Closing -TB GAPs - for People Living With HIV: TB Guidance for Adaptable Patient-Centered Service

Study Overview
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Brief Summary
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Tuberculosis (TB) is the world's leading infectious cause of mortality and responsible for 1/3 of deaths in people living with human immunodeficiency virus (PLHIV). Children and adolescents living with HIV (CALHIV) are disproportionately affected due to inadequate preventive services, large case detection gaps, treatment and adherence challenges, and knowledge gaps. This project will generate evidence to inform interventions targeting several of these weaknesses in the TB/HIV cascade of care. Early detection and treatment of TB improve outcomes in people living with HIV (PLHIV). A key challenge in the detection of HIV-associated TB has been the implementation of screening that identifies the correct population for diagnostic testing. Increasing evidence demonstrates the poor performance of recommended symptom screens and diagnostic approaches. Hence, the investigators aim to define a more accurate TB screening and testing strategy among PLHIV (Objective 1 and Objective 2). TB preventive treatment (TPT) averts HIV-associated TB. Nevertheless, among PLHIV, TPT initiation and completion rates are sub-optimal and effective delivery strategies are not defined. As such, the investigators aim to identify the most effective TPT delivery strategy through shared decision making and by integrating approaches proven to be effective at improving HIV treatment adherence (Objective 3). Although evidence demonstrates that isoniazid preventive therapy (IPT) is cost-effective in young children living in TB/HIV high burden settings, the cost-effectiveness of newer short-course TPT has primarily been studied in the context of a TB low-burden, high-income setting. The investigators aim to generate evidence to fill this knowledge gap and inform policy for PLHIV living in TB/HIV high burden settings (Objective 4). This study is supported by the Centers for Disease Control and Prevention of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award totaling an anticipated $5,000,000 over five years with 100 percent funded by CDC/HHS.

Official Title
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Closing -TB GAPs - for People Living With HIV: TB Guidance for Adaptable Patient-Centered Service

Conditions
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Tuberculosis, HIV Coinfection, Tuberculosis Infection

Intervention / Treatment
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* Other: patient-centered TB preventive therapy
* Other: TB preventive therapy adherence support


