Optimizing antiretroviral therapy (ART) for maternal and child health (MCH): Rationale and design of the MCH-ART study

Abstract

Background:
Prevention of mother-to-child transmission of HIV implementation faces significant challenges globally, particularly in the context of universal lifelong antiretroviral therapy (ART) for all HIV-infected pregnant women.

Methods:
We describe the rationale and methods of the Maternal and Child Health-Antiretroviral Therapy (MCH-ART) study, an implementation science project examining strategies for providing HIV care and treatment to HIV-infected women who initiate ART during pregnancy and their HIV-exposed infants.

Results:
MCH-ART is composed of 3 interrelated study designs across the antenatal and postnatal periods. Phase 1 is a cross-sectional evaluation of consecutive HIV-infected pregnant women seeking antenatal care; phase 2 is an observational cohort of all women from phase 1 who are eligible for initiation of ART following local guidelines; and phase 3 is a randomized trial of strategies for delivering ART to breastfeeding women from phase 2 during the postpartum period. During each phase, a set of study measurement visits is carried out separately from antenatal care and ART services; a maximum of 9 visits takes place from the beginning of antenatal care through 12 months postpartum. In parallel, in-depth interviews are used to examine issues of ART adherence and retention qualitatively, and costs and cost-effectiveness of models of care are examined. Separate substudies examine health outcomes in HIV-uninfected women and their HIV-unexposed infants, and the role of the adherence club model for long-term adherence and retention.

Discussion:
Combining observational and experimental components, the MCH-ART study presents a novel approach to understand and optimize ART delivery for MCH.

Full text

SUPPLEMENT ARTICLE
Optimizing Antiretroviral Therapy (ART) for Maternal
and Child Health (MCH): Rationale and Design
of the MCH-ART Study
Landon Myer, MBChB, PhD,*†Tamsin K. Phillips, MPH,*†Allison Zerbe, MPH,‡
Agnes Ronan, MPH,†Nei-Yuan Hsiao, MBBCh, MMed, FCPath, MPH,§
Claude A. Mellins, PhD,kRobert H. Remien, PhD,kStanzi M. Le Roux, MBChB, MPH,*
Kirsty Brittain, MPH,*†Andrea Ciaranello, MD, MPH,¶ Greg Petro, MBChB, FCOG(SA),#
James A. McIntyre, MBChB, FRCOG,*** and Elaine J. Abrams, MDࠠ
Background: Prevention of mother-to-child transmission of HIV
implementation faces significant challenges globally, particularly in
the context of universal lifelong antiretroviral therapy (ART) for all
HIV-infected pregnant women.
Methods: We describe the rationale and methods of the Maternal
and Child Health-Antiretroviral Therapy (MCH-ART) study, an
implementation science project examining strategies for providing
HIV care and treatment to HIV-infected women who initiate ART
during pregnancy and their HIV-exposed infants.
Results: MCH-ART is composed of 3 interrelated study designs
across the antenatal and postnatal periods. Phase 1 is a cross-
sectional evaluation of consecutive HIV-infected pregnant women
seeking antenatal care; phase 2 is an observational cohort of all
women from phase 1 who are eligible for initiation of ART
following local guidelines; and phase 3 is a randomized trial of
strategies for delivering ART to breastfeeding women from phase 2
during the postpartum period. During each phase, a set of study
measurement visits is carried out separately from antenatal care and
ART services; a maximum of 9 visits takes place from the beginning of
antenatal care through 12 months postpartum. In parallel, in-depth
interviews are used to examine issues of ART adherence and retention
qualitatively, and costs and cost-effectiveness of models of care
are examined. Separate substudies examine health outcomes in
HIV-uninfected women and their HIV-unexposed infants, and the role
of the adherence club model for long-term adherence and retention.
Discussion: Combining observational and experimental compo-
nents, the MCH-ART study presents a novel approach to understand
and optimize ART delivery for MCH.
Key Words: HIV, antiretroviral therapy, PMTCT, integration,
adherence, retention
(J Acquir Immune Defic Syndr 2016;72:S189–S196)
BACKGROUND
Over the last 2 decades, there have been unprecedented
advances globally in prevention of mother-to-child trans-
mission of HIV (PMTCT). Studies have demonstrated highly
efficacious approaches to prevent vertical transmission using
combination antiretroviral therapy (ART) during pregnancy,
delivery, and breastfeeding.
1–3
Meanwhile, increased access
to ART within PMTCT services has resulted in substantial
population-level reductions in new pediatric infections in
South Africa and across Sub-Saharan Africa.
