Integration of postpartum healthcare services

for HIV-infected women and their infants in

South Africa: A randomised controlled trial
 Landon Myer ,
 Tamsin K. Phillips,
 Allison Zerbe,
 Kirsty Brittain,
 Maia Lesosky,
 Nei-Yuan Hsiao,
 Robert H. Remien,
 Claude A. Mellins,
 James A. McIntyre,
 Elaine J. Abrams

 Published: March 30, 2018

 https://doi.org/10.1371/journal.pmed.1002547
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Abstract
Background

As the number of HIV-infected women initiating lifelong antiretroviral therapy (ART)

during pregnancy increases globally, concerns have emerged regarding low levels of
retention in HIV services and suboptimal adherence to ART during the postpartum
period. We examined the impact of integrating postpartum ART for HIV+ mothers
alongside infant follow-up within maternal and child health (MCH) services in Cape
Town, South Africa.

Methods and findings

We conducted a randomised trial among HIV+ postpartum women aged ≥18 years who
initiated ART during pregnancy in the local antenatal care clinic and were breastfeeding
when screened before 6 weeks postpartum. We compared an integrated postnatal service
among mothers and their infants (the MCH-ART intervention) to the local standard of
care (control)—immediate postnatal referral of HIV+ women on ART to general adult
ART services and their infants to separate routine infant follow-up. Evaluation data were
collected through medical records and trial measurement visits scheduled and located
separately from healthcare services involved in either arm. The primary trial outcome was
a composite endpoint of women’s retention in ART care and viral suppression (VS) (viral
load < 50 copies/ml) at 12 months postpartum; secondary outcomes included duration of
any and exclusive breastfeeding, mother-to-child HIV transmission, and infant mortality.
Between 5 June 2013 and 10 December 2014, a total of 471 mother–infant pairs were
enrolled and randomised (mean age, 28.6 years; 18% nulliparous; 57% newly diagnosed
with HIV in pregnancy; median duration of ART use at randomisation, 18 weeks).
Among 411 women (87%) with primary endpoint data available, 77% of women (n =
155) randomised to the MCH-ART intervention achieved the primary composite outcome
of retention in ART services with VS at 12 months postpartum, compared to 56% of
women (n = 117) randomised to the control arm (absolute risk difference, 0.21; 95% CI:
0.12–0.30; p < 0.001). The findings for improved retention in care and VS among women
in the MCH-ART intervention arm were consistent across subgroups of participants
according to demographic and clinical characteristics. The median durations of any
breastfeeding and exclusive breastfeeding were longer in women randomised to the
intervention versus control arm (6.9 versus 3.0 months, p = 0.006, and 3.0 versus 1.4
months, p < 0.001, respectively). For the infants, overall HIV-free survival through 12
months of age was 97%: mother-to-child HIV transmission was 1.2% overall (n = 4 and n
= 1 transmissions in the intervention and control arms, respectively), and infant mortality
was 1.9% (n = 6 and n = 3 deaths in the intervention and control arms, respectively), and
these outcomes were similar by trial arm. Interpretation of these findings should be
qualified by the location of this study in a single urban area as well as the self-reported
nature of breastfeeding outcomes.

Conclusions
In this study, we found that integrating ART services into the MCH platform during the
postnatal period was a simple and effective intervention, and this should be considered
for improving maternal and child outcomes in the context of HIV.

Trial registration

ClinicalTrials.gov NCT01933477.

Author summary
Why was this study done?

 More than 1 million HIV-infected women of reproductive age become pregnant

globally each year, and World Health Organization policies call for initiation of
lifelong antiretroviral therapy (ART) in all HIV-infected pregnant and breastfeeding
women.
 However, keeping HIV-infected women retained in care, adherent to ART, and
with HIV viral suppression is a major public health challenge, particularly
postpartum.
 Integration of ART services into existing maternal and child health (MCH)
programmes is one intervention approach that has been widely discussed to address
this challenge, but this approach has not been rigorously evaluated.

What did the researchers do and find?

 Working in Cape Town, South Africa, we recruited immediately postpartum 471

HIV-infected, breastfeeding women who had initiated ART during pregnancy.
 We randomised mother–infant pairs to either referral to general adult ART clinics,
with their children referred to child health clinics (the local standard of care, which
acted as a control condition), or keeping mothers and infants in care together in an
MCH-focused ART service (the intervention).
 We followed mother–infant pairs through 12 months postpartum with regular
study visits that were scheduled and conducted independent of routine services in
either the intervention or control arms; batched viral load testing was conducted at
these study visits, separate from routine care.
 We found that women randomised to the integrated care intervention had higher
levels of retention in care and viral suppression through 12 months postpartum. This
difference was observed in all subgroups of women, including younger and older
women, those newly diagnosed with HIV, those with lower CD4 cell counts, and
those with longer durations of ART use before delivery.
 Women in the integrated care intervention also reported breastfeeding their infants
for longer periods. Levels of infant mortality and mother-to-child HIV transmission
were low and similar between the intervention and control arms.