Participation Criteria
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Eligibility Criteria
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OBJECTIVES 1 and 2: Inclusion Criteria: HIV positive or HIV exposed and presumptively positive while awaiting confirmatory testing in infants Exclusion Criteria: do not provide informed consent or assent as appropriate or are currently being treated for TB OBJECTIVE 3: Inclusion Criteria: negative TB symptom screen OR for whom TB disease has been ruled out in accordance with WHO Guidelines in adults and according to consensus definitions for child TB Exclusion Criteria: do not provide informed consent or assent as appropriate or are currently being treated for TB
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The study will be implemented within a non-randomized stepped-wedge pragmatic intervention study design with nested randomized screening, diagnostic and adherence studies.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of care<br>No intervention will be administered. Observational data regarding TPT uptake and adherence will be captured on all participants presenting for care | |
| Experimental: TB screening and evaluation followed by TPT via a decentralized delivery system<br>The intervention phase includes i) enrolling participants who have had TB disease excluded and allowing participant selection of a preferred TPT regimen, and ii) randomizing participants to one of two participant adherence support modalities. | Other: patient-centered TB preventive therapy<br>* The intervention phase includes i) enrolling participants who have had TB disease excluded and allowing participant selection of a preferred TPT regimen, and ii) randomizing participants to one of two participant adherence support modalities.<br>Other: TB preventive therapy adherence support<br>* As part of this study, enhanced adherence support will be provided via bi-directional messaging and/or via clinic phone calls. All participants randomized to enhanced adherence support will receive a weekly text reminder beginning seven days after the initiation. Each message will ask participants if they would like to be contacted to discuss any questions and will prompt participants to ask questions by text if more convenient or preferable. All text-based questions from participants will be answered by a trained nurse with back up from a physician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TB screening | Sensitivity of C-reactive protein for TB screening compared to the sensitivity of the WHO symptom screening using the McNemar test | 24-32 months | 
| TB diagnosis | Sensitivity of Xpert Host Response Cartridge compared with the sensitivity of Xpert Ultra on sputum or on gastric aspirate using the McNemar test | 24-32 months | 
| TPT prevention outcomes | Comparing TPT completion rates in participants randomized to bi-directional messaging support vs. standard support | 48 months | 
| Cost-effectiveness | Estimating the incremental cost-effectiveness of new shortened TPT regimens measured as cost per DALYS averted for each TPT strategy and the enhanced participant support modality compared with current standard of care | 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants selecting 3HP and the proportion selecting 6H when offered a choice within a decentralized model |  | 48 months | 
| Proportion of participants completing 6H and the proportion completing 3HP among participants randomized to standard support vs. bidirectional messaging | Treatment completion will be defined as receipt of at least 80% of doses during a pre-specified period of time and consistent with WHO definitions. | 48 months | 
| Proportion of participants initiated on TPT in the control phase vs. the intervention phase | Initiation rates will be estimated by the number of participants initiating TPT divided by the number of instances that TPT was offered | 48 months | 
| Description of the number of participants with different TB treatment and TPT outcomes at the completion of respective therapies | At individual study end point or at study closure, participants will be classified as i) retained in care, ii) died, iii) lost to follow-up, or iv) transferred out. | 48 months | 
| Number of life years saved through novel TPT approaches |  | 32 months | 
| Number of active TB cases averted through novel TPT approaches |  | 32 months | 
| Measure the association between participant factors and screening and diagnostic positivity rates | Participant factors are inclusive but not limited to TB infection status, immunologic, virologic, demographic, socioeconomic and clinical factors. The screening and diagnosis approaches are: point of care C-reactive protein, chest radiography, Fuji-LAM, Xpert Ultra performed on oral swabs and stool specimens and ultrasound. | 24-32 months | 
| Laboratory turnaround time | For all screening and diagnostic tests of the study | 24-32 months | 
| Result reporting rate | For all screening and diagnostic tests of the study | 24-32 months | 
| Time-to-treatment initiation | For all screening and diagnostic tests of the study | 24-32 months | 
| Diagnostic performance of mask sampling with differing forms of quiet and forced expiration (i.e., talking, singing) against standard approaches of sampling |  | 24-32 months | 
| Compare alternative stool processing techniques and molecular diagnostics/tests of MTB resistance against clinical and microbiologic reference standards | Done using de-identified stool collected and bio-banked during the study. | 24-32 months | 
| Compare Alere-LAM diagnostic accuracy with that of the SILVAMP-LAM with both spot and early-morning urine samples |  | 24-32 months | 
| Analyze different processing approaches for oral swabs prior to testing by Xpert Ultra vs. other microbiological diagnostic and drug susceptibility tests |  | 24-32 months | 
| Compare clinician read of chest radiograph with point-of-care ultrasound interpretation to determine agreement and additive yield of each method | this outcome will be studied only in Eswatini and Malawi | 24-32 months | 
| Prevalence of extrapulmonary TB by means of point of care ultrasound in participants diagnosed with TB |  | 24-32 months | 
| Assess ultrasound inter-reader agreement between hands-on operators |  | 24-32 months | 
| Assess ultrasound inter-reader agreement between hands-on operators AND remote expert reviewers |  | 24-32 months | 
| Compare the proportion of clinician and computer aided detection chest radiograph interpretation with algorithmic approaches against clinical and microbiologic reference standards |  | 24-32 months | 
| Sensitivity of point of care CRP versus the WHO symptom screening | CRP will be performed on whole blood using the FDA approved POC iChroma assay. A CRP of > 10 mg/L will be considered positive | 24-32 months | 
| Specificity of point of care CRP versus the WHO symptom screening | CRP will be performed on whole blood using the FDA approved POC iChroma assay. A CRP of > 10 mg/L will be considered positive | 24-32 months | 
| Area under the receiver operator curve of point of care CRP versus the WHO symptom screening | CRP will be performed on whole blood using the FDA approved POC iChroma assay. A CRP of > 10 mg/L will be considered positive | 24-32 months | 
| Sensitivity of chest radiography versus the WHO symptom screening | Chest radiography will be interpreted as normal or abnormal for the purposes of TB screening and will be evaluated using a standardized interpretation form | 24-32 months | 
| Area under the receiver operator curve of chest radiography versus the WHO symptom screening | Chest radiography will be interpreted as normal or abnormal for the purposes of TB screening and will be evaluated using a standardized interpretation form | 24-32 months | 
| Specificity of chest radiography versus the WHO symptom screening | Chest radiography will be interpreted as normal or abnormal for the purposes of TB screening and will be evaluated using a standardized interpretation form | 24-32 months | 
| Sensitivity of SILVAMP-LAM versus the WHO symptom screening |  | 24-32 months | 
| Area under the curve of SILVAMP-LAM versus the WHO symptom screening |  | 24-32 months | 
| Specificity of SILVAMP-LAM versus the WHO symptom screening |  | 24-32 months | 
| Sensitivity of Xpert Ultra performed on an oral/buccal swab versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Specificity of Xpert Ultra performed on an oral/buccal swab versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Area under the ROC curve of Xpert Ultra performed on an oral/buccal swab versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Sensitivity of Xpert Ultra performed on stool versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Specificity of Xpert Ultra performed on stool versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Area under the receiver operator curve of Xpert Ultra performed on stool versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Sensitivity of LF-LAM versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Specificity of LF-LAM versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Area under the receiver operator curve of LF-LAM versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Sensitivity of Xpert Ultra performed on a gelatin filter removed from a participant's mask versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Specificity of Xpert Ultra performed on a gelatin filter removed from a participant's mask versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Area under the receiver operator curve of Xpert Ultra performed on a gelatin filter removed from a participant's mask versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Sensitivity of point of care ultrasound versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Specificity of point of care ultrasound versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Area under the receiver operator curve of point of care ultrasound versus Xpert Ultra completed on sputum or gastric aspirate |  | 24-32 months | 
| Sensitivity of Xpert Host Response Cartridge on blood specimen versus Xpert Ultra completed on sputum or gastric aspirate | The blood specimen is collected at the time of positive screening | 24-32 months | 
| Specificity of Xpert Host Response Cartridge on blood specimen versus Xpert Ultra completed on sputum or gastric aspirate | The blood specimen is collected at the time of positive screening | 24-32 months | 
| Area under the receiver operator curve of Xpert Host Response Cartridge on blood specimen versus Xpert Ultra completed on sputum or gastric aspirate | The blood specimen is collected at the time of positive screening | 24-32 months | 
| Sensitivity of chest radiography for TB screening compared to the sensitivity of the WHO symptom screening using the McNemar test |  | 24-32 months | 
| Sensitivity of SILVAMP-LAM for TB screening compared to the sensitivity of the WHO symptom screening using the McNemar test |  | 24-32 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB/HIV co-infection, pediatric tuberculosis, tuberculosis preventive therapy