4,5
Although the successes to date in PMTCT are encourag-
ing, current approaches to implementation face significant
challenges.
6
There is growing concern that in many settings
women’s adherence to ART, both during pregnancy and the
postpartum period, may be suboptimal.
7–9
Retaining women in
ART services is necessary for treatment adherence, and with
mounting evidence that failure to retain patients in care is the
most widespread form of treatment nonadherence, disengage-
ment of women on ART from care is a major concern.
10,11
From the *Division of Epidemiology & Biostatistics, School of Public Health &
Family Medicine, University of Cape Town, Cape Town, South Africa;
†Centre for Infectious Diseases Epidemiology & Research, School of
Public Health & Family Medicine, University of Cape Town, Cape Town,
South Africa; ‡ICAP, Columbia University Mailman School of Public
Health, New York, NY; §National Health Laboratory Services, Groote
Schuur Hospital & Division of Medical Virology, University of Cape
Town, Cape Town, South Africa; kHIV Center for Clinical & Behavioral
Studies, New York State Psychiatric Institute and Columbia University,
New York, NY; ¶Division of Infectious Diseases, Department of Medicine,
Medical Practice Evaluation Center, Massachusetts General Hospital,
Boston, MA; #Department of Obstetrics & Gynaecology, New Somerset
Hospital, University of Cape Town, Cape Town, South Africa; **Anova
Health Institute, Johannesburg, South Africa; and ††College of Physicians
& Surgeons, Columbia University, New York, NY.
Supported by the President’s Emergency Plan for AIDS Relief through the
National Institute of Child Health and Human Development, Grant
1R01HD074558. Additional funding comes from the Elizabeth Glaser
Pediatric AIDS Foundation, the South African Medical Research Council,
the Fogarty Foundation (NIH Fogarty International Center Grant
#5R25TW009340), and the Office of AIDS Research.
The authors have no conflicts of interest to disclose.
Correspondence to: Landon Myer, MBChB, PhD, Division of Epidemiology
& Biostatistics, School of Public Health & Family Medicine, University
of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa
(e-mail: landon.myer@uct.ac.za).
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. This is an
open access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND),
which permits downloading and sharing the work provided it is properly
cited. The work cannot be changed in any way or used commercially.
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Although nonadherence and nonretention are widespread con-
cerns in adult and paediatric ART care, these are particularly
problematic in pregnancy as nonadherence and failure to
suppress HIV viral load increase the risk of transmission. In
addition, retention in ART services and long-term adherence are
also critical to sustaining maternal health over time.
Multiple impediments to providing ART to pregnant and
postpartum women have been described across Sub-Saharan
Africa. These include both health systems concerns [eg, multiple
appointments in different services and settings for maternal and
child health (MCH) care and ART] and patient-level barriers
(including patient readiness for ART initiation, HIV-related
stigma and disclosure, transport and other costs).
12
There have
been recent advances that help address some of these factors
during the antenatal period, including the integration of ART into
antenatal care rather than through referral to separate ART
services, and more recently, the shift to universal initiation of
lifelong ART in all HIV-infected pregnant women, which
removed CD4-based ART eligibility criteria.
13
Critical threats
to adherence and retention remain, however, with important
questions about the optimal location of ART care during the
postpartum period, and when and how to transfer postpartum
women to routine adult ART services after ART initiation in the
MCH setting during pregnancy.
14,15
Given the concerns around ART adherence and reten-
tion in PMTCT services during the postpartum period, there is
a need for greater attention to services and outcomes that
include the complete PMTCT cascade, from entry into
services through determination of infants’HIV status and
maternal engagement in adult services, to identify feasible
and effective interventions to eliminate new pediatric infec-
tions and keep mothers healthy.
16
This is the overarching
purpose of the MCH-ART study.
METHODS
The principal aim of the MCH-ART study (ClinicalTrials.
gov NCT01933477) is to evaluate strategies for delivering HIV
care and treatment services during the postpartum period to
eligible HIV-infected women who initiate ART during preg-
nancy and their HIV-exposed infants. The primary objective is
to compare an MCH-focused ART service to general adult ART
services during the postpartumperiodonthecompositeout-
comes of (1) maternal HIV viral suppression and (2) maternal
retention in ART services by 12 months postpartum. Secondary
objectives focus on understanding how MCH-focused ART
services may differ from general adult ART services on other
MCH outcomes [eg, breastfeeding practices, infant health,
mother-to-child transmission (MTCT)], examining the feasibil-
ity, acceptability and cost-effectiveness of the MCH-focused
ART service, characterizing the PMTCT cascade from the first
antenatal visit through the cessation of breastfeeding, and
describing patterns and predictors of ART adherence and
retention in care antenatally and postpartum.
