Hybrid Effectiveness-Implementation Trial for ART Adherence and Substance Use in HIV Care in South Africa
Phase: NA
Conditions: Human Immunodeficiency Virus, Alcohol-Related Disorders, Drug Use
Sponsor: University of Maryland, College Park

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Project Title: 
Hybrid Effectiveness-Implementation Trial for ART Adherence and 
Substance Use in HIV Care in South Africa 
 
UCT Principal Investigator:  
Dr. John A. Joska  
UCT Co-Investigator:  
 
Dr. Lena Andersen 
UCT Co-Investigator: 
 
Dr. Bronwyn Myers 
US Principal Investigator:   
Dr. Jessica Magidson 
 
 
Version:   
 
11.0 
Version Date:  
1 June 2020  
 
TABLE OF CONTENTS 
 
1. Project Summary 
…………………………………………………………………...2 
2. Specific Aims 
………………………………………………………………..….3 
3. Background and 
Significance 
……………………………………………………………….......4 
a. Significance 
 
b. Innovation 
 
c. Preliminary Studies 
 
4. Methods  
…………………………………………………………………....7 
a. Approach 
 
b. Study sample 
 
c. Study procedures 
 
d. Primary and 
secondary 
outcomes 
 
e. Data analytic plan 
 
5. Ethical Considerations and 
Risks to the Subjects 
 
……………………………………………………………….….17 
a. Risks to participants  
b. Minimization of risks  
c. Expected benefits 
 
d. Participant 
remuneration  
 
e. Data monitoring 
and management 
protocols 
 
f. Data safety and 
monitoring plan 
 
6. List of Measures 
…………………………………………………………..……...27 
7. References 
………………………………………………………………….29 
 
 
 
 

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PROJECT SUMMARY 
Background: South Africa has the highest number of HIV-infected individuals in the world 
(approximately 7 million), and increasing numbers of patients are initiating antiretroviral therapy 
(ART), leading to greater risk of ART nonadherence and HIV transmission. Alongside the 
HIV/AIDS epidemic, there has been an alarming increase in substance use in South Africa, 
particularly in the Western Cape. South Africa also has one of the highest per capita global 
rates of alcohol consumption. Despite the impact of untreated substance use on poor HIV 
treatment outcomes and continued HIV transmission, there is little integration of substance use 
treatment into HIV care in this area.  
Preliminary Work: In the first phase of this trial (HREC ref: 210/2015), semi-structured 
interviews were conducted to identify key barriers and facilitators in implementing an evidence-
based intervention for ART adherence and substance use in this setting (n=30). Findings from 
these interviews were used to guide the treatment adaptation and implementation strategy for 
the present study.  
Design: This next phase of this study is a randomized, hybrid effectiveness-implementation trial 
designed to assess the feasibility, acceptability, and effectiveness of a paraprofessional-
delivered intervention for ART adherence and substance use in HIV care in South Africa. The 
adapted, integrated care model will be compared to an enhanced standard of care in this 
setting. To provide care for those most in need, participants will be patients with HIV who are 
struggling with ART adherence and have elevated substance use risk (indicated by the WHO-
Assist). Primary outcomes include adherence to ART, substance use, and 
acceptability/feasibility of the intervention.  
 
 
 

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SPECIFIC AIMS 
South Africa (SA) is home to the largest number of HIV-infected individuals in the 
world (6.8 million).1 As increasing numbers of patients are initiating antiretroviral therapy (ART) 
in SA, there is greater risk of ART nonadherence and failure of the only available first and 
second line ART regimens.2,3 Given recent evidence of higher likelihood of HIV transmission 
with detectable virus, nonadherence may also increase HIV transmission.4 
Alongside the HIV/AIDS epidemic, there has been an alarming increase in substance 
use in SA, particularly in Western Cape.1,5 In Cape Town, there have been drastic increases 
in the use of methamphetamine (“tik”). Only 0.3% of patients in substance use treatment in 
Cape Town in 2002 used tik, whereas this was estimated to be 50% by 2012.5 South Africa also 
has one of the highest global rates of per capita alcohol consumption.6   
In SA, substance use is largely not addressed in HIV care. This is a “missed opportunity” 
for maximizing HIV treatment outcomes, as substance use is prevalent among HIV-infected 
individuals in SA—with an estimated 13-37% of patients in HIV clinics presenting with 
substance use7—and when untreated, associated with worse ART adherence, greater likelihood 
of failing the available first- and second-line ART regimens, lower rates of viral suppression, and 
greater likelihood of HIV transmission.7-10  
The success of treatment as prevention (TasP) relies on the implementation of 
evidence-based interventions to address substance abuse and ART adherence. Evidence-
based interventions exist to address ART adherence, such as problem solving therapy.11-13 
Developed initially in high-income settings, problem solving has accumulated empirical support 
to address ART adherence in resource-limited settings, including sub-Saharan Africa.14,15 
Problem solving therapy also has accumulating support to reduce substance use in South 
Africa, particularly when combined with other brief interventions, such as behavioral 
activation16,17 and motivational interviewing.18,19 Yet, there is a gap between efficacy research 
and actual implementation of these evidence-based interventions in HIV care in SA.  
Sustainable and scalable implementation will require task shifting/sharing with 
paraprofessionals. SA has a shortage of trained health care workers to address the growing 
HIV epidemic, making task shifting/sharing with paraprofessionals, such as lay adherence or 
peer counselors, essential.20 Problem solving, behavioral activation, and motivational 
interviewing have been delivered by lay counselors in sub-Saharan Africa to separately address 
substance use18,19,21 and ART nonadherence.18,19,21,22 Yet, there is less empirical support 
evaluating the effectiveness and implementation of a paraprofessional-delivered, integrated 
intervention to address both substance use and ART adherence in HIV care.  
Important implementation questions remain before an integrated, paraprofessional-
delivered intervention could be rolled out in HIV care, which could be addressed in a Type I 
hybrid effectiveness-implementation trial.23 This design assesses the effectiveness of an 
intervention in a new setting, while also collecting pilot implementation outcomes on feasibility, 
acceptability, and barriers/facilitators to implementation). 
The current study proposes a hybrid effectiveness-implementation design to evaluate 
an evidence-based, paraprofessional-delivered intervention for ART adherence and substance 
use (compared to standard of care). Aims follow a well-established implementation model (RE-
AIM24; see Figure 1, p.8). The overall aim is to evaluate an adapted, paraprofessional-
delivered intervention in a randomized, hybrid effectiveness-implementation design1 (n=60; 
compared to standard of care) on the following:  
a) Effectiveness: Primary: (1) ART adherence (measured using real-time wireless 
electronic adherence monitoring); (2) Substance use (urinalysis and self-report); 
Exploratory: (3) viral suppression  
b) Implementation: Feasibility and acceptability: (1) Provider fidelity to intervention 
delivery; (2) Patient participation and retention; and (3) Qualitative perceptions on 
feasibility, acceptability, and barriers and facilitators to implementation. 

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BACKGROUND AND SIGNIFICANCE 
A. SIGNIFICANCE 
South Africa (SA) is home to the largest number of HIV-infected individuals in the 
world (6.8 million).1 HIV/AIDS is the leading cause of life years lost in South Africa and 
disproportionately affects individuals living in peri-urban areas. The country has a large 
antiretroviral therapy (ART) program, but some individuals exhibit poor ART adherence, which 
increases the likelihood of developing drug resistance and failing the only available first and 
second line ART regimens in South Africa.2,3 Given recent evidence of higher likelihood of HIV 
transmission with detectable virus, nonadherence may also increase HIV transmission.4 
Alongside the HIV/AIDS epidemic, there has been an alarming increase in 
substance use in SA, particularly in Western Cape.1,5 In Cape Town, the largest city in the 
Western Cape, there have been drastic increases in the use of methamphetamine (“tik”). Only 
0.3% of patients in substance use treatment in Cape Town in 2002 used tik, whereas this was 
estimated to be 50% by 2012.5 South Africa also has one of the highest global rates of per 
capita alcohol consumption.6  An estimated 13-37% of HIV clinic-attending patients in peri-urban 
areas of Cape Town present with substance use,7 which is concerning as untreated substance 
use is associated with worse ART adherence, lower rates of viral suppression, and HIV 
transmission risk.7–10 
In South Africa, substance use is largely not addressed in HIV care. Despite the 
impact of untreated substance use on poor HIV treatment outcomes and continued HIV 
transmission, there is little if any integration of substance use treatment into HIV care in South 
Africa,24 which creates a fragmented and incomplete system of care.25 This is a “missed 
opportunity” for maximizing HIV treatment outcomes, as substance use is prevalent among HIV-
infected individuals in South Africa, with an estimated 13-37% of patients in HIV clinics 
presenting with substance use.7,8 Furthermore, when untreated, substance use is associated 
with worse ART adherence, greater likelihood of failing the available first- and second-line ART 
regimens, lower rates of viral suppression, and greater likelihood of HIV transmission.1,7–10 This 
lack of integration is also present despite evidence that lay adherence counselors have been 
shown to reliably screen for substance use in HIV clinic settings.26,27 Implementing evidence-
based screening and treatment to address substance use and ART adherence in HIV care in 
the Western Cape may maximize effectiveness of HIV treatment and reduce the likelihood of 
HIV transmission in this population. 
The success of treatment as prevention (TasP) relies on the implementation of 
evidence-based interventions to address substance use and ART adherence. Evidence-
based interventions to address ART adherence and substance use exist and have accumulated 
support in resource-limited settings. Although first developed and tested in the U.S., problem-
solving based interventions to improve ART adherence11-13 have empirical support in resource-
limited settings, including sub-Saharan Africa. Additionally, when combined with other brief 
interventions such as behavioral activation (BA) and motivational interviewing (MI), problem-
solving therapy also has empirical support for reducing alcohol and other substance use,16,17,28-32 
including evidence specifically in South Africa.18,19,21 However, to date, there has been minimal 
research to evaluate an integrated intervention using problem solving, BA, and MI to address 
ART adherence and substance use in HIV care.  
Sustainable and scalable implementation will require task shifting/sharing with 
paraprofessional providers. Given that South Africa has the highest burden of HIV/AIDS, yet 
a shortage of trained health care workers to address the growing epidemic, task shifting/sharing 
(i.e. shifting/sharing health service responsibilities with lower cadres of health workers20) is 
essential for a treatment model to be sustainable and scalable in this setting. In South Africa, 
“lay counselors” deliver adherence counseling in public HIV clinics. While lay counselors 
typically have a high school education or less and do not have formal professional training, prior 

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studies have shown that problem solving, BA, and MI can be feasibly and effectively delivered 
by lay counselors (e.g., in Kenya33 and South Africa18,19,21,22). 
 
