Adaptive Evaluation of mHealth and Conventional Adherence Support Interventions to Optimize Outcome With New Treatment Regimens for Drug-resistant Tuberculosis and HIV in South Africa
Phase: NA
Conditions: Multi Drug Resistant Tuberculosis, HIV Infections
Sponsor: Columbia University

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PROTOCOL 
Adaptive evaluation of mHealth and conventional adherence support interventions to optimize 
outcomes with new treatment regimens for drug-resistant tuberculosis and HIV in South Africa 
 
Version 1.0, 8 April 2022 
Sponsored by 
National Institutes of Health (NIH) 
Grant #: R01 AI167795-01A1 
 
 
 
 
Study Principal Investigators 
Max O’Donnell, MD, MPH, Principal Investigator (US) 
Kogieleum Naidoo, MBChB, PhD Principal Investigator (South Africa) 
 
 
 

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Acronyms 
ART 
Antiretroviral Therapy 
AIDS 
Acquired Immunodeficiency Syndrome 
BAR 
Bayesian adaptive randomization 
BDQ 
Bedaquiline 
BREC 
Biomedical Ethics Research Council 
CAPRISA 
Centre for the AIDS Programme of Research in South Africa  
CDC  
Centers for Disease Control and Prevention (United States) 
CD4 
CD4 lymphocyte or helper T cell (a type of white blood cell) 
DR-TB 
Drug resistant tuberculosis 
DSD 
Differential Service Delivery 
FGD 
Focus Group Discussion 
GCP 
Good Clinical Practice 
HCW 
Health care worker 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Offices 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
KDH 
King DinuZulu Hospital Complex 
KZN 
KwaZulu-Natal 
MDR-TB 
Multi-drug resistant tuberculosis 
MMAS-8 
Morisky Medication Adherence Scale 
M/XDR-TB 
Multi-drug resistant tuberculosis or Extensively drug resistant tuberculosis 
MI 
Motivational Interviewing 
MTB 
Mycobacterium tuberculosis 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NTP 
South African National TB Program 
PE 
Peer educator 
PEPFAR 
President’s Emergency Plan for AIDS Relief 
PLWH 
People Living with HIV 
PID 
Patient Identifier 
RA 
Research Assistant 
sIMB 
situated-Information Motivation Behavioral Skills Model 
SOC 
Standard of Care 
SOP 
Standard Operating Procedures  
TB 
Tuberculosis 
TLD 
Tenofovir/lamivudine/DTG Combination Pill 
UNAIDS 
Joint United Nations Programme on HIV/AIDS 
USAID 
United States Agency for International Development 
VAS 
Visual Analog Scale 
WHO  World Health Organization 
 

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Table of Contents
1
STUDY OVERVIEW
6
2
PERSONNEL AND TRAINING
9
3
BACKGROUND AND SIGNIFICANCE
10
4
STUDY OBJECTIVES AND AIMS
11
5
METHODS 
13
6
DATA COLLECTION
17
7
DATA MONITORING AND QUALITY ASSURANCE
23
8
DATA ANALYSIS
25
9
HUMAN SUBJECTS PROTECTIONS
26
10 REFERENCES
30
S
E

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Adaptive evaluation of mHealth and conventional adherence support 
interventions to optimize outcomes with new treatment regimens for drug-
resistant tuberculosis and HIV in South Africa (ADAP-TIV)
INVESTIGATOR SIGNATURE FORM
Version 1.0
08 April 2022
Funded by:
THE NATIONAL INSTITUTES OF HEALTH (NIH)
Grant # R01 AI167795-01A1
I, the Investigator of Record/Principal Investigator, agree to conduct this study 
in full accordance with the provisions of this protocol. I have read and 
understand the protocol and will ensure that all associates, colleagues, and 
employees assisting in the conduct of the study are informed about the 
obligations incurred by their contribution to the study.
Principal Investigator
Signature ____________________________  
 ___________________________ 
Date of Signature 
(DD/MMM/YY)
Name 
Kogieleum Naidoo
Title 
Prof 
Institution 
Address 
CAPRISA
Doris Duke Medical Research Institute, 2nd Floor, Nelson R 
Mandela
School of Medicine, University of KwaZulu Natal, 719 
Umbilo Road,
Durban, 4001, South Africa
Tel: +27 31 260 4687
Fax: +27 31 260 4566
Email: Kogie.Naidoo@caprisa.org
14/Apr/22

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Principal Investigator (US-based) 
 
 
 
 
 
Signature ____________________________                        ___________________  
 
                                                                                                       Date of Signature 
 
 
              (DD/MMM/YY) 
Name  
Max O’ Donnell 
Title  
Prof  
Institution  
Columbia University:Division of Pulmonary, Allergy, and Critical 
  
Address  
Care Medicine 
New York, NY 10027, United States 
Email: mo2130@columbia.edu 
 
 
 
 
 
 
 
 
 
 
11/APR/22

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1 
STUDY OVERVIEW 
Adaptive evaluation of mHealth and conventional adherence support interventions to optimize 
outcomes with new treatment regimens for drug-resistant tuberculosis and HIV in South Africa 
 
1.1 
Summary  
The availability of shorter, more effective, entirely oral bedaquiline (BDQ) containing drug-
resistant tuberculosis (DR-TB) treatment regimens (1), and highly potent, low drug-drug 
interaction profile, integrase strand transfer inhibitor (INSTI)-based combination ART have 
transformed the treatment paradigm for DR-TB HIV (2-4). However, without similar ground-
breaking advances in adherence support, we will not realize the potential of these revolutionary 
therapeutics and novel regimens may rapidly lose their benefits due to emergent resistance to 
either antimycobacterial agents and/or antiretrovirals (5, 6). 
1.2 
Background 
Tuberculosis (TB) is now the second leading cause of death due to a single infectious agent (7), 
recently displaced by SARS-Cov-2 (8). TB remains the single leading cause of death for persons 
living with HIV/AIDS (9). Although TB incidence is slowly decreasing (7, 10), global End TB 2020 
incidence and mortality milestones were not achieved (11). An important reason for this missed 
opportunity is an increase in DR-TB cases with high mortality and poor treatment outcomes (12, 
13). Approximately ~820,000 incident TB cases globally occur in HIV co-infected patients (7). 
The majority (59%) of TB patients in South Africa with known HIV status are co-infected (14, 15), 
and there are ~14,000 incident DR-TB HIV cases per year (7). South Africa has ~18% of global 
MDR-TB burden and the highest number of DR-TB HIV cases (7, 16, 17). 
Medication adherence, a key predictor of outcomes in DR-TB and HIV treatment, is understudied 
in high burden TB-HIV settings (18-20). Patient losses during transitions in the care continuum 
are frequent (21), increase mortality and limit control of the linked epidemics. Demands of DR-
TB HIV treatment are severe including extraordinary pill burden, severe adverse effects, lengthy 
treatment, isolation, and stigma with few parallels in modern medicine (22-24). 
1.3 
Specific Aims 
Aim 1. To compare the effect of a multi-arm adaptive adherence intervention on DR-TB 
HIV outcomes 
Aim 1 overview. This Aim seeks to use an adaptive implementation platform to randomize DR-
TB HIV patients initiating BDQ and TLD to compare the effect of different interventions on 
biological and clinical endpoints (1a) and determine BDQ threshold adherence value associated 
with DR-TB culture conversion (1b). 
Hypothesis 1a In a randomized, adaptive implementation trial, the psychosocial + mHealth 
support arm will improve a composite DR-TB HIV clinical outcome compared to separate 
mHealth, psychosocial support, or enhanced standard of care arms. (N=360) 
 