Setting
The study took place at the Midwife-Obstetric Unit
(MOU) at the Gugulethu Community Health Centre in Cape
Town, South Africa. The MOU sees .4000 women annually
for primary care antenatal, obstetric, and postpartum services.
The service is operated by nurse-midwives with obstetrician
support twice weekly on site and through referral to
a secondary-level obstetric hospital. The local antenatal
HIV prevalence is high (;26%), and the MTCT rate is
estimated at 2%–4% based on HIV-exposed infant HIV
polymerase chain reaction testing at 6 weeks. PMTCT
services have been offered at the Gugulethu MOU since
2001, with ART integrated into PMTCT services since 2012.
Study Design
The design of MCH-ART is composed of 3 interrelated
phases with observational and experimental elements, in
which HIV-infected pregnant women are followed up during
the antenatal and postnatal periods (Fig. 1). Throughout,
participants attend study measurement visits conducted
separately from routine ART service appointments.
Phase 1 is a cross-sectional evaluation of consecutively
enrolled HIV-infected pregnant women seeking antenatal
care. This phase of the study allows characterization of the
health status of the population of HIV-infected pregnant
women seeking care at the Gugulethu MOU and the services
they receive. Phase 2 of the study is an observational cohort
of all women in phase 1 who are eligible for initiation of ART
(following local public sector guidelines), from their second
antenatal clinic visit until their first postpartum clinic visit
(conducted within 7 days postpartum). This phase of the
study provides detailed description of ART initiation and
antenatal follow-up in the population of women who will be
involved in the postnatal component of the study.
Phase 3 of the study is a randomized trial of strategies
for delivering ART to women during the postpartum period.
Women enrolled in phase 2 who are breastfeeding their
infants (regardless of infant HIV status) are approached to
participate in the trial at the first routine postpartum clinic
visit. Consenting eligible women are randomized to 1 of 2
approaches to providing ART:
•Referral to general adult ART services from approximately
4–8 weeks postpartum (the local standard of care), or,
•Continued receipt of ART in the antenatal clinic, as part of
an MCH-focused ART service that only refers women to
general adult ART services after the end of breastfeeding.
Women participating in phase 3 are asked to return for
5 additional study visits at approximately 6 weeks, 3, 6, 9,
and 12 months postpartum. The primary outcomes are
assessed through 12 months postpartum, and further follow-
up of the cohort through 18 months postpartum is planned to
assess long-term maternal retention in care after transfer to
general adult ART services.
The sample sizes for each phase are shown in Figure 1.
An estimated 480 women are required in phase 3 to detect
a 15% absolute difference in the combined endpoint of
maternal viral suppression and retention in care through 12
months postpartum. To achieve this sample size, we antici-
pated enrolling up to 600 women in phase 2, and for this,
a maximum of 1600 women were enrolled into phase 1.
Ethical approval for the study, including the informed consent
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process, was provided by the Human Research Ethics
Committee of the University of Cape Town, Faculty of
Health Sciences and the Columbia University Medical Centre
Institutional Review Board.
Postpartum ART Services
Postpartum women randomized to the MCH-focused
ART management strategy are retained in the MOU ART
service, along with their infants, throughout the period of
breastfeeding. After the end of breastfeeding, the women are
referred to their nearest adult ART clinic. ART visits are
scheduled every 1–2 months throughout this period. The
package of services delivered in MCH-focused ART services
are identical to those provided through the standard of care for
both HIV-infected mothers and their infants (Table 1). The key
difference between the study arms is the location of care: in the
MCH-ART arm, these services are co-located at the Gugulethu
MOU, whereas under the standard of care, mothers are referred
to general adult ART services and their infants receive care at
their nearest routine “well baby”clinic (including polymerase
chain reaction testing for early infant diagnosis).
Postpartum women and infants randomized to the
standard of care ART management strategy are referred from
the MOU ART service to their nearest adult ART clinic at
their first postpartum ART clinic visit, at around 4 weeks
postpartum. The precise timing of this referral depends on the
scheduling of women’s ART visits, and in practice takes
place approximately 2 and 8 weeks after delivery. Infants in
this arm are referred for routine “well baby”care to local
primary care clinics that operate separately from adult ART
services, following practice in this setting.
