TB Screening Improves Preventive Therapy Uptake

Study Overview
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Brief Summary
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HIV-infected people have an increased risk of developing active tuberculosis (TB). To reduce the burden of TB among people living with HIV (PLHIV), the World Health Organization (WHO) recommends systematic TB screening followed by 1) confirmatory TB testing for all those who screen positive and 2) TB preventive therapy (TPT) for all TPT-eligible PLHIV who screen negative. The objective of the TB Screening Improves Preventive Therapy Uptake (TB SCRIPT) trial is to determine whether TB screening based on C-reactive protein (CRP) levels, measured using a rapid and low-cost point-of-care (POC) assay, improves TPT uptake and clinical outcomes of PLHIV, relative to symptom-based TB screening.

Detailed Description
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The overall objective of the TB SCRIPT trial is to evaluate the effectiveness and cost-effectiveness of POC CRP-based TB screening, which is the next step required for successful scale-up of both systematic TB screening and TPT. The study's central hypothesis is that compared to symptom-based TB screening, a TB screening strategy based on CRP levels measured at the point-of-care will improve TPT uptake, thereby reducing TB incidence and its associated mortality among PLHIV. To test this hypothesis, the investigators will conduct an individual randomized control trial enrolling PLHIV presenting to clinics in Uganda for routine antiretroviral therapy (ART) initiation. Eligible participants will be randomized to either POC CRP-based TB screening (intervention arm) or symptom-based TB screening (control arm). In both arms, screen-positive participants will undergo confirmatory TB testing; participants found to have prevalent TB will be initiated on standard TB treatment. In both arms, screen-negative participants will be assessed for TPT eligibility; TPT-eligible participants will be initiated on standard TPT. All participants will be followed for 2 years.

Official Title
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TB Screening Improves Preventive Therapy Uptake Trial

Conditions
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HIV, Tuberculosis, Latent Tuberculosis, Tuberculosis Prevention

Intervention / Treatment
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* Device: CRP, point-of-care assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Confirmed HIV+ test result CD4 T lymphocyte count of ≤ 350 cells/μL Capacity to provide written (or witnessed verbal, if illiterate) informed consent Exclusion Criteria: Completed treatment for active pulmonary or extra-pulmonary TB within the past 2 years Completed a full course of TPT within the past year Actively taking any internationally-approved medication for TB treatment for any reason, within 2 weeks of study entry Prior history of combined ART for HIV treatment for any duration (does not include single-dose ART for prevention of vertical transmission of HIV) Currently resides 25 km outside their enrollment site, plans to move 25 km outside their enrollment site in the next 2 years, or plans to transfer their HIV care from their current enrollment site

Ages Eligible for Study
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Minimum Age: 18 Years

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: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: POC CRP-based TB screening<br>Participants randomized to the intervention arm will undergo POC CRP-based TB screening at study entry. Participants with elevated POC CRP levels (≥8 mg/L) will be regarded as screen-positive and will be referred for confirmatory TB testing. Participants with non-elevated POC CRP levels (<8 mg/L) will be regarded as screen-negative and will be assessed for TPT eligibility. | Device: CRP, point-of-care assay<br>* CRP is a non-specific marker of inflammation whose levels rise in the setting of interleukin 6 (IL-6)-mediated inflammation, such as active TB. In clinical settings, CRP is used to identify patients with systemic inflammation from infection or non-infectious cases. In settings with high TB prevalence, the investigators hypothesize that CRP can be used to accurately screen individuals for active TB (i.e., distinguish individuals with high likelihood of having active TB from those individuals unlikely to have active TB).<br>* Other names: Boditech Med Inc.;|
| No Intervention: Symptom-based TB screening<br>Participants randomized to the control arm will undergo symptom-based TB screening at study entry. Participants reporting ≥1 TB symptom (current cough, fever, night sweats, weight loss) will be regarded as screen-positive and will be referred for confirmatory TB testing, in accordance with WHO guidelines. Participants with none of the 4 TB symptoms will be regarded as screen-negative and will be assessed for TPT eligibility. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiologically-confirmed incident TB and all-cause mortality | Time to first diagnosis of microbiologically-confirmed incident TB or death from any cause | two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TB incidence: number diagnosed | Number diagnosed with microbiologically-confirmed incident TB | two years | 
| TB incidence: incidence | Incidence of microbiologically-confirmed TB (excluding prevalent TB cases) | two years | 
| TB incidence: Time to microbiologically-confirmed incident TB diagnosis | Days from three months post-enrollment to incident TB diagnosis (or censoring) | two years | 
| TB incidence: incidence rate | Incident rate of microbiologically-confirmed TB | two years | 
| TB incidence: drug resistant TB | Number diagnosed with drug-resistant incident TB | two years | 
| TB incidence: drug resistant TB among people receiving TPT | Proportion of participants receiving TPT diagnosed with incident drug resistant TB | two years | 
| Mortality: number of deaths from any cause | Number who died from any cause | two years | 
| Mortality: time to death from any cause | Number of days from enrollment to death from any cause | two years | 
| Mortality: all-cause death rate | Rate of deaths from any cause | two years | 
| Mortality: number who died from TB | Number who died from confirmed or probable TB | two years | 
| TPT uptake: number screen-negatives prescribed TPT | Number of screen-negatives prescribed TPT | two years | 
| TPT uptake: number screen-positives prescribed TPT | Number screen-positives prescribed TPT | two years | 
| TPT uptake: number initiated on TPT | Number screen-negatives prescribed TPT + number screen-positives prescribed TPT | two years | 
| TPT uptake: time to TPT initiation | Days from baseline TB screening to initiation of TPT | two years | 
| TPT uptake: number completing TPT | Number initiated on TPT who completed ≥90% of treatment over prescribed TPT period | two years | 
| Prevalent TB diagnosis: number microbiologically-confirmed prevalent TB cases detected by screening test | Number screen-positives diagnosed with prevalent TB | two years | 
| Prevalent TB diagnosis: number microbiologically-confirmed prevalent TB cases missed by screening test | Number screen-negatives diagnosed with prevalent TB | two years | 
| Prevalent TB diagnosis: number diagnosed with microbiologically-confirmed prevalent TB | Number screen-positives diagnosed with prevalent TB + number screen-negatives diagnosed with prevalent TB | two years | 
| Prevalent TB treatment: Number treated for prevalent TB | Number initiated on TB treatment 3 months or less after study entry | two years | 
| Prevalent TB treatment: number with microbiologically-confirmed prevalent TB completing treatment | Number diagnosed and treated who completed treatment | two years | 
| Prevalent TB treatment: time to treatment of microbiologically-confirmed prevalent TB | Days from prevalent TB diagnosis to initiation of TB treatment | two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Tuberculosis, Latent tuberculosis, Tuberculosis preventive therapy, C-reactive protein, Symptom screening, Intensified case finding