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Hypothesis 1a overview. This study aims to evaluate the impact of different adherence support 
elements informed by a DSD framework in patients with DR-TB HIV. Specifically, in this 
hypothesis we will use a four-arm, adaptive randomized design to study the impact of adherence 
support interventions on clinical outcome. The four arms will include: enhanced standard of care 
(ESOC) (I), psychosocial support (II), mHealth (III), psychosocial support + mHealth. 
Components of the intervention have been informed by preliminary qualitative research that 
elucidated critical patient needs at key stages in DR-TB HIV treatment. 
Aim 1 Hypothesis 1b Quantitative adherence measurement using EDM will define BDQ 
adherence thresholds that are more predictive for TB outcomes than conventional adherence 
measures. (N=180) 
Hypothesis 1b overview Medication adherence is widely considered to be a critical determinant 
of response in the treatment of infectious pathogens - including M. tuberculosis - but is severely 
understudied. For BDQ, quantitative adherence thresholds sufficient to ensure TB culture 
conversion at 6 months and optimal end of treatment clinical outcome are not known.  
1.4 
Methods  
 
The overall structure is a 4-arm adaptive platform of mHealth and psychosocial adherence 
support interventions informed by a differentiated service delivery (DSD) approach. The 
framework is a study of mHealth and psychosocial adherence support interventions using a 
Bayesian adaptive design to allow comparison of elements of the intervention separately and in 
combination.  
Participants will be randomized into one of 4 arms and followed monthly through the 6 months 
of intervention, then through the end of treatment telephonically, with an additional in-person visit 
to establish the primary outcome. Primary outcome is a combined clinical/biological outcome at 
12 months described below. Hypothesis 1a utilizes all participants while 1b utilizes only those in 
the mHealth intervention arms (3+4) since granular EDM-measured adherence is required. 
Detailed methods are described in section 4.3 below. 
1.5 
Population 
Eligible patients will be consecutively recruited adult patients (age ≥ 18 years) presenting with all 
of the following inclusion criteria: (1) Culture or molecular test positive for MTB, (2) Molecular 
test positive for HIV or a documented HIV positive history (3) Drug-susceptibility testing by 
molecular (i.e. GeneXpert MTB/RIF) or conventional testing consistent with at least rifampicin-
resistant TB, (4) Initiating treatment with a BDQ-containing TB regimen within 4 weeks of 
enrollment and first-time being treated with BDQ (5), On treatment with ART regimen, including 
dolutegravir-containing combination ART regimen (i.e. TLD), or starting within 4 weeks of 
enrollment, (5) Capacity for informed consent in either isiZulu or English.  
Patients will be excluded from the study if they are prisoners, and if they are pregnant on 
enrollment. Patients will be recruited from King DinuZulu Hospital, a centralized TB referral 

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hospital near Durban, South Africa which initiates the majority of BDQ treatment regimens in the 
province, and/or referral clinics for King DinuZulu Hospital. 
1.6 
Study Duration 
Approximately two years will be allowed for enrollment. Patients will be followed until the end of 
treatment (approximately 4 years total).  
1.7 
Participant Duration 
Study visits will occur monthly until 6 months with a follow-up visit at 12 months. A telephonic 
visit will occur at the end of treatment (9 to 18 months after treatment initiation DR-TB). See 
Schedule of Evaluations for further details. 
1.8 
Potential Significance 
The availability of shorter, more effective, oral bedaquiline (BDQ) containing drug-resistant 
tuberculosis (DR-TB) treatment regimens (1), and highly potent, low drug-drug interaction profile, 
integrase strand transfer inhibitor-based combination ART have transformed the treatment 
paradigm for DR-TB HIV (2-4). However, without similar ground-breaking advances in adherence 
support, we will not realize the potential of these revolutionary therapeutics and novel regimens 
may rapidly lose their benefits due to emergent resistance to either antimycobacterial agents 
and/or antiretrovirals (5, 6). 
The NIAID has identified improved treatment of DR-TB and TB/HIV as a research priority (25). 
The proposed research will increase local scientific capacity in South Africa and train local 
investigators, including women and minorities (26). Successful completion of our Aims will 
substantially advance our understanding of DR-TB and HIV adherence dynamics in an integrated 
research strategy n land program and develop an innovative set of tools for the assessment and 
support of dual TB and ART medication adherence. Conceptually, our work will advance the 
differentiated service delivery model into DR-TB HIV treatment. Practically, we will evaluate 
components of adherence support using an adaptive platform to determine the effectiveness of 
mHealth and psychosocial support (Aim 1). We will characterize potential intervention 
mechanisms of action by measuring model-based socio-behavioural variables and contextualize 
the longitudinal intervention impact in key stages of DR-TB HIV treatment using qualitative 
methods. 
 
The study findings may be used to inform programmatic management and the development of 
further interventions that promote adherence for DR-TB HIV patients. 
 