The specific facility to which women are referred is
determined by their area of residence. After transfer to routine
FIGURE 1. Overall design of the MCH-
ART study.
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ART care, postpartum women are incorporated into the general
population of adults receiving ART, including transfers from
other ART services. Throughout the study, all clinical care is
provided according to the South African national protocols and
using the same record-keeping systems. Briefly, routine public
sector adult ART services (outside of the context of the study)
that dispense ART 2-monthly include viral load and CD4
monitoring after 6 and 12 months on ART, then annually
thereafter, with serum creatinine measures for patients on
tenofovir-containing regimens.
Measurements
During each phase of MCH-ART, a set of study
measurement visits is carried out separately from antenatal
care and ART services. A maximum of 9 visits takes place
from the beginning of antenatal care through 12 months
postpartum. The schedule of study measurement visits is
shown in Table 2, including data collected on mothers and
infants. Viral load testing at study measurement visits is
separate from routine clinical monitoring, with batch testing
by the South African National Health Laboratory Services
using the Abbott Realtime HIV-1 assay (Abbott Laboratories,
Waltham, MA). Questionnaire data include demographics,
HIV testing and other medical history, disclosure of HIV
status, and a range of measures of ART adherence. Further
quantitative process evaluation measures are collected over
time including patient–provider relationships and breastfeed-
ing practices. The separation of study measurement visits
from routine care services is important to allow participants to
engage in study procedures independent of their site of care
and to assist in masking study personnel to the routine
services attended by study participants.
Of note, a series of behavioral, mental health and
psychosocial measures, drawing on social action theory,
17
are
examined during the study as potential mediators or modifiers
of the intervention’s effect and are also of interest as
independent factors, which may influence adherence-related
behaviors. These include assessments of HIV knowledge,
treatment knowledge, and medication-related beliefs, and
measures of depression, alcohol and substance use, psycho-
logical distress, intimate partner violence, adherence self-
efficacy, availability of social support, and HIV-related stigma.
Additional measures for the study come from the
review of routine medical records. Specifically, we abstract
data from local health-care services on participants’(1)
antenatal and obstetric care, (2) ART initiation and follow-
up in routine care, and (3) infant health and health care. The
primary endpoint of phase 3 of the study is measured at 12
months postpartum based on the combination of viral load
measures (from study measurement visits) and evidence of
maternal retention in ART services (from routine medical
record review).
Qualitative in-Depth Interviews
In addition to the quantitative study measurements,
a parallel qualitative investigation is used to understand how
the MCH-focused ART service may influence adherence and
retention outcomes in the broader context of factors influ-
encing these behaviors during the postpartum period. Qual-
itative in-depth interviews are conducted with a random
subset of participants by a trained isiXhosa-speaking research
assistant using an interview guide to examine experiences
including: ART adherence and its determinants, postpartum
experience of clinical services, and transitions to routine adult
ART care. These interviews provide an additional “process
evaluation”of the MCH-focused ART service and how and
why it may be different from general adult ART services for
postpartum women and their infants.
TABLE 1. Key Features of MCH-Focused ART Service Versus Standard of Care Control for Providing Postpartum Care in Phase 3 of
the MCH-ART Study
MCH-Focused ART Service
(Intervention) Standard of Care (Control)
Service Maternal ART and Child Health
services (integrated)
Maternal ART services Child health services
Location of service Midwife Obstetric Unit (integrated
maternal and child service)
General adult ART services “Well baby”primary care clinics
Transfer into service postdelivery No transfer—continuation of
antenatal ART initiation and
follow-up at the Midwife Obstetric
Unit
Transfer out of Midwife Obstetric
Unit 4–8 wk postpartum
Transfer out of Midwife Obstetric
Unit 4–8 wk postpartum
Ongoing ART clinical and
counseling services based on local
protocols
XX
Routine infant health care (including
infant weight monitoring,
vaccination, and early infant HIV
diagnosis) based on local protocols
XX
Duration of service Until cessation of breastfeeding Ongoing care Ongoing care