What do these findings mean?

  Integrating MCH and ART services appears effective in keeping HIV-infected
mothers retained in care and virally suppressed.
 Integrated services may also contribute to longer durations of breastfeeding, and
thus contribute to child health.
 These data should be interpreted carefully, as they come from a single part of
South Africa, and further research is needed to examine the generalisability of the
findings to other settings.

Citation:Myer L, Phillips TK, Zerbe A, Brittain K, Lesosky M, Hsiao N-Y, et al. (2018)
Integration of postpartum healthcare services for HIV-infected women and their infants in
South Africa: A randomised controlled trial. PLoS Med 15(3): e1002547.
https://doi.org/10.1371/journal.pmed.1002547

Academic Editor:Elvin H. Geng, University of California, San Francisco, UNITED

STATES

Received:August 14, 2017; Accepted:February 28, 2018; Published: March 30, 2018

Copyright: © 2018 Myer et al. This is an open access article distributed under the terms
of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are
credited.

Data Availability:Data are available on request pending approval of protocol for

secondary analysis from the University of Cape Town Faculty of Health Sciences Human
Research Ethics Committee (email: [email protected]).

Funding:This research was supported by the President’s Emergency Plan for AIDS
Relief (PEPFAR) through the National Institute of Child Health and Human Development
(NICHD), Grant Number 1R01HD074558. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations:ANC, antenatal care; ART, antiretroviral therapy; ARV, antiretrovira;

EBF, exclusive breastfeeding; MCH, maternal and child health; NHLS, National Health
Laboratory Services; PMTCT, prevention of mother-to-child HIV transmission; SOC,
standard of care; VL, viral load; VS, viral suppression

Introduction
The past decade has witnessed a paradigm shift in the science of and services for
prevention of mother-to-child HIV transmission (PMTCT) [1,2]. Lifelong triple-drug
antiretroviral therapy (ART) for all women living with HIV regardless of disease status
(per the World Health Organization’s Option B+ approach) has emerged as the standard
for reducing vertical HIV transmission and promoting maternal health [3]. With this
approach, there have been substantial increases globally in ART use by HIV+ pregnant
and postpartum women, with consequent reductions in new paediatric HIV infections,
providing a potent example of the synergies of ART use for HIV treatment and prevention
[4].

Alongside the successes of universal ART for pregnant and postpartum women, multiple
studies from around the world have raised major concerns regarding low levels of
retention in HIV services and adherence to ART medications in this population [5–8].
These findings appear especially marked in the postpartum period and contribute directly
to failures in maintaining viral suppression (VS) [8,9]. This limits the benefits of ART,
and, in turn, there is an urgent need to help HIV+ women to remain engaged in ART
services over the long term. Moreover, with new WHO guidelines recommending that
HIV+ mothers breastfeed for at least 12 months postpartum [10], the ability of health
services to support mothers on ART has direct implications for the health of their HIV-
exposed infants. Yet there have been few rigorous evaluations of interventions to promote
postpartum engagement in ART services, and existing evaluations have been limited in
their duration of follow-up [11].

Related to this, there has been a call for integrating HIV care and treatment services into
the broader platform of primary healthcare, particularly in the context of PMTCT [12].
Integration of ART into antenatal care (ANC) services has proven critical to the
successful delivery of ART to pregnant women under Option B+ across sub-Saharan
Africa [13]. However, there has been little consideration given to the integration of health
services during the postpartum period, when HIV+ women’s retention and adherence may
be under greatest threat. In many settings, women initiating ART as part of ANC are
referred immediately post-delivery to general adult ART services [14,15]. This change in
the location of care and the separation of maternal and infant services has been a point of
loss to follow-up, and there may be a major missed opportunity for linking ART services
within the broader maternal and child health (MCH) care platform. To address this gap,
we examined the impact of integrating postpartum ART for HIV+ mothers and infant
follow-up within MCH services on maternal retention in care and VS through 12 months
postpartum in Cape Town, South Africa.

Methods
Design and setting

We conducted a parallel-arm randomised trial comparing an integrated postnatal care

service within the MCH setting for HIV+ mothers and their infants (the MCH-ART
intervention) to the local standard of care (SOC, control)—immediate postnatal referral
of HIV+ women on ART to general adult ART services and their infants to routine infant
follow-up. The trial took place in a subdistrict of Cape Town as described previously
[16]. Within the subdistrict, the study was based at a large, primary-level antenatal and
obstetric facility located in a community of approximately 300,000 where levels of both
poverty and HIV infection are high; referral was to one of a number of primary care
services in the subdistrict [17]. The study was registered on ClinicalTrials.gov
(NCT01933477); final registration was approved 3 months after the start of enrolment
due to an administrative error. The study protocol is provided as S1 Text. The study
protocol was approved by the Human Research Ethics Committee of the University of
Cape Town Faculty of Health Sciences, as well as by the Institutional Review Board of
Columbia University Medical Center.

