Interferon-Gamma Release Assay Testing for Latent Tuberculosis Infection: A Health Technology Assessment.

Abstract

Background: Many people infected with the Mycobacterium tuberculosis complex (the bacteria that cause tuberculosis [TB]) have an inactive stage of infection known as latent tuberculosis infection (LTBI). A person with LTBI is at risk of developing active TB. Screening for, and treating people with, LTBI is an important part of preventing adverse health outcomes, reducing the risk of reactivation and the further spread of tuberculosis in a community. We conducted a health technology assessment of interferon-gamma release assay (IGRA) for the detection of LTBI, compared to the standard tuberculin skin test (TST) to evaluate the diagnostic accuracy, cost-effectiveness, the budget impact of publicly funding, and health care provider preferences and values.

Methods: We performed a systematic literature search of the clinical evidence as an overview of systematic reviews. We reported the findings of the identified reviews, including their quality assessment of the body of evidence. We performed a systematic literature search of the economic evidence and included published Canadian cost-effectiveness studies. We assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We developed a probabilistic decision-tree model to estimate the incremental costs of IGRA strategies versus TST alone over 1 year in eligible population subgroups. IGRA was examined as a single test and in a sequential pathway with tuberculin skin test (TST; the test order depended on the type of population). We considered subpopulations at high risk of LTBI for whom IGRA would be preferred, as indicated by the Canadian TB Standards published in 2022 (hereinafter, the Standards); e.g., people who received a Bacille Calmette-Guérin (BCG) vaccine, such as BCG-vaccinated immigrants and people identified in contact investigations. We also considered people with comorbid conditions or who were undergoing treatments that may cause low immune function and, hence, may test incorrectly negative. We estimated the total 5-year budget impact (in 2024 CAD) for publicly funding IGRA testing in Ontario. To contextualize the potential value of IGRA, we spoke with health care providers about people requiring TB testing for LTBI. We attempted to reach out to people who had experience with IGRA or TST but did not receive any feedback.

Results: We included 12 systematic reviews that included over 500 unique primary studies in the clinical evidence overview of reviews and found good evidence aligned with the uses of IGRA outlined in the Standards. This overview of reviews summarizes the existing evidence on diagnostic accuracy and the clinical utility of IGRA for LTBI. Interferon-gamma release assay was found to have good evidence as a rule-in test for LTBI due to consistently high specificity. The reviews reported slightly lower sensitivity among people who have underlying immunosuppression conditions (e.g., people who are HIV positive or have received an organ transplant, or are on cancer treatment or dialysis) compared to a more general population. However, compared to TST (the standard test for TB), IGRA appears to have fewer false-positive results, as signaled by a lower risk difference of developing active TB among those who tested positive on both LTBI tests in head-to-head comparisons. This was particularly notable in immunocompromised populations and was also observed in children and the elderly (e.g., people in nursing homes) and those who have received an anti-tuberculin vaccination known as the BCG vaccine.Additionally, IGRA may be informative for people with immunocompromising conditions who are at risk of a false-negative result from a TST, as it yields indeterminate findings, signaling that further clinical investigation may be needed.We included 5 economic studies from Canada (using a public payer perspective), which found that IGRA, either as a sequential test following TST or as a standalone test, was cost-effective or cost-saving compared with TST alone for LTBI in high-risk populations as identified in the Standards. All reviewed studies were of good quality and 3 studies were directly applicable to the Ontario context (GRADE: High). Therefore, we did not conduct a primary economic evaluation for Ontario.Our reference case budget impact analysis showed that publicly funding IGRA in Ontario in all examined subpopulations over the next 5 years was associated with additional costs ranging from $2.99 million (IGRA alone) to $18.80 million (IGRA in sequential pathways with TST). These overall estimates include potential savings in some subpopulations and additional costs in others. In the population-specific analyses, we estimated cost savings of $1.63 million or higher over 5 years with publicly funded IGRA testing in BCG-vaccinated immigrants or BCG-vaccinated people identified via contact investigations (who are susceptible to a false positive result with the TST alone). These cost-savings resulted from reductions in costs of follow-up evaluation and treatment (due to prevention of reactivated LTBI). We found additional costs of about $6.26 million or higher over 5 years with publicly funded IGRA testing in immunocompromised people due to increased appropriate medical evaluations for those who were previously incorrectly identified as negative. In sensitivity analyses, if we assumed a high chance of reactivation of LTBI into active TB in immunocompromised populations, then IGRA testing resulted in cost savings.Health care providers who we surveyed had positive comments about IGRA, and expressed it as patients' preferred test for LTBI, partly because this test requires only 1 office visit (compared to the multiple visits needed for TST), thus reducing the effect of barriers such as transportation, language, childcare and employment arrangements.

Conclusions: Interferon-gamma release assay testing was found to have good diagnostic accuracy and to be cost-effective or cost-saving for LTBI in populations aligned with the recommended uses of the Standards. We estimate that publicly funding IGRA in Ontario for all examined population subgroups would result in additional costs of between $2.99 million and $18.80 million over 5 years, depending on how the test is used. In the population-specific analyses, we estimate a cost savings of $1.63 million or higher with IGRA testing in eligible BCG-vaccinated immigrant populations or BCG-vaccinated people identified via contact investigations. There was a preference for IGRA among health care practitioners, particularly to support people who may have challenges with the available alternative tests (e.g., TST).