Transfer out of service Transfer to general adult ART services
and “well baby”clinics after
cessation of breastfeeding
No transfer—continuation of general
adult ART service
No transfer—continuation of routine
“well baby”care
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TABLE 2. Schedule of Study Measurements in the MCH-ART Study
Study Phase Phase 1 Phase 2 Phase 3
Study Population
Consecutive
HIV+ Pregnant
Women
All HIV+ Pregnant Women From
Phase 1 Eligible for ART
All Women From Phase 2 on
ART and Breastfeeding
Timing of Study Visit
First
Antenatal
Visit
Second
Antenatal
Visit
Late
Third
Trimester
,7d
Postpartum
6wk
Postpartum
3mo
Postpartum
6mo
Postpartum
9mo
Postpartum
12 mo
Postpartum
Questionnaire-based
measures
Demographics and
medical history
X
Intercurrent maternal
medical history
XXXXXXXX
Maternal adherence to
ART
X XXXXXXXX
Alcohol/substance use
screen
XX X X
Trauma/abuse
assessment
XX X
Unplanned pregnancy
assessment
X
Family planning and
future pregnancies
XXXXXX
Patient–provider
relationship scale
XX X X X X
HIV knowledge, HIV
treatment knowledge,
ART beliefs
inventories
XX X X
Adherence self-efficacy X X X X X
Mental health
assessments
XX X
Social impact and
stigma scale
XX X
Availability of social
support scale
XX X X
Infant demographics
and medical history
XXXXXX
Infant feeding
intentions/practices
XXXXXXX
Infant adherence to
chemoprophylaxis
XXXXXX
Child grants XXX
Food security X
Patient resource
utilization interview
XX
Laboratory and clinical
measures
Maternal and infant
anthropometry
XXXXX
Infant
neurodevelopmental
assessment
X
Batched HIV viral load X X X X X X X X X
Infant HIV polymerase
chain reaction testing
X
Infant rapid antibody
test
X
(continued on next page)
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Cost-Effectiveness Analysis
Costing data are being used alongside findings on
clinical outcomes to understand the costs and cost-
effectiveness of the 2 strategies for maternal ART and infant
care services during the postpartum period. We collect
detailed data on health-care resource utilization for mothers
and infants during the study period, defined as (1) from start
of ANC through delivery and then (2) from delivery through
12 months postpartum. Resources include health services
visits for mothers and infants, laboratory investigations, and
antiretroviral costs and the program-level costs (eg, patient
education and adherence support materials) for each study
group. Calculations follow standard methods, with total costs
as quantities of resources used multiplied by unit costs; we
measure costs from both health system and patient perspec-
tives. These costs are used as data inputs into a detailed
simulation model of MTCT, pediatric HIV, and adult HIV,
and the Cost-effectiveness of Preventing AIDS Complications
model. This allows us to project short-term and long-term
clinical outcomes and costs for both mothers and infants and
to estimate the cost-effectiveness of the integrated care
strategy compared with standard of care.
18,19
Substudies
Two substudies to MCH-ART are underway, which
build on the implementation science platform. The first is
a cohort study of HIV-negative women and their infants, the
HIV-unexposed, uninfected (HU2) study. The main purpose
of the HU2 study is to provide an HIV-unexposed compar-
ison group to assist in interpreting key MCH-ART findings,
particularly related to infant health outcomes. This study is
enrolling up to 600 HIV-negative pregnant women from their
first antenatal clinic visit and following up on them through
delivery until 12 months postpartum. The schedule of study
visits is identical to that of the MCH-ART cohort, and the
panel of measures is adapted from MCH-ART for HIV-
negative women and their HIV-unexposed infants.
In addition, there is growing interest in the role of
community-based models of chronic ART care for HIV-
infected individuals in resource-limited settings, most notably
the “adherence club”(AC) model.
20
Given the large numbers
of women initiating ART in pregnancy, adherence clubs may
be particularly well suited to postpartum women. The Post-
partum Adherence Clubs to Enhance Retention (PACER)
study seeks to describe AC uptake and key programmatic
outcomes in a group of women referred to ACs in the
postpartum period and to examine the acceptability and cost-
effectiveness of ACs to manage postpartum HIV-infected
women on ART. The design is a cohort study, enrolling
women immediately postpartum and following them for up to
12 months, with a schedule of measures identical to those
used in MCH-ART. PACER is intended to provide pre-
liminary insights into how ACs may assist in the management
of women on ART in the postpartum period and to provide
a valuable comparator to the MCH-focused and standard of
care services examined in the parent study.