Routine PMTCT and ART services

In this setting, routine ANC is provided in the MCH clinic and includes PMTCT services
with nurse-midwives initiating women on ART and providing follow-up with support
from counsellors. ART eligibility is based on local public sector guidelines. For women
making their first ANC visit before July 2013, eligibility was based on CD4 cell count ≤
350 cells/μl or WHO stage III/IV disease, per WHO 2010 recommendation Option A.
From July 2013, all HIV+ pregnant women were ART eligible (WHO 2013
recommendation Option B+) [18]. All women initiated the local first-line ART regimen of
tenofovir (300 mg) + emtricitabine (200 mg)/lamivudine (300 mg) + efavirenz (600 mg)
provided as a fixed-dose combination pill taken once daily. For all women in the study,
ART initiation, all clinical care, and infant follow-up was provided by government health
services based on public sector policies. Routine infant HIV diagnostic testing in this
setting, based on nucleic acid amplification tests, was carried out at 6–10 weeks of age.

Participants and eligibility

Participants were HIV+ women and their infants (regardless of HIV infection status)
recruited immediately postpartum during routine clinical follow-up visits. As part of a
larger implementation science study, all HIV+ women seeking ANC who were eligible
for enrolment were interviewed and followed from their first ANC visit. To be eligible for
the trial, women were required to be at least 18 years of age and less than 6 weeks
postpartum, to have initiated ART during the recently completed pregnancy (regardless of
previous antiretroviral [ARV] exposure or evidence of VS), and to be breastfeeding their
infants at the time of screening.

Randomisation

After providing written informed consent, eligible mother–infant pairs were allocated 1:1
to the intervention or control arm via computer-generated block randomisation with
dynamically permuted block sizes from 2 to 8. Allocations were via opaque sealed
envelopes kept securely and accessed by the study coordinator. The study coordinator
communicated the random allocation to nurse-midwives in the MCH clinic via a
standardised letter.

MCH-ART intervention

Women randomised to the intervention continued to receive postnatal care in the MCH
clinic for the duration of breastfeeding, with care provided to their HIV-exposed infants
in the same service. As part of this, nurse-midwives provided ongoing HIV-specific
services (including ART and routine infant HIV diagnostic testing) in addition to general
care (including contraception for mothers and routine infant care such as anthropometry
and vaccinations). At each postnatal visit, nurse-midwives asked mothers about their
infant feeding; when mothers reported having stopped breastfeeding, nurse-midwives
conducted additional infant HIV diagnostic testing per local guidelines and referred
mother–infant pairs out of the MCH clinic, although study-specific follow-up persisted
regardless of the site of care.

SOC control

Women and their infants randomised to the control arm followed the local SOC, with
referral out of the MCH clinic—to general adult ART services for the mother and “well
baby” (child health) services for the infant—by nurse-midwives as soon as possible
postpartum, typically at their first postnatal visit.

Referrals

For both the intervention and control arms, referrals out of the MCH clinic followed
routine local practice. Women were counselled on ART adherence, infant feeding and
care including HIV testing, and related aspects of maternal and infant health. They were
provided with a referral letter to attend the ART clinic of their choosing (typically based
on area of residence) and dispensed a 1-month supply of ART. Mothers were advised to
take infants as soon as possible to their nearest routine child health services, which
incorporated care for HIV-exposed infants.

Counselling and patient support

Under both the intervention and control conditions, ART counselling was provided by the
routine public sector ART counsellors based either in the MCH clinic (intervention) or
general adult ART services (control). These counsellors undergo standardised training and
supervision; throughout the study, counselling messages and frequency were based on
local standards without adaptation in either the intervention or control arm.

Missed clinic visits

Procedures for tracing women who did not attend a scheduled clinic appointment in either
the intervention or control arm were based on local public sector norms: as feasible
according to available information and clinic workloads, clinic personnel attempted to
contact patients who missed a clinic visit via telephone and/or home visit.

Sources of data

Evaluation data were collected through a series of trial measurement visits scheduled and
located separately from the public sector healthcare services involved in either arm of the
trial. Visits took place at 6 weeks and then 3, 6, 9, and 12 months postpartum. For
attendance at each trial measurement visit, women received R 150 (approximately
US$12) in a combination of food vouchers and/or child-related consumables (such as
diapers or clothing); no reimbursement was provided for attendance at routine healthcare
visits in either the intervention or control arm.

