Peer-led Implementation of TB-HIV Education and Adherence Counseling in Uganda
Phase: NA
Conditions: Tuberculosis, HIV
Sponsor: Yale University

Last Updated: March 16, 2026 
1
Peer-led Implementation of TB-HIV 
Education and Adherence Counseling in 
Uganda (TEACH) 
Study Protocol  
Version 1.2 
March 15, 2026 
 
Principal Investigator: 
J. Lucian Davis, MD, MAS 
Associate Professor, Yale University 
Epidemiology of Microbial Diseases, Yale School of Public Health 
Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine 
P.O. Box 208034, 60 College Street, LEPH 816 
New Haven, CT 06520 
Office 203.785.2912; Fax 203.785.4782 
Lucian.Davis@yale.edu 
 
Uganda Study Site Principal Investigator: 
Achilles Katamba, MBChB, MSc, PhD 
Senior Lecturer, Makerere University College of Health Sciences 
School of Medicine, Mulago Hospital Complex 
Upper Mulago Hill Road 
Kampala, Uganda 
Phone: +256-(0)414-530-692 
Fax: +256-(0)414-540-524 
amkatamba@gmail.com 

Last Updated: March 16, 2026 
2
PROTOCOL SUMMARY 
Title 
Peer-led Implementation of TB-HIV Education and Adherence Counseling in Uganda 
(TEACH) 
Target Population 
≥1920 persons newly diagnosed with TB, including 578 persons living with HIV 
Sites 
16 TB treatment units located in clinics and hospitals in Central Uganda 
Study Design 
Parallel, cluster-randomized trial, with staggered site initiation 
Study Duration 
12 months for enrollment; Up to 14 months for follow-up to allow 6 months of TB treatment, two 
months to ensure final outcome assessments are complete, and 6 months of post-TB treatment 
surveillance. In addition, the 14 months allows up to two months for ART initiation, and 12 
months of follow-up afterwards. 
Objectives 
Aim 1: To evaluate the effectiveness and implementation of a peer-navigation strategy for 
TB education and counseling (TB-EC) to improve TB treatment success and ART retention 
compared to usual care. We will conduct a parallel, cluster-randomized trial with phased rollout 
of sites in site volume-matched pairs, enrolling ≥1920 adults (≥578 living with HIV) initiating TB 
treatment at 16 TB units in Uganda. The unit of randomization is the health facility; the unit of 
analysis is the individual participant, with clustering accounted for using mixed-effects models. The 
two arms of the trial will be  
• 
Usual Care TB-EC Strategy (Comparator Strategy): 
1) TB-EC routinely delivered by health facility staff 
2) Use of Ministry of Health endorsed TB education flipchart 
3) Involvement of a designated treatment supporter (community DOT) 
• 
Peer-Navigation TB-EC Strategy (Experimental Strategy): 
Usual Care TB-EC Strategy plus 
1) Individual-level components 
a. Peer navigators  
b. Illustrated TB-EC booklet with a structured checklist of core topics 
c. Individualized adherence planning 
d. Behavior-change messaging from peer navigators 
2) Clinic-level components  
a. Task-sharing of TB-EC with trained peer navigators 
b. Workflow restructuring to accommodate peer navigators 
c. Community of practice for peer navigators 
d. Implementation Champion at each site 
Our co-primary outcomes will be the effectiveness measures of TB treatment success and ART 
retention. Our implementation outcomes will be secondary, with the two lead outcomes defined as 
adherence to TB treatment and adherence to ART, each measured at five months We will also 
assess multiple secondary implementation outcomes, including timely initiation of TB medication 
and of ART; adherence to these medications at 2 months, and persistence in attending monthly 
refill visits for TB treatment and quarterly ART refill visits. Finally, as secondary effectiveness 
outcomes, we will assess TB recurrence-free survival 6 months after TB treatment completion, and 
HIV RNA suppression 6 months after ART initiation, and overall survival at 12 months. 
Aim 2: To evaluate social-behavioral mechanisms for the effects of peer navigation on 
implementation outcomes. We will measure social and behavioral factors (i.e., TB knowledge, 
perceived social support, stigma, and self-efficacy) using validated scales among peer navigators 
in both trial arms and conduct mediation analyses to identify causal mechanisms of impact on 
adherence.  
Aim 3: To assess the implementation feasibility, acceptability, appropriateness, fidelity, and 
context of peer-navigation. We will conduct a nested, convergent mixed-methods study involving  
1) Surveys of peer navigators and healthcare workers on the feasibility, acceptability, and 
appropriateness of peer navigation,  
2) Direct observation and interviews with peer-PWTB dyads and focus groups with HCW to 
characterize implementation fidelity/adaptation and contextual factors.  

Last Updated: March 16, 2026 
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Protocol Background 
TB is the leading cause of infectious death, both overall and among people living with HIV (PLH), despite 
the widespread availability of highly effective treatment. In 2024, there were 1.23 million TB deaths globally, 
including 150,000 deaths in PLH.1 Standard TB treatment cures >95% of persons with drug-susceptible TB2, 
which accounts for 98% of PWTB worldwide.3 For PLH with TB, timely initiation or continuation of ART within two 
weeks of initiating TB treatment, as per local and international guidelines4,5, is proven to reduce mortality by 75% 
and help PLH achieve similar TB treatment outcomes as PWTB without HIV.6-8 Sex also strongly affects 
diagnosis and outcomes of HIV9 and TB.3 
Failing to initiate and adhere to TB treatment and ART leads to poor TB/TB-HIV outcomes (Figure 1). Not 
linking PWTB to treatment at TB diagnosis is common and contributes to excess mortality.10 Medication 
nonadherence after initiation is also common11,12 and has major implications: missing as few as 1-2 doses/week 
of TB medications is associated with a 2-to-29-fold higher risk of treatment failure.13 Examining the ability to 
reach all persons with HIV-TB with ART, a recent meta-analysis of 27 studies of PWTB newly diagnosed with 
HIV found a pooled ART uptake of only 53% (95%CI 42-63%).14 Clinic understaffing, stigma, and a lack of TB-
HIV service integration were the most common barriers to ART uptake. Better staff education, multidisciplinary 
care, and peer support were the most potent enablers of timely ART initiation.14  
Preliminary data from Uganda show that stepwise and cumulative losses in adherence and completion 
remain high across the TB/TB-HIV treatment cascade. Using TB register data15, Co-I Katamba et al. found 
that 20% of new TB patients did not start TB treatment 
within 2 weeks of diagnosis. Using the Behaviour 
Change Wheel16, they found low TB knowledge and 
TB stigma to be major barriers, with education and 
restructuring of TB service delivery acting as possible 
facilitators.17 Routine data from 31 TB units in Central 
Uganda found only 8 sites with treatment success 
ratios >80%.18 Although most data14 on the ART care 
cascade for PWTB-HIV precedes the major global 
push to meet the UNAIDS 95-95-95 goals, our group 
found that major gaps persist in 2022: just 77% started 
ART ≤14 days; ≤50% were retained in care at 6-12 
months, and ≤40% were virally suppressed at 6-12 
months (Figure 1). 
An extensive quantitative and qualitative literature has identified low TB literacy and demotivation as 
two principal barriers to TB treatment adherence.11,12,19-21 Education, defined as interventions to enhance 
knowledge, attitudes, and practices; and counseling, defined as interventions to provide tailored advice and skills 
for problem-solving, are two feasible and low-cost approaches to promoting adherence.22 Unfortunately, 
operational guidance on implementation of TB/TB-HIV EC is limited and incompletely specified in the 
international TB and HIV guidelines23,24 as well as in the Uganda National TB Progamme guidelines.4 
WHO guidelines recommend TB education and counseling (TB-EC) with integrated HIV content as the 
preferred implementation strategy to promote adherence to TB treatment and ART. However, there is 
limited evidence on the effectiveness or implementation of TB-EC in high TB-HIV burden settings. A 
Cochrane systematic review identified only 3 small studies on TB education and counseling to promote 
adherence, all of which focused on TB preventive therapy in high-income countries; no trials of education and 
counseling adherence interventions for TB disease treatment were identified.25 Two more recent studies 
demonstrated the benefits of multidimensional counseling and social support interventions, but in one, from 
Senegal26, the content and training of counseling were not specified, and in the other, from Ethiopia27, the benefits 
for person-important outcomes were minimal. In our prior work in Uganda and South Africa, health workers 
reported little time for counseling, describing TB-EC as often short, non-standardized, or non-existent, regardless 
of the recipient’s HIV status.28,29 Integration of HIV-TB services has been associated with decreased TB 
mortality30, but analyses of ART outcomes among PWTB living with HIV are underpowered.31 There is a particular 
need to fill this gap since existing global health financing models have collapsed in 2025, and high TB-HIV burden 
countries like Uganda are now rapidly adopting integrated service-delivery models for TB-HIV services. 
Evidence from the HIV literature supports peer navigation as an effective strategy to promote ART 
adherence, but this has not been applied to TB-EC. Peer navigation, defined as “trained personnel who help 
Figure 1. HIV care cascade among PWTB newly diagnosed with HIV at 7
TB units in Central Uganda in 2022. ~35% of PWTB-HIV were ART-naïve.  
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PWTB Newly
HIV Diagnosed
(n=269)
Initiated ART 
≤14 days 
(n=206)
Retained in care
at 6 months
(n=134)
HIV RNA <50
at 6 months
(n=106)
Retained in care
at 12 months
(n=116)
HIV RNA <50
at 12 months
(n=71)
Preliminary Data: 
HIV Care Cascade among PWTB-HIV in Uganda 