STUDY PROGRESS
MCH-ART commenced enrolment into phase 1 in
March 2013, the final deliveries from phase 2 were in
December 2014, and the final follow-up visits are being
completed in early 2016. The final sample sizes are: 1554
women enrolled into phase 1, 628 women initiating ART
TABLE 2. (Continued) Schedule of Study Measurements in the MCH-ART Study
Study Phase Phase 1 Phase 2 Phase 3
Study Population
Consecutive
HIV+ Pregnant
Women
All HIV+ Pregnant Women From
Phase 1 Eligible for ART
All Women From Phase 2 on
ART and Breastfeeding
Timing of Study Visit
First
Antenatal
Visit
Second
Antenatal
Visit
Late
Third
Trimester
,7d
Postpartum
6wk
Postpartum
3mo
Postpartum
6mo
Postpartum
9mo
Postpartum
12 mo
Postpartum
Clinical data abstraction
measures
ART initiation and
follow-up
XXXXXX X
Antenatal and obstetric
information
XXXX
Pharmacy ART
dispensing records
XXXXXXXX
Maternal laboratory test
results
XX X X X
Infant health-care
services received
XXXXXX
Infant HIV polymerase
chain reaction test
results
XX
Health services
utilization and costs
XXXXXXXX
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from phase 1 enrolled into phase 2, and 471 breastfeeding
women enrolled postpartum from phase 2 into phase 3.
Although follow-up of phase 3 is ongoing, analyses
from phases 1 and 2 have already yielded important insights
into the PMTCT cascade. An analysis of all HIV-infected
women making their first antenatal clinic visit as part of phase
1 highlighted both the sizable number of HIV-infected
pregnant women who conceive on ART in this setting and
the relatively high levels of nonsuppressed viral loads in this
group.
21
Phase 1 data also demonstrated the discordance
between depressed CD4 cell count and elevated viral loads in
women not yet on ART—with a substantial proportion of
women with viral load .10,000 copies per milliliter despite
CD4 cell counts .350 cells per microliter—an important
finding that speaks to the limitations of CD4-based ART
eligibility for PMTCT programs. Other analyses have shown
high levels of unintended pregnancy,
22
intimate partner
violence,
23
and mental health problems among HIV+ women
in this setting,
24
raising important concerns for long-term
PMTCT outcomes.
Among women enrolled into phase 2, the vast
majority initiated the local standard of care regimen of
tenofovir 300 mg + emtracitabine or lamivudine 300 mg +
efavirenz 600 mg once daily, provided as a fixed-dose
combination. The follow-up of women initiating ART in
pregnancy as part of phase 2 has demonstrated rapid
declines in viral load immediately after ART initiation
(median gestation at initiation, 20 weeks), with .90% of
women achieving viral loads ,1000 copies per milliliter
before delivery. However, approximately one-quarter of
women had detectable viral loads at the time of delivery,
and viremia at delivery was a direct function of pretreatment
viral load and duration of ART before delivery. The overall
risk of MTCT in the cohort was 1.3% (95% confidence
interval: 0.5% to 2.6%) by 56 days postpartum. This
transmission was strongly associated with viral loads at
the time of delivery, with risks of 0.25%, 2.0%, and 8.5%
among women with viral loads ,50, 50–1000, and .1000
copies per milliliter, respectively, at delivery (P,0.001).
25
Additional analyses from phase 2 of the study have
also shown the high burden of side effects among women
initiating ART in this setting, with .95% of women
reporting at least one class of side effect before delivery.
Interestingly, although no single type of side effect was
independently associated with missed ART doses in preg-
nancy, the total number of side effects experienced was
a strong predictor of nonadherence. Although it is difficult
to distinguish ART side effects from symptoms of HIV
disease and/or “normal”physiologic changes in pregnancy,
this finding has important implications for adherence
counseling under Option B+.
26
Key Features of MCH-ART
The approach of the MCH-ART study features several
noteworthy design elements that position it to help advance
knowledge around optimal implementation of ART services
for pregnant and postpartum women.
Integration of Multiple Study Designs
Rather than a single study addressing a single step in
the PMTCT cascade, each phase of MCH-ART uses a differ-
ent design to address interrelated implementation questions
with nested study populations across the PMTCT cascade.
This approach, with different designs within a program of
research used to approach a single issue from different
perspectives, can help maximize the knowledge generated
by investments in PMTCT implementation science.
Multidisciplinary Measures
Within each phase of MCH-ART, study questions are
investigated through different study designs using a multidis-
ciplinary set of measures that include virologic, psycholog-
ical, behavioral, interpersonal, and social and economic
considerations. This diversity of approaches and measures
within a single conceptual framework is unusual in PMTCT
implementation science and allows the study to examine an
array of factors shaping PMTCT outcomes.