 

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2 
PERSONNEL AND TRAINING 
 
2.1 
Roles  
Roles of Lead Investigators: Investigators will provide leadership and mentorship, supervise the 
study team and monitor the project, develop the study protocol. Drs. Naidoo and O’Donnell are 
the co-Principal Investigators of this study. 
Dr. O’Donnell with Dr. Naidoo will be responsible for the overall conduct of the study and will 
supervise all study related activity. 
2.2 
Staff Training 
All study staff will have current good clinical practice (GCP) training.  The study timeline will 
include 6 months for training study staff. Training in study protocols will be performed prior to 
recruitment of patients and refresher training will be performed regularly.  
Dr. Cheung will lead a training on the randomization strategy and software use. Study staff 
assigned to randomization duties will participate in training prior to study initiation.  
Supervision will be provided to ensure participant safety and good study conduct.    
Enhanced standard of care (Arm 1) will include usual care as administered by hospital and 
clinic staff enhanced by study staff-provided treatment literacy and study-provided training for 
treating physicians, nurses, pharmacists, and social workers prior to study initiation and 
periodically with refresher trainings 
 
 

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3 
BACKGROUND AND SIGNIFICANCE 
Tuberculosis (TB) is the leading cause of mortality for people living with HIV, causing over 
200,000 deaths annually (7). Approximately 860,000 incident TB cases occur in HIV co-infected 
patients worldwide (27). In southern Africa, interaction between TB and HIV epidemics has led 
to increased community transmission of drug-resistant TB (DR-TB) (17, 28-30),critically 
undermining TB and HIV-related treatment goals (31, 32).  
 
In South Africa, there are approximately 14,000 incident DR-TB HIV cases per year (7). 
Antiretroviral therapy (ART) in DR-TB HIV is challenged by older regimens and drug-drug 
interactions. Dolutegravir, an integrase strand transfer inhibitor, formulated as once-daily 
combination ART (tenofovir/lamivudine/dolutegravir (TLD)) (33, 34), is recently available in South 
Africa (35). TLD is superior to older comparator regimens, protective for ART discontinuation, 
and proposed as first-line ART including for treatment of DR-TB HIV (36, 37), but adherence in 
this context is not well studied.   
 
Medication adherence is a key predictor of TB treatment outcomes and emergent drug-
resistance (38-40), and is severely understudied in high burden TB/HIV settings (41, 42). DR-TB 
HIV treatment demands are daunting, including high pill burden, adverse effects, lengthy 
treatment, and stigma (23, 43, 44) with challenges in key treatment stages (45, 46). Bedaquiline 
(BDQ), a highly effective antimycobacterial, is the first new DR-TB drug in 40 years, and WHO-
recommended as a key component of all new DR-TB treatment regimens (1, 47). Research by 
our team in South Africa, shows high mean BDQ adherence in DR-TB HIV measured using 
cellular-enabled EDM (48). However, a substantial adherence challenged subgroup (~16% 
patients) is at high risk for treatment failure, mortality, and emergent bedaquiline resistance (1, 
49).  
 
Patient-centered adherence support strategies using psychosocial support and mHealth (health 
practices supported by mobile technologies and devices) may improve DR-TB HIV outcomes. 
These modalities have improved medication adherence in HIV (50-55), hypertension (56, 57), 
diabetes (58), and psychiatric disease (59-61). Our team has done important early work in 
mHealth adherence support and comprehensive psychosocial support for DR-TB HIV (48, 62). 
A critical gap, addressed by our proposal, is to understand the relative contributions of mHealth 
and psychosocial adherence support to improve clinical and biological outcomes in DR-TB HIV 
treatment. 
Differentiated service delivery (DSD) is an innovative person-centered care model tailored to 
the health status and clinical needs of persons living with HIV/AIDS, informed by social, 
behavioral and structural factors (63-65). DSD methods include mHealth (health practices 
supported by mobile technologies), psychosocial support, and community-based care (65, 66). 
We have piloted mHealth-guided adherence support in DR-TB HIV treatment in South Africa, 
using electronic dose monitoring (EDM) to measure real-time adherence (48). 
 
For our study in, we use an adaptive design including patient-centered care concepts derived 
from DSD. Using elements of the DSD approach within each of the 3 intervention arms (excluding 

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the enhanced standard of care arm) the intensity of each intervention will be calibrated based on 
empirically determined participant requirements. DSD evaluation will be performed by 
incorporating monthly questions regarding DSD acceptability and patient preference, intensity of 
DSD inputs will be recorded, but due to limited resources a statistical power stratified analysis 
by DSD will not be performed. 
 
The burden of stigma for patients with DR-TB/HIV Stigma was initially described by Goffman 
as a “deeply discrediting” attribute understood through a “language of relationships” and social 
interactions (67). Contemporary scholars have called attention to social interactions, structures 
and practices that set up normative expectations about what is acceptable versus devalued (68, 
69). Stigma characterizes the lived experience of HIV and is acknowledged as a key obstacle to 
global HIV control (69). Health activists and persons with HIV have confronted HIV stigma (70) 
to protect patients from systemic discrimination (71). Persons with TB have long been 
stigmatized due to their association with poverty and the fear of contagion (72, 73). High rates 
of HIV co-infection in countries such as South Africa and emergence of nearly untreatable DR-
TB, have renewed fears about TB patients leading to new forms of TB-HIV stigma (71, 74, 75). 
Intersectional DR-TB/HIV stigma has been identified by our group as an important obstacle to 
treatment success (76).
 
4 
STUDY OBJECTIVES AND AIM 
4.1 
Rationale 
 
Improved treatment of drug-resistant tuberculosis and HIV has been identified as a research 
priority (25). Implementation of the project will increase local scientific capacity to conduct 
implementation research by 1) developing programmatic links between central hospitals and de-
centralized, community-based treatment programs for drug-resistant TB-HIV, 2) building on 
existing President’s Emergency Plan for AIDS Relief (PEPFAR) program strengths using the 
Centre for the AIDS Programme of Research in South Africa’s (CAPRISA) excellent research 
infrastructure to generate evidence-based recommendations, 3) training and developing junior 
researchers in implementation science and mixed methods approaches (26).  
 
We will implement an adaptive trial for improving adherence and retention. We will explore the 
impact of the intervention on reducing barriers and improving facilitators to adherence and 
qualitatively explore the feasibility and acceptability of an integrated intervention for adherence 
and retention in care. We will carry out this work in the inpatient setting by expanding the standard 
of care and focusing on the transition to outpatient care. We will also extend the intervention to 
focus on the outpatient community setting where patients may have the greatest adherence 
challenges and highest likelihood of treatment default.  
4.2 
Specific Aim and Hypotheses 
 
Aim 1 overview. This Aim seeks to use an adaptive implementation platform to randomize DR-
TB HIV patients initiating BDQ and TLD to compare the effect of different interventions on 

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biological and clinical endpoints (1a) and determine BDQ threshold adherence value associated 
with DR-TB culture conversion (1b). 
Aim 1. To compare the effect of a multi-arm adaptive adherence intervention on DR-TB 
HIV outcomes Using a 4-arm Bayesian, adaptive trial design (77), we will prospectively evaluate 
adherence support components in DR-TB HIV patients treated with BDQ and TLD. The primary 
outcome will be a composite of HIV viral load, TB culture conversion, survival, and retention in 
care at 12 months.  Within each intervention arm, required adherence support will be empirically 
determined and delivered using a DSD framework.  
 