Last Updated: March 16, 2026 
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patients overcome modifiable barriers to care and achieve their care goals by providing a tailored approach to 
addressing individual needs,” has proven effective in many chronic medical conditions.32 Although its core 
components and mechanisms of action still need to be defined, studies suggest that peers draw on shared 
identities, circumstances, and life experiences to more effectively serve target populations.33 Peer-navigation 
programs empower patients by enhancing knowledge transfer, engagement in care, and adherence to therapy 
to optimize health outcomes.34 Studies of PLH show that peer navigation reduces missed clinic appointments35, 
improves retention in care36, accelerates ART initiation37, and increases viral suppression.38 Moderate-quality 
evidence from systematic reviews finds that 86-90% of studies of peer support as a single intervention showed 
significant positive effects39, and 86% of studies of 1:1 peer support found significant improvements in 
adherence, emphasizing the effectiveness of peer navigation for HIV engagement.40 However, the benefits can 
be inconsistent if peer navigation is not adapted to the local context and target populations.41 Factors influencing 
peer navigation outcomes include trust in the peer-client relationship, peer accessibility, and the presence of 
peer supervisors.42 Finally, HIV peer-navigation studies documenting high fidelity to protocols and adaptation to 
target populations and context were more effective than ones that did not tailor their approaches.43 Larger, well-
controlled studies with long-term data on effectiveness, implementation, and impact mechanisms are needed.44 
Unstructured support via family DOT does not improve TB outcomes.45 Only one small positive study has 
examined peer navigation for TB46, despite calls for more peer interventions by PWTB.47 
 
We have developed a community-engaged, theory-informed strategy to promote TB-EC delivery and 
adherence to TB treatment and ART (Figure 2). In 11 FGDs exploring the experiences of healthcare workers 
(HCW) and PWTB48 with TB-EC, we found that PWTB wanted TB-EC to improve TB knowledge and adherence, 
and reduce individual and household stigma. However, HCWs felt they lacked the training to deliver effective 
TB-EC. Both HCW and PWTB agreed that unappealing TB-EC materials, as well as limited time and private 
clinic space for TB-EC, further curbed their motivation to engage in TB-EC. Yet, both HCW and PWTB strongly 
advocated for change and suggested bringing in trained peer navigators to deliver TB-EC, following counseling 
models used in HIV clinics. Based on these suggestions, we used CFIR and the Behaviour Change Wheel 
framework to develop a targeted “peer-navigation” strategy with 3 components: (1) task-sharing of TB-EC 
between HCWs and current or former PWTB; (2) restructuring of TB clinic workflows to incorporate dedicated 
Figure 2. Implementation Research Logic Model (IRLM) for the Peer-Navigation Strategy. We used the IRLM to specify Proctor’s
implementation, service, and clinical outcomes (Column 4) for our clinical interventions: TB treatment (TB Rx) & antiretroviral therapy
(ART) (Column 2, Row 5). We applied the Capability-Opportunity-Motivation Behavioral (COM-B) model to identify adherence
determinants (Column 3) using focus groups with healthcare workers (HCWs) and PWTB/TB-HIV. We applied the Consolidated
Framework for Implementation Research (CFIR, Column 1), to identify determinants of standard TB Education and Counseling (TB-EC)
delivery (Column 2, Row 4), focusing on the Innovation (i.e., adaptability, relative advantage, complexity, design), Individual (i.e.,
innovation deliverers), Inner Setting (i.e., physical & work infrastructure, communications, culture, mission alignment) domains. Finally,
we used the Behavior Change Wheel framework and Behavior Change Techniques Taxonomy to adapt TB-EC and tailor our multi-
component, peer-navigation strategy (Column 2, Rows 1-3) to specify mechanisms for TB-EC to improve client outcomes. 
 