B. INNOVATION 
The present study seeks to identify methods to integrate substance use screening 
and treatment into HIV care. It addresses a key research priority put forth by the South African 
Medical Research Council (MRC) and the World Health Organization (i.e., examining the 
integration of substance use interventions in HIV care settings and evaluating the impact on HIV 
and substance use outcomes).24 
The study proposes a hybrid effectiveness-implementation design, which aims to 
simultaneously collect data on effectiveness of an intervention in a new setting while 
also collecting important data on implementation. This hybrid approach is meant to speed 
the translation of knowledge from efficacy trials to actual implementation. Although this is a 
recommended approach in the implementation science field, to date, efforts to apply this model 
have largely been focused on domestically in the VA system.23 This study would extend the use 
of the hybrid effectiveness-implementation design to a resource-limited global setting in order to 
speed the translation of knowledge into the clinical setting.  
The present study also evaluates a collaborative care model for the integration of 
HIV and substance use services, and substance use screening and treatment into 
primary care.34 This study lays the framework for supporting the development of innovative and 
collaborative care models in the US in the future.  
Additionally, individuals who have failed first-line ART are at risk for ongoing 
nonadherence because they did not achieve viral suppression with first line agents. By 
selecting these multiply challenged patients from the clinics, the potential impact of the 
intervention is maximized in that, if successful, it will minimize the chances that these patients 
will need third-line treatment, not currently available in public SA clinics. The long-term success 
of TasP relies on addressing substance use and ART adherence. 
Finally, the use of real-time wireless electronic adherence monitoring technology 
is an innovative strategy for real-time assessment of our primary outcome, ART 
adherence. This study will provide important pilot data on the acceptability and feasibility of 
real-time wireless monitoring among HIV-infected substance users in sub-Saharan Africa.  
 
C. PRELIMINARY STUDIES 
Paraprofessional counsellors can reliably screen for substance use in Cape Town. 
Dr. Magidson recently collaborated with co-mentors Drs. Joska and Myers to document the 
feasibility of lay counselor screening for substance use using the WHO-ASSIST, the proposed 
screening tool in this study for patients presenting to a co-located substance use/HIV treatment 
setting.35,36 Additionally, in other studies, co-mentor Dr. Joska has shown that lay counselors 
can reliably screen for and detect substance use in HIV care in South Africa with good 
sensitivity (94%) and specificity (85%).26,27 
Paraprofessional counsellors can be trained in and deliver problem solving and 
behavioral activation-based interventions in sub-Saharan Africa. Dr. Myers, K co-mentor, 
has led a series of studies in South Africa showing the feasibility of training peer counselors to 
deliver problem solving, MI, and behavioral activation. Additionally, these studies have shown 
significant reductions in substance use at a three month follow up.18,19,21 Dr. Magidson and Dr. 
O’Cleirigh co-trained five lay counselors in Zimbabwe in a problem solving intervention for 
adherence, which was found to be feasible and acceptable.37,38 Other work led by Drs. Joska, 
Andersen, and Safren has demonstrated the feasibility and acceptability of a nurse-delivered 
problem solving intervention for adherence, which was associated with increases in ART 
adherence over 3 months (p=.01), and >90% retention.39 
There is evidence that problem solving for ART adherence may need tailoring for 

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substance users. Prior studies by co-mentor Dr. Safren have shown that maintenance of 
adherence gains following a problem solving intervention for ART adherence is compromised by 
substance use relapse.40,41 This suggests that an intervention not specifically tailored for 
substance users may not be effective alone to improve ART adherence, and that ART 
nonadherence and substance use should be addressed simultaneously. 
Real-time wireless electronic adherence monitoring (EAM) is feasible and 
acceptable for assessing ART adherence in a resource-limited setting in sub-Saharan 
Africa. Prior work has shown the feasibility and acceptability of using Wisepill, a wireless EAM 
device to assess real-time ART adherence among HIV clinic attendees in Uganda10 and among 
HIV-infected substance users in China.42 Drs. Joska and Andersen also have used Wisepill as a 
feasible assessment of ART adherence in South Africa.39 
Qualitative data to inform intervention. In Phase 1 of this study, individual semi-
structured interviews (n=30) were conducted to identify key barriers and facilitators to 
implementing an evidence-based intervention for ART adherence and substance use in this 
setting. The findings from these interviews were used to guide the treatment adaptation and 
implementation strategy for the present study. The interviews focused on (1) the 
appropriateness of existing evidence-based interventions for adherence and substance use for 
the SA HIV clinic setting; (2) cultural and linguistic considerations for the behavioral intervention 
adaptation; (3) identifying who may be most appropriate to deliver the intervention and 
adaptations for paraprofessional delivery; (4) feasibility and appropriateness of focusing on 
substance use more broadly rather than a single substance; and (5) identifying barriers and 
facilitators to implementation of the intervention in this setting.43 
Based on the findings from the qualitative analysis in Phase 1, in addition to a review of 
behavioral intervention components that are (1) empirically supported for both ART adherence 
and substance use; (2) have been evaluated in SA; and (3) feasibly delivered by 
paraprofessional counsellors 18,19,21,22,44, the treatment was adapted for the present study for 
paraprofessional delivery. Adaptations to content were suggested, including focusing on myths 
associated with mixing ART and substance use, identifying specific substance free enjoyable 
activities that are feasible and acceptable in the community, identifying healthy coping strategies 
for psychological distress, cravings, and high risk situations for substance use, and the role of 
HIV and substance use stigma as potential barriers to integration in this setting.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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METHODS 
A. Approach 
 
Overview. The goal of this study is to optimally adapt and implement an integrated 
intervention for ART adherence and substance use in the HIV care setting in South Africa (n= 
60). The integrated intervention is specifically designed to be implemented by non-specialist 
counsellors in local HIV clinics to support sustainability and facilitate dissemination. Based on 
our qualitative work, a randomized, Type I hybrid effectiveness-implementation design will be 
conducted to assess the effectiveness, feasibility and acceptability of the intervention.  
 
Conceptual Framework. A Type 1 hybrid effectiveness-implementation design23 
assesses the effectiveness of an intervention in a new clinical setting, while simultaneously 
collecting pilot implementation outcomes on feasibility, acceptability, and barriers/facilitators to 
implementation.23 This study will use a mixed-methods, hybrid-effectiveness implementation 
design to evaluate the effectiveness and implementation of a paraprofessional-delivered 
intervention to address ART nonadherence and substance use in HIV care in SA.  
Our preliminary conceptual framework is based on the RE-AIM model (Figure 1). This 
conceptual model is suggested to guide hybrid effectiveness-implementation trials and was 
selected due to its dual focus on effectiveness and implementation outcomes, its inclusion of 
patient-and provider-level outcomes, and its prior application to guide implementation in sub-
Saharan Africa.45,46 The RE-AIM model emphasizes an intervention’s reach, effectiveness, 
adoption, implementation, and maintenance.  
 
Figure 1. RE-AIM Framework. 
B. Study Sample  
Inclusion and exclusion criteria. The study plans to recruit 
and enroll approximately 60 individuals who meet the 
following inclusion criteria: (1) HIV positive and on ART; (2) 
18 to 65 years of age; (3) Elevated substance use risk for 
any substance except tobacco (ASSIST score of ≥11 for 
alcohol or ≥4 for all other non-tobacco substances); and who 
meet one of the following four criteria: (1) did not attain viral 
suppression from first-line ART per local clinic standard in 
the past three months (VL>400 copies/mL); (2) on second-
line treatment; (3) reinitiated on first-line treatment within 
the past three months; (4) had a pharmacy non-refill at least 
once in the past three months. 
Exclusion criteria include: (1) severe risk/likely dependence for opiates (ASSIST: >26) 
because opiate substitution therapy may not be available; (2) severe alcohol dependence 
symptoms that may warrant medical management of potential withdrawal symptoms; (3) active 
untreated, major mental illness (with untreated psychosis or mania) that would interfere with the 
paraprofessional adapted intervention; (4) inability to provide informed consent, or complete 
procedures in English or isiXhosa; (5) currently enrolled in the Matrix program, or another 
substance use treatment program or research study, aimed at improving ART adherence or 
substance use; (6) in the third-trimester of pregnancy during screening or baseline. 
Patients excluded due to an active untreated, major mental illness will be referred to 
appropriate services. Likewise, patients excluded due to substance use severity will be referred 
to higher level of care, such as local substance use treatment facilities. To follow real-world 
implementation, exclusion criteria for substance use severity was operationalized based on local 
substance use treatment guidelines for referral to a higher level of care. 
Recruitment procedures. Participants will be recruited from HIV-positive patients who 
are currently receiving primary care at the Town II clinic. The study research assistant and field 
worker will coordinate subject recruitment through routine clinical screening, and potential 
participants will be screened for eligibility by a field worker or research assistant in conjunction 
with a parent study (010/204). Potentially eligible patients (identified by their HIV primary care 
• What proportion of the target 
population is participating in 
the intervention? 
Reach
• How effective is the 
intervention as implemented 
in this context? 
Effectiveness
• What are provider/staff 
perceptions of 
feasibility/acceptability?
Adoption
• To what extent is the 
intervention implemented as 
intended in this setting? 
Implementation
• Are intervention delivery and 
outcomes sustained over time?
**Maintenance

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clinic as failing first line treatment in the past 3 months: VL > 400 copies/mL, on second-line 
treatment, reinitiated on first-line treatment within the past three months, or pharmacy non-refill 
at least once in the past three months) will be screened for substance use. Eligible patients will 
be briefed on study procedures, and if interested, will provide informed consent. All individuals 
meeting inclusion criteria will be provided the opportunity to participate.  
 