Hypothesis 1a In a randomized, adaptive implementation trial, the psychosocial + mHealth 
support arm will improve a composite DR-TB HIV clinical outcome compared to separate 
mHealth, psychosocial support, or enhanced standard of care arms. (N=360) 
 
Aim 1 Hypothesis 1b Quantitative adherence measurement using EDM will define BDQ 
adherence thresholds that are more predictive for TB outcomes than conventional adherence 
measures. (N=180) 
 

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5 
METHODS  
5.1 
Overview 
Time line 
Dates are approximate 
x 
6 months for staff training 
x 
Obtain regulatory and ethical approvals 
x 
Approximately 36 months for enrolment (360 patients)  
x 
Participants will be followed monthly until 6 months  
x 
Follow-up visit at 12 months 
x 
End of treatment telephonic visit 
 
Overview of Study Processes (see 6.1 Schedule of Study Evaluations) 
All participants  
x 
Informed consent 
x 
Baseline (Intake) Assessment 
x 
Social and Medical history, etc.  
x 
Monthly and Follow-up Assessments 
x 
Sputum and blood collection 
x 
Collect HIV viral loads, sputum cultures through routine clinical care 
x 
Collect monthly pharmacy records 
x 
Determine clinical end of treatment outcome 
 
Arm 1 Enhanced Standard of Care 
x 
Usual clinical care enhanced by: 
x 
Treatment literacy counseling 
x 
Monthly physician visits 
x 
Social work and other services initiated routinely 
x 
Study team provides extra training for physicians, nurses and social workers to enhance 
standard of care 
 
Arm 2 Psychosocial Support 
In addition to Arm 1: 
x 
Discharge planning (if inpatient) 
x 
Community treatment planning (if outpatient) 
x 
Individual counseling 
x 
Community adherence support group 
x 
Home visits* 
x 
Monthly TB adherence assessment questionnaire (MMAS-8)** 
 
Arm 3 mHealth 
In addition to Arm 1: 
x 
Weekly text messaging* 

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x 
Wisepill RT2000 devices: one or bedaquiline and one for TLD 
x 
Troubleshooting phone calls for detected non-adherence* 
x 
Weekly assessment of adherence measured by the Wisepill RT2000 device$ 
 
Arm 4 Psychosocial support + mHealth 
Combination of Aims 2 and 3**$ 
 
*These elements may be increased in intensity or frequency depending on empirically assessed 
patient needs within each arm 
**If the participant has a Morisky Medication Adherence Scale (MMAS-8) score <6 he/she will 
be considered ‘at-risk’ for non-adherence and will have the intensity of the intervention increased 
in the following stepwise fashion:  A) Telephonic check in by study staff B) Increased frequency 
of counselling sessions from monthly to biweekly C) home visit by a multidisciplinary study team. 
 
$Less than 85% observed/expected doses will be considered at risk for non-adherence and will 
have the intensity of the intervention increased in a stepwise fashion: A) Telephonic check in by 
study staff B) Increased frequency of text messaging from weekly to daily. 
 
5.2 
Study Design 
 
This study will follow a 4-arm Bayesian, adaptive trial design. As patients are enrolled, they will 
be randomized into one of the four arms. 
 
The study will be carried out within a common structure to allow for efficient enrollment and 
analysis. The overall structure is a 4-arm adaptive platform of mHealth and psychosocial 
adherence support interventions informed by a differentiated service delivery (DSD) approach.  
 
Aim 1 is an adaptive study of mHealth and psychosocial adherence support interventions using 
a Bayesian adaptive design to allow comparison of elements of the intervention separately and 
in combination. Aim 1 participants will be randomized into one of 4 arms and followed monthly 
through the 6 months of intervention, then through the end of treatment telephonically, with an 
additional in-person visit to establish the primary outcome. Primary outcome is a combined 
clinical/biological outcome at 12 months described below. Hypothesis 1a utilizes all participants 
while 1b utilizes only those in the mHealth intervention arms (3+4) since granular EDM-measured 
adherence is required. 
 
5.3 
Population and Study Setting 
 
These studies will be conducted within the established implementation science research 
infrastructure at the CAPRISA Treatment Clinical Research Site in Durban, South Africa which 
has a track-record of performing high quality, impactful implementation science studies (78, 79). 
 
5.4 
Recruitment  

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This is a prospective interventional cohort study for people with HIV that have been diagnosed 
with DR-TB and are initiating treatment at King DinuZulu Hospital (KDH), a centralized TB referral 
hospital in Durban, South Africa, which initiates the majority of BDQ treatment regimens in the 
province. Eligible patients include those from referral clinics for King Dinuzulu Hospital. 
Consecutive patients meeting inclusion criteria will be approached for enrolment into the study 
by a member of the study staff. Patients willing to participate will complete an Informed Consent 
form.  
5.4.1 Inclusion Criteria  
1) 
Age ≥ 18 years  
2) 
MTB culture positive with at least isoniazid and rifampicin resistance OR   
Molecular drug susceptibility test confirming resistance to at least rifampicin resistance OR 
Polymerase chain reaction test (Xpert MTB/RIF) result showing MTB positive and RIF resistance.  
3) 
Initiating treatment for DR-TB which includes Bedaquiline (BDQ) containing TB regimen 
within 4 weeks of enrollment and first-time being treated with BDQ 
4) 
Have capacity for informed consent 
5) 
Molecular test positive for HIV or a documented HIV positive history. On treatment with 
ART regimen, including dolutegravir-containing combination ART regimen (i.e. TLD), or starting 
within 4 weeks of enrollment, as per clinician recommendation 
 