Last Updated: March 16, 2026 
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time for TB-EC earlier in the diagnostic journey; (3) printed education materials, including a checklist of essential 
TB-EC topics; (4) individualized adherence planning; and (5) behavior-change messaging tailored to adherence 
barriers. We developed the checklist using existing TB-EC materials49 and drawing on adherence principles 
identified in a systematic review of TB-EC materials.50 We designed the first 2 components to enable TB units to 
initiate TB education while clients wait for TB evaluation results, freeing time and space for individualized HCW 
counseling after TB diagnosis. We designed the last 3 components to make peer-client interactions more 
comprehensive, individualized, and motivating. In a pre-post study of 161 PWTB, our peer navigation strategy 
was found to be feasible and acceptable, and it significantly improved TB literacy and treatment outcomes.51 
Mean within-subject TB disease knowledge increased by 16% (95%CI 12-19%, p<0.0001) and TB treatment 
knowledge by 40% (95%CI 36-44%, p<0.0001). Successful TB treatment completion increased from 70% to 
87.5% (+17.5%, 95%CI 4-31%, p=0.011).52 Study limitations included possible unmeasured confounding due to 
secular trends, a lack of data on ART outcomes, and the contextual disruption of the COVID pandemic during 
the final months of the peer navigation period. These initial results strongly support a large, well-controlled trial 
of peer navigation to improve HIV/TB outcomes. In the preparation phase for this trial, we conducted an 
adaptation exercise using ADAPT-ITT53, to refine this strategy, and add additional components at two levels, to 
address both facility-level and individual-level implementation determinants, as described further below. 
A multi-modal approach to TB/ART adherence monitoring, including novel point-of-care (POC) urine 
assays, is a strength. Digital adherence technologies pairing electronic pillboxes and medication sleeves with 
SMS54 are widely promoted for HIV and/or TB, yet systematic reviews show high costs55, inconsistent 
effectiveness56,57, selection biases in per-protocol analyses from clinical trials58, and inequitable access to mobile 
technologies.59 Monitoring of adherence using biological specimens offers alternatives, but implementation is 
limited by high assay costs, the low acceptability of blood draws, and the frequent inaccessibility of hair in African 
populations. In contrast, POC urine assays for isoniazid (INH) metabolites offer a feasible, acceptable, low-cost 
biomarker60,61 for TB medication adherence, and are highly sensitive and specific for semi-quantitatively 
detecting doses of isoniazid-containing regimens taken within the prior 48-72h.62,63 Novel, low-cost POC urine 
tenofovir assays are highly sensitive and specific for dichotomously assessing adherence to standard ART 
regimens taken within the prior 4 days.64,65 When combined with refill attendance, self-report measures, and 
clinical outcomes, these biomarkers provide a pragmatic indicator of adherence behavior in implementation trials. 
Furthermore, if these tests prove feasible, sharing results with PLH/PWTB before assessing adherence by self-
report66 could provide a future, testable strategy to enhance real-time adherence monitoring and facilitate 
tailoring of TB-EC using behavior change messaging. 
We propose a hybrid type 2 study, guided by a novel tool from Curran et al for choosing hybrid study 
type.67 A hybrid type 2 trial is appropriate for four reasons, First, existing data on TB-EC effectiveness is of only 
low-to-moderate quality.45 Second, although TB treatment and ART delivery are highly standardized under 
WHO5,68 and Uganda NTP guidelines69, data is needed on whether locally adapted TB-EC strategies can improve 
programmatic TB/TB-HIV outcomes.70 Third, the determinants of medication adherence in Uganda48 and 
beyond12 are well-known, as are the possible implementation strategies.21,71 Thus, a Type 2 study will help us 
evaluate if the peer-navigation TB-EC implementation strategy can overcome these barriers to adherence.48 
Fourth, a Type 2 study will allow us to adapt a novel TB-EC strategy to the local context and evaluate its real-
world effectiveness and implementation.51 If the strategy proves effective, concurrently generating new 
knowledge about implementation will add rigor and promote reproducibility and scalability.72 
This proposal advances NIH HIV Research Strategic Goal 3 for 2021-2025, “to promote implementation 
of research discoveries for public health impact globally.” It also addresses NIH OAR HIV research 
priorities, including “addressing HIV-associated coinfections”; “improving health outcomes of people with HIV”; 
developing “implementation strategies to improve systematic uptake of evidence-based treatments in diverse 
settings and populations”; and using “novel design approaches, such as mixed methods, and alternative clinical 
trial designs to estimate and improve outcomes and public health impact.” 
This study features an innovative design of the implementation strategy. A growing evidence base suggests 
that implementation strategies co-designed with community partners and tailored to address factors that impede 
delivery are more impactful than those developed without community consultation or a theoretical basis.73,74 We 
and others have repeatedly shown that tailored strategies can overcome a variety of implementation problems 
with TB and HIV-related interventions.75-77 The proposed peer-navigation strategy has been developed using 
such an approach48, and its implementation and evaluation will apply up-to-date theoretical approaches in 
implementation science.78-80 

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This study features an innovative multi-component implementation strategy. Implementation strategies 
that include multiple components can address multiple barriers to uptake and are therefore associated with 
greater impact than single-component strategies.73 However, multi-component strategies are also more costly to 
implement, so we have decided to target multiple related endpoints in this study (i.e., adherence to both TB 
treatment and ART). We consider this an innovative, yet rarely used approach to potentially enhance impact and 
cost-effectiveness.  
This study features innovative measurements of intervention fidelity. We will assess adherence to TB 
medications and ART through a multi-phase process evaluation that frames adherence as a dynamic process 
with multiple distinct phases from initiation to implementation to persistence. We will measure TB and ART 
adherence using established scales and validated point-of-care urine biomarker assays for isoniazid metabolites 
and tenofovir. Many of these aspects are novel and informed by an NIH Notice of Special Interest (NOSI) in 
adherence research (NOT-OD-21-100), including its call for multi-level, multi-component, and peer-led 
interventions.  
This study features innovative measurements of implementation fidelity. Recent editorials and research 
agendas emphasize the need for studies exploring mechanisms of change as a key element of fidelity.73,81 Our 
plans to apply rigorous, causal methods to assess the social and behavioral mechanisms by which peer-led TB-
EC improves TB/TB-HIV adherence is thus highly responsive. Such measures are almost never employed, as a 
recent systematic review found that only 3% of NIH-funded trials with adherence as an outcome assessed 
behavior change mechanisms.82 
Aim 1: Evaluating the effectiveness and implementation of 
Peer-Navigation for TB-EC  
Introduction 
We will conduct a parallel, cluster-randomized trial in Uganda to evaluate the effectiveness and implementation 
of a novel, peer-led TB education and counseling (TB-EC) strategy to improve TB and HIV treatment outcomes 
among persons with TB (PWTB), including persons with and without HIV. Here, we outline the study procedures 
for this aim.  
Study Objective 
To evaluate the effectiveness and implementation of a peer-navigation strategy for TB education and 
counseling (TB-EC) to improve TB treatment success and ART retention compared to usual care. 
Hypotheses 
Effectiveness 
1. The peer-navigation strategy will increase TB treatment success compared with usual TB-HIV education and 
counseling. 
2. The peer-navigation strategy will increase retention in ART care after TB treatment initiation. 
Implementation 
3. The peer-navigation strategy will improve TB medication adherence compared with usual care. 
4. The peer-navigation strategy will improve ART adherence compared with usual care. 
Study Design 
We will conduct a parallel, cluster-randomized, hybrid Type 2, effectiveness-implementation trial with phased 
rollout at 16 health facilities in Central and Eastern Uganda. Following a three-month run-in period (October, 
2025 through January, 2026) to refine and establish the feasibility of data collection procedures at participating 
sites, we will publicly randomize the sites. Once the trial begins in March 2026, two new sites will launch every 
four weeks in pairs matched based on the monthly average of TB disease notifications in the run-in period, with 
one site assigned to the experimental implementation strategy (i.e., peer navigation) and one to the comparator 
strategy (i.e., usual care). Clusters remain in their assigned arm (i.e., experimental or usual care) for the entire 

Last Updated: March 16, 2026 
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trial. For statistical efficiency, effectiveness outcomes are designated as primary outcomes while implementation 
outcomes are prespecified secondary outcomes. 
 
Trial Design Characteristics 
The TEACH study is a pair-matched, cluster-randomized trial. Health facilities are randomized 1:1 to the peer-
navigation strategy or usual TB-HIV education and counseling. Allocation occurs at the facility level. The 
intervention model is a cluster-randomized parallel assignment. Due to the nature of the intervention, participants 
and providers are not blinded (open-label design). 
Study Setting and Sites  
The study will be conducted at 16 sites. 
 