Based upon preliminary studies and published work screening for substance use in HIV 
care7,26,27 the study estimates to recruit 1-2 eligible patients per week. At this rate, the study can 
conservatively estimate recruiting and randomizing 60 patients feasibly within 1.5 years.  
Retention. Bilingual research assistants will track retention. Staff will be trained to place 
reminder calls to participants 1 week and then three days prior to each scheduled follow-up 
session. This approach has been used successfully in past work by the US team, and has 
achieved an 84% retention rate at 3-month follow-up. Each participant will also be asked for 
updated contact information (e.g. phone number, address) at each follow-up assessment to 
ascertain if phone numbers have changed.  
 
C. Study Procedures  
Study setting. This study will be conducted through the University of Cape Town (UCT).  
The proposed clinic (where Phase 1 data collection also occurred) and where the parent study 
(010/2014) is being conducted is the Town II clinic in Khayelitsha.   
Consent procedures. Potentially eligible patients identified by their HIV primary care 
clinic as either (a) having a VL > 400 copies/mL, (b) being on second-line treatment, (c) having 
been reinitiated on first-line treatment within the past three months, or (d) having a pharmacy 
non-refill at least once in the past three months, will be screened for substance use by the 
research assistant or field worker using the WHO-ASSIST. If preliminary criteria are met, eligible 
patients will be briefed on study procedures; if interested, they will provide informed consent. 
Before signing the consent form, participants will receive a comprehensive and interactive 
explanation of the study by staff. Study personnel will receive training regarding procedures 
required to obtain informed consent, and training and supervision will be completed on an 
ongoing basis to continually reinforce such procedures. All study personnel will also be 
appropriately trained in the ethical conduct of human subjects research and will be required to 
recertify annually.  
The consent form will include all the study participations, information about potential 
risks and benefits of participation, and information regarding whom they can contact for further 
questions. It also will state that participation is voluntary, that participants can refuse to answer 
any question, that participants can withdraw from the study at any time, and that study 
participation is in no way related to their care received at the clinic. All participant questions will 
be answered before they are asked to sign the consent form. Additionally, patients who provide 
informed consent will also be invited to sign a release of information to allow access to their 
medical record for current ART regimen, time on ART, viral load, and CD4 count (for up to two 
years after study entry for study monitoring purposes). Participants will be provided with a copy 
of the consent form for their own records. 
All procedures and protocols will be approved by the University of Cape Town HREC 
and the US-based site (University of Maryland) before study initiation. Study staff will review all 
informed consents within one week of their completion. 
Study procedures.  Study procedures are illustrated in Figure 2 (below). Participants 
who meet screening criteria and would like to be part of the study will go through an informed 
consent process, described above. Following consent procedures, participants will complete the 
baseline assessment. When the baseline assessment is finished, all eligible participants will 
receive a wireless adherence monitoring device, also known as Wisepill. Participants will then 
use the device for two weeks to enable two weeks of wireless medication monitoring as a 
baseline assessment of ART adherence. Approximately two weeks after the baseline 

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assessment, participants will be invited to come back to the clinic for randomization. Participants 
will be randomized into either 1) the intervention group (the paraprofessional adapted 
intervention to improve ART adherence and substance use) or 2) the control group (the 
enhanced standard of care). Randomization assignment will not affect patients’ use of other 
ART clinic services. Regardless of condition, participants who attend all mandatory visits 
(intervention: all assessments and all six intervention sessions; control: all assessments and 
midpoint urinalysis) will receive a completion certificate at the end of their final assessment (six-
month follow-up assessment).  
Assessment visits. All participants will first attend a baseline assessment where they 
will begin monitoring their ART medications with Wisepill. Approximately two weeks later, 
participants will return to the clinic to undergo randomization. Those randomized into the 
intervention group will receive their first intervention visit, and have a total of six intervention 
sessions over a total of eight weeks. Those randomized into the control condition will receive an 
enhanced standard of care, described below. Approximately 3 months after the baseline 
assessment (and directly after intervention group members’ last intervention visit), participants 
will come back to the clinic for a post-treatment assessment. They will return the Wisepill device 
at this assessment. Approximately 3 months after this assessment (6 months after baseline), 
participants will come in again for a final post-treatment assessment (6-month follow-up). Both 
post-treatment assessments will contain the same psychosocial self-report questionnaires as 
the baseline assessment (with exception of the demographic questionnaire) and the same 
biological assessments. Assessments and participant tracking will be done by bilingual research 
assistants. Participants will receive modest reimbursements for the follow-up assessments (150 
Rand grocery voucher), and a 50 Rand reimbursement for local travel expenses to the study 
clinic will be provided for all non-major assessment visits.  
When it is medically appropriate, the study will obtain permission from the participants to 
communicate their CD4 and viral load results and/or their struggles with substance use to their 
medical provider. This will only be done on a case-by-case basis, when, for example, study staff 
are aware that the clinic does not have the latest blood results of the participant or the 
participant needs more help with substance use than our study can offer. The study will only 
release this information with participants’ permission, asking them to sign a medical release 
form. With this information, their provider can then make informed treatment decisions.  
 
 
 Figure 2: Study Design  
  
 
Control Group (Enhanced Standard of Care). The control group will receive an 
enhanced standard of care (ESOC), which is a referral to a local substance use treatment clinic 
(there is a co-located Matrix47,48 program at the recruitment site, which is an evidence-based 16-

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week program to treat substance use). Although the Matrix model47,48 was originally developed 
for stimulant use, there is accumulating research on its use for other substance types.49,50 In the 
area where the study will occur, Matrix will be used as the preferred treatment for all substances 
so that the access to care for treatment-seeking patients is not restricted. While the majority of 
Matrix patients are primary meth (“tik”) users (58%), some patients use other primary 
substances (alcohol, marijuana, heroin), and recent intake data has shown that over 60% of 
Matrix patients are using multiple substances.35 
Patients’ normal referral to Matrix will be enhanced for control participants by promoting 
follow up for the referral. Specifically, a referral note will be issued and study staff will either help 
the participant make an appointment as soon as possible or directly walk the participant across 
to Matrix, as the Matrix operates a walk-in screening approach. This follow up has been shown 
to boost referral attendance in this setting. The uptake of this referral will be assessed in the 
control condition through self-report at the follow-up assessments. Finally, those in the control 
group will also receive a Wisepill, the real-time electronic monitoring of ART device.  
Intervention Group. The intervention group will receive the paraprofessional adapted 
intervention (a total of six sessions). Before the study begins, interventionists will undergo a 
week-long training in the intervention, which will be led by the U.S. investigator team in 
conjunction with the S. Africa investigators. For ease of use in the sessions, the intervention 
manual will be converted into a flip-chart in Xhosa. Each session will be approximately one hour 
long, and will contain problem solving for adherence, motivational interviewing, behavioural 
activation and mindfulness-based relapse prevention modules. The first four sessions will focus 
on new content, while the last two will review the first four sessions and focus on relapse 
prevention. The sessions are as follows:  
 Session 1: Life-Steps (Problem solving for Adherence). Life-Steps51,52 is a single-session 
counselling intervention for ART adherence. It is based on the general principles of 
cognitive-behavioral therapy and more specific principles of problem solving therapy.51,52 
Life-Steps has eleven components: (1) psychoeducation, (2) transportation to appointments, 
(3) obtaining medications, (4) communication with providers, (5) coping with side effects, (6) 
formulating a daily medication schedule, (7) medication storage, (8) cues for pill-taking, (9) 
imagery review of successful adherence in response to daily cues, (10) responses to slips in 
adherence, and (11) review of procedures. In this study, Life-Steps will be adapted to focus 
on myths/beliefs around mixing alcohol/drugs and ART. Specifically, this session will place a 
great emphasis on the beliefs participants have about how drug/alcohol use affects how 
ART works in their body, their understanding of what their doctors’ messages have been 
around drugs/alcohol and ART, and how these beliefs relate to their desire to cut down on or 
stop alcohol/drug use.  
 Session 2: Increasing Motivation and Introduction to Behavioral Activation. Session 2 will 
start out with a brief review of the previous session (Life-Steps), followed by a brief 
motivational exercise. More specifically, the participant will receive psychoeducation about 
substance use, and the interventionist and participant will discuss items including the extent 
to which substance use is causing problems in the participant’s life and how substance use 
affects HIV disease progression. The interventionist and participant will also discuss the 
participant’s goals for alcohol/drug use, how ready the participant is to change, and the pros 
and cons of change. Next, the interventionist will introduce the participant to behavioral 
activation for substance use, focusing on the cycle of negative reinforcement from 
substance use and how it disrupts HIV medication adherence. The interventionist will 
introduce behaviour monitoring in behavioural activation and end with a brief mindfulness 
exercise as an example of a healthy, substance free activity.  
 Session 3: Behavioral Activation Continued and Intro to Mindfulness Based Relapse 
Prevention (MBRP) Skills: Session 3 will focus on behavioral activation and skills from 
mindfulness based relapse prevention (MBRP). The session will consist of checking in about 

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the participant’s substance use and medication adherence, reviewing behavioral activation 
from the previous week, including continuing to identify health, substance-free rewarding 
activities in the patient’s life.  Next, basic skills of mindfulness-based relapse prevention will 
be introduced (i.e.., increase one’s awareness of how craving feels in one’s body, strategies 
for slowing down and not acting on urges/cravings, and coping with and responding to 
cravings in the moment). The session will end with a mindfulness exercise and participants 
are encouraged to schedule healthy, substance-free activities in between sessions.  
 Session 4: Mindfulness-based relapse prevention (MBRP). The focus of Session 4 will be 
MBRP. In this session, the interventionist and participant will check in about the participant’s 
substance use and medication adherence in the past week, review content from past 
sessions, and continue to build upon prior week’s introduction to mindfulness-based relapse 
prevention strategies. This session will also end with a mindfulness exercise, which 
participants are encouraged to practice between sessions.  
 Sessions 5 & 6: Relapse prevention continued. Sessions 5 and 6 will focus on reviewing the 
material learned in previous sessions and working more on relapse prevention. The 
interventionist and participant will check in about the participant’s substance use and 
medication adherence in the previous week, review items learned in previous sessions, and 
plan ahead to prevent future relapse. Both sessions will end with a mindfulness exercise.  
 Optional Booster Sessions: After completing the 6 intervention sessions, participants will be 
allowed to attend up to 6 booster sessions. These sessions must be completed after the 6th 
intervention session and before the six-month follow-up assessment. Booster sessions will 
consist of topics and skills from the previous 6 sessions to address any difficulties with 
adherence and/or substance use. The purpose of the booster sessions is to help those who 
may need additional time to reinforce the strategies of the intervention.  
 