At the start of each measurement visit, participating mothers were instructed to not
disclose to study personnel where they were receiving HIV care, and questionnaires did
not investigate this. Mothers provided 5 ml of venous blood at each study visit for
batched HIV RNA viral load (VL) testing by the South African National Health
Laboratory Services (NHLS) using the Abbott RealTime HIV-1 assay (Abbott
Laboratories, Abbott Park, Illinois, US); this testing was conducted independently from
routine VL monitoring for patients on ART. At the 12-month study visit, infants
underwent phlebotomy for HIV PCR testing at NHLS using the Roche COBAS
AmpliPrep/COBAS TaqMan HIV-1 assay (Roche Diagnostics, Branchburg, New Jersey,
US). In the event of missed trial measurement visits, participants were traced by a study
fieldworker working independently of routine healthcare services.

Additional data on maternal and infant use of healthcare services were drawn from
routinely collected public sector medical records, abstracted for all participants at the end
of the study period. Data sources for this were identical across facilities involved in both
arms of the trial and included medical record review at all care facilities (both from
folders and electronic medical records, when available, and including infants’ Road to
Health Booklets), provincial electronic pharmacy dispensing records, and centralised
NHLS databases of laboratory tests.

Outcomes

The primary trial outcome was a composite endpoint of women’s retention in ART care
and VS (VL < 50 copies/ml based on VL testing at trial measurement visit) at 12 months
postpartum. Retention in care at 12 months postpartum was measured using routinely
collected medical records and defined as evidence of an HIV-related clinical contact from
the period 9–18 months postpartum. Data used to define a clinical contact came from
routinely collected records of ARV dispensing, HIV-related laboratory testing, and
clinical care visits. In sensitivity analyses, we examined (i) alternate window periods used
to define 12-month retention and (ii) whether the source of retention data influenced trial
findings. Secondary outcomes included the separate components of the primary outcome,
time to loss of VS, duration of any breastfeeding and exclusive breastfeeding (EBF),
infant engagement in appropriate care including HIV testing and use of ARV prophylaxis,
maternal family planning use, mother-to-child HIV transmission, and infant mortality.
Because outcome data on retention in ART care came from medical records and did not
require separate study follow-up, this outcome was available for all participants
(regardless of completion of trial measurement visits and availability of VL outcome
data) and is presented for all women enrolled as well as restricted to women who also had
VL outcome data.

Statistical analysis
The trial sample size was based on a superiority comparison using 90% power and a 2-
sided alpha at 0.05. With 1:1 randomisation, we aimed to detect an absolute difference in
the primary outcome between trial arms of at least 15%, based on an estimated 90% and
75% of women retained in care and virally suppressed in the MCH-ART and SOC arms,
respectively. With an estimated 20% loss to follow-up from the trial by 12 months
postpartum, we calculated that approximately 390 women would need to be randomised.
When local PMTCT policies changed from Option A to Option B+ in July 2013, we
revised the target sample size to be based on 390 women initiating ART under Option B+
but continued to follow up women enrolled in the trial who initiated ART under Option
A.

Analyses used Stata version 13.0 (StataCorp, College Station, Texas, US) and R (R
Foundation for Statistical Computing, Vienna, Austria). Throughout, results are presented
both for all women enrolled and those initiating ART under Option B+; because findings
did not differ between these two groups, we focus primarily on the total randomised
population. Unless otherwise specified, all analyses are by intention to treat. Variables
were described using means (with standard deviations), medians (with interquartile
ranges), and proportions (with 95% confidence intervals). We used rank-sum and chi-
squared (replaced in the case of sparse data by Fisher’s exact) tests for bivariate analyses;
all statistical tests are 2-sided at α = 0.05. Product-limit methods were used for time-to-
event analyses, with the log-rank test used to compare survival times. VS was defined as
VL < 50 copies/ml for the primary outcome, with additional analyses for VL < 1,000
copies/ml based on international guidelines. Additive binomial regression models [19]
were used to examine the effect of trial arm on the primary outcome after adjusting for
participant clinical and demographic characteristics; results are presented as absolute risk
differences with 95% CIs. Covariates for consideration in these models were selected
based on a priori plausibility in predicting either component of the composite endpoint,
while not being plausible causal intermediates of any intervention effect; we included in
the final model those covariates whose inclusion altered the association of interest (the
main trial effect) or which appeared independently associated with the outcome. To
examine the potential influence of missing VL outcome data, multiple imputation via
chained equations was used to create 25 datasets with complete composite endpoint data
for use in sensitivity analyses [20]. Estimates and CIs for imputed data analyses were
pooled using Rubin’s rules [21].