Site-level Inclusion Criteria  
• 
Hosts a national TB programme (NTP)-recognized TB treatment unit 
• 
Notified at least ~100 PWTB annually during the period 2022-2024 
• 
Located within 180 km of Kampala 
 
Site-level Exclusion Criteria  
• 
≤40 km from another included site 
• 
Existing TB treatment adherence program in addition to usual NTP adherence-support package of 
healthcare worker TB education and counseling and use of treatment supporters 
• 
Don’t agree to participate in a study  
 
In total, we considered 34 sites for trial participation. Study staff visited all sites in early 2025 to collect data on 
standard TB and HIV-TB treatment practices and to verify numbers of notified PWTB, treatment outcomes, and 
persons with HIV-TB averaged over three years from 2022-2024 (Table 1).  
Table 1. Study Sites, by number of eligible persons with TB (2022-2024) 
Facility Name 
Level 
Type 
Location 
Eligible 
PWTB 
TB Rx 
Complete 
%  
Complete 
Eligible  
HIV-TB 
% HIV 
Kiboga 
General Hospital 
Public 
Rural 
327 
251 
77% 
28 
9% 
Mityana 
General Hospital 
Public 
Urban 
277 
227 
82% 
112 
40% 
Kasanda 
H/C IV 
Public 
Rural 
220 
163 
74% 
89 
40% 
Iganga Islamic 
H/C III 
Private-Not-for-Profit 
Urban 
203 
178 
86% 
76 
37% 
Kawolo 
General Hospital 
Public 
Urban 
188 
119 
63% 
0 
0% 
Bugiri 
District Hospital 
Public 
Urban 
169 
127 
76% 
170 
101% 
Bukuya 
H/C IV 
Public 
Rural 
148 
109 
74% 
9 
6% 
Nakaseke 
District Hospital 
Public 
Rural 
142 
109 
75% 
58 
41% 
Nkozi 
General Hospital 
Private-Not-for-Profit 
Rural 
134 
25 
19% 
33 
25% 
Kigandalo 
H/C IV 
Public 
Rural 
130 
80 
61% 
19 
15% 
Kyanamukama 
H/C IV 
Public 
Rural 
128 
105 
83% 
100 
78% 
Butenga 
H/C IV 
Public 
Rural 
121 
87 
72% 
63 
52% 
Nawaikoke 
H/C IV 
Public 
Rural 
112 
65 
58% 
9 
8% 
Nakifuma 
H/C III 
Public 
Rural 
105 
57 
54% 
19 
18% 
Buwenge 
H/C IV 
Public 
Rural 
99 
65 
66% 
40 
40% 
Kiganda 
H/C IV 
Public 
Rural 
96 
78 
81% 
60 
63% 
Total 
 
 
 
2599 
1844 
71% 
885 
34% 
Alternate Sites: 
Facility Name 
Level 
Type 
Location 
Eligible 
PWTB 
TB Rx 
Complete 
% Complete 
Eligible  
HIV-TB 
% HIV 
Kamuli 
General Hospital 
Public 
Rural 
188 
168 
89% 
36 
19% 
Mpigi 
H/C IV 
Public 
Urban 
132 
117 
89% 
76 
58% 
St. Benedict 
General Hospital 
Public 
Rural 
212 
190 
90% 
31 
15% 
 
Ultimately, the three sites shaded in grey were excluded, either because a large proportion of their TB diagnoses 
and treatment initiations occurred in the community rather than at the health facility (Buwenge) or because they 
had non-standard peer or nurse-led adherence support interventions at the sites (Kigandalo and Kiganda).  

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Study Population 
Consecutive adults (aged ≥18 years) starting treatment for TB/TB-HIV in public and private, not-for-profit primary 
care clinics in Uganda will be the target study population. Below are the inclusion and exclusion criteria: 
Individual Inclusion Criteria 
• 
Age ≥18 years 
• 
Registered as a new, relapse, failure, lost-to-follow-up person with TB in the on-site NTP TB Treatment 
Register 
• 
Screened and invited to participate within 30 days of TB treatment initiation 
Individual Exclusion Criteria 
• 
Diagnosed with possible or confirmed drug-resistant TB 
• 
Transferring their TB care into the clinic from off-site 
• 
Residing >~40 km from the enrolling clinic 
• 
Lacking mental capacity to provide informed consent 
Study Duration 
We will conduct our cluster randomized trial over 26 months, with individual participants followed for at least 6 
months after the end of TB treatment. Under both the usual care and the peer-led TB-EC strategies, participants 
usually have up to 10 clinical visits, including 1-2 visits for diagnosis and TB treatment initiation, and 8 visits for 
follow-up and medication refills (4 bi-weekly visits in weeks 2-8, then 4 monthly visits in months 3-6). Health 
workers have discretion to drop some of these visits to give longer follow-up intervals, especially for persons 
doing well with treatment. Alternatively, persons may have additional visits in the event of adverse drug events 
or if treatment is extended because of extensive disease or a slower than usual response to treatment. Each 
visit requires ~30-60 minutes plus waiting time. Most of these visits will be devoted to clinical activities that 
directly support the person with TB in their treatment, such as the ~15-30-minute peer-led TB-EC sessions at 
each visit. In addition, there will be research activities at the baseline TB treatment initiation visit, at the two- and 
five-month visits, and at the end-of-treatment visit. According to WHO guidelines on ascertaining treatment 
outcomes, participants should complete 6 months of treatment as detailed below, for a total of 180 daily doses 
of TB medication within 8 months of treatment initiation. The additional two months are provided in case there 
are minor treatment interruptions (e.g., either prescribed to address adverse treatment effects, or unprescribed 
due to missed or delayed follow-up visits). 
 
Figure 3. Enrollment Schema. 12 months of enrollment, with 14 months of follow-up (i.e., 8 months for assessment of TB outcomes, plus 6 months for 
post-treatment surveillance). Note: The planned 8-month run-in period was reduced to 3-4 months because of interruptions in funding. 