5.4.2 Exclusion Criteria  
Pregnancy 
Prisoners 
Discretion of IOR or clinician 
 
5.5 
Randomization Strategy 
 
Eligible participants will be assigned to one of four intervention arms at baseline using a two-step 
randomization. In the first step, participants will be randomized to (Arm 1) vs (Arms 2-4) in a 1:3 
ratio, using a minimization method to achieve balance over the following baseline stratifying 
variables: inpatient vs. outpatient treatment; MDR-TB vs. higher level MTB drug resistance; 
baseline CD4 T-cell count >200. In a second step, a Bayesian adaptive randomization (BAR) 
scheme will be used to further randomize the DSD participants to one of three DSD arms: 
psychosocial support (Arm 2), mHealth support (Arm 3), or mHealth + psychosocial support (Arm 
4) based on the posterior distribution of the success rates of the three arms. Specifically, the 
randomization probability to an arm will be proportional to posterior probability that arm has the 
highest success rate (80, 81). For example, the randomization probability to Arm 2 (psychosocial 
support alone) will be calculated as Prob (P2 > P3 and P2 > P4 | data), where P2, P3, P4 denote 
the success rates of achieving the combined treatment outcome; in Arms 2, 3, 4 respectively, 
and data are updated continuously throughout the study. Under this randomization scheme, 90 
participants will receive ESOC and 270 participants will receive random allocation among the 
three arms (360 participants total). In addition, we will adopt some practical implementations 
of the BAR scheme. First, we will apply an initial run-in period in which DSD participants will be 
assigned with equal probability to the three arms. The run-in period will end once the first 30 

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DSD participants have completed their 12-month evaluation. Second, while the primary endpoint 
is 12-month outcome, we will incorporate outcome at 6-months in updating the randomization 
probability during the study (81, 82). Third, web applications will be used to facilitate adaptive 
randomization in real time with up-to-date data.  Intermediate outcomes at 6-month, the final 12-
month combined treatment outcomes, and the stratifying factors will be updated on a continuous 
basis by the study coordinator via a data entry app.  Randomization probabilities will be updated 
based on the updated data; and the study coordinator will obtain randomization code based on 
these updated probabilities via a randomization app.

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6 
DATA COLLECTION 
6.1 Schedule of Study Evaluations 
 
Procedures+  
Baseline 
(enrolment) 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 
12 
End of 
Treatment 
(6-18 
months) 
All Participants 
 
 
Informed consent  
x 
 
 
 
 
 
 
 
 
Randomization to 
group (Arms 1-4) 
x 
 
 
 
 
 
 
 
 
Treatment literacy 
counseling 
x 
 
 
 
 
 
 
 
 
Baseline (Intake) 
Assessments 
x 
 
 
 
 
 
 
 
 
Complete medical 
history chart 
abstraction 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up 
Assessments 
 
x 
x 
x 
x 
x 
x 
x 
x 
Early morning 
sputum sample 
collection for 
storage 
x 
 
x 
 
 
 
x 
x 
 
Blood Sample 
collection for 
storage 
x 
 
x 
 
 
 
x 
 
 
Depression 
Screen 
x 
 
 
 
 
 
x 
x 
 
Stigma Screen 
x 
 
 
 
 
 
x 
x 
 

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sIMB 
Questionairre 
x 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Intervention 
groups only 
 
Arm 2 
 
TB adherence 
assessment 
(MMAS-8) 
 
x 
x 
x 
x 
x 
x 
x* 
 
Monthly 
counseling 
intervention 
(MCI)$ 
 
x 
x 
x 
x 
x 
x 
 
 
Adherence 
Support Groups 
(ASG) 
 
x 
x 
x 
x 
x 
x 
 
 
Home visits& 
As needed basis 
 
Post discharge 
phone call (PDP) 
 
 
 
Within 7 days post hospital 
discharge 
 
 
 
Arm 3 
 
Pill count by 
Wisepill electronic 
pillbox 
Daily from time of randomization into intervention arm until discharge from study. 

TB adherence 
assessment 
(Wisepill) 
 
x 
x 
x 
x 
x 
x 
x*

Issue Wisepill 
device, training 
Within 14 days 
post-
randomization 
into the 
intervention 
arm. 
 
 
 
 
 
 
 
 

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Adapted Wisepill 
Intervention 
(AWI) 
Intervention (phone call, home visits) triggered by non-adherence as detected by Wisepill non-opening. 
Arm 4 
 
 
Will include all available interventional tools** 
+Monthly pharmacy records will be obtained; Routine HIV viral loads, sputum culture results will be collected from the clinic  
*If participant remains on treatment 
$Frequency may increase based on need 
&Participant may opt out. Timing and frequency based on the discretion of the investigator 
**Arm 4 is the combination of each intervention. Participants that are randomized to Arm 4 will complete all tasks at each time point 
specified for Arms 1-3. 
 

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6.2 
Study Data and Sample Collection 
All participants 
All participants will receive Enhanced Standard of Care (ESOC). 
Enhanced Standard of Care: 
ESOC will consist of care from trained and supported physicians, nurses, and social workers who 
have received repeated trainings from study staff on medical and behavioral aspects of DR-TB 
HIV care, which will be documented in terms of date, attendance, and content. 
All participants who receive care as inpatients will receive an orientation to DR-TB treatment in 
form of a group session designed to impart key behavioral information and health knowledge 
about the disease, treatment, and skills to obtain optimal outcome.  
All participants will receive pamphlets and informational materials designed to support the above 
goals. 
All participants who receive care as inpatients will receive an exit counseling session scheduled 
prior to discharge where the PRAXIS staff will review key behavioral information and health 
knowledge about the disease, treatment, and skills as well as review challenges to reproducing 
care as an outpatient. 
Study participants will complete study assessments at baseline (enrollment) and monthly for the 
first six months. Ideally follow-up questionnaires will be completed in person but allowance will be 
made for telephonic completion of questionnaires. Additional questionnaires will be completed 
following discharge (community treatment follow-up) and at the end of treatment. See section 6.1 
for additional details. 
Psychosocial support methods  
Psychosocial support methods include individual counseling/case management, home visits (if 
warranted and consented to), and adherence support groups which can support patient motivation 
and provide information to assist behavioral change. Participants in arms 2 and 4 will participate 
in individual counseling aligned with their monthly clinic visit, or more frequently if indicated. 
Individual counseling will use motivational interviewing (MI) techniques, based on the 4-part 
engaging, focusing, evoking and planning approach for each participant to set goals and 
anticipate barriers to successful engagement in care (83). Counselors will be qualified mental 
health counselors or credentialed social workers trained in MI skills using validated training 
materials (84).  If required, the same trained counselors known to patients would conduct home 
visits. To minimize potential stigma and increase confidentiality, home visitors would arrive in 
unmarked vehicles and discuss the visit only with the patient or agreed upon contacts. 
Participants in arms 2 and 4 will attend monthly, gender specific, structured adherence support 
groups. Adherence support groups will be facilitated by counselors trained in group facilitation 
methods; group curriculum will include 6 sessions that focus on practical topics including 
accessing social grants, economic stability, and family issues and will utilize guest speakers as 