Results
Between 5 June 2013 and 10 December 2014, a total of 587 women were screened
postpartum for inclusion in the trial, of whom 471 were enrolled and randomised (Fig 1).
The main reasons for ineligibility of postpartum mother–infant pairs were the mother’s
decision not to breastfeed (13%) or presentation outside the 6-week eligibility window
(4%); 8 refusals were noted (1%). Of the 471 breastfeeding mother–infant pairs
randomised into the trial at a median of 5 days postpartum (IQR, 4–7), 381 (81%)
initiated ART under Option B+.
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Fig 1. Study enrolment, randomisation, and follow-up.

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Characteristics at randomisation

Table 1 shows pre-ART and immediate postpartum characteristics by allocation of

women to trial arms, overall and restricted to women enrolled under Option B+. At the
first ANC visit, the mean age was 28.6 years, 18% of women (n = 87) were nulliparous,
and the median gestational age at the start of ANC was 21 weeks (IQR, 16–27). The
median CD4 cell count was 354 cells/μl (IQR, 248–517), and the median log10 VL was
4.0 copies/ml (IQR, 3.4–4.6). At the time of randomisation, women had been on ART for
a median duration of 18 weeks (IQR, 12–23), 76% (n = 355) were suppressed to VL < 50
copies/ml, and 6% of women (n = 29) had VL ≥ 1,000 copies/ml. By design, 100% of
women were breastfeeding at randomisation, and 91% (n = 430) reported EBF.
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Table 1. Baseline characteristics of the study sample.

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Referral out of the MCH service

Fig 2 shows the distribution of time to referral out of the MCH service in the SOC versus
MCH-ART arm. Among the 238 postpartum women (51%) allocated to be referred out of
the MCH clinic immediately per SOC, the median time to referral out was 11 days (IQR,
1–21), and 90% of women were referred out within 30 days of delivery to 1 of 18 ART
clinics. Women allocated to the intervention MCH-ART arm were retained in the MCH
service until a median of 32 (IQR, 10–51) weeks postpartum.

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Fig 2. Time to referral out of the maternal and infant health (MCH) service for women in
the intervention and control arms.

Log-rank test, p < 0.001.

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Follow-up in trial measurement visits

All women participating in the trial, regardless of trial arm, were followed with separate
trial measurement visits up to 12 months postpartum through 21 January 2016. During
this time, 59 women (13%) were lost from scheduled trial measurement visits
(independent of their retention in routine HIV care), including 5 women who withdrew
(1%) and 1 maternal death (<1%). Of the 412 women who completed the study outcome
visit, 1 woman was missing VL measurement, and thus 411 women were available for the
primary outcome (87% of those randomised; Fig 1). There was no difference in the
completion of trial follow-up and availability of VL outcome data by trial arm or PMTCT
option, but on average women who completed the 12-month trial measurement visit were
older, were less likely to be diagnosed with HIV during their most recent pregnancy, and
entered ANC at an earlier gestational age, compared to women lost from scheduled trial
measurement visits (S1 Table). The median duration of ART use at the time of outcome
assessment was 15.9 months (IQR, 14.5–17.3; median, 16.1 and 15.9 months in the
intervention and control arms, respectively).

Primary outcome

Table 2 compares the primary outcome overall and in its constituents between the trial
arms, and shows almost identical results in the Option B+ population and the total trial
population. Among the 411 women in the total trial population who completed trial
follow-up and had VL data available, 77% of women (n = 155) randomised to the MCH-
ART arm achieved the primary composite outcome of retention in ART services with VL
< 50 copies/ml at 12 months postpartum, compared to 56% (n = 117) of women
randomised to the SOC arm (risk difference, 0.21; 95% CI: 0.12–0.30; risk ratio, 1.37;
95% CI: 1.19–1.58; p < 0.001). Within this composite outcome, 80% of women (n =
330) had evidence of retention in ART services at 12 months postpartum: 88% (n = 178)
in the MCH-ART arm and 72% (n = 151) in the SOC arm (p < 0.001). When the analytic
population for the retention outcome was extended to all 471 women randomised
(regardless of the availability of VL data), these proportions were 81% and 71%,
respectively (p = 0.013). The observed differences between the MCH-ART and SOC
arms persisted, for both retention in care and VS, under various definitions of these
outcomes. For example, 80% of women (n = 162) in the MCH-ART arm and 68% (n =
142) in the SOC arm had VL < 1,000 copies/ml at the study outcome visit (p = 0.005),
and the median times to VL ≥ 50 and VL ≥ 1,000 copies/ml, among those with VL < 50
copies/ml at randomisation, were significantly longer among women in the MCH-ART
arm compared to women in the SOC arm (S1 and S2 Figs). Moreover, the findings
related to retention did not differ appreciably by the data source or window period used to
define retention (Tables 2 and S2).
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Table 2. Comparison of primary outcome and variants between trial arms through 12
months postpartum.