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9
Standard TB Treatment and Usual Care Strategy 
Standard TB/TB-HIV Treatment Protocols. All TB units follow Uganda NTP guidelines69 recommending WHO-
standard 4-drug, 6-month treatment regimens for drug-susceptible TB disease, starting with an 8-week “intensive 
phase” (i.e., daily isoniazid, rifampicin, pyrazinamide, and ethambutol plus pyridoxine, also known as vitamin B6, 
all typically dispensed as a 14-day medication supply at every other week refill visits). HIV testing is 
recommended before or at the time of TB diagnosis, and subsequently every 3 months for those testing HIV-
negative.4 As per WHO/NTP, PLH should start (or resume ART, if treatment was interrupted) within 14 days of 
TB diagnosis. If doing well at the 8-week (“2-month”) visit, clients transition to the 2-drug “continuation phase” 
(i.e., daily isoniazid, rifampicin, and vitamin B6), with monthly refill visits. Monitoring for adverse effects is based 
on symptoms and signs. Monitoring for response to TB treatment includes sputum smear microscopy at two 
months, and if positive, again at 5 months. It is also recommended to collect sputum for smear microscopy at 
the end of treatment visit, to document cure; otherwise, the outcome is designated as treatment completed. HIV 
treatment monitoring includes CD4 count measures every three months, and viral load assessment six months 
after ART initiation and then annually.  
Usual TB-EC Implementation Strategy. National TB Program guidelines recommend that TB unit staff provide 
TB education and counseling, but do not specify the topics, frequency, or duration. Most sites have a TB 
education and counseling flipchart in the TB unit that staff may use to counsel PWTB, with or without their 
treatment supporters. Guidelines recommend that all PWTB designate a treatment supporter to oversee 
community directly observed therapy (DOT) by observing PWTB take their pills daily. Treatment supporters or 
other designees may be allowed to attend follow-up visits to collect medications instead of the PWTB attending.  
Peer-Navigation TB-EC Strategy 
Experimental 
Implementation 
Strategy 
(Peer-Navigation 
TB-EC). 
The 
proposed 
experimental 
implementation strategy includes multiple components at multiple levels, and will be introduced concurrently at 
each intervention site during a 1-month training and run-in period: 
Individual-level implementation components. 
(1) Peer Navigators. Peer navigators are lay persons with lived experience of TB or TB/HIV (sometimes referred 
to as expert clients) who will be recruited to assist with delivering adapted TB education and counseling 
(TB‑EC) at participating sites. Drawing on their personal experience as persons living with TB (or rarely as 
treatment supporters), peer navigators will all complete a specific training program to deliver TB-EC that we 
will develop and deliver during the 4-week run-in period before we launch the trial at each site. Peer 
navigators will provide TB‑EC during TB evaluation, at the time of treatment initiation, and throughout 
follow‑up visits, offering daily support within the clinic to address gaps arising from limited health‑care worker 
time and training in TB-EC. By integrating peer navigators into routine service delivery, this component is 
designed to enhance the adoption of TB‑EC by expanding the workforce capable of providing individualized, 
person‑centered education and counseling. Their involvement aims to strengthen engagement, improve 
continuity of support, and ensure that core TB‑EC content is delivered consistently across clinical encounters. 
(2) Illustrated TB-EC Book with embedded checklist. To ensure each enrolled participant receives the relevant 
education and counseling, the TB‑EC Checklist lists the twenty essential topics (Table 2) that every person 
with TB (PWTB) should understand. It also provides a structured tool for peer navigators to guide client 
education across multiple clinical encounters. We adapted the checklist for Uganda using TB-EC materials 
from Médecins Sans Frontières South Africa. The 20 core TB-EC topics are covered in 4 short modules:  
a. TB Disease Knowledge (before TB testing),  
b. TB Treatment Knowledge (after TB testing),  
c. Adherence Planning (after diagnosis); and 
d. TB & HIV Monitoring (at return visits for medication refills).  
Peer navigators will review each topic with clients during TB evaluation, at treatment initiation, and throughout 
follow‑up visits, ensuring that individuals progressively master all core content. By reinforcing key information 
at baseline, again at two weeks, and as needed thereafter, the checklist is designed to strengthen TB 
knowledge and build the adherence skills necessary for successful treatment initiation, sustained adherence, 
and eventual completion. This component addresses critical gaps in patient understanding by standardizing 
educational content and supporting consistent, iterative learning tailored to each client's needs in a way that 
is more engaging and person-centered than standard TB-EC materials. 

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10 
(3) Individualized adherence planning. During the Adherence Planning module, peer navigators will help PWTB 
complete a brief individualized adherence plan on key treatment and follow-up topics (items 13-17). They 
may take the plan home for reference. The goal of the individual adherence plan is to elicit individual needs 
to facilitate adherence and persistence in treatment through targeted counseling. 
(4) Behavior-change messaging. Each TB-EC module includes person-centered messaging prompts from the 
Behavior Change Techniques Taxonomy83 (Table 1, Column 2). 
Clinic-level implementation strategy components. 
(1) Task-sharing of TB-EC with peer navigators. In collaboration with clinic leaders, the research team will recruit, 
interview, and employ persons with lived experience of TB, including current and former PWTB (including 
some PLH), as part-time peer navigators. We will select 6-8 individuals/site, typically from those doing well 
on the continuation phase of TB treatment or who have completed TB treatment within the past two years. 
We will provide a daily living wage, transportation costs, personal protective equipment (i.e., N95 respirators), 
and on-site supervision by an experienced TB-HIV community health worker (CHW). After an initial ~5-day 
training conducted at or near the site, including didactics and role-plays, peer navigators will complete a ~3-
week probationary period under the oversight of the CHW supervisor, clinic TB focal person, and 
implementation champion, as peer navigators provide TB-EC to clients and demonstrate that they have 
attained competency. Peer navigators will also attend weekly group problem-solving sessions (i.e., 
Community of Practice meetings) convened these supervisors to share challenges they face as peer 
navigators delivering TB-EC- as in prior studies.84,85 We will contract with peer navigators to work ~2 clinic 
days/week (~8-10 days/month) with 4 weeks of annual leave and 4 days of sick leave, and require 8 weeks’ 
notice for termination of employment. This plan provides an adequate workforce of 2-3 peer navigators per 
clinic day, with 1-2 peer navigators providing group education in the clinic waiting area and 1 providing 
individual adherence and follow-up counseling in the TB unit. Peer navigators will record all PWTB counseled 
in a logbook for daily review with their supervisor. Logbooks will be stored in the TB unit in locked cabinets. 
Peer navigators not reaching or maintaining competency or leaving their positions will be replaced with newly 
recruited peers to serve in this role. The goal of task-sharing of TB-EC with peer navigators is to increase 
physical and social opportunities for those in the inner setting of the clinic to inform and support PWTB with 
individually tailored, high-quality TB-EC. 
(2) Workflow restructuring. As in prior studies86-88, we will work with TB unit staff at intervention clinics during site 
launch to restructure the flow of TB-EC services as needed to facilitate TB-EC through peer navigation. An 
experienced research team member will co-lead a workflow mapping exercise with the site-level TB focal 
person during pre-service training. In three 60-90 minute sessions with intake, lab, ART clinic, and TB unit 
staff, we will map workflows and identify structures (e.g., waiting areas) and processes (e.g., timing of TB-
EC, screening, testing, reporting) for change, describing plans using the Model for Adaptation Design and 
Impact (MADI).79 As noted above, we will engage lead clinic administrators and each district-level TB 
supervisor in this process during group problem-solving sessions attended by peer navigators and their 
supervisors.86-88 As in prior studies76,84, we will provide a modest budget to aid workflow changes (e.g., 
updated signage and seating). Staff will implement changes in workflow through training. The goal of 
workflow restructuring is to overcome health-system barriers related to the CFIR constructs of physical and 
work infrastructure, using collaborative processes that address the CFIR constructs of communications, 
culture, and mission alignment related to TB-HIV/TB-EC services. 
(3) Community of practice meetings for peer navigators. With support from the implementation champion and 
TB focal person, the peer navigator supervisor will convene community of practice meetings. A community 
of practice is a group of individuals with a shared domain (work as peer health counselors) who form a 
community around a shared practice (TB-EC). Weekly meetings provide a structured forum for social support, 
shared learning, and accountability through performance review. In the meetings, peer navigators will 
collectively go over their logbooks, discuss challenges in delivering TB‑EC, and engage in collaborative 
problem‑solving to refine skills and strengthen the consistency of peer‑navigation activities. The meetings 
will be held weekly, with timing determined jointly by peer navigators and the Implementation Champion to 
accommodate workflow and clinic demands. By addressing gaps in peer knowledge, skills, and social 
support, these sessions are designed to enhance both fidelity to TB‑EC delivery and fidelity to the broader 
peer‑navigation model. This component facilitates the ongoing adoption and adaptation of the 
peer‑navigation program by creating an enabling environment for continuous improvement and reinforcing 
the capability, confidence, and cohesion of the peer workforce. 