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appropriate. Structured support groups have been used in patient-centered healthcare to address 
both support and information needs among similarly affected individuals (85). Gender specific 
groups have been found to promote open sharing and allow for focus on gender specific topics 
(86). 
mHealth Methods 
The portable Wisepill RT2000 cellular-enabled electronic pill boxes (‘Wisepill’) uses 2G/3G 
cellular network to automatically synchronize with the Wisepill Cloud service and was designed 
for use in research and clinical trials. Participants will receive 2 Wisepill devices and training on 
loading, charging and storage. One Wisepill will be designated and externally labeled for ART 
and the other device for BDQ, to avoid confusion. Pill box openings serve as a surrogate for 
adherence to ART (which may be either TLD, or NVP or LPV/RTV) and BDQ respectively. Each 
participant will select a text message reminder from a guided menu of choices and receive a 
weekly text message encouraging adherence. For >2 missed openings or openings outside of the 
programmed dose-window (not due to technical issues) the participant will receive a semi-scripted 
study call to support regular adherence. Participants will be assessed weekly using Wisepill 
percent adherence. Less than 85% observed/expected doses will be considered at risk for non-
adherence and will have the intensity of the intervention increased in a stepwise fashion: A) 
Telephonic check in by study staff B) Increased frequency of text messaging from weekly to daily. 
Reimbursement  
Patients will be reimbursed for study visits at baseline, monthly 1-6 months, 12 months, and end 
of treatment.  
Clinical Data Elements 
Data for the study will be collected at the following visits: a) baseline (enrolment) visits, b) monthly 
clinical visits, c) follow-up or end of treatment visits, and d) at community adherence support 
groups. See Appendix for all questionnaires. Questionnaires will be administered by study staff 
fluent in both English and isiZulu. 
A standardized data collection instrument will be used in this study. 
Clinical Study visits 
Baseline (enrolment) visits: Data will be abstracted from patient charts and medical history. Study 
staff will administer baseline (intake) assessment collecting sociodemographic characteristics, 
medical history, knowledge, attitudes and beliefs.  These data will include date of TB treatment 
initiation, date of ART initiation, information regarding past history of TB, smear and culture 
results. 
Participant Contact Information: At the time of study enrolment, participants will disclose their 
names, addresses and phone numbers so that they may be contacted by the study staff regarding 
study visits.  Sensitive data will be kept separately from study materials and will not contain patient 
study identifiers. This will be updated at monthly visits. 

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Electronic Data: Participants will be provided with electronic pillboxes at baseline (enrolment).  
Electronic data regarding adherence will be collected monthly until Month 6. 
End-of-treatment Interview: When participants complete treatment, he or she will complete an 
interviewer-administered standardized questionnaire to collect data including knowledge, 
attitudes, adherence, treatment acceptability, beliefs and outcome. 
6.3 
Biological Specimen Collection, Preparation, Handling and Shipping 
6.3.1 Biological Specimen collection 
In addition to a medical chart review, participants will have specimens collected.  
At the baseline (enrolment) visit, specimen collection may include: 
- 10 ml blood 
- Two sputum samples 
 
At month 2, 6, 12 additional specimen collection may include: 
- 10 ml blood 
- One sputum sample 
 
The biological specimens will be stored for future studies of transcriptomic and immune 
biomarkers of TB treatment response.    
 
The specimens will be coded with the patient identifying number and stored separately from any 
personal or sensitive information or link to the consent form. The investigators will receive only 
the coded specimens.  
 
Participants will be followed-up for additional specimen collection: 
See Section 6.1. 
 
6.3.2 Laboratory Evaluations 
 
Blood 
-HIV viral load, biobanking for future studies including metabolomics, proteomics, and 
transcriptomics 
 
Sputum 
Sputum tests may include but are not limited to: 
- Culture smear microscopy 
- Rapid test for isoniazid, rifampicin and fluoroquinolone resistance 
- First and second line drug resistance testing 
- Rapid molecular diagnostics (eg. Hain and GeneXpert) 
- Nucleic acid amplification testing 
- Pathogen whole genome sequencing  

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7 
DATA MONITORING AND QUALITY ASSURANCE 
7.1 
Statistical and Data Management 
 
Prior to enrollment, all research staff will participate in human subjects protection training/Good 
Clinical Practice training to ensure sensitive data confidentiality for all study participants. Informed 
Consent Forms and all forms containing patient identifiers will be kept separate from study forms 
in a secure, locked location. Upon enrolment, participants will be assigned a unique study 
identifier (PID) assigned by the CAPRISA Data Management Center. Relevant clinical data will 
be collected by chart abstraction. Baseline (enrolment), Monthly Clinical Visits, and Follow-up 
Interviews will be collected with tablet-based collection forms (Case Report Forms (CRFs)). The 
PID will be used on all CRFs to identify the participant for the duration of the study. 
 
Prior to capturing any study data into CRFs, instructions will be given by the CAPRISA Data 
Management core. Completed CRFs must be checked by the Quality Control (QC) officers. 
CAPRISA Data Managers will verify and validate patient data. Quality control reports are 
produced and approved per CAPRISA data management Standard Operating Procedures 
(SOPs). 
 
RedCap software will be utilized for the development of study forms, data entry, and data 
management of electronic data. Electronic data will be kept securely on encrypted and password 
protected end point devices with support from the CAPRISA Data Management Core. Users on 
the study team will have access to the study database with individual login credentials including 
username and password. 
 
Only the designed members of the study staff will have access to the key linking the study PID 
data to patient identifiers.   
 
7.1.1 CAPRISA Data Management Core 
 
The Data Management Core comprises 3 components: a) IT section, b) DataFaxing, data entry 
and data encoding and c) data management. Skills, technical support, and infrastructure to enable 
quality data collection and efficient transfer of data from the sites to the data management center 
are available through the CAPRISA data management core. They are also responsible for 
purchase and maintenance of all data management equipment such as the DataFax machines.  
 
7.1.2 Quality Control/Assurance 
 
Quality checks will be performed on the data entered into the RedCap database. 
 
 
 
-Responses are clearly documented within designated spaces. 
 
-All fields are completed with participant data; if no data was available, this is specified. 
 
-The participant PID is recorded on all pages of the study forms. 

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-The CAPRISA laboratory manager will ensure that all involved laboratories are compliant with 
Good Laboratory Practices (GLP).  
- The CAPRISA pharmacist will provide oversight for the preparation of the electronic pillboxes 
and pill counts. 
 
QA/QC of data will be undertaken according to CAPRISA SOPs. 
 