Collaborations Across Disciplines
Increasingly, the key questions facing PMTCT services
extend beyond the efficacy of specific antiretroviral interven-
tions to encompass the factors that determine programmatic
effectiveness and implementation at scale. Implementation
science frequently draws on multidisciplinary collaborations
to help address these broader issues, and in the case of
MCH-ART, the study team draws input from clinical
disciplines (including pediatrics, obstetrics, and HIV med-
icine), epidemiology, psychology, health economics, virol-
ogy, biostatistics, and health systems research. This diversity
has exciting potential but is not uncomplicated, as bringing
together wide-ranging disciplinary traditions and perspec-
tives to focus on a specific set of implementation questions
can be challenging. We have found that having a “core”set
of investigators providing constant scientific oversight, and
then coordinating the inputs from different disciplines and
substudies, can be an effective approach to managing
multidisciplinary collaborations.
Choice of Outcomes in PMTCT
Implementation Science
To date, a wide range of endpoints have been used in
PMTCT implementation science, with studies drawing on
varying behavioral and health service outcomes focused on
specific steps of the PMTCT cascade. This diversity is
understandable, but may diffuse the impact of implementation
science on policy and programs. We use maternal HIV viral
load over time—a robust biological endpoint—as a unifying
outcome to measure effective implementation of PMTCT
services across all 3 phases of MCH-ART. Viral load is the
most appropriate outcome in this context as it encompasses
health service functioning, patient and provider behaviors,
and the real-world effectiveness of treatments. In the phase 3
trial, MCH-ART uses a composite endpoint of maternal viral
load coupled with retention in care to capture the ultimate
goal of ART use within PMTCT services: to keep HIV-
infected mothers engaged in care and virologically suppressed
J Acquir Immune Defic Syndr Volume 72, Supplement 2, August 1, 2016 Design of MCH-ART Study
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to maximize the benefits of ART for both treatment
and prevention.
Generalizability
The external validity of implementation science findings—
their generalizability to different settings and broader
populations—is an ongoing major concern for the field that
requires careful and constant consideration. One facet of
generalizability affecting MCH-ART centers on the patient
populations, burden of HIV disease, and health-care systems
contexts where research takes place. The setting of the
MCH-ART study in a public sector, primary health-care
system in Cape Town may facilitate the generalization of
results to other urban, high-burden settings, in South Africa
and other resource-limited settings. However, the questions at
the center of MCH-ART—issues of women’s retention in care,
adherence to ART and viral suppression, and how these may
be influenced by the integration of health-care services—are
clearly of importance across countries where HIV is prevalent.
SUMMARY
The emerging challenges of delivering ART effectively
in the context of PMTCT services—particularly engaging
HIV-infected mothers and their children across the full
cascade of care—require robust implementation science to
document critical problems and the interventions to address
these. Combining observational and experimental compo-
nents, the MCH-ART study presents one approach to
understand the optimization of ART delivery for MCH.
Key features of the study design have the potential to add
novel insights in the field, and the study’s progress to date
suggests that the MCH-ART study will make an important
contribution towards maximizing the benefits of universal
initiation of lifelong ART for HIV-infected women.
REFERENCES
1. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in
pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362:
2282–2294.
2. Chasela CS, Hudgens MG, Jamieson DJ, et al; BAN Study Group.
Maternal or infant antiretroviral drugs to reduce HIV-1 transmission.
N Engl J Med. 2010;362:2271–2281.
3. Coovadia HM, Brown ER, Fowler MG, et al; HPTN 046 protocol team.
Efficacy and safety of an extended nevirapine regimen in infant children
of breastfeeding mothers with HIV-1 infection for prevention of postnatal
HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-
controlled trial. Lancet. 2012;379:221–228.
4. Abrams EJ, Myer L. Can we achieve an AIDS-free generation?
Perspectives on the global campaign to eliminate new pediatric HIV
infections. J Acquir Immune Defic Syndr. 2013;63(suppl 2):S208–S212.
5. Barron P, Pillay Y, Doherty T, et al. Eliminating mother-to-child HIV
transmission in South Africa. Bull World Health Organ. 2013;91:70–74.
6. Chi BH, Stringer JS, Moodley D. Antiretroviral drug regimens to prevent
mother-to-child transmission of HIV: a review of scientific, program, and
policy advances for sub-Saharan Africa. Curr HIV/AIDS Rep. 2013;10:
124–133.
7. Ahmed S, Kim MH, Abrams EJ. Risks and benefits of lifelong
antiretroviral treatment for pregnant and breastfeeding women: a review
of the evidence for the Option B+ approach. Curr Opin HIV AIDS. 2013;
8:474–489.
8. Nachega JB, Uthman OA, Anderson J, et al. Adherence to antiretroviral
therapy during and after pregnancy in low-income, middle-income, and
high-income countries: a systematic review and meta-analysis. AIDS.
