Depression Care to Improve Adherence to Prevention of Mother-to-Child-Transmission (PMTCT) Care Continuum & Pregnancy Outcomes
Phase: PHASE2
Conditions: Depression
Sponsor: RAND

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Study Protocol and Statistical Analysis Plan 
Protocol Title: Depression Care to Improve Adherence to PMTCT Care Continuum and Pregnancy Outcomes  
NCT03892915 
Date: 4/16/19 
 
 

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Investigators:  
 
1. Dr. Rhoda Wanyenze, Makerere University, School of Public Health (Co-PI) 
2. Dr. Glenn Wagner; RAND Corporation (Co-PI) 
3. Dr. Linda Nabitaka; Ministry of Health (Co-I) 
4. Dr. Dickens Akena, Makerere University, School of Medicine (Co-I) 
5. Dr. Jolly Beyeza-Kashesya; Mulago Hospital (Co-I) 
6. Dr. Barbara Mukasa; Mildmay Uganda (Co-I) 
 
Brief outline of the rationale for the study 
Depression is common among HIV+ pregnant women, in both prenatal and post natal phases and depression often 
impedes adherence to PMTCT care, parenting, and early child health development. Treating depression could 
mitigate these consequences and help ensure optimum pregnancy and maternal and child health outcomes. The 
proposed cluster randomized controlled trial will compare the effects of evidence-based depression care vs. usual 
care on adherence to each step of the PMTCT care continuum at 8 ANC clinics and with 400 HIV+ depressed 
pregnant women (50 per site).  Four (4) clinics will implement usual care and 4 will implement usual care plus 
depression care [anti depressant therapy(ADT) and problem solving therapy (PST)]. Peer mothers will be trained 
to assist in depression screening and implement PST, while nurses will be trained to diagnose depression and 
provide ADT, under the supervision of psychiatric specialists. PST will be recommended for all women deemed 
eligible for treatment, while ADT will be recommended for only those with severe or refractory depression.  
Primary aims of the study: 
1. Integrate evidence-based PST and ADT into usual care, using the gold standard, stepped care approach. 
2. Assess whether the integrated depression care model is superior to usual care on (1) adherence to each step 
of the PMTCT care continuum and maternal viral suppression (primary outcomes); (2) prevention of infant 
HIV infection, and maternal and child health outcomes (secondary outcomes), and 3) depression treatment 
uptake and depression alleviation (depression care processes).  
Secondary aim; 
Examine how (1) depression and (2) depression alleviation are associated with maternal viral load, adherence 
to each step of the PMTCT care continuum, and mother and child health outcomes; and identify potential 
mediators (e.g., HIV disclosure; stigma; problem solving skills) of these relationships. 
Methods 
The two arm cluster RCT will compare the effects of task-shifted, evidence-based depression care vs. usual 
care on adherence to each step of the PMTCT care cascade at 8 ANC clinics in Uganda. At 4 experimental 
sites, task-shifted, depression care will include (1) depression screening and psychoeducation, (2) depression 
diagnosis, and (3) provision of evidence-based problem solving therapy (PST), or antidepressant therapy 
(ADT) for those with severe and refractory depression (or who decline PST), to be implemented by trained 
peer mothers and midwife nurses. The 4 control sites will use usual care services for managing depression, 
which consist of the FSG program and referrals to a mental health specialist. At each site, 50 HIV+ newly 
pregnant women (total n=400) who screen positive for potential depression will be enrolled and followed until 
18-months post-delivery to assess how depression and depression alleviation relate to primary (adherence to 
each component of the PMTCT care continuum, maternal virologic suppression) and secondary (infant HIV 
status; post-natal maternal and child health outcomes) outcomes, as well as processes of depression care 
(treatment uptake and depression alleviation among clinically depressed patients). The PST/ADT treatment 
will be provided only to study participants, not all depressed clients, because our focus is the effects of 
depression treatment on PMTCT adherence and pregnancy outcomes, not implementation research for scaling 

