic reviews and meta-analyses
as well as clinical trials, cohort, surveillance, and
pharmacokinetic studies pertinent to contemporary
questions around the use of ART in pregnancy. We focused
on articles published in the last 10 years.
when used in combinations (similar to the PROMISE
trial results). Surveillance in Botswana also found a
concerning risk for stillbirth among women taking
zidovudine, lamivudine, and nevirapine compared with
other ART regimens.80 Together, this emphasises the
need to evaluate the comparative safety of specific ART
regimens in future research and surveillance.
Uncertainties remain around the role of timing of ART
initiation and adverse birth outcomes. Results from
the UK and Ireland73 showed an association between
ritonavir-boosted ritonavir and risk of preterm birth, but
only if treatment with the drug was initiated before
conception. A meta-analysis of 19 189 mother and child
pairs indicated a 20% increased risk of preterm birth in
pregnancies conceived on ART compared with those
with ART initiated during pregnancy, alongside a
53% increased risk of very preterm birth, and 30%
increased risk of low birthweight.87
Stage of maternal disease is a key confounder in the
association between timing of ART initiation and adverse
outcomes, as illustrated in the UK and Ireland study, in
which those conceiving on ART with CD4 counts greater
than 350 cells per µL had a lower unadjusted preterm
birth rate (8·7%) than the groups initiating ART in
pregnancy (11·3% if CD4 cell count ≤350 cells per µL,
10·7% if CD4 >350 cells per µL).73 Interpretation of
observational data on ART safety is complicated by the
potentially confounding role of indication or channelling
bias, changes over time in treatment guidelines and
comparator groups, inaccuracies in ascertainment of
gestational age in some studies (especially in settings
without routine confirmation by ultrasound), and the fact
that women starting ART later in pregnancy have less
time on ART at risk of preterm birth than do those
conceiving on treatment. In the treat-all era, as more
women conceive on ART with high CD4 cell counts, safety
data are needed that are relevant to the changing
population of pregnant women with HIV and to
8 www.thelancet.com/hiv Published online June 26, 2018 http://dx.doi.org/10.1016/S2352-3018(18)30059-6
new antiretroviral drugs, and that address limitations
in the existing evidence base (eg, around ascertainment of
gestational age). A thorough understanding of mechanistic
links between antiretroviral drugs and adverse outcomes
will, if found to be causal, provide the basis for
development of interventions or risk-stratification
strategies.
Looking to the future
The benefits of ART for prevention of MTCT and for
maternal, child, and public health are indisputable.
Harmonised, universal regimens have been key to the
magnitude of scale-up of ART in low-income and middle-
income countries, with 76% of all pregnant women with
HIV receiving ART in 2016 and declining MTCT rates
documented worldwide. Every year, over a million fetuses
are exposed to ART, which has safety implications on a
population level, as even a very small increased risk of an
adverse outcome might affect many women and children.
The unprecedented scale of exposure to antivirals in
pregnancy has been a catalyst for pharmacovigilance
strengthening in low-income and middle-income
countries, which remains work in progress.26
More data are needed on pharmacokinetics, safety, and
toxicity of newly authorised antiretroviral drugs, particularly
given the increasing numbers of women of reproductive
age requiring second-line regimens.26,62 Safety data based on
observational, real-world evidence are accumulating for
new drugs and the VESTED trial (NCT03048422, table) will
provide much needed randomised trial data comparing
the use of efavirenz, emtricitabine, tenofovir disoproxil
fumarate with dolutegravir and emtricitabine plus either
tenofovir alafenamide or tenofovir disoproxil fumarate in
women starting ART in pregnancy.
New antiretroviral drugs might be licensed despite
there being few data on key characteristics, such as
transplacental passage in pregnancy, and summaries of
product characteristics often recommend avoiding use in
pregnancy (table); however, most women on ART are of
reproductive age and at least half of pregnancies in
women with HIV are likely to be unplanned.88,89 This fact
raises the question of whether more regulatory push is
needed to ensure that pharmaceutical companies
expedite the necessary studies to obtain pregnancy data,
in a process similar to that for paediatric investigation
plans. The potential safety signal with dolutegravir at
conception emphasises the importance of large-scale
pharmacovigilance studies. Clinical trials of new drugs,
including long-acting injectable drugs, should have
provision to follow-up women who become pregnant
during the study, with consideration to remain on the
drug if appropriate. The Pregnancy and HIV/AIDS:
Seeking Equitable Study (PHASES) initiative90 is an
ongoing initiative to develop guidance for ethical HIV
research among pregnant women, with the goal of
providing accelerated access to treatment.
The relations between antenatal ART and adverse

pregnancy and birth outcomes are complex and not
completely understood and there are gaps in our
understanding of any potential short-term or long-term
effects of exposure either via breastmilk or intrauterine
to antiretrovirals among HIV-exposed uninfected
children. Assessing the potential health risks of such
exposures is challenging but important, as the numbers
of HIV-exposed uninfected children will continue to
increase.26 Adverse health outcomes in these children
reported to date include increased mortality and
infectious disease morbidity, impaired growth, metabolic
changes, neurodevelopmental delays, altered immunity,
and mitochondrial abnormalities.26,91,92 For all these
outcomes, our understanding of potential causal path-​
ways needs to improve to explore whether any health
risks can be mitigated.
Treat all for life is a clear public health message, but it
requires not only adherence to ART and sustained
engagement in HIV care on an individual level, but also
recognition of and interventions to overcome structural
barriers to effective long-term treatment. Pregnant
women face specific challenges in this regard, particularly
those who are newly diagnosed with HIV. Further
implementation research is needed to ensure that
the health of women living with HIV, and that of their
families, is optimised.
Contributors
HB, VR, CT, and RZ all contributed to the literature search and drafting
sections of the text. HB, VR, CT, and RZ made crucial revisions to and
approved the final draft of the manuscript. VR and CT prepared the
figure, table, and panel.
Declaration of interests
CT reports personal fees and grants from ViiV Healthcare via the
PENTA Foundation, and grants from AbbVie, outside the submitted
work. All other authors declare no competing interests.
Acknowledgments
This review contains data from the Antiretroviral Pregnancy Registry
and, as requested, we include the following acknowledgment: in
reviewing all reported defects from the prospective registry, informed
by clinical studies and retrospective reports of antiretroviral exposure,
the Registry finds no apparent increases in frequency of birth defects
with first trimester exposures compared to exposures starting later in
pregnancy and no pattern to suggest a common cause. While the
Registry population exposed and monitored to date is not sufficient to
detect an increase in the risk of relatively rare defects, these findings
should provide some assurance when counselling patients. However,
potential limitations of registries such as this should be recognised.
The Registry is ongoing. Given the use of new therapies about which
data are still insufficient, health-care providers are strongly
encouraged to report eligible patients to the Registry at
SM_APR@INCResearch.com via the data forms available at www.
APRegistry.com.
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