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The overall findings for superior retention in care and virologic outcomes among women
in the MCH-ART arm appeared consistent across subgroups of participants according to
demographic and clinical characteristics (Figs 3, S3 and S4). Of note, the strongest
intervention effects were observed in women initiating ART during the third trimester of
pregnancy (risk difference, intervention minus control, 42%) compared to the second and
first trimesters (risk differences, 16% and 4%, respectively). In a multivariable model
(Table 3), the overall difference in the primary outcome between intervention and control
persisted. In addition, ART initiation later in pregnancy, previous diagnosis with
tuberculosis infection, and increased VL at the time of randomisation were associated
with decreased VS and/or retention postpartum. In a secondary analysis with missing VL
outcome data imputed, the observed differences between the intervention and control
arms persisted (S3 Table).

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Fig 3. Forest plot of primary outcome across a priori subgroups of demographic and
clinical characteristics.

ARV, antiretroviral.

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Table 3. Results of additive binomial models examining the association between trial arm
and primary outcome adjusted for demographic and clinical characteristics (n = 411).

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Effect of duration of MCH-ART service

S4 Table compares outcomes among women randomised to the intervention who were
retained in the MCH-ART service for different durations postpartum. Women randomised
to the intervention who stopped breastfeeding and were referred out within 3 months
postpartum had VL and ART retention outcomes measured at 12 months postpartum that
were similar to those of women randomised to the control arm. Conversely, women who
breastfed and were retained for longer periods in the MCH-ART service experienced
improvements in outcomes measured at 12 months postpartum in a graded manner, with
the largest intervention effects observed in women retained for at least 9 months
postpartum; this trend persisted after adjusting for demographic and clinical covariates
(S5 Table). Among women in the intervention arm, each additional month spent in the
integrated MCH-ART service was associated with a 2.5% increase (95% CI: 1.9%–3.1%)
in the absolute risk of being retained in care and virally suppressed at 12 months
postpartum in adjusted models.

Secondary outcomes

Patterns of breastfeeding during the study differed between women randomised to the
intervention and control arms (Figs 4 and 5). The median duration of any breastfeeding
was longer among women randomised to the MCH-ART arm than among those
randomised to the SOC arm in the total trial population (6.9 versus 3.0 months; p =
0.006) and when restricted to women initiating ART under Option B+ (6.0 versus 3.0
months; p = 0.023). By 12 months postpartum, 16% in the MCH-ART arm and 12% in
the SOC arm reported still breastfeeding in the total trial population. The duration of EBF
was shorter but followed a similar pattern, with a median of 3.0 months in the MCH-ART
arm versus 1.4 months in the SOC arm (p < 0.001) in the total trial population.

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Fig 4. Time to cessation of any breastfeeding for women in the intervention and control
arms.

Log-rank test, p = 0.006.

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Fig 5. Time to cessation of exclusive breastfeeding for women in the intervention and
control arms.

Log-rank, p < 0.001.

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Table 4 compares MCH outcomes between trial arms, which did not differ significantly
between the intervention and control arms. Among 478 infants in the study, there were 9
deaths and 5 HIV infections observed in the first 12 months postpartum. Overall HIV-free
survival through 12 months of age was 97%: mother-to-child HIV transmission at 12
months was 1.2% overall (comparison by trial arm, p = 0.178), and infant mortality was
1.9% (comparison by trial arm, p = 0.296).
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Table 4. Comparison of secondary outcomes between the intervention and control arms.

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Discussion
This study demonstrates that integration of ART services into the MCH platform can lead
to significant improvements in HIV+ women’s retention in care and VS up to 12 months
postpartum. We also found longer durations of any BF and EBF among women who were
randomised to integrated MCH and ART services. Overall, the integration of MCH and
ART services may represent a simple intervention that can enhance the health of HIV+
women and their children in the first year after delivery.

This is one of the few randomised studies presenting evidence that integration of MCH
and ART services can enhance women’s engagement in HIV care during the postnatal
period and improve biomedical outcomes. While the challenges of retention in care and
adherence to ART in HIV+ women during the postnatal period have been widely
documented, rigorously evaluated interventions to strengthen women’s engagement in
services are scant. Existing intervention modalities typically target individual women as
the locus of intervention, for example through intensified patient counselling, mobile
health interventions, services offered by lay health workers, and/or incentivising health
behaviours, often with mixed results over short durations postpartum [11]. While these
approaches may be useful to address single, specific causes of women’s disengagement
from care, the intervention effects observed to date have been modest, and the feasibility
of scaling up these interventions remains unclear.