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11 
(4) Implementation Champions. An influential healthcare worker with expertise in TB-HIV care (e.g., TB focal 
person or clinic in-charge) will be selected in collaboration with facility leadership as an implementation 
champion to advocate for, support, and sustain the peer-navigation strategy. Champions will coordinate with 
facility leadership to recruit, train, and supervise peer navigators, while also monitoring the peer navigation 
program's performance to ensure consistent delivery and quality. By targeting key determinants of 
implementation (e.g., tension for change among clinic staff; staff capability, opportunity, and motivation) 
implementation champions will play a central role during the initial training period and throughout ongoing 
implementation. Their engagement with peer navigators will occur on a daily to weekly basis, and their role 
will be to promote high implementation fidelity, feasibility, acceptability, and appropriateness of the peer 
navigation strategy for TB-EC. This component is justified by its potential to mitigate social and motivational 
barriers that commonly impede adoption of new service-delivery approaches in high-burden TB-HIV settings. 
Table 2. Individual-level Components of the Peer-Navigation TB-EC Strategy. The components include (1) Peer navigators, persons 
with lived experience of TB, equipped with printed educational materials designed to facilitate the other three individual components of 
the experimental strategy, including (2) a 20-point knowledge & adherence checklist (Column 1), (3) individual adherence planning (#13-
17), and (5) behavior change messaging (Column 2), with the relevant behavior change mechanisms indexed by number to the Behavior 
Change Techniques Taxonomy.83 
GROUP TB/TB-HIV EDUCATION TOPICS CHECKLIST  
BEHAVIOR CHANGE MESSAGING & MECHANISMS 
Front Cover: Tuli Wamu Naawe 
“We are together with you” (3.1-3.3, Social support-general, practical, emotional) 
Peer Navigator Introduction 
“I have lived through TB & been trained to guide you.” (9.1, Credible source) 
Part 1: What you need to know about TB (Before testing) 
TB/HIV Disease Knowledge Module 
1. What is tuberculosis (TB)? How is TB spread? 
 
2. What is HIV/AIDS? How is HIV spread? 
 
3. What is the relationship between HIV & TB? 
 
4. What are signs & symptoms of TB disease? 
 
5. What are signs & symptoms of HIV/AIDS? 
 
6. How is TB diagnosed? HIV? How do I produce sputum for TB dx? 
“Let me show you” (6.1, Demonstrate & 4.1, Instruct to perform behavior) 
Summary: What you need to know about TB & HIV 
“TB is treatable & curable, just like malaria. (13.2, Framing via comparison) 
Take your drugs & you will be cured. (5.1, Information on health consequences) 
The drugs are free.” (1.2 Problem solving / barrier reduction) 
Part 2: Understanding how TB is treated & prevented (After testing) 
TB/HIV Treatment Knowledge Module 
7. How do health workers test for TB and give the right treatment? 
 
8. Why is HIV medicine important for people with TB/HIV?  
 
9. What do I eat or drink, & what do I avoid, while on TB/HIV medicine? 
 
10. Why is it important to not to miss your doses of TB/HIV medicine?  
“The pills only work if you take them. I took my medicine every day for six 
months, and now I am TB free.” (5.1, Information on health consequences) 
11. What are the possible side effects of TB/HIV medicine? 
“If you have any symptoms, stop your medicine & call/visit your health worker” 
(5.2, Make consequences salient) 
Summary:  How TB is treated and prevented 
 
INDIVIDUAL TB/TB-HIV COUNSELING TOPICS CHECKLIST 
EXAMPLES OF BEHAVIOR CHANGE MESSAGING & MECHANISMS 
Part 3: How to keep taking your TB/HIV medicine (After diagnosis)  
Individual Adherence Planning Module 
12. What is your personal goal in taking TB/HIV medicine? 
“Keep your eyes on the prize.” (1.1, Set goals for adherence & 1.3, outcome) 
13. Where will you store TB/HIV medicine while at home/away?  
“Do it the same way each time.” (8.3, Form habits) 
14. When will you take TB/HIV medicine & how will you remember?  
“Take the pills at first light before eating.” (7.1, Use prompts/cues) 
15. When do you need to return for refills & how will you get here? 
“Let us make a plan for your refill visit.” (1.4, Engage in action planning) 
16. Who can remind you about your medicine/refills & support you? 
“Let us find a friend or family member to support you.” (3.1, 3.2, 3.3, Social 
support - unspecified, practical, emotional) 
Part 4: How you are doing on your TB/HIV medicine (Follow-up visits) 
TB & HIV Monitoring Module 
17. How are you feeling?  
 
18. What challenges are you facing in taking your TB/HIV medicine? 
“Believe in yourself.” (15.1, Reinforce capability, & 15.4 Self-talk) 
19. Do you sometimes miss doses of your TB/HIV medicine? 
 
20. When are the TB/HIV monitoring visits? 
 
Peer Navigators Contact Information 
 
Back Cover: Tuli Wamu Naawe 
“We are together with you” (3.1-3.3, Social support-general, practical, emotional) 

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12 
Trainers from the Walimu study team will organize and deliver an on-site, in-person training on the peer 
navigation TB-EC at one new site per month, according to the waitlist scheme established during the 
randomization ceremony. This will include recruiting and training peer navigators, as well as training the health 
facility on how to work with and supervise them. After the in-person training, there will be a follow-up supervisory 
visit from the trainers 12 weeks after the peer navigators gain experience with the new components, but with the 
4-week cross-over period. 
Randomization & Blinding 
After 3 months of baseline data collection, we will select 16 sites for randomization. In previous trials, <5% of 
sites have been excluded for data quality. The unit of randomization is the clinic. As explained above; sites will 
be matched in pairs based on TB client volume (which is the primary measurable site-level factor that could 
influence outcomes) then randomly allocated to intervention or control, and finally to a start time.  
 
This sequence of allocation restricted by sites will be determined through a two-stage random drawing. In the 
first, so-called “Cluster Stage”, health facilities will be ordered from smallest to larges in client volume, and each 
assigned to a neighboring pair. The order with which these clusters will draw will be randomly determined, and 
then a representative of each health center in the pair will come forward to witness the draw of the intervention 
assignment, either experimental or usual care, until all sites are assigned to their intervention in their paired 
clusters. In the second and final stage, the two representatives of each cluster will assign one representative to 
draw, without replacement, 1 of 8 balls (labelled 1, 2, 3, 4, 5, 6, 7, 8) from an opaque bag to choose the sequence 
of launching the trial, at equally spaced, 4-week intervals during the trial period. 
 
Given the complex, behavioral nature of the intervention, it is not feasible to blind providers or participants to the 
intervention, although all data analyses will be blinded. 
 
Final allocation (January 30, 2026) 
Launch 
Date 
Facility Name 
Allocation 
3/16/26 
St Benedict 
Usual Care 
Nkozi 
Peer Navigation 
4/13/26 
Nawaikoke 
Usual Care 
Nakifuma 
Peer Navigation 
5/11/26 
Iganga Islamic 
Usual Care 
Kyanamukaka 
Peer Navigation 
6/8/26 
Butenga 
Usual Care 
Bukuya 
Peer Navigation 
7/6/26 
Kamuli 
Usual Care 
Nakaseke 
Peer Navigation 
8/3/26 
Mpigi 
Usual Care 
Bugiri 
Peer Navigation 
8/31/26 
Kiboga 
Usual Care 
Kawolo 
Peer Navigation 
9/28/26 
Mityana 
Usual Care 
Kasanda 
Peer Navigation 
Study Procedures  
Recruitment of Participants 
A research assistant at each site will work with routine healthcare workers at the study clinics to ensure 
that all eligible patients are consecutively screened and invited to participate in the proposed activities. 
Research assistants will oversee recruitment, informed consent procedures, and collection of all clinical and 
research data, with oversight by a full-time data manager overseeing all sites. 
 