While it is preferred for intervention sessions to be done in person at the clinic, 
intervention participants who are unable to go to the clinic will have the option of telephone 
sessions. Allowing interventions over the phone will make the intervention accessible to 
participants who have difficulty traveling to the clinic or who may be traveling.  
 
If a participant still has severe substance use symptoms at the end of the study period, 
the participant will receive a referral for a local Matrix clinic. Additionally, if a participant’s 
symptoms worsen at any point of the study and a higher level of care is needed, the participant 
will also receive a referral for a local Matrix clinic.  
 
Wisepill battery monitoring. Participants in both conditions will be contacted 
approximately half-way between their baseline assessment and the post-treatment assessment 
to check in on their use of the Wisepill device. The point of this check-in is to ensure that 
participants continue to use their Wisepill devices, to remind participants to bring their Wisepill 
devices back at the post-treatment assessment, and to ensure that participants continue to 
charge their Wisepill devices. Although participants will only use the device for approximately 3 
months and the battery life of a Wisepill device lasts approximately 4 months, participants will 
still be asked to charge their Wisepill device to ensure that no valuable data is lost. These 
check-ins may happen over the telephone or, in the event that the participant is at the clinic, on 
site. 
 
D. Primary, secondary, and other outcome measures.  
Primary, secondary, and other outcomes are specified below (separate primary outcomes to 
evaluate implementation and effectiveness). Non-primary assessment measures will be used as 
potential covariates for primary analyses and/or mechanisms of intervention effectiveness.   
 

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1. Primary & Secondary Outcomes  
 
A. HIV Medication Adherence  
a. Title: Electronic monitoring (Wisepill)  
Description: Wisepill is a real-time, wireless, electronic adherence 
monitoring device used to assess ART adherence in real time.54,55 Wisepill 
uses cell phone technology to transmit a real-time signal to a web server 
when the pill box is opened. Participants do not need to come into the clinic 
for the study to obtain readings. A dose will be considered ‘taken’ if the box is 
opened ± 2 hours from the prescribed time.54 The study will also use the 
recommended methods for Wisepill data collection and analysis, which are to 
adjust for technical malfunctions, loss of signal, and self-reported pocket 
doses.54,55 Participants in both conditions will be given a Wisepill box at the 
baseline visit, and the 2-week period between baseline and randomization 
will serve as the baseline adherence measure. We will calculate % doses 
missed vs. prescribed. Participants will use the Wisepill box during the first 
three months of the study (which maps onto the intervention period), and 
return the device at their post-treatment assessment. 
Time Frame: Approximately 10-weeks post-randomization (post-intervention 
assessment)  
 
 
B. Substance Use  
 
 
a.   Title: Biological measure of substance use (alcohol, drugs)  
Description: Biological measure of substance use. Drug use will be 
assessed using urinalysis (rapid detect 6-panel urine tests (cocaine, 
marijuana, amphetamines, opiates, phencyclidine, alcohol).  
Time Frame: Approximately 10-weeks post-randomization (post-treatment 
assessment, primary outcome) and 22-weeks post-randomization (6-month 
follow-up assessment, secondary outcome)  
b.   Title: WHO-ASSIST  
 
 
      Description: Score on the Alcohol, Smoking, and Substance Involvement  
Screening Test (WHO-ASSIST). The WHO-ASSIST was developed for the 
World Health Organization (WHO), and is used to detect and manage 
substance use and related problems in primary and general medical care 
settings. The test screens for alcohol, cannabis, cocaine, opiates, 
amphetamines, hallucinogens, and other drug-related problems in primary 
care and has been validated in South Africa. It categorizes individuals into 
low (0-3 for illicit drug use), moderate (4-26 for illicit drug use), or high risk 
(>26 for illicit drug use) for substance use related problems.  
Time Frame: Approximately 10-weeks post-randomization (post-treatment 
assessment: primary outcome) and 22-weeks post-randomization (6-month 
follow-up assessment: secondary outcome) 
 
 
C. Feasibility & Acceptability of Intervention  
 
 
a.   Title: Provider fidelity  
 
 
      Description: Provider fidelity to intervention delivery, assessed by an  
independent assessor. This will be assessed on an ongoing basis throughout 
the intervention period (Sessions 1-6). Intervention sessions will be 
audiotaped, and a minimum of 20% of tapes will be translated and reviewed 
an independent rater. Fidelity ratings will be based on previously validated 
assessment53 of therapist adherence and competency, which will be adapted 

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for the specific intervention components and context, as has been done 
previously in sub-Saharan Africa.33 Following recommendations for 
implementation science research,6 a “fidelity score” will be calculated based 
on the proportion of key intervention components delivered as intended 
across sessions. 
Time Frame: Measured ongoing from first intervention participant’s 
intervention session until last intervention session for final participant 
b.   Title: Participant participation and retention  
Description: The percentage of participants assigned to the intervention 
who agree to enroll in the intervention, the percentage of these attending 
>75% of sessions, and the percentage who dropped out of treatment. This 
method of assessing participation and retention follows recommendations 
from a prior effectiveness-implementation trial,51 and the rates of our patient 
participation and retention will be compared with other similar pilot trials.33,57 
Time Frame: Measured ongoing from first intervention participant’s 
randomization until about 10-weeks post-randomization for the final 
intervention participant. Final overall measurement at about 10-weeks post-
randomization for the final intervention participant.  
 
2. Other Outcome Measures  
These measures were based upon the qualitative findings from Phase 1 and existing 
literature.  The following measures include potential covariates, potential mechanisms of 
intervention effectiveness, and exploratory outcomes. Please see Table 1 below for 
when each assessment measure is administered and Table 2 below for when each 
weekly measure is administered. 
 
1. Demographics: At baseline, participants will answer a questionnaire about basic 
demographics, including questions regarding age, sex, race, sexual orientation, 
and educational history. 
2. Mode of HIV Infection: At baseline, participants will be asked a single-item (six 
subpart) ACTG question assessing risk factors for likelihood of means of HIV 
infection.  
3. Economics & Resource Utilization: At all major assessments, participants will 
answer a questionnaire about economics and resource utilization. They will be 
asked about items that include their approximate monthly household income, 
their current work situation, their household’s spending habits, if they own objects 
such as cell phones, how they get to the clinic, how much money it costs them to 
go to the clinic, and if they use any other clinics or other health services outside 
of the clinic. This will be used to inform future cost effectiveness analyses of the 
intervention.  
4. AUDIT. The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item 
screening tool also developed by the World Health Organization (WHO), and is 
used to specifically assess alcohol consumption, drinking behaviors, and alcohol-
related problems.  
5. Ira Wilson’s Three-Item Self-Report Measure: Ira Wilson’s Three-Item Self-
Report Measure is a 3-item self-report scale used to assess antiretroviral therapy 
adherence.56 The scale has a Cronbach’s alpha of 0.83 for HIV medication. This 
measure will be given at all major assessments. 
6. Interactive Toxicity Beliefs: At all major assessments, participants will answer 4 
questions about their beliefs regarding combining substances and antiretroviral 

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therapy. These questions were included following our findings from Phase 1 and 
are based on prior research on interactive toxicity beliefs in Uganda.59 
7. Behavioral Activation for Depression Scale (BADS): This 25-item measure tracks 
weekly changes in the behaviors hypothesized to explain the effectiveness of a 
behavioral activation intervention. It examines activation, avoidance/rumination, 
work/school impairment, and social impairment.60 BADS will be given at all major 
assessments to measure a potential mechanism of intervention effectiveness. 
8. Barriers to Adherence: Participants will answer questions about barriers to their 
antiretroviral therapy adherence at all major visits. Reasons for non-adherence 
include wanting to avoid side effects, not having food with which to take the 
medication, sharing the medication with others, forgetting, forgetting due to 
alcohol use or drug use, fear of stigmatization, and an open-ended “other.” This 
measure will be given at all major assessments. 
9. Robbed, Recreational ARVs: At baseline, participants will be asked if anyone has 
ever tried to steal their ARVs from them, or if they have ever used their ARVs 
recreationally. At the follow-up assessments, participants will be asked the same 
two questions regarding the past 3 months. 
10. Brief RCope: This 14-item measure assesses how participants use religion to 
cope with stressors61 that has been shown to strongly correlate with substance 
use in this population. Participants will fill out this scale at all major assessments.  
11. Penn Craving Scale: This five-item, self-report measure asks participants about 
the frequency, intensity and duration of their craving (for alcohol and/or other 
drugs), and how well they are able to resist drinking and/or using.62 For alcohol 
vs. other drug use, the items in both craving scales are identical, with the 
exception of using the word “alcohol” or “drugs.” This scale will be administered 
at all major assessments.  
12. Patient Health Questionnaire (PHQ-9): This 9-item measure of depression63 has 
been shown to be a good outcome measure of depression.64 It will be used at all 
major assessments to assess participants’ depression, which is highly comorbid 
with HIV and substance use disorders.  
13. Reinforcement-Punishment Inventory (RPI): This 20-item measure assesses 
reinforcement in one’s environment and is a potential mechanism of behavioral 
activation interventions.65 It will be used at all major assessments as a potential 
mechanism of intervention effectiveness.  
14. Perseverative Thinking Questionnaire (PTQ): This 15-item measure assesses 
“thinking too much” (i.e., rumination and/or worry), which is a primary target of 
mindfulness-based interventions. It will be used at all major assessments.66  
15. Sexual Risk Taking: Participants will answer questions about their sexual risk 
taking behaviors at all major assessments. Items include questions about 
number of sexual partners, sexual partners’ HIV status, and condom use. This is 
being used to identify the level of HIV transmission risk among individuals who 
have detectable HIV virus.  
16. Shortened Inventory of Problems – Alcohol, Drugs (SIP-AD): This 15-item 
measure examines perceived adverse consequences of substance use.67 It will 
be used at all major assessments to identify the impact of the intervention on 
problems associated with substance use. 
17. Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) –: 
This scale assesses participant motivation to change alcohol use or other drug 
use behavior.68 It will be used at all major assessments (alcohol use and drug 
use are asked separately) and is an important covariate and potential moderator 
of intervention effectiveness. 

