Risk-Targeted Preventive TB Treatment Works, Particularly With Infection Testing

Treating all household contacts of someone with tuberculosis (TB) helped prevent active TB disease across age groups in the real world, but the effectiveness was highest when treating individuals who tested positive for infection, according to a meta-analysis utilizing individual participant-level data.

Overall effectiveness of risk-targeted treatment in preventing TB disease was 49% (adjusted hazard ratio [aHR] 0.51, 95% CI 0.44-0.60), reported Leonardo Martinez, PhD, MPH, of the Boston University School of Public Health, and colleagues.

Individuals with a skin or blood test positive for infection gained more from preventive treatment, with 80-91% effectiveness in disease prevention, the findings in Lancet Respiratory Medicine showed.

And that was consistent across age groups, although WHO guidelines generally recommend preventive treatment most strongly for those under 5 years of age living in a household with a confirmed TB patient, regardless of TB testing availability. The U.S. Preventive Services Task Force also recommends screening for latent TB in adults who are high-risk for infection due to a weakened or compromised immune system or living in close contact with those who may have TB.

Latent TB, when Mycobacterium tuberculosis bacteria are present but inactive in a patient’s body, will lead to a positive TB test result but is not contagious. While patients may report no symptoms, they can develop active disease if untreated. Latent TB, along with subclinical TB in asymptomatic but potentially contagious patients, poses serious challenges to managing the spread of the disease across the globe and in the U.S., which in 2023 had its highest number of cases in a decade.

“Tuberculosis affects tens of millions of people every year and has long-term lasting effects, even after people recover,” said Martinez in a press release. “Finding ways to optimize prevention is really important to tackle the epidemic.”

Prevention strategies have demonstrated benefit in clinical trials, including among at-risk populations like those living with HIV and among young children. However, there is debate surrounding how best to apply these strategies and which populations would benefit the most.

The meta-analysis findings help fill in gaps regarding preventive treatment among household contacts, Gavin Churchyard, MBBCh, MMed, PhD, of Vanderbilt University in Nashville, Tennessee, and Nicole Salazar-Austin, MD, SCM, of Johns Hopkins University in Baltimore, wrote in an invited commentary. However, they argued that more must be done to address uptake, noting that WHO global targets for preventive measures were only met in 40% of household contacts under 5 years old and 3% of those over age 5 in 2022.

“We need a household-centred approach that eases client-focused barriers to accessing tuberculosis preventive care,” the pair wrote. “Community-based interventions have been shown to identify and reach more household contacts and can be personalized to the setting they are being implemented in. Addressing programmatic, supply chain, monitoring, financial, and diagnostic and treatment barriers while also generating demand are necessary to support and ensure success of these models of care.”

The review scoured four different databases for cohort studies published from Jan. 1, 1998 to April 6, 2018, leading to an analysis of 19 prospective cohort studies and 13 retrospective studies. Within a population of 439,644 participants followed for 1.4 million person-years, there were 2,496 individuals diagnosed with incident TB while 12% received preventive treatment.

Case-control studies and outbreak reports were excluded, as were studies that included a drug-resistant TB index patient that came in contact with the study participant. Included studies had a follow-up period of at least 6 months for TB and participants had either household or close exposure to someone with TB.

Cohorts were from 26 countries — 10 cohorts in the region of the Americas, nine in the African region, five cohorts in the Western Pacific region, five in the European region, and three in the Southeast Asia region.

The preventive treatment regimens utilized included isoniazid for a duration of 6 months (used in all the cohorts) or, less commonly, rifampicin and isoniazid for 3 months, rifampicin for 4 months, or isoniazid and rifapentine for 3 months. Some cohorts utilized multiple preventive regimens. Incident TB infection was the primary outcome.

The rates of effectiveness for preventive treatment varied by study type: prospective (aHR 0.29, 95% CI 0.23-0.38) and retrospective (aHR 0.62, 95% CI 0.51-0.74). The type of TB also played a slight role, with adjusted hazard ratios for effectiveness of 0.49 in pulmonary TB and 0.42 for extrapulmonary TB.

In participants who had HIV, the effectiveness of preventive treatment was 54% (aHR 0.46, 95% CI 0.22-0.99).

When broken down by age, those with a baseline positive skin or blood test for TB saw greater protection, both in participants under 5 years old (aHR 0.09, 95% CI 0.05-0.17), those 5-17 years old (aHR 0.20, 95% CI 0.15-0.28), and in adults (aHR 0.17, 95% CI 0.13-0.22).

Protection was more pronounced in countries that face a high versus low TB burden (aHR 0.31 and 0.58), although significant in both. This effect was even greater in patients who tested positive for infection (aHR 0.27 in high-burden countries vs aHR 0.12 in low-burden countries).

The effectiveness of preventive treatment against incident TB was found to be statistically similar between children under the age of 5 (aHR 0.33, 95% CI 0.22-0.50), participants who were 5-17 years old (aHR 0.41, 95% CI 0.32-0.54), and in adults (aHR 0.56, 95% CI 0.45-0.71).

The number needed to treat (NNT) in test-positive populations was nine to 34, depending on age. For all contacts, regardless of testing results, the NNT ranged from 29 to 43 in high-burden settings and 213 to 455 in low-burden settings.

“Our findings support risk-targeted strategies for tuberculosis preventive treatment prioritizing contacts with evidence of M. tuberculosis infection, regardless of age,” the researchers concluded. “Although contacts with negative [tuberculin-skin-test] or [IFNγ release assay] results from high burden settings do not appear to benefit from preventive treatment, the overall low NNT to prevent one case of tuberculosis in all tuberculosis contacts in high burden settings might justify preventive treatment for all contacts when testing for M. tuberculosis infection is inaccessible.”

Researchers note that the observational nature of the study limited its findings, citing selection bias, potential residual confounding despite propensity matching, and inability to identify the reasons for preventive treatment failure, such as non-adherence.

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