In contrast, the integration of services represents a structural health systems intervention

that may impact on multiple aspects of service engagement. We observed strong
associations involving the primary outcome, women’s retention in care, and VS, as well
as infant feeding practices; we had limited power to detect associations with outcomes
that occur more commonly (such as maternal family planning use) or rarely (such as
mother-to-child HIV transmission) in this setting. While not all research has shown
improvements in care associated with integration of HIV and MCH services [22], our
results are congruent with previous findings that models of care for postnatal ART
services can influence outcomes for HIV+ women and their families. One health services
evaluation from Malawi suggested that clinics that combined maternal and infant care
yielded superior maternal retention outcomes compared to disaggregated forms of care
where mothers received treatment within general adult ART services [14]. Similarly, a
randomised controlled trial in Nigeria found significant increases in maternal retention in
HIV care up to 3 months postpartum with a multicomponent package intervention that
included co-scheduling of care for HIV+ mothers and their infants [23]. Building on these
results, our trial findings advance the state of knowledge by providing compelling
evidence demonstrating the specific effects of integrated postnatal services on multiple
MCH outcomes.

The differences observed in the primary outcome between the intervention and control
arms were generally similar across a range of subgroups. Of note, there is considerable
interest in the impact of ART initiation on the same day as the first ANC visit, compared
to delaying ART initiation to allow time for patient preparation [24]; we found the
intervention effect persisted regardless of this timing. Moreover, it is plausible that
women who are newly diagnosed with HIV in pregnancy may face particular challenges
in ART retention and adherence, though intervention effects were similar regardless of
when women were diagnosed with HIV infection. In addition, there are special concerns
around the provision of lifelong ART for young pregnant and postpartum women [25],
but here the intervention effects were consistent across all age groups.

We found that the strength of the intervention effect varied according to the amount of
time postpartum spent in the intervention service in a graded manner: the largest
improvements in the primary outcome were observed among women retained in the
intervention beyond 9 months postpartum, with smaller but appreciable differences
observed in women retained for 3 to 9 months. Meanwhile, among women in the
intervention arm referred out to general ART services before 3 months postpartum,
outcomes measured at 12 months postpartum were identical to those observed in the
control arm. From these findings, we hypothesize that the integrated care intervention
may provide a critical foundation for establishing and maintaining positive ART-related
behaviours [26]. Related to this, we observed the strongest intervention effects in women
who initiated ART later in pregnancy—a high-risk group that warrants special attention
[27]. Specifically, women who started ART earlier in pregnancy, and thus spent more
time establishing positive ART-related behaviours before delivery, may have benefitted
less from remaining engaged in the integrated MCH-ART intervention service for longer
durations postpartum. In contrast, women initiating ART later in pregnancy may have
experienced greater benefit from the longer durations spent in the integrated service
afforded by the intervention.

Alternate explanations for several findings warrant consideration. It is possible that some
part of the intervention effect may be attributable to delaying the referral of women out of
the MCH setting to adult ART clinics. Women retained in the intervention service after 9
months would have had less opportunity to disengage from care before the outcome visit
at 12 months postpartum, though this would not explain the intervention effect observed
among women referred out before 9 months. Here, we used 12 months postpartum for the
primary outcome as most breastfeeding ends before this time in this setting, but it is
critical to note that breastfeeding and mother-to-child transmission risk may be for longer
periods, and challenges in maternal non-adherence and non-retention in services extend
beyond this window. The transfer of patients between chronic care services is recognised
as a high-risk window for non-adherence and non-retention [15,28], and longer durations
of follow-up will be required to evaluate whether the effects of the intervention appear in
keeping with this hypothesis. In addition, it is possible that differential availability of
routine care data across health facilities in this setting could have explained some of the
differences observed in retention outcomes between the intervention and control arms.
However, we note consistency in the retention findings according to routine data source
used, and further consistency with directly measured VS outcomes, making this
explanation unlikely.

There are a range of mechanisms that may have contributed to the improved maternal
health outcomes associated with the integrated services assessed here. The co-location of
maternal and infant care may lower the burden of clinic visits, reducing the time and
economic costs of healthcare attendance. For some women, receiving ART in the MCH
setting may be associated with less HIV-related stigma compared to general adult ART
services, and thus be more acceptable. In addition, nurse-midwives and other MCH
providers may maintain better relationships with postpartum women, and in turn be better
able to promote positive health behaviours. While these and other mechanisms warrant
investigation, we posit that the reasons why integrated services lead to improved health
outcomes are likely to be diverse and multifactorial, with different women benefitting
from different aspects of integrated care for different reasons.

