David W. Dowdy

Background: People living with HIV (PLHIV) have an increased risk of developing active tuberculosis (TB). To reduce the burden of TB among PLHIV, the World Health Organization (WHO) recommends systematic TB screening followed by (1) confirmatory TB testing for all who screen positive and (2) TB preventive therapy (TPT) for all TPT-eligible PLHIV who screen negative. Symptom-based screening remains the standard of care in most high TB burden settings, including Uganda. Despite having high sensitivity for active TB among antiretroviral-naïve PLHIV, symptom screening has poor specificity; as such, many high-risk PLHIV without active TB are not referred for TPT. C-reactive protein (CRP) is a promising alternative strategy for TB screening that has comparable sensitivity and higher specificity than symptom screening, and was endorsed by WHO in 2021. However, the impact of CRP-based TB screening on TB burden for PLHIV remains unclear. Methods: TB SCRIPT (TB Screening Improves Preventive Therapy Uptake) is a phase 3, multi-center, single-blinded, individual (1:1) randomized controlled trial evaluating the effectiveness of CRP-based TB screening on clinical outcomes of PLHIV. The trial aims to compare the effectiveness of a TB screening strategy based on CRP levels using a point-of-care (POC) assay on 2-year TB incidence and all-cause mortality (composite primary trial endpoint) and prevalent TB case detection and uptake of TPT (intermediate outcomes), relative to symptom-based TB screening (current practice). Discussion: This study will be critical to improving selection of eligible PLHIV for TPT and helping guide the scale-up and integration of TB screening and TPT activities. This work will enable the field to improve TB screening by removing barriers to TPT initiation among eligible PLHIV, and provide randomized evidence to inform and strengthen WHO guidelines. Trial registration: ClinicalTrials.gov NCT04557176. Registered on September 21, 2020.

Efficient and effective strategies for identifying cases of active tuberculosis (TB) in rural sub-Saharan Africa are lacking. Household contact tracing offers a potential approach to diagnose more TB cases, and to do so earlier in the disease course. Adults newly diagnosed with active TB were recruited from public clinics in Vhembe District, South Africa. Study staff visited index case households and collected sputum specimens for TB testing via smear microscopy and culture. We calculated the yield and the number of households needed to screen (NHNS) to find one additional case. Predictors of new TB among household contacts were evaluated using multilevel logistic regression. We recruited 130 index cases and 282 household contacts. We identified 11 previously undiagnosed cases of bacteriologically-confirmed TB, giving a prevalence of 3.9% (95% CI: 2.0–6.9%) among contacts, a yield of 8.5 per 100 (95% CI: 4.2–15.1) index cases traced, and NHNS of 12 (95% CI: 7–24). The majority of new TB cases (10/11, 90.9%) were smear negative, culture positive. The presence of TB symptoms was not associated with an increased odds of active TB (aOR: 0.3, 95% CI: 0.1–1.4). Household contacts of recently diagnosed TB patients in rural South Africa have high prevalence of TB and can be feasibly detected through contact tracing, but more sensitive tests than sputum smear are required. Symptom screening among household contacts had low sensitivity and specificity for active TB in this study.