TB Screening Improves Preventive Therapy Uptake (TB SCRIPT)

Makerere University, Infectious Diseases Research Collaboration, Uganda, Johns Hopkins University, National Heart, Lung, and Blood Institute (NHLBI)

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.

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.

Tuberculosis, Latent tuberculosis, Tuberculosis preventive therapy, HIV, C-reactive protein, Symptom screening, Intensified case finding

Masking will be maintained by administering finger prick tests to all participants, irrespective of trial arm. Intervention arm participants will have CRP levels measured from blood obtained by finger prick. Control arm participants will have beta-human chorionic gonadotropin (beta-hCG) levels measured from blood obtained by finger prick. Only participants, study investigators and routine clinical care providers will be masked. Study staff performing TB screening in accordance with the participant's randomization assignment and activities downstream of TB screening (i.e., confirmatory TB testing, TPT eligibility assessment) will not be masked. The database administrator will have access to the randomized assignments.

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.

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.

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).

Prevalent TB diagnosis: number microbiologically-confirmed prevalent TB cases detected by screening test

Prevalent TB diagnosis: number microbiologically-confirmed prevalent TB cases missed by screening test

Number screen-positives diagnosed with prevalent TB + number screen-negatives diagnosed with prevalent TB

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

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