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13 
The facility staff will be oriented to inclusion criteria and encouraged to enroll all eligible individuals to the study. 
To support these efforts, the research assistant at each site will review the TB treatment register daily to ensure 
that all eligible patients are being recruited and to coordinate with TB facility staff to approach and recruit any 
eligible individual not yet recruited whenever feasible. 
Cohort Retention 
At enrollment, site staff will be trained to ensure that all required demographic and personal contact information, 
including telephone numbers, place of residence, and the contact information for a treatment supporter are 
recorded in the TB and HIV registers according to national TB program and national HIV program guidelines.  
 
The timing of follow-up visits will be scheduled at enrollment according to routine TB program guidelines; 
however no additional efforts at retaining the cohort will be made outside of routine efforts conducted by clinic 
staff because minimizing losses-to-follow-up is among the primary study outcomes that the intervention seeks 
to change and we do not wish to contaminate our intervention with additional interventions that are not usual 
care, such as reminders from research staff to return. 
 
Data Collection 
Most data that we are collecting for study purposes is already collected as part of standard clinical care. 
Procedures that are part of standard clinical care include:  
• 
Baseline Clinical and Demographic Data. (client name, date of birth, sex, client category, disease 
classification, type of TB patient, risk group, referral, sputum smear result, GeneXpert result, HIV status, 
other comorbidities, client phone number, name of treatment supporter, treatment supporter type, 
treatment supporter’s phone number) 
• 
TB Treatment Initiation Data. (Unit TB number, ART number, date of initiation, DOT treatment model, TB 
regimen name, number of daily doses dispensed, date of next appointment) 
• 
TB Persistence Data. (date of actual follow-up visit, date of next appointment, side effects documented, 
ART regimen, number of daily doses dispensed, date of next appointment, smear microscopy result) 
• 
ART Initiation Data. (ART number, date of initiation, date of next appointment, ART regimen, number of 
daily doses dispensed, CD4 count, HIV RNA, DSD model) 
• 
ART Persistence Data. (ART number, date of actual follow-up visit, date of next appointment, side effects 
documented, ART regimen, number of daily doses dispensed, CD4 count, HIV RNA, differentiated service 
delivery (DSD) model) 
• 
12-Month Follow-Up Data. (TB-recurrence free survival, vital status) 
 
Procedures to be conducted solely for research purposes include:  
• 
Adherence Measures. 
o 7-day recall 
o Urinary INH and INH metabolites, measured by trained on-site RAs using point-of-care, urine 
colorimetric testing for isoniazid metabolites (Endana Labs, India)89, 
o Urinary tenofovir metabolites, measured by trained on-site Ras using point-of-care urine tenofovir 
ELISA testing (Monica Gandhi HAL Lab, UCSF). For logistical reasons, urinary assays are 
measured concurrently. 
• 
Overall Survival and TB Recurrence-Free Survival 
o Data collectors will telephone participants and/or treatment supporters to document TB 
recurrence-free survival using previously developed methods. 
• 
Peer Navigator Logbook (Peer navigator name, participant name, date, type of TB-EC: group vs. 
individual, module, duration) 

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14 
Study Outcomes  
Primary Outcomes 
Co-Primary Effectiveness Outcomes 
1. TB Treatment Success, defined according to WHO as the proportion of persons with TB initiated on TB 
treatment documented in the TB register as having achieved 
a. TB treatment completion (i.e., a person with TB completing TB treatment without evidence of failure), 
OR 
b. TB cure (i.e., a person with microbiologically confirmed TB who was smear-negative in the last month 
of treatment and on at least one previous occasion). 
c. The time frame of assessment will be at the end of TB treatment. 
2. ART Retention, defined as the proportion of participants living with HIV and initiated on ART who are  
a. Alive, and  
b. Receiving ART, as evidenced by a documented ART medication pickup or ART supply at a clinical 
visit recorded in the on-site ART register or on the ART treatment card. 
c. The time frame of assessment will be 6 months after ART initiation (±30 days). 
Secondary Outcomes 
Lead implementation outcomes  
1. TB Treatment Adherence, as measured by detectable urine isoniazid metabolite testing 5 months after 
TB treatment initiation (±30 days), as a proportion of all participants  
2. ART Adherence, as measured by detectable urine tenofovir testing 5 months after TB treatment initiation* 
(±30 days), as a proportion of all participants living with HIV initiated on ART. The time point 
 
Secondary effectiveness outcomes 
1. 6-month post-treatment TB recurrence-free survival, as a proportion of all participants  
2. 6-month post-ART initiation viral suppression (HIV RNA ≤50 copies/mL), as a proportion of persons living 
with HIV initiated on ART  
3. 12-month overall survival, as a proportion of all participants  
 
Secondary implementation outcomes 
TB implementation outcomes: 
1. TB Treatment Initiation within 2 weeks of TB diagnosis, as a proportion of all participants  
2. TB Treatment Adherence, as measured by  
a) Urine isoniazid metabolite testing 2 months after TB treatment initiation, within ±3 days of the 
scheduled refill date, as a proportion of all participants 
b) Urine isoniazid metabolite testing at both 2 months and 5 months after TB treatment initiation, 
within ±3 days of the scheduled refill date, as a proportion of all participants 
c) 7-day medication adherence recall66, assessed 2 months (±7 days) and 5 months (±30 days) after 
TB treatment initiation, as a proportion of all participants 
3. Persistence, defined as attending scheduled TB medication refill visits within ±3 days of the scheduled 
monthly refill date, as a proportion of all participants  
HIV implementation outcomes: 
1. ART Initiation within 2 weeks of TB treatment initiation, as a proportion of all participants living with HIV  
2. ART Adherence, as measured by  
a) Urine tenofovir testing 2 months after TB treatment initiation*, within ±7 days of the scheduled refill 
date, as a proportion of all participants living with HIV initiated on ART 
b) Urine tenofovir testing at both 2 months and 5 months after TB treatment initiation*, within ±7 days 
of the scheduled refill date, as a proportion of all participants living with HIV initiated on ART 
c) 7-day medication adherence recall66, assessed 2 months (±7 days) and 5 months (±30 days) after 
TB treatment initiation, as a proportion of all participants living with HIV initiated on ART 
3. Persistence, defined as attending ART refill visits within ±7 days of scheduled quarterly refill dates, as a 
proportion of all participants living with HIV initiated on ART. 