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18. Substance Use History and Substance Use Treatment Utilization: Substance use 
history at baseline will ask participants about their lifetime substance use history, 
while the measure at both follow-up visits will ask participants about their 
substance use treatment utilization since their last assessment visit. Items 
include questions about referrals to treatment, money spent in the last 30 days 
on substances, incarcerations related to substances, and how much participants 
would pay for a day free of problems from alcohol/drugs.  
19. Substance Use and HIV Stigma (SU-SMS and SU-SMS HIV): These self-report 
measures assess beliefs about personal alcohol use and HIV related stigma 
(administered separately), which was identified in Phase 1 as a major barrier to 
integration of HIV and substance use treatment services.69,70 This measure will 
be given at all major assessments. 
20. AIDS Clinical Trials Group 21-Item Short Form Survey (ACTG SF-21): This 21-
item survey assesses general quality of life in people living with HIV.71 This scale 
is broken up into several subscales: physical functioning, role functioning, pain, 
current health perceptions, emotional well-being, cognitive functioning, 
energy/fatigue, and social functioning.64 This survey will be used at all major 
assessments to also be included to inform future cost effectiveness analyses. 
21. Acceptability & Feasibility Questionnaire: At the post-treatment assessment, 
intervention participants will answer questions about how acceptable and feasible 
they found the intervention. This measure is derived from a validated measure of 
acceptability and feasibility developed by the Applied Mental Health Research 
Group at Johns Hopkins.58 At the 6-month follow-up, participants will be asked 
only about continuation of skill use from the intervention.   
22. Semi-structured intervention exit interviews: To supplement and allow for 
interpretation of the quantitative implementation outcomes, a six-month follow up 
qualitative assessment will also be conducted following some of the intervention 
participants randomized to the intervention condition (up to n= 30) to assess 
perceptions of acceptability and feasibility of the intervention. 
23. Semi-structured provider interviews: To better understand the feasibility and 
acceptability of the intervention and barriers to implementation, individual 
interviews will be conducted with up to 11 providers at Town II Clinic. These 
interviews may be conducted in-person or over the phone.  
24. Semi-structured control exit interviews: To supplement and allow for a better 
understanding of quantitative outcomes, individual interviews will also be 
conducted with control participants after the six-month follow up assessment. A 
maximum of 30 interviews will be conducted.  
25. Timeline Followback. The Timeline Followback72 method is a technique for 
assessing substance use. The method consists of an interview where 
participants reference a calendar to estimate their daily substance use over a 
specified period of time. The method has been successful in assessing both 
alcohol72 and drug73 use. In the present study, the calendar used will be derived 
from the participants’ Wisepill output (i.e., indicating the days doses were 
missed) to further aid participants in remembering their substance use, and to 
help participants and researchers understand how substance use impacts 
antiretroviral therapy adherence. Timeline Followback will be used at all major 
assessment visits and at each intervention session 
26. SRA Weekly Adherence: At each intervention session, participants will answer 2 
self-report questions to assess their HIV medication adherence in the past week. 
 
3. Other Collected Data: 

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1. CD4 count and Viral Load: CD4 count and viral load will be extracted from 
participants’ medical record at each major visit. If results are not available within 
3 months of the baseline assessment and 30 days of the follow-up assessments 
(post-treatment assessment and 6-month follow-up assessment), participants will 
be invited to undergo a blood draw. These procedures will not add any cost to 
the patient. CD4 count will be used as a measure of immune function and 
disease progression.  Viral load will be used as a biological indicator of ART 
adherence. Viral load will also be used to document the percentage of the 
sample with virological suppression (measured dichotomously at < 400 
copies/mL).  
2. Dried Blood Spot (DBS): We will be collecting and storing dried blood spots. 
Analysis by DBS will allow for a gross confirmation that at least some recent ART 
is present in the system.79 This biological confirmation will be used as verification 
of Wisepill data. One vial of blood for DBS will be taken at each major 
assessment. In addition to adherence, we are storing DBS for future biomarkers 
in our freezer.  We will ship and then destroy samples before five years after the 
study is completed.   
3. Urinalysis.  Urinalysis will be used as a biological indicator of alcohol and drug 
use. Urinalysis will be conducted at all major assessments (baseline, post-
treatment assessment, 6-months follow-up assessment) and at intervention 
participants’ third session (halfway through the intervention) by a trained 
research assistant using rapid detect urine tests. Control participants will also be 
asked to come into the clinic for urinalysis between their baseline and post-
treatment assessment (approximately 5-weeks post-randomization). These urine 
tests detect cocaine, marijuana, amphetamines, opiates, phencyclidine and 
alcohol, and give dichotomous results. Since there is potential sigma related to 
substance use, and participants may falsely believe that ART will be withheld in 
the context of use,66 study procedures include dialogue with the participant to 
ensuring anonymity of the results.  
4. Chart Extraction: Patients who provide informed consent will also be invited to 
sign a release of information to allow access to their medical record for current 
ART regimen, time on ART, viral load, CD4 count, tuberculosis (TB) treatment 
information, mental health information (including diagnoses and substance use 
treatment referrals) and appointment attendance (HIV treatment program and 
Matrix if applicable). This information will be specifically extracted from their 
medical charts at all major assessments.  
 
E.  Data analytic plan.  
 
Power calculation and sample size.  
The study plans to enroll 60 participants. The main analysis which the sample size 
calculation was based on is the effect of the intervention vs. enhanced standard of care on ART 
nonadherence (Wisepill) at 6 months. Previous objective measures of ART adherence in 
substance using populations have estimated average adherence of approximately 55% with a 
standard deviation of 0.25.74-76 Assuming similar characteristics in standard of care, and based 
on a sample size of 30 in each arm as recommended as the upper limit sample size for pilot 
RCTs, the study will have 80% power to detect an 18% difference in objectively measured ART 
adherence between study arms using a two-sided test with an alpha level of 0.05. Given that the 
intervention will be adapted and has not been implemented prior in this setting, the table has 
been included below to demonstrate the levels of power based on varying differences in 
average adherence that may be detected between groups. These estimates are based on 30 

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participants in each arm, in keeping with the recommendations for pilot RCTs and pilot,77 Type I 
hybrid-effectiveness-implementation designs.23,53  
 
Data analytic plan. 
Quantitative longitudinal 
analysis will examine changes in 
primary effectiveness outcomes: 
1) ART nonadherence; 2) 
substance use; 3) and viral load 
(exploratory) from baseline to 6-
month follow-up between the 
conditions. Descriptive measures 
will be used to summarize data 
(e.g., means, SD, median, IQR for 
continuous variables). Exact 
binomial confidence intervals will 
be used to estimate confidence 
intervals for categorical variables. 
Statistical tests (such as t-test and Wilcoxon rank sum test) will be used to compare continuous 
study outcomes (e.g., ART nonadherence) between the two arms at baseline. For comparison 
of categorical outcomes (e.g., urinalysis), Fisher's exact test will be used. Longitudinal data 
analysis using generalized linear mixed models (GLMM) will be used to compare the study 
endpoints (ART nonadherence, substance use, viral load at 6 months) between the two arms 
after adjusting for the effect of other covariates (e.g., gender, age). This approach increases 
power by including all available data points. Intent-to-treat will be utilized, where all individuals 
will be analyzed according to the condition that they were randomized. Effect size estimates will 
be generated to provide estimates to power for a larger future grant application.  
 
ETHICAL CONSIDERATIONS AND RISKS TO THE SUBJECTS 
 
A. Risks to participants.  
 
 
Human subjects involvement and characteristics.  
Participants will be HIV-positive men and women, between 18 and 65 years of age, who 
have an elevated substance use risk, excluding tobacco, as determined by a WHO-ASSIST 
score of ≥4 (for all non-tobacco substances) or an ASSIST score of ≥11 for alcohol, and who 
either (a) did not attain viral suppression from first-line ART per local clinic standard (VL>400 
copies/mL), (b) are on second-line treatment, (c) were reinitiated on first-line treatment within 
the past three months, or (d) had a pharmacy non-refill at least once in the past three months. 
All participants also must not be at a severe risk for dependence for opiates, as determined by a 
WHO-ASSIST score of >26, may not have severe alcohol dependence symptoms, and must be 
able to provide informed consent. Based upon results of Phase 1 and other preliminary data at 
the recruitment site, it is anticipated that participants will be 95% Black African, and 5% will be 
the South African demographic group of “coloured” (the NIH category of more than one race). 
Also based upon results of Phase 1 and other preliminary data at the recruitment site, it is 
anticipated that 50% of the sample will be women. 
The field worker and research assistant will coordinate the subject recruitment. 
Interested potential participants recruited through the clinic will speak with the research 
assistant or field worker to do a brief initial screen. If preliminary criteria are met and the 
participant is still interested in joining the study, the participant will complete the informed 
consent process and a baseline assessment (explained above).  
Predicted 
Avg 
Adherence 
in Control 
Group 
Predicted 
Avg 
Adherence 
in Tx 
Group 
Difference 
in Avg 
Adherence 
SD of 
Estimated 
Adherence Power 
0.55 
0.85 
0.30 
0.25 
0.99 
0.55 
0.80 
0.25 
0.25 
0.97 
0.55 
0.75 
0.20 
0.25 
0.88 
0.55 
0.73 
0.18 
0.25 
0.80 
0.55 
0.70 
0.15 
0.25 
0.64 
0.55 
0.65 
0.10 
0.25 
0.34 
Table 1. Levels of power based on varying differences in 
adherence detected. 

