Testing for TB infection will be beneficial from an individual and a programmatic perspective if it identifies people who will benefit most from TPT. From a programmatic perspective, investments into capacity for TB infection testing will be justified if this results in greater efficacy and efficiency in the use of resources to provide TPT, increased acceptance and enhanced coverage. This will include not only the cost of drugs but also the human resources for medical evaluation, TPT initiation and follow-up. Testing will also save unnecessary expenditure on medication or adverse events to those receiving unnecessary treatment. Therefore, testing for TB infection before TPT is a valuable way to increase the TPT benefit–risk ratio.
The use of TPT has been shown to reduce the risk of developing TB disease among People with HIV, particularly in those who were TST positive. The updated systematic review undertaken during the development of the WHO guidelines on programmatic management of TPT in 2018 clearly demonstrated benefits of systematic testing and treatment of TB infection among People with HIV in terms of prevalence of TB infection, risk of progression to TB disease and incidence of TB disease when compared with the general population.
Household contacts were found to be at a substantially higher risk for progression to TB disease than the general population. The highest risk progression to active disease was among contacts who were aged below 5 years; hence, a strong recommendation to start TPT irrespective of availability of test for TB infection was issued. In addition, TPT was conditionally recommended for household contacts in other age groups following assessment of harms versus benefits. Among household contacts aged above 5 years, TB infection testing before TPT initiation may be desirable, although treatment was considered justifiable even without testing (19).
Among other risk groups, the evidence of benefits from systematic TB infection testing and TPT varied. The benefits clearly exceeded the risks among people starting anti-TNF treatment, receiving dialysis, preparing for an organ or haematological transplant, or having silicosis. In other risk groups, the risk versus benefit was less clear. Therefore, prioritization of target groups for systematic testing and TPT based on individual risk and the local and national context was considered to be acceptable to people with TB infection and to key stakeholders, including clinicians, nurses and programme managers.
In summary, TPT will provide the greatest individual health benefits if given to individuals with clinical or epidemiological characteristics that increase the risk of TB disease. Among those with a specific risk factor, the benefit will be maximized by prioritizing TPT for people with a positive TB infection test. However, testing is not a prerequisite in contacts of TB patients who are aged below 5 years and People with HIV. Hence, TB infection testing is associated with significant advantages for individuals.
The most important disadvantage of TB infection testing is the potential for significant delays between initial identification of someone at risk of developing TB disease and TPT initiation. In contacts, particularly young children (19) and People with HIV, TB disease can develop rapidly after exposure and TB infection. In all contacts, the highest risk period for progression to TB disease is within the first 6 months after exposure (4, 5). Hence, prompt initiation of TPT is crucial to prevent TB disease. TB infection testing may contribute to substantial delays, either owing to lack of trained personnel to administer the test or read the skin test result, or to delays in laboratory processing and communication of IGRA test results. Since the results of IGRA testing should be available within 24–36 hours (although there may be additional delays due to sample transport and batch testing) and within 72 hours for TST or TBST, TB infection testing should not delay the initiation of TPT by more than 3 days after initial identification.
The second potential challenge with testing is the greater burden on patients, including discomfort, fear of injections or blood collection, and the need for more visits before starting TPT with associated potential patient costs, time, delays and resulting losses from the cascade of care. However, effective organization of health services can minimize cascade of care losses related to testing (15, 20), both in high-income countries and in low- and middle-income countries (LMIC).
False negative and indeterminate TB infection tests are a third potential challenge (21). Such test outcomes are more frequent among immunocompromised individuals. However, the high relative risks of developing TB disease in people with positive TB infection tests compared with those with negative tests suggests that false negative results are not major determinants of patient-important outcomes. Additionally, some people at risk (e.g. older contacts) may test negative but become infected later, or show infection shortly after; in such cases, not giving TPT would be a missed opportunity to protect people.