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up the model in ANC care (with HIV and non-HIV women), which is a much broader focus. A cost-
effectiveness analysis will be used to compare the two study arms. 
We will enroll all consenting eligible clients and survey them at baseline, month 6, 12 and 18 following 
delivery. For those who miscarry, a final survey will take place 6 months after the miscarriage to assess 
successful transition to receive HIV care at the HIV clinic. At all sites, HIV+ adult patients who are early 
enough in their gestation period to be eligible for the study will be informed of the study and screened for 
potential depression by trained peer mothers using the EPDS-2. The screening will take place in a private room 
and those who screen positive will receive depression psycho-education. Eligible women who express interest 
in participating in the study will be connected by the peer mother to the study coordinator (via phone if the 
coordinator is not at the clinic that day) so that the coordinator can describe the study in detail, confirm 
eligibility and obtain written consent; these procedures are done during the same clinic visit, or the next day 
that the coordinator is at the clinic. 
Qualitative data will be collected from peer mothers and midwife nurses at baseline, 12 and 24 months, at 
the intervention sites to assess: successes and challenges in screening, diagnosing and treating patients for 
depression; the training and supervision process; and impact of depression and its treatment on pregnancy and 
PMTCT care, clinic functioning, and provider job satisfaction and burnout. We will also interview 40 client 
participants (20 clinically depressed who were treated, and 20 not treated) at their final study assessment to 
assess their experiences with pregnancy. 
 
Data analysis 
Statistical Analysis. We will first compare clinic-level differences, using standard t-tests or, where the 
observations per clinic vary, t-tests weighted by cluster-size. Like most cluster RCTs, we do not have the 20+ 
clusters needed to reliably adjust standard errors for clustering, so we will use the conventional approach of 
using regression methods on individual level data for most analyses, but will conduct sensitivity analyses using 
a range of plausible ICC values for the outcomes. 
Primary Aim 1: intervention effects on primary outcomes. We will use logistic regression to test for differences 
between the two study arms on (i) PMTCT adherence, coded as a binary variable, at each stage of the PMTCT 
care continuum, and (ii) maternal viral suppression. The regression models will include patient characteristics 
such as age, CD4 and HIV disclosure status that may explain variance in observed differences. We will also 
explore significant interactions between the covariates and study arm to assess which patient types are likely 
to be adherent and virally suppressed in depression care vs. usual care. The effect of depression care on PMTCT 
adherence will be examined using intention to treat as the primary approach.  We will use a repeated-measures 
model that will allow us to incorporate correlation in measurements of each person over time.  The sample size 
of individuals for such models is adequate.  The model formulation is: adherence it= α +  βGi  + γ(t)  +  δGix t 
+  θi +  εit  where i is individual, t is continuous time, G is binary indicator of treatment group, β allows for 
baseline differences between the two groups, γ is the time trend in the outcome common to both groups, and δ 
is the interaction of treatment group and time, and shows the intervention effect (i.e. effect of depression care 
relative to usual care). Further, θiis an individual-level random effect (to allow for variation across participants) 
and εit is time period-specific error.  With a vector of individual-level covariates Xi included in the model, we 
can assess main effects of patient characteristics and interactions between these Xi and indicator of treatment 
group.  Such a model will allow us to test for significance of potential mediators: e.g., do effects of the 
depression care model vary by the patient’s physical health at baseline? As the primary approach is intention-
to-treat, the estimates will capture the average benefit for depressed patients, regardless of compliance or use 
of depression treatment. A secondary “completers only” analysis will be conducted as well. In addition, we 
will conduct a dose-response type analysis to explore the relationship between continuous implementation 
variables (e.g. treatment sessions attended), which are collected for all participants, and primary outcomes. 
Further, to better understand how or why the intervention exerted its effect, we will model the relationship 

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between fidelity measures (e.g. quality) and primary outcomes, as well as conduct mediation analysis including 
fidelity as a mediator, in the subgroup of patients enrolled in clinics receiving the intervention arm (depression 
care). 
 
 
Secondary Aims 1 & 2: Explore relationship of depression and depression alleviation with primary and 
secondary outcomes. Hypothesis: Depression will be associated with lower adherence to each step of the 
PMTCT care continuum, maternal viral suppression and maternal and child health, while depression 
alleviation will be associated with better adherence, viral suppression and health outcomes. We will conduct 
(unadjusted) bivariate analysis to initially examine significant associations between baseline depression 
(EPDS>13) and depression alleviation over time with the primary and secondary outcome measures. Next, 
longitudinal analysis will be conducted to incorporate repeated observations of individuals and to explore the 
relationship between change in depression and outcomes over time, and to test whether depression alleviation 
(EPDS<6) is related to change in these outcomes.  Models will control for observed individual characteristics 
and unobservables through a random effect term to incorporate characteristics that may affect both depression 
and the dependent variables. However, this model does not control for simultaneity (e.g., change in viral 
suppression leads to lower depression). With multiple time-points, instrumental variable approaches combined 
with fixed effects potentially can deal with this problem, using baseline depression to predict change in 
depression from time 2 to time 3, if baseline depression is strongly correlated with change in depression over 
time. The fixed effects model will indicate important time trends in depression and the primary and secondary 
outcomes.