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If the participant is eligible for the study and provides consent to participate in the study, 
the participant will be given a Wisepill container and Wisepill instructions after the baseline 
assessment, conducted by the study research assistant. Participants will then be scheduled for 
a randomization visit, approximately two weeks after the baseline assessment. At the 
randomization visit, participants will be randomized into either the control group (enhanced 
standard of care group) or the intervention group, as described above.  
Participants randomized to the intervention condition will have six individual counseling 
sessions over the course of 6-8 weeks. These sessions will focus on using improving ART 
adherence and substance use. All participants will have two post-treatment assessments, one 
immediately after the intervention (the post-treatment assessment, about three months after 
baseline), and a second six months after baseline (six-month follow-up assessment). At each of 
these assessments, participants will repeat the assessment they took at baseline, with the 
exception of the demographics section and the addition of self-report section about the 
acceptability of the program (the intervention for the intervention group, or the utilization of the 
Matrix program for the control participants who were referred to Matrix).  
 
Sources of material.  
Data will be obtained from patients recruited specifically for this protocol, including self-
report assessment and biological assessments. A trained research assistant will conduct follow-
up assessments. Chart information will also be extracted from medical records to determine HIV 
outcomes and other relevant information (e.g., tuberculosis information, mental health 
diagnoses, previous substance use treatment referrals), and whether individuals followed up on 
our substance use treatment referral. 
 
Therapy training and supervision.  
The therapy manual was systematically developed and adapted based on preliminary 
studies and formative work in Phase 1. Specifically, the therapist manual was adapted into a 
flip-chart format for ease of use for the interventionists. Dr. Magidson will be the primary trainer 
and supervisor of the interventionists in consultation with Drs. Andersen, Safren, Myers, and 
Joska and supervision and training will co-led by Dr. Magidson’s UMD research team. 
Supervision will be a multi-day training with proficiency testing and booster trainings scheduled 
as needed based on ongoing proficiency testing and review. Ongoing supervision will be 
achieved through regular Skype meetings, audiotape review, and site visits to provide in-person 
training and supervision as needed.  
 
Foreseeable risks and discomforts  
It is unlikely that participants will be at any risk for physical harm as a result of study 
participation. Participants may find some of the questions asked in the interview or assessment 
to be emotionally upsetting and may experience short-term elevations in negative affect during 
active treatment sessions. As with any study of participants with substance use, there is always 
the risk of symptoms worsening. At any point in the study if a patient exhibits increasing 
substance use severity that warrants a higher level of care, they will be referred to a local 
substance use treatment facility. Given that this is standard of care at the recruitment site (Town 
II), a referral system is already in place. If withdrawal symptoms require immediate medical 
management, patients will be brought to the nearest emergency room.  
Participants with HIV viral load or CD4 cell counts missing from their medical record within 3 
months prior to their baseline assessment or within 30 days prior to their follow-up assessments 
(post-treatment assessment and 6-month follow-up assessment) will be invited to undergo a 
blood draw at all major visits to provide 3 vials of blood. The blood draw procedures will be 
carried out by staff trained in phlebotomy to minimize the accidental injury or discomfort to the 

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participants. Potential risks to subjects could include bleeding, swelling or bruising at the site of 
the blood draw.  
Other potential risks include possibility that confidentiality could be breached, discomfort 
about the treatment sessions and assessments being audio-recorded for supervision and 
treatment adherence review purposes, and the possibility of treatment non-response or 
relapse/recurrence. A discussion of how risks will further be minimized is described below.  
 
B. Minimization of risks.  
It is unlikely that participants will be at any risk for physical harm as a result of study 
participation. The design of the current study provides an evidence-based intervention for ART 
adherence and substance use in the experimental condition, a referral option for substance use 
treatment and efforts to promote follow up on this referral in both conditions, and monitoring of 
symptoms in both conditions. The interventions will be implemented by bilingual interventionists 
who will be trained in the study protocol. Treatment fidelity procedures will help ensure that 
clinical protocols are being implemented as designed. Study interventionists will receive specific 
training to address distress related to substance use and HIV management. They will also 
receive focused training on screening for substance use and in particular the detection of severe 
symptoms that may warrant medical management.  
 
Informed Consent  
All participants will complete informed consent procedures, as described above. To join the 
study, participants must fully understand and sign the consent form. The participant will have as 
much time as they want to review the consent form and ask questions. A study staff member will 
also review the form with each participant. The consent form will include all study procedures, 
information about potential risks and benefits of participation, and information regarding whom 
they can contact for further questions. It will also state that participation is voluntary, that 
participants can refuse to answer any question, that participants can withdraw from the study at 
any time, and that study participation is in no way related to the care they receive at the clinic. 
All procedures and protocols will be approved by the coordinating site University of Maryland 
IRB and the University of Cape Town HREC before study initiation.  
 
Distress 
Additional procedures will be in place to further protect participants who may experience 
higher than usual levels of distress, regardless of treatment assignment. Interventionists and 
assessors will be trained by Dr. Magidson in consultation with Drs. Andersen, Joska and Myers 
to be vigilant and sensitive to signs of distress in our participants, as well as signs of substance 
use withdrawal symptoms. 
 
Worsening symptoms.   
For those in the integrated treatment condition, interventionists will be free to deviate from 
the protocol to ensure participant safety. Referrals will be made for a higher level of care if at 
any point symptoms worsen and are no longer manageable with the integrated treatment alone, 
or if withdrawal symptoms require medical attention. For those in the control condition, if there 
are increases in severity of substance use and/or signs of potentially medically dangerous 
withdrawal symptoms at study visits, the independent assessor will make appropriate referrals 
for next-level of care. In addition, Drs. Bronwyn Myers and Lena Andersen are clinical 
psychologists with specializations in addiction and mental health concerns, respectively. They 
will be contactable by cell phone in the case of emergency to provide supervision if required. 
Further, there are community health psychologists and psychiatrists in the clinic where 
recruitment will occur who will be available in the case of emergency. In the event that a higher 
level of substance use treatment is required, there are substance use treatment clinics that 

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regularly receive referrals from the clinic site where recruitment will occur (i.e., Matrix), and 
there are existing protocols in place for making this referral. If an inpatient level of care or 
emergency services is required for management of withdrawal symptoms, treatment is available 
at either of two local area hospitals in Cape Town, a short distant from both clinic sites: G.F. 
Jooste Hospital and Karl Bremer Hospital. In the event that study participants need this level of 
care, transport will be arranged for them in-line with clinic protocols either through the Health 
Transport System NetCare or by ambulance. Referral options may also include referral to 
mental health and social sector services. Study procedures do not preclude participant referral 
for additional care and treatment and in each case where additional levels of care are required, 
decisions regarding the participant’s continuation in the study will be based solely on a 
consideration of the participants' welfare. In both conditions, referrals for substance use 
treatment and/or a higher level care will also be made at the end of the study period if severe 
symptoms are present. 
Finally, the exclusion criterion for participants with severe dependence symptoms that may 
warrant medical attention and/or opiate dependence ensures that those who would be most 
likely to experience serious physiological withdrawal symptoms are not enrolled. Any patient 
excluded from study procedures due to severity of substance use will also be offered a referral 
to a local substance use clinic or to a higher level of care.  
 
Blood draws.   
Participants will be invited to give a blood sample for dried blood spots (1 vial) and when 
CD4 count and viral load results are not available in the past 3 months at the baseline 
assessment or in the past 30 days at the follow-up assessments (1 vial each for CD4 and viral 
load). The blood draw procedures will be carried out by trained phlebotomists, nurses or 
physicians at the ART clinic settings to minimize the accidental injury or discomfort to the 
participants. Participants who experience harm as a result of these procedures will receive first 
aid from study staff and referral to medical professional if needed.  
 
Confidentiality.  
 In terms of confidentiality, all data will be kept confidential, under lock-and-key (or password 
protected only to authorized staff) which will change periodically, accessible only to specified 
study staff. Participants’ data will be identified by an ID number only, and a link between names 
and ID numbers will be kept separately under lock and key or password protection. As part of 
the informed consent process and throughout the study therapy and assessment procedures, all 
participants will be advised that they may decline to answer any study questions. These 
procedures will be implemented to provide study participants with the assurance of 
confidentiality around very sensitive and personal information relating to their mental health and 
substance use, sexual and substance use history, and HIV status. All study personnel working 
on the project will be educated about the importance of strictly respecting participants' rights to 
confidentiality and will have completed study specific trainings.  
Additionally, urinalysis will be conducted by a trained research assistant in a private area of 
the clinic using six-panel urinalysis alcohol and drug testing kits. All testing results will be 
confidential, available only to the study staff, and will not be documented in the patient’s medical 
record. It is indicated in the consent form that the drug results will only be available to the 
research study staff and will not be shared with the clinic providers nor the study interventionist 
unless requested by the patient. 
Audio files may be transcribed to written text using a secure transcription service. All audio 
files sent for transcription will be de-identified and saved only using participant ID numbers in 
order to protect participants’ confidentiality. Team members at the University of Maryland will 
only use the transcription services for assistance; they will still check and correct any errors in 
the transcripts from the service. Either Otter.ai (by AISense) or Home Row Inc. will be used for 

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            Date Approved: 10 June 2020 
transcription services. Otter.ai uses artificial intelligence technology and syncs data over an 
encrypted connection and stores it in a secure data center that has both physical and electronic 
security. When the user deletes the recording, there will be no record retained by AISense. 
Home Row Inc. offers military-grade 128-bit Secure Socket Layer (SSL) encryption security in 
transit and 256-bit AES at rest. Their typists are carefully vetted industry United States veterans 
who work under strict non-disclosure agreements, and all audio files are promptly and 
permanently deleted from servers as each project is completed.  
 