This study also provides novel evidence that integrated postnatal services are associated
with prolonged breastfeeding, including EBF, by HIV+ women. Our finding may be
unsurprising given the emphasis on breastfeeding within MCH services, in marked
contrast to general adult services, where infant feeding practices may receive less
attention [29]. While the relatively short overall duration of breastfeeding in this setting is
in keeping with local norms, the trial’s findings of longer breastfeeding and higher levels
of VS in women randomised to the MCH-ART intervention suggest that such integrated
models of postnatal care may play an important role in implementing new WHO infant
breastfeeding policies [21]. Furthermore, we found that the integrated MCH-ART service
was associated with higher levels of recording of routine early infant diagnostic testing
for HIV; given the challenges in implementing effective infant testing services in many
settings [30], this is an important feature that warrants further investigation.

Several strengths and limitations require attention in interpreting these data. The trial took
place in primary care public sector services in a single part of South Africa, and as with
any health systems intervention, the generalisability of results should be considered with
caution. The control condition used here needs particular consideration when seeking to
extrapolate these results regarding the effects of integrated services. The SOC here may
be broadly representative of how MCH and ART are provided across urban and high-
burden areas of South Africa and southern Africa. However, this is not the SOC in all
countries, and in different settings there may be other models of delivering integrated
postnatal MCH and HIV care to mothers and infants, particularly in smaller primary care
facilities. In this light, we suggest that the key findings here are for the value of integrated
service delivery approaches for providing care in the postnatal period, rather than
suggesting a single, universally ideal model of care. To evaluate the intervention, we used
a novel composite primary endpoint incorporating both healthcare utilisation and the key
biomarker of interest in HIV treatment, VL, though few interventions in this field have
utilised such robust measures. We examined outcomes through 12 months postpartum—
among the longest postpartum evaluations to date—but given that ART is lifelong,
investigations of extended outcomes for both mothers and children are warranted. Here
breastfeeding data were self-reported by mothers, raising ubiquitous concerns around
biased reporting [31], though our study visits took place separately from routine care to
help minimise such errors. Of note, this intervention does not address the phenomenon of
loss to follow-up during pregnancy immediately after ART initiation, which is a separate
and important consideration [8,14]. As discussed above, this trial only examines
outcomes through 12 months postpartum, and the outcomes of transfers after that period
require further investigation. Finally, the acceptability of service integration among
patients and providers, as well as costs and cost-effectiveness, are important
considerations not addressed in these data, but will be important avenues for future
research.

In summary, these findings have substantial implications for policy and programme
design. With few previous insights into the integration of HIV care into postnatal MCH
settings, this study demonstrates that integrating ART services into the MCH platform for
the duration of breastfeeding may be a simple and effective intervention for improving
MCH outcomes in the context of HIV.

Supporting information
S1 Fig.Time to HIV viral load (VL) ≥ 50 copies/ml, among participants with VL < 50
copies/ml at randomisation.

Log-rank test, p = 0.003.

https://doi.org/10.1371/journal.pmed.1002547.s001

(TIF)

S2 Fig.Time to HIV viral load (VL) ≥ 1,000 copies/ml, among participants with VL <
50 copies/ml at randomisation.

Log-rank test, p = 0.002.

https://doi.org/10.1371/journal.pmed.1002547.s002

(TIF)

S3 Fig.Forest plot of primary outcome across a priori subgroups of demographic

and clinical characteristics in the total study population.

https://doi.org/10.1371/journal.pmed.1002547.s003

(TIF)

S4 Fig.Forest plot of primary outcome across a priori subgroups of demographic

and clinical characteristics among women initiating ART under Option B+.

https://doi.org/10.1371/journal.pmed.1002547.s004

(TIF)

S1 Table.Characteristics of participants completing study visits in person through 12

months, versus those not completing study visits through 12 months for any reason.

https://doi.org/10.1371/journal.pmed.1002547.s005

(DOCX)

S2 Table.Sensitivity analysis of retention in care outcomes re-analysed using

retention outcome defined using windows of >9 to <15 months and >12 to <18
months postpartum.

https://doi.org/10.1371/journal.pmed.1002547.s006

(DOCX)

S3 Table.Results of multiple imputation of viral load data with adjusted results from
additive binomial models (n = 471).

Model includes all covariates shown.

https://doi.org/10.1371/journal.pmed.1002547.s007

(DOCX)

S4 Table.Primary outcome measured at 12 months postpartum, among women

randomised to the intervention arm, stratified by duration of retention in the
integrated maternal and child health service.

https://doi.org/10.1371/journal.pmed.1002547.s008

(DOCX)

S5 Table.Results of additive binomial models examining the association between

duration of time spent in the intervention arm and primary outcome adjusted for
demographic and clinical risk factors (n = 411).

https://doi.org/10.1371/journal.pmed.1002547.s009

(DOCX)

S6 Table.CONSORT checklist.

https://doi.org/10.1371/journal.pmed.1002547.s010

(DOC)

S1 Text.Study protocol.

https://doi.org/10.1371/journal.pmed.1002547.s011

(PDF)

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