2012;26:2039–2052.
9. Ngarina M, Popenoe R, Kilewo C, et al. Reasons for poor adherence to
antiretroviral therapy postnatally in HIV-1 infected women treated for
their own health: experiences from the Mitra Plus study in Tanzania.
BMC Public Health. 2013;13:450.
10. Shaffer N, Abrams EJ, Becquet R. Option B+ for prevention of mother-
to-child transmission of HIV in resource-constrained settings: great
promise but some early caution. AIDS 2014;28:599–601.
11. Phillips T, Thebus E, Bekker LG, et al. Disengagement of HIV-positive
pregnant and postpartum women from antiretroviral therapy services:
a cohort study. J Int AIDS Soc. 2014;17:19242.
12. Gourlay A, Birdthistle I, Mburu G, et al. Barriers and facilitating factors
to the uptake of antiretroviral drugs for prevention of mother-to-child
transmission of HIV in sub-Saharan Africa: a systematic review. J Int
AIDS Soc. 2013;16:18588.
13. Myer L, Phillips T, Manuelli V, et al. Evolution of antiretroviral therapy
services for HIV-infected pregnant women in Cape Town, South Africa.
J Acquir Immune Defic Syndr. 2015;69:e57–65.
14. Phillips T, McNairy ML, Zerbe A, et al. Implementation and operational
research: postpartum transfer of care among HIV-infected women
initiating antiretroviral therapy during pregnancy. J Acquir Immune
Defic Syndr. 2015;70:e102–e109.
15. Chi BH, Bolton-Moore C, Holmes CB. Prevention of mother-to-child
HIV transmission within the continuum of maternal, newborn, and child
health services. Curr Opin HIV AIDS. 2013;8:498–503.
16. Bhardwaj S, Carter B, Aarons GA, et al. Implementation research for the
prevention of mother-to-child HIV transmission in sub-Saharan Africa:
existing evidence, current gaps, and new opportunities. Curr HIV/AIDS
Rep. 2015;12:246–255.
17. Ewart CK. Social action theory for a public health psychology. Am
Psychol. 1991;46:931–946.
18. Ciaranello AL, Myer L, Kelly K, et al. Point-of-care CD4 testing to
inform selection of antiretroviral medications in South African antenatal
clinics: a cost-effectiveness analysis. PLoS One. 2015;10:e0117751.
19. Ciaranello AL, Perez F, Engelsmann B, et al. Cost-effectiveness of
World Health Organization 2010 guidelines for prevention of mother-
to-child HIV transmission in Zimbabwe. Clin Infect Dis. 2013;56:
430–446.
20. Grimsrud A, Sharp J, Kalombo C, et al. Implementation of community-
based adherence clubs for stable antiretroviral therapy patients in Cape
Town, South Africa. J Int AIDS Soc. 2015;18:19984.
21. Myer L, Phillips TK, Hsiao NY, et al. Plasma viraemia in HIV-positive
pregnant women entering antenatal care in South Africa. J Int AIDS Soc.
2015;18:20045.
22. Phillips T, Zerbe A, McIntyre JA, et al. Pregnancy Intentions Among
HIV-infected Women Seeking Antenatal Care in Cape Town South
Africa. 21st Conference on Retroviruses and Opportunistic Infections.
Boston, MA; 2014.
23. Bernstein M, Phillips T, Zerbe A, et al. Intimate Partner Violence Among
HIV-infected Pregnant Women Initiating Antiretroviral Therapy in South
Africa. Poster MoPeb192. 8th International Conference on HIV
Pathogenesis, Treatment and Prevention. Vancouver, Canada; 2015.
24. Wong M, Myer L, Zerbe A, et al. Psychosocial Factors in Younger
versus Older HIV-infected Pregnant Women Initiating Antiretroviral
Therapy in Cape Town, South Africa. Abstract 16. 7th International
Workshop on HIV Pediatrics. Vancouver, Canada; 2015.
25. Myer L, Phillips T, McIntyre J, et al. HIV viraemia and mother-to-child
transmission risk after antiretroviral therapy initiation in pregnancy in
Cape Town, South Africa. HIV Med. In press.
26. Phillips T, Zerbe A, Ronan A, et al. Side Effects and Treatment Adherence
after ART Initiation in Pregnancy in South Africa. 22nd Conference on
Retroviruses and Opportunistic Infections. Seattle, WA; 2015.
Myer et al J Acquir Immune Defic Syndr Volume 72, Supplement 2, August 1, 2016
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