Summary.   
To emphasize, in the case of treatment non-response or other deterioration or relapse, the 
interventionists or assessors will refer patients to appropriate clinical care. Participants who 
begin treatment and experience adverse outcomes sufficient to require removal from the study 
will also receive linkage to an appropriate level of clinical care. The exact nature of "appropriate 
clinical care" will be determined by the judgment of clinicians familiar with the specific participant 
and may include substance use treatment referrals, arrangements for evaluation in a local 
Emergency Department, or referrals to partial hospital or inpatient levels of care. 
 
C.  Expected benefits.  
Although it is possible that there will be no direct benefit to participants in the study, they 
may benefit from the close monitoring of substance use and ART adherence. Participants 
assigned to the integrated treatment condition may benefit from the interventions provided to 
address substance use and support improvements in their ART medication adherence.  
Information provided as part of the treatment program may also help participants better 
understand ART adherence, their substance use, and maintain improvement over the long-term.  
All participants will have the opportunity to participate in active treatment for ART medication 
adherence and receive a referral for substance use treatment outside of the study. Participants 
are also provided with a small amount of financial remuneration for completing their 
participation. It is hypothesized that the active treatment will be associated, on average, with 
beneficial effects for both substance use and medication adherence and it is anticipated that 
some of our study participants may reap these benefits. 
 
D.   Participant remuneration.  
Participants will be given a 150 Rand (~$5 USD) grocery voucher for each assessment. At 
the post-treatment assessment, participants must return their Wisepill Devices to receive the 
grocery voucher. If a participant forgets his/her Wisepill at this visit, he/she will be given the 
voucher whenever he/she returns the device. Travel costs will also be reimbursed for all non-
major visits (50 Rand).  
 
E.   Data monitoring & management procedures.  
 
 
Data acquisition and transmission. 
 
Assessment integrity.  
 
All assessments will be conducted by a trained study research assistant who will be 
trained and supervised throughout the study by the project director.  
 
Treatment sessions.   
Recording of treatment sessions will be a required procedure to ensure appropriate 
monitoring and supervision for interventionists. The purpose of the recording will be explained, 
confidentiality will be respected, and both informed consent and authorization for recording will 
be obtained. All digital audio recordings of therapy sessions will be uploaded to the study 
computer immediately following the session and the audio file deleted from the digital recorder. 
Computer audio files will be secured by password and will be accessed only by authorized study 

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personnel (i.e., PI, site-PI, the study staff member conducting the fidelity check). Digital 
recordings will be stored and moved between sites using a secure, password-protected and 
HIPAA-compliant website. For fidelity purposes, approximately 20% of recordings will be 
translated into English by a bilingual research assistant, and all personal information relating to 
the participant will be removed. Recordings will be maintained until five years after the 
publication of study results in line with the guidelines of the American Psychological Association.  
 
Data acquisition and transmission.  
Data collection occurs only in South Africa at the specified data collection site. Data will 
be obtained from patients recruited specifically for this protocol, including self- report 
assessments administered via computer, medical chart review, and biological assessments 
when relevant clinical data is not available in chart review. All data will be directly entered into 
an electronic REDCap database. All participants will be given a study ID. Identifying and 
personal information of study participants will be kept entirely separate from their coded data. 
Lastly, the database administrator will export requested data to the investigators in a de-
identified file format that can be easily read by most statistical packages. In addition, data on 
interventionist training, independent assessor training, clinical supervision, participant progress 
through the study procedures will also be entered and uploaded into REDCap. 
 
Data entry methods.  
Data collection occurs only at the Cape Town study implementation site. Data entry will 
occur as close to real time as possible to facilitate data management and monitoring of study 
operations. The Research Assistant at the University of Maryland site will provide regular 
reports to Dr. Magidson.  
 
REDCap 
All data entry will utilize REDCap, a software toolset and workflow methodology for 
electronic collection and management of research and clinical trial data in real-time. REDCap 
provides a web-based application with an intuitive interface for users to enter data and have real 
time validation rules (with automated data type and range checks) at the time of entry. REDCap 
data collection projects data on a thorough study-specific data dictionary defined in an iterative 
self-documenting process by all members of the research team with planning assistance from 
the University of Maryland. All information entered on REDCap will be de-identified in order to 
protect participants’ identities.  
Quality assurance  
 
Data completeness.  
To ensure the usability of self-report data, the research assistant will review all self-
report measures to ensure their completeness. Using an electronic data capture system such as 
REDCap is meant to reduce errors in the data entry and management process. Using REDCap, 
missing data can be reduced by making items required to answer before moving on to the next 
item and effort and error associated with data entry can be reduced because there is no manual 
entering of data by research assistants. A secure database that is password-protected will be 
kept and located on a secure server on a local network at UCT. Confidentiality can be ensured 
as identifying and personal information of study participants will be kept entirely separate from 
their coded data. Lastly, the database administrator will export requested data to the 
investigators in a file format that can be easily read by most statistical packages.  
 
Treatment sessions.  
A subset of treatment sessions will be audio-taped and 20% (of all intervention sessions) 

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            Date Approved: 10 June 2020 
will be rated shortly thereafter by independent raters to assess therapist adherence to, and 
competence with, the protocol, using rating checklists and scales developed for this use. 
Weekly clinical supervision will be provided by Dr. Magidson and her team at UMD. Supervision 
will include reviewing translated session recordings. Audio recordings of selected translated 
sessions will be made available for download using secure file transfer. 
 
Regular reports.  
Regular reports will be generated and monitored by the PI to ensure validity and integrity 
of the data at all phases of the study, including:  
 
Activity 
Report Generated  
Monitoring by PI 
Study recruitment 
and retention 
Research Meeting Report - RA to 
study team 
Monitored frequently by PI at 
research team meetings 
Enrollment and 
Randomization 
Research meeting report of 
enrollment updates (inclusion and 
exclusion criteria) and tracking of 
assignment to condition  
Monitored frequently by PI at 
research team meetings 
Self-report data  
RA will review data at 
participants’ visits for 
completeness, accurate 
downloading of data, and tracking  
Monitored frequently by PI at 
research team meetings 
Intervention 
A random selection of 20% of 
sessions for each therapist will be 
reviewed for therapist adherence 
to protocol by PI 
Monitored at frequent clinical 
supervision  
 
 
Confidentiality. 
Confidentiality is assured as participants will be identified on all study materials only by 
participant number, visit number, and date of visit. By recording the study data in this manner, 
the information can be considered 'de-identified.’ 
 
F. Data safety and monitoring plan.  
 
Regulatory Issues 
The following procedures will be followed, in compliance with NIH requirements, to ensure 
the safety of study participants and the validity and integrity of data. 
 
Mechanisms for reporting adverse events.  
Adverse events are defined as harmful occurrences to study participants, either study 
related or non-study related.  
At yearly intervals during the course of the study and then again at its completion, unblinded 
summaries of the numbers and rates of adverse events by treatment group will be summarized 
by the research team. These reports will include types of events, severity, and treatment phase. 
Data on individual non-serious adverse events is not expected to be needed. 
 
 
Reporting of SAEs to the IRB and NIDA.  
Expedited review will occur for all events meeting the FDA definition of Serious Adverse 
Events (SAEs; i.e., any fatal event, immediately life-threatening event, permanently or 
substantially disabling event, event requiring or prolonging inpatient hospitalization, or any 

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congenital anomaly). This also includes any event that a study investigator or the DSM 
Committee judges to impose a significant hazard, contraindication, side effect, or precaution. 
Additional reporting to site-specific IRBs will be done within 24 hours of the study team being 
made aware of the SAE. Reporting of any study-related SAEs and SAEs that severely impact 
participants (i.e., participant deaths) will be made to NIDA within 24-72 hours of the study team 
being made aware of the SAE. 
 
Reporting of IRB actions to NIDA.  
The principal investigator will report, via email, and, if appropriate hard copies of action 
logs or reports, of any major IRB actions. These will also be reported on the written, yearly 
progress report to NIDA.  Minor amendments (i.e. advertisements, minor changes to 
procedures) are not regularly reported to NIDA.  
 
 
Report of changes or amendments to the protocol.  
Any changes to the protocol or amendments will be submitted to the IRB before they are 
implemented.  For each yearly annual review, the detailed protocol will be updated and sent to 
the IRB as well.  
Following guidelines by NIH, the NIDA project officer will be kept informed of any major 
changes to the protocol prior to being conducted via email from the principal investigator to the 
project officer. This will include any changes involving key personnel. Additionally, these 
changes will be recorded in the annual progress report submitted to the NIDA project officer.   
 
 
Trial stopping rules.  
There are no articulated stopping rules in advance of this study (i.e. for futility or for a 
stronger than expected effect). However, if at any time during the course of the study the 
Committee judges that risk to subjects outweighs the potential benefits, the Committee shall 
have the discretion and responsibility to recommend that the study be terminated. In such 
cases, the PI will immediately consult the DSM committee and consider the most appropriate 
course of action up to and including the immediate discontinuation of the intervention. There is 
no pre-specified stopping rule given the low anticipated risk of participation and small sample 
size. The power analysis is such that the full N would be required to make this determination. 
However, as with any DSMB, this DSMB will have the power to request analyses, post-
randomization data, or any other information about the study, and has the power to suspend the 
study should they deem it necessary and a potential participant safety issue.  
 
 
Disclosure of any conflict of interest.  
Each investigator has completed a conflict of interest statement, which is kept on file by 
the study team and has been submitted to their respective institutions’ IRBs. Any new 
investigators or key study staff will complete these forms, which will be stored kept on record. 
Any changes to conflict of interest statements will be reported to NIDA. Conflicts of interest will 
be disclosed to the DSMB at the time of each report. There are no financial conflicts of interests 
in this behavioral study, and no other conflicts of interests at this time.  
 