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15 
Specification and Timing of Measurements and Outcomes† 
 
Month 0 
Month 2 
Month 3 
Month 5 
Month 6 
Month 8 
Month 9 
Month 12 
Confirm eligibility and enroll ≤30 days after TB treatment initiation 
X 
 
 
 
 
 
 
 
Measurements (Timed from TB Diagnosis date) 
 
 
 
 
 
 
 
 
Clinical & Demographic Data, including multiple telephone contacts  
X 
X 
 
 
X 
 
 
 
TB Effectiveness Outcomes 
 
 
 
 
 
 
 
 
1º: TB Treatment Success (Treatment Completion + Cure) 
 
 
 
 
X 
X 
 
X 
2º: TB Recurrence-free Survival 
 
 
 
 
 
 
 
X 
2º: Overall Survival 
 
 
 
 
 
 
 
X 
TB Implementation Outcomes 
 
 
 
 
 
 
 
 
1º: Adherence Measures (Urine INH metabolites89, 7-day Recall66) 
 
X 
 
X 
 
 
 
 
2º: Initiation Measure (TB Treatment Initiation ≤2 weeks) 
 
X 
 
 
 
 
 
 
2º: Persistence Measures (Attendance of refill visits) 
 
X 
X 
X 
X 
 
 
 
Measurements (Timed from ART Initiation date, except as indicated) 
 
 
 
 
 
 
 
 
ART Effectiveness Outcomes 
 
 
 
 
 
 
 
 
1º: ART Retention 
 
 
X 
 
X 
X 
 
X 
2º: Virally suppressed (HIV RNA ≤50 copies/mL) 
 
 
 
 
X 
 
 
 
2º: Overall Survival (Timed from TB diagnosis date) 
 
 
 
 
 
 
 
X 
ART Implementation Outcomes 
 
 
 
 
 
 
 
 
1º: Adherence Measures (Urine TFV90*, 7-day Recall66) 
 
X 
 
X 
 
 
 
 
2º: Initiation Measure (ART Initiation ≤2 weeks) 
X 
 
 
 
 
 
 
 
2º: Persistence Measures (Attendance of refill visits) 
 
 
X 
 
X 
 
X 
X 
Legend: *Urine-based adherence biomarkers for both TB and ART will be collected at the same scheduled TB treatment visit (2 months 
after TB treatment initiation ±7 days and 5 months after TB treatment initiation ±30 days) to simplify field procedures and minimize 
missed measurements. Because urine tenofovir assays reflect recent ingestion (approximately 48–72 hours), the exact timing relative 
to ART initiation does not materially affect the interpretation of the adherence measure. †Where multiple outcomes are listed, bolded 
outcomes and X’s indicate the primary measure and timepoint for that outcome. 
Aim 1 Sample Size Estimates and Statistical Analysis Plan 
Sample Size Estimates 
We estimate that a trial with 16 sites (8 per arm) and ~140 eligible patients/site over the 12-month recruitment 
period will result in ≥2,246 PWTB recruited. Accounting for 15% attrition due to voluntary study withdrawals, 
≥1920 enrolled PWTB will give ≥80% power at alpha 0.05 to detect a ≥15% increase in TB completion from a 
baseline of 75% at usual care sites to 90% at peer-navigation sites, assuming an intraclass correlation coefficient 
(ICC) of 0.001.59 For ART retention at 6 months, we project ≥36 PWTB-HIV per site (already accounting for 
voluntary withdrawals) will provide ≥578 enrolled PWTB-HIV and give ≥80% power to detect a ≥12% increase 
from 50% for standard TB-HIV/TB-EC to ≥62% at peer-navigation sites. Power calculations are adjusted to 
support 2 co-primary outcomes using a Bonferroni correction for multiple hypothesis testing.91,92 For the 
secondary implementation outcome of ART initiation within 2 weeks, 302 PWTB-HIV who are newly HIV-
diagnosed and ART-naïve (i.e., 35% of PLH) will give >90% power to detect a ≥15% increase from 75% with 
standard TB-EC to 90% with peer navigation. 
 
Statistical Analysis Plan 
The unit of randomization is the health facility. The unit of analysis is the individual participant with pulmonary 
TB (PWTB). Analyses will account for clustering at the facility level using mixed-effects models with facility-level 
random intercepts. 
 

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16 
We will assess the effectiveness of the peer-navigation strategy vs. usual care using two separate log-binomial, 
mixed-effects regression models, with TB treatment success and ART retention as the two outcome variables 
and study arm (peer-navigation strategy vs. usual care) as the independent variable in each model; the ART 
retention and other subsequent ART models will only include participants with confirmed HIV. Our primary 
analysis will consider the intention-to-treat population; as a secondary analysis, we will consider the per-protocol 
population including any PWTB with ≥1 documented interaction with a peer navigator. We will also conduct per-
protocol analyses excluding persons who transferred their TB care out to another TB unit (for the TB outcome 
model) or their HIV care out to another HIV clinic (for the ART outcome model). 
 
We will construct similar log-binomial, mixed-effects regression models for the implementation outcomes of 
treatment initiation (for TB treatment and for ART) and adherence. Each model will include a random intercept 
to account for clustering within sites, inducing a working exchangeable matrix. We will use robust score tests93 
to estimate intervention effects and assess the significance of the difference between the peer-navigation 
strategy and usual care, adjusting for multiple testing using the Bonferroni correction. In secondary analyses, we 
will include interaction terms of the intervention arms with pre-specified participant-level (e.g., age, sex, HIV 
status), peer-level (e.g., age, sex), and clinic-level characteristics (e.g., clinic volume, facility type, rural vs. urban 
location, public vs. private/not-for-profit ownership) to determine sources of heterogeneity of effects, again 
assessing statistical significance using robust score tests. Because participants may interact with different peer 
navigators across visits, we will investigate the heterogeneity of the causal effect for the characteristics of the 
peer navigator assigned at the first visit or for the average characteristics of peer navigators across all visits for 
each participant. Although the study is cluster-randomized, in secondary analyses, we will adjust for confounding 
by other known or hypothesized determinants of the outcome variables for the intervention-outcome effect 
estimates, focusing on those where we observe baseline imbalances. 
We will report study findings using the CONSORT guidelines for cluster-randomized trials, including the 
embedded recommendations for pragmatic trials.94,95 We will record and document reasons for losses to follow‑
up and missing covariates. As part of our examination of missing data, we will assess differences in baseline 
characteristics across treatment arms. We will use two-sample t-tests (or Wilcoxon rank-sum tests) for 
continuous variables and χ2 tests for categorical variables. In secondary analysis, we will use inverse probability 
weighting (IPW)96,97 to adjust for possible selection bias due to loss to follow-up and missing covariate values in 
the secondary covariate-adjusted analyses, to examine the impact of these potential sources of bias on the 
estimates and tests. We will also use multiple imputation as an additional sensitivity analysis to explore the 
impact of this alternative method for handling loss to follow‑up and missing covariate data on the results.98 
 
Trial Reporting 
Trial reporting will follow the CONSORT guidelines for cluster-randomized trials. A participant flow diagram will 
document the number of clusters randomized, clusters initiating the intervention, participants screened, enrolled, 
allocated to each study arm, completing follow-up, and included in analyses. 
 
Aim 2. Within the Aim 1 study, we will conduct a longitudinal observational study nested in both arms of the 
cluster-randomized trial to assess the feasibility, acceptability, and appropriateness of a peer-navigation strategy 
for TB-EC. We will concurrently assess biological adherence using urine biomarkers. We will also perform a 
mediation analysis of social and behavioral factors (i.e., TB knowledge, perceived social support, general self-
efficacy, HIV/TB stigma) to identify causal mechanisms of impact.  
 
Aim 3. The team will also conduct a qualitative and mixed-methods studies to assess the implementation 
fidelity and context of the peer-navigation strategy for TB-EC: 
a. Process evaluation of intervention fidelity to quantify the adoption, reach, implementation, and 
maintenance of the peer navigation strategy,  
b. In-depth interviews with PWTB with and without HIV,  
c. In-depth interviews with and direct observation of peer navigators, and  
d. Focus-group discussions (FGDs) with healthcare workers. 
 

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