# Rapid molecular testing or chest X-ray or tuberculin skin testing for household contact assessment of tuberculosis infection: A cluster-randomized trial

## TL;DR

This study compares three testing strategies for household contacts of tuberculosis patients to determine which is most effective for starting preventive treatment.

## Contribution

The study provides high-quality evidence that rapid molecular tests can replace chest X-rays in evaluating household contacts of TB patients.

## Key findings

- Over 94% of eligible household contacts started TB preventive therapy across all strategies.
- Rapid molecular tests had lower societal costs compared to standard and no-TST strategies.
- The no-TST strategy had 13% lower completion of preventive therapy compared to the others.

## Abstract

The World Health Organization recommends evaluation of all household contacts (HHC) of index tuberculosis (TB) patients for TB disease (TBD) and TB infection (TBI). Tests to identify TBI and TBD are preferred but can be skipped in persons living with HIV and children <5 years. There is equipoise on the need for these tests in other HHC.

We conducted a superiority, open label cluster-randomized trial in Benin and Brazil to compare three strategies to evaluate HHC aged 5–50 of persons newly diagnosed with drug susceptible pulmonary TBD: Standard: tuberculin skin testing (TST) for TBI and if positive, chest X-ray (CXR) to rule out TBD; rapid molecular test (RMT): same as Standard, except CXR replaced by an RMT; and No-TST: CXR for all but no TST. Randomization was computer-generated and stratified by country, in blocks of variable length. The primary outcome was TB preventive therapy (TPT) initiation among HHC considered eligible (positive TST, if done, and no evidence of TBD on CXR or RMT). Secondary outcomes were: completion of investigations to detect TBI and TBD, detection of TBD, TPT completion, severe adverse events, and societal costs.

Among 1,589 participating HHC enrolled from 29 January 2020, to 30 November 2022, 474 were randomized to the standard, 583 to the RMT, and 532 to the no-TST strategies; all were included in the analyses. Of 848 HHC considered eligible for TPT, 802 (94.6%) initiated TPT, with no difference between strategies (95%, 94%, and 95% for the standard, RMT, and no-TST strategies, respectively). Of the secondary outcomes, protocol-mandated investigations to detect TBI and exclude possible TBD were completed for 93.4% overall, with slight differences between arms (93%, 95%, and 93% for the standard, RMT, and no-TST strategies, respectively). Adverse events resulting in discontinuation of TPT occurred in 3 (0.4%) participants in total (with 1, 0, and 2 events among participants in the Standard, RMT, and no-TST arms, respectively). The proportion completing TPT was similar with Standard and RMT strategies but was 13% lower (95% confidence interval: 3% to 23% lower) with the No-TST strategy. Societal costs per HHC completing investigations were $61 ($56–$65) with the standard strategy, compared to $52 ($49–$55) with the RMT strategy and $74 ($72–$77) with the no-TST strategy.

This randomized trial provides high-quality evidence that TST followed by selected use of CXR or an RMT to exclude disease can achieve high rates of TPT initiation at reasonable costs. A limitation of the trial is the potential study effect, which may have affected adherence by providers and HHCs. RMT could replace CXR in the management of HHC in resource limited settings.

clinicaltrials.gov NCT04528823

There are many potential barriers in the investigation of household contacts (HHC) of persons with TB disease. These barriers often result in HHC not starting TB preventive treatment (TPT), which is recommended by the World Health Organization (WHO), because HHC are at high risk of developing TB disease themselves. We conducted an open-label cluster randomized trial in Benin and Brazil to compare three strategies of investigation and management of HHC. The three strategies were the standard strategy recommended by WHO, an experimental strategy using a rapid molecular test (RMT) instead of chest X-ray (CXR), and an experimental strategy of CXR performed in all HHC, but no Tuberculin skin testing (no-TST). We enrolled 1,589 HHC, of whom 474 were randomized to the standard arm, 583 to the RMT arm, and 532 to the no-TST arm. Among the HHC who were considered to have TB infection, but not disease more than 95% started TPT, of whom only 68% completed this treatment. The proportion who started TPT was the same in three strategies, although completion was lower in the no-TST strategy. Only three persons stopped therapy because of side effects of the medications. Overall costs for the strategies were lowest with the RMT, and highest with the noTST. We conclude that more intense investigations can identify people at higher risk for TB disease, and do not pose a barrier if services are well organized. Rapid molecular tests appear promising to replace CXR in the management of HHC, and may resolve a long-standing bottleneck in many countries.

In an open-label, cluster randomized trial, three different strategies to evaluate tuberculosis (TB) infection and disease in household contacts of persons with newly diagnosed TB were assessed for their effects on the initiation of TB preventive therapy.