 
Collection and reporting of AEs to SAEs  
All staff will receive extensive training on ascertaining, monitoring, and documenting 
adverse events. The K23 mentors have extensive experience in clinical trials organization and 
management, including data safety monitoring for single site and multi-site trials. All 
investigators and study staff will be trained in monitoring and documenting adverse events. 
Expedited review will occur for all events meeting the FDA definition of Serious Adverse Events 
(SAEs). This also includes any event that a study investigator judges to impose a significant 
hazard or precaution. The study sites will report AEs and SAEs to the UCT site PI, Dr. Joska, 

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            Date Approved: 10 June 2020 
and PI Dr. Magidson.  
AEs will be labelled according to severity, which is based on their impact on the patient. 
An AE will be termed “mild” if it does not have a major impact on the patient, “moderate” if it 
causes the patient some minor inconvenience, and “severe” if it causes a substantial disruption 
to the patient’s well-being. A severe AE and an SAE are distinct terms. A subject could 
experience a severe AE that does not meet the above-listed definition of an SAE; alternatively, 
a subject could experience a moderate AE that meets the SAE definition. AEs will be 
categorized according to the likelihood that they are related to the study intervention. 
Specifically, they will be labelled definitely unrelated, definitely related, probably related, or 
possibly related to the study intervention.  
For the purposes of this study, all SAEs will be required to be reported to the Committee, 
regardless of any judgment of their relatedness to the study. All relevant information will be 
reported to the DSMB for each SAE including information about the event and its outcome, 
study condition, concomitant medications, the subject’s medical history and current conditions, 
and all relevant laboratory data. This will be provided annually at the DSMB committee meeting.  
Reporting to site-specific IRBs will be done within 24 hours of the study team being 
made aware of the SAE. Reporting of any study-related SAEs and SAEs that severely impact 
participants (i.e., participant deaths) will be made to NIDA within 24-72 hours of the study team 
being made aware of the SAE.  
Non-Serious Adverse Events. At yearly intervals during the course of the study and 
then again at its completion, the DSMB will be provided with unblinded summaries of the 
numbers and rates of adverse events by treatment group. These reports will include types of 
events, severity, and treatment phase. Data on individual non-serious adverse events is not 
expected to be needed for this review. 
Other Safety-Related Reports. At yearly intervals throughout the course of the study, 
the DSMB will also receive unblinded summary reports of treatment retention and reasons for 
dropout, by treatment arm and study phase.  
  
 
Trial Efficacy  
 
 
Plans for interim analysis for efficacy data.  
If at any time during the course of the study, the Committee judges that risk to subjects 
outweighs the potential benefits or a safety concern arises, the Committee shall have the 
discretion and responsibility to recommend that the study be terminated. However, there are no 
pre-specified interim analysis for efficacy data given that (1) this is not an efficacy trial, rather a 
hybrid effectiveness-implementation trial; (2) the low anticipated risk of participation in the 
behavioral intervention and (3) small sample size. The power analysis is such that the full N 
would be required to make this determination.  However, the DSMB will have the power to 
request analyses should they deem it necessary.  
 
 
DSM Plan Administration  
 
 
Responsibility for data safety and monitoring.  
The principal investigator and primary mentor are ultimately responsible for data and 
safety monitoring. The processes described above ensure that the principal investigator will be 
aware of important study related issues on a regular basis. If any staff becomes aware that an 
adverse event occurs, this will immediately report it to the principal investigator and site project 
director. In addition, a yearly DSM committee review of all SAEs will occur.  
To fulfil its mission of ensuring the safety and integrity of the study, it is necessary that 
the DSM Committee be comprised of members who possess a high degree of competence and 
experience, as well as the ability to function independently of all other parties involved in the 

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            Date Approved: 10 June 2020 
study. The DSMB members will function free of the career and financial interests of its members 
and will consist of three members with experience in conducting clinical intervention research 
for psychiatric and substance use disorders, expertise in biostatistics, and a thorough 
knowledge of clinical trial ethics and human subject protection issues.  
 
 
Frequency.  
The DSM Committee will be updated annually with a report containing randomization 
data as well as adverse events. These adverse events are tracked for IRB submission as well. 
All SAEs are reported annually at continuing review. The DSM Committee will be comprised of 
nominees from both the Cape Town and US study sites. 
 
 
Content of DSM report  
The DSM report will include a tally and description of adverse events and serious 
adverse events. It will include a description of how these were handled, which experimental 
group the participant was assigned to (treatment or control), and if and how the participants’ 
physician was notified. The DSM meeting will also involve a presentation from the P.I. regarding 
any emerging clinical issues involved in delivering the treatment, expected versus actual 
recruitment rates, treatment retention rates, any quality assurance or regulatory issues that 
occurred during the past year relevant to the trial, and any actions or changes with respect to 
the protocol. Sections of the DSM report will include:  
 
A. Brief description of the trial 
 
B. Baseline sociodemographic characteristics  
 
C. Retention and disposition of study participants 
 
D. Q.A. Issues 
 
E. Regulatory Issues  
 
F. AEs 
 
G. SAEs 
 
H. Efficacy 
 
DSM Board Plan  
 
Members. The Data and Safety Monitoring Board (DSMB) will function as an 
independent body charged with ensuring that the safety of study subjects is protected in Phase 
3 and that the scientific goals of the study are being met. To support those purposes, the DSMB 
will review any proposed major amendments to the study protocol at the annual review, perform 
ongoing monitoring of drop-outs and all adverse events, determine whether study procedures 
should be changed or the study should be halted for reasons related to the safety of study 
subjects, and perform periodic review of the completeness and validity of data to be used for 
analysis of safety and efficacy. The DSMB will also ensure subject privacy and research data 
confidentiality. The DSM Committee will include both US- and South Africa-based investigators.  
The Chairperson of the DSMB will communicate by e-mail and telephone conference 
with the other members. Reporting and communication about other matters will occur on a 
yearly basis, for the duration of Phase 3. Decisions of the DSMB will be made based on a 
majority vote of the members. 
Conflict of interest. The DSMB members will function free of the career and financial 
interests of its members. 
Protection of confidentiality. Adverse event reports and annual summaries will not 
include identifiable information. Each report will only include the participants’ identification 
numbers.  
Monitoring activities. At a minimum, the DSMB report includes an overview of the 
progress of participant intake and retention; summary reports describing participant compliance 
with visits, evaluations, and dosing as described in the protocol; a summary of all adverse 
events and major amendments to the protocol; and a summary of the completeness and quality 

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            Date Approved: 10 June 2020 
of key data elements needed to characterize participants, their dosing, and their primary and 
secondary outcomes. These reports are used by the DSM Committee to evaluate the capacity 
of the data capture and processing to support scientifically valid analyses. For ease of 
understanding, reports are done graphically, similarly to the CONSORT figures.  
Communication plan to IRB and NIDA. The annual IRB Continuing Review will include 
the DSMB report for review. DSMB activity will be reported in annual NIH progress reports when 
applicable.  
 
 
LIST OF MEASURES 
A description of each measure can be found above in the outcomes section. 
 
Table 1. Measures at Major Assessments 
Measure 
 Screening 
Baseline 
Post-
Treatment 
6- Month 
Follow-Up 
Demographics 
 
 
 
X 
 
 
 
 
Mode of HIV Infection  
 
 
 
X 
 
 
AUDIT 
 
 
 
X 
 
X 
X 
WHO-ASSIST 
 
 
X 
 
 
X 
 
X 
 
Substance Use History 
Questionnaire  
 
 
X 
 
X 
X 
Economics & RUQ 
 
 
X 
 
X 
X 
Sexual Risk-Taking 
Questions 
 
 
 
X 
X 
X 
ACTG- SF-21 
 
 
 
X 
 
X 
X 
Barriers to Adherence  
 
 
 
X 
X 
X 
Robbed, Recreational 
ARVs 
 
 
 
X 
X 
X 
Brief RCope  
 
 
 
X 
X 
X 
PHQ-9 
 
 
X 
 
X 
 
X 
 
PTQ 
 
 
 
X 
 
X 
X 
BADS 
 
 
 
X 
 
X 
 
X 
 
RPI 
 
 
X 
 
X 
 
X 
 
SOCRATES  
 
 
X 
 
X 
 
X 
 
SIP  
 
 
X 
X 
X 

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            Date Approved: 10 June 2020 
 
PACS  
 
 
 
X 
X 
X 
Interactive Toxicity Beliefs 
Questionnaire 
 
 
X 
 
X 
 
X 
 
Ira Wilson’s Three-Item 
Self-Report Measure 
 
 
X 
 
X 
X 
Substance Use and HIV 
Related Stigma Scale (SU 
and HIV- SMS) 
 
 
X 
 
X 
X 
Acceptability/Feasibility 
Questionnaire 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
X 
X 
X 
Blood Draw (DBS; CD4 
count and viral load – 
when results not available 
in clinic records in past 3 
months for baseline/ 30 
days for follow-ups) 
 
 
 
X 
X 
X 
Chart Extraction 
 
 
 
X 
X 
X 
Wisepill 
 
 
 
X 
X 
 
Timeline Follow-Back 
 
 
 
X 
X 
X 
Exit Interview (subset of 
intervention participants) 
 
 
 
 
X 
 
 
Table 2. List of Measures During Intervention  
(Participants randomized to intervention condition only) 
Measure 
 
S1 
S2 
S3 
S4 
S5 
S6 
SRA Weekly Adherence 
 
 
X 
X 
X 
X 
X 
X 
Wisepill 
 
X 
X 
X 
X 
X 
X 
 
Timeline Followback* 
 
X* 
X 
X* 
X 
X 
X 
 
Urinalysis* 
 
 
 
X* 
 
 
 
 
*Control participants will also be invited to the clinic for urinalysis and timeline follow-back approximately 
5-weeks post-randomization (approximately equivalent in time to Session 3). Control participants will also 
do timeline follow-back at their randomization visit (corresponding to intervention participants’ Session 1).  
 
 
 
 
 

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