7.1.3 Electronic Data Storage 
CAPRISA It is the responsibility of the CAPRISA data management core to assure the quality of 
computerized data for the study. Study staff will be trained in source documentation requirements 
in accordance with the study SOP for Source Documentation and in proper forms completion 
techniques. 
Database files will be password-protected, and access to the files will be limited to authorized 
study staff members only. Quality control and validation checks will be performed and data 
cleaning steps will be undertaken prior to finalizing the study database for analysis. Analyses will 
be conducted by study statisticians.  
7.1.3.1 Long Term Data Storage  
Electronic copies of study CRFs and related documents will be stored securely both during and 
after study completion. During the study, the original completed forms for each participant will be 
kept on-site at the CAPRISA KDH site in accordance with federal (both NIH and US guidelines).  
Upon completion of the study, and finalization of the database for analysis, any original, paper-
based forms will be bound and kept off-site (separate site) for long-term storage. Personal 
information collected in this study will be archived in accordance with applicable guidelines and 
laws, including the Protection of Personal Information Act, 2013. CAPRISA has a standing 
agreement with a document storage company to archive large amounts of documents.  CRF data 
on the RedCap server will be accessible to the study staff and the statistician in a read-only mode. 
The data management team will have write-access, with access being restricted by passwords 
and validation levels. Study staff that has access to the data on the computer systems will be 
trained in how to access the system and the importance of system security. All information will be 
backed-up at regular intervals, and backups will be stored in file cabinets or secure areas with 
limited access 
Columbia University Medical Center Data transported to Columbia University will be sent as 
coded with the PID.  Only the South African study designees will have access to the key. Study 
personnel at Columbia University will not have access to identifying or sensitive patient data at 
any point. Study data will be kept in electronic format and will be kept confidential in accordance 
with 
Columbia 
University 
Medical 
Center 
guidelines 
http://www.columbia.edu/acis/security/users/index.html. 
 
 

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7.2 
Instructions for Biological Specimen Management 
Maximal infection control precautions will be taken by the research team members during 
specimen collection and preparation including use of double gloves, safe venipuncture equipment 
and a fit-tested N-95 respirator during sputum induction. Specimens will be collected in 
designated containers and labeled with a printed, barcoded labels that contain the patient 
identification number, the study visit, the specimen type, the intended assays and the specimen 
destination. Specimens for testing at the commercial laboratories will be directly transported there 
by courier. 
Specimens for processing at the CAPRISA laboratory will be placed on ice and transported by 
courier to the CAPRISA laboratory where they will be appropriately aliquoted.  
7.2.1 Biohazard Containment and Specimen Shipment 
All specimens will be labeled by barcode and identifiable by PID. A specimen tracking log 
(including attestation of appropriate temperature maintenance during transport) will be utilized to 
document all transport of specimens between sites. 
Transmission of HIV and other pathogens can occur through contact with contaminated needles, 
blood, blood products, and other secretions; appropriate blood and secretion precautions will be 
employed by all personnel in the drawing of blood and collection of other specimens and shipping 
and handling of all specimens for this study, in accordance with guidelines by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
All dangerous materials, including diagnostic specimens and infectious substances, must be 
transported using packaging mandated by CFR 42 Part 72. Please refer to instructions detailed 
in the International Air Transport Association (IATA) Dangerous Goods Regulations. 
7.2.2 Future Use of Stored Specimens 
A portion of the blood or sputum may be frozen and kept at CAPRISA for future research. A 
portion of these specimens may be kept for 10 years for assays developed in the future in 
accordance with NIH polies and practices.  
Specimens will be stored confidentially with the barcoded patient identifier, separately from the 
key or any other identifying or sensitive patient information. The Biomedical Research Ethics 
Committee will monitor and provide permission for their ethical use in the future.  
Specimens may be shipped at a later date. The appropriate regulatory documents will be 
completed and submitted prior to shipment. 
8 
DATA ANALYSIS  
8.1 
Power Calculations and Statistical Methods 
Hypothesis 1a 
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of four intervention arms. Since retention in care is a component of the composite 12-month 
outcome, we expect that missing data will be minimal. Since ‘missingness’ will be part of the 
primary outcome (i.e., lack of retention in care or loss to follow up) patients who are ‘lost’ will 
actually provide important study data. A Bayesian adaptive randomization algorithm will be used 
to assign interventions to patients to improve the power of detecting any superior arm(s) and to 
increase the number of patients treated in the better arm(s) during the study.  
Hypothesis 1a 
Assuming EDM have an accuracy of 85% (for either positive and negative outcome) against a 
random guess (i.e., a null 50% accuracy), the statistical power for a one-sample binomial test 
(two-sided at 5% level) will be greater than 99% when the sample size available for this aim is 90; 
while we expect the sample size available for this aim will be random due to BAR and will be at 
least 180. 
 
9 
HUMAN SUBJECTS PROTECTIONS 
9.1 
Ethical Considerations 
This protocol and supporting documents will be submitted concurrently to the HRPO IRB at 
Columbia University and BREC ethics boards.   
The study will be conducted in compliance with South African, US, national and local regulations 
and guidelines applicable to research involving human subjects, and in accordance with the 
International Conference on Harmonization (ICH)/Good Clinical Practice (GCP). Should 
regulations and guidelines differ between countries, the more restrictive regulations and 
guidelines will apply. The protocol, informed consent forms, and study materials to be completed 
by study participants will be reviewed by the ethical review boards at Columbia University and 
CAPRISA. Modifications to any study materials will be submitted to regulative authorities as 
necessary and on an ongoing basis. 
9.2 
Human subjects considerations 
The investigators are committed to the protection of the rights of all participants in the proposed 
research, in accordance with USAID policy. Prior to study enrolment, all research staff will be 
trained in principles of human subjects protection and management of confidential study 
materials. Study consent forms and protocols, including intervention materials, questionnaires, 
and data abstraction tools will be approved by the Human Research Protection Office Institutional 
Review Board (IRB) at Columbia University Medical Center and BREC. 
9.2.1 Exclusion of Subpopulations. Children under the age of 18 will be excluded. It is likely that 
factors associated with ART and TB medication initiation and retention in children will vary from 
that of adults and subsequently would obscure the sensitivity of the analysis. 
9.2.2 Vulnerable Populations. Pregnancy is an exclusion criterion for this study as risks 
associated with drug resistant TB treatment are different for pregnant women. Prisoners will 
excluded from this study.  

