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, psychological 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 influencing these behaviors during the postpartum period. Qualitative 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.
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 perspectives. 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
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 comparison 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 Postpartum 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 preliminary 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.
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 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 pregnancy, 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 different 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.
Within each phase of MCH-ART, study questions are investigated through different study designs using a multidisciplinary set of measures that include virologic, psychological, 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 interventions 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 medicine), epidemiology, psychology, health economics, virology, biostatistics, and health systems research. This diversity has exciting potential but is not uncomplicated, as bringing together wide-ranging disciplinary traditions and perspectives 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 to maximize the benefits of ART for both treatment and prevention.
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.
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 components, 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.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
HIV; antiretroviral therapy; PMTCT; integration; adherence; retention