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9.3 
Informed Consent Process 
Only participants providing informed consent per IRB/IEC requirements will be enrolled in this 
study. Informed Consent Process will begin with a concise and focused presentation of the key 
information about the research study. A member of the study staff will explain the protocol and 
informed consent documents prior to obtaining informed consent in the preferred language of the 
potential participant (English or isiZulu). The informed consent document contains information on 
the study purpose, study procedures, possible risks/discomforts, possible benefits, alternatives, 
confidentiality, compensation for participation, and rights (including the right to withdraw from the 
study) and will provide contact information to the study staff and human protection offices. 
Potential participants will have the opportunity to discuss the protocol and address questions with 
a member of the study staff. Participation in the study is voluntary and refusal to participate will 
not affect the quality of care that individuals receive. Participants will be informed that he or she 
may withdraw from the study at any time. Withdrawal will not affect the quality of care that he or 
she receives.  
When the potential participant fully understands the details of the study, his or her rights and 
responsibilities and expresses a wish to participate, the participant and the person explaining 
consent will sign and date the informed consent form. The person will be provided with a copy of 
the consent form as a record. If the participant chooses to withdraw at any time, he or she may 
simply contact the person obtaining consent or another member of the study team. 
There will be a separate section detailing risks and benefits of permitting biobanking of 
serum/plasma for future studies including metabolomics, proteomics, and transcriptomics. 
Participants will be be given the opportunity to decline participation in the biobanking component 
and still participate in the overall study. 
9.4 
Confidentiality 
Every effort will be made to ensure that participant information will remain confidential and, to the 
extent permitted by applicable laws and/or regulations will not be made publicly available. To 
prevent breaches of confidentiality, participants’ identifying data will be coded to a patient 
identifying number. Personal and identifying information will be kept separately and securely from 
study forms and study databases. Only the South African PI and the study team at CAPRISA will 
have access to the data key and identifier-containing documents. In accordance with the law, data 
may be reviewed by representatives of the IRB/IEC and individuals tasked with duties of 
monitoring and quality assurance. 
Paper forms used to collect study data will be stored in secure locked cabinets. Electronic forms 
used to collect study data will be encrypted and accessible only through a password protected 
portal. Data from questionnaires and study materials will be entered into electronic databases.  

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Both paper study forms and electronic database data will be identifiable only by participant ID. 
Electronic databases will be stored on encrypted and password protected endpoint devices in 
accordance with guidelines. Study staff will be the only persons with access to the study database 
and paper records. 
 
9.5 
Quality Assurance 
The study will be conducted in compliance with the protocol, Standard Operating Procedures 
(SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements in South Africa. 
All relevant study documents, including recruiting materials, informed consent documents and the 
protocol will be approved by the local ethics board. CAPRISA’s Quality Assurance team will 
ensure compliance with applicable regulations and ethical standards regarding protocol 
compliance, proper completion of informed consent procedures, eligibility verification, source 
documentation collection and maintenance, and CRF completion. 
The study coordinators based in South Africa and US will hold bi-weekly teleconferences with 
members of the Quality Assurance team to review data and procedures. Additional external 
monitoring will occur quarterly by Dr. O’Donnell and the US-based Study Coordinator. External 
monitoring will include review of all study documentation, collected data and study team 
performances. QC reports will be available from the CAPRISA Data Management Core, which 
will be reviewed periodically. 
9.6 
Potential Risks and Protections 
This study is of minimal risk. There is no drug or device intervention involved with this study. This 
study involves a behavioral intervention and increased monitoring of adherence to both TB 
medications and ART. Participants will answer questions about the standard care they receive. 
Below are possible risks associated with participating in the study and protections against them. 
Loss of confidentiality: There is a risk of loss of confidentiality throughout the course of the study. 
Every effort will be made to keep study participants’ identifying information confidential. Personal 
identifiers (including name, address) will be kept in a separate and secure location from data 
collected for the purpose of the study.  Participants will be provided with a study ID; all forms will 
use the PID for identification. Only the South African study team will have access to the key to 
decode the study ID. 
All study forms will be identified with only the study ID. Study documents will be accessible only 
by study personnel. Paper study forms will be kept securely in locked cabinets; electronic study 
forms will be secured on an encrypted and password protected study portal. Study databases will 
be kept on encrypted and password protected end point devices in accordance with privacy 
guidelines. 
Staff will be trained on Good Clinical Practices prior to the start of this study with periodic refresher 
training to ensure compliance with privacy principles and laws. 

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Risk of Discomfort: All participants will complete questionnaires at specified time points. Study 
participants in the intervention group will be asked to meet with a social worker at regularly 
scheduled clinic visits at month 2, 6, and 12. These questionnaires and discussions may be 
uncomfortable. Study staff trained in facilitation of questionnaires will conduct baseline interviews. 
Study staff will be trained with communication and interview skills to address and navigate 
potential stressors and discomfort. Social workers that conduct social work sessions will be 
trained in Y. In accordance with the informed consent, participants will be instructed that they are 
not required to disclose any personal or uncomfortable information and may withdraw from the 
study at any time. 
As this study requires blood samples to be drawn, there is a risk of discomfort. There is a risk of 
mild pain, local irritation, bleeding or bruising at the puncture site. There is a small risk for light-
headedness and/or fainting. 
9.7 
Potential Benefits 
Patients in each of the four arms will receive enhanced care. The goal of this study is to improve 
adherence and long-term outcomes through differential service delivery. There is no guarantee 
of a direct benefit received by taking part in this study. However, the knowledge gained may guide 
investigators in improving treatment support and programs for individual patients in the current 
study and in the future. 
9.8 
Alternatives 
Taking part in this study is voluntary. If potential participants decide not to take part in the study, 
he or she will not lose any of the regular benefits. Tuberculosis treatment is provided without cost 
in accordance with the South African TB Program (NTP) guidelines. If the participant decides not 
to continue this study, he or she may leave the study at any time without penalty. Leaving the 
study will not affect the standard of medical care. 
9.9 
Adverse Events Reporting 
The risk of adverse events (AE) is low for participating in this study as there is no medicinal 
interventional in this study. However, as this study does include a behavioral intervention, AEs 
will be closely monitored. 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
the treatment. All adverse events will be documented and reported to the PI. Study related serious 
AEs will be reported to the proper Ethics Committee in accordance with regulations. The study 
team will discuss adverse events as they occur and steps to prevent recurrence. 
 
An AE may include the loss of electronic data, paper-based data, or other potentially sensitive or 
identifying information. The Columbia University Medical Center Human Research Protection 
Office (HRPO) Institutional Review Boards (IRB) and BREC will be informed of potential privacy 
breaches in accordance with reporting guidelines. 
 

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