QuantiFERON-TB Plus (QFT-Plus) is the new version of the QFT-Gold In-Tube. Compared to the QFT-Gold In-Tube containing antigens optimized to stimulate CD4⁺ T cells, QFT-Plus contains new antigens optimized for both CD4⁺ and CD8+ T cell stimulation [18]. QFT-Plus has potential to indicate recent infection and disease activity. A recent meta-analysis has revealed that QFT-Plus is a more sensitive test compared to QFTGIT for detecting M. tuberculosis infection [19].

The C-Tb test is a recently developed skin test utilizing early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) antigens. The C-Tb test is as simple as conducting a TST but has a higher specificity. In several phase III trials of C-Tb [20,21], C-Tb positivity using a 5-mm cutoff correlated with exposure risk, performed better than TST in Bacillus Calmette– Guérin (BCG)-vaccinated people, and had a high correlation with the results of the QFT-GIT.

The key purpose of diagnosing LTBI is to identify who is very likely to progress to active TB [22]. Incipient TB is an attractive target for the development of new diagnostics. Host blood transcriptomic mRNA signatures have emerged as a promising platform for discovering biomarkers for incipient TB [23]. Recent studies have shown that transcriptomic signatures can predict the development of active TB [24,25]. These studies analyzed whole blood RNA sequencing data from large cohorts and revealed that some combinations of gene signatures showed a good correlation with the risk for progression to active TB in 6 to 12 months. Further research is needed for its validation and further development as a point-of-care test.

Isoniazid has been the main drug for LTBI treatment during the past decades. However, the 6 to 9 months of isoniazid regimen has shown low acceptance and completion rates due to the long treatment duration and poor tolerability [26,27]. These are the main barriers in the implementation and scale up of the programmatic LTBI treatment.

Recent studies have shown that shorter regimens using rifampicin or rifapentine are as effective as isoniazid-based regimens with higher completion rates and better safety [28-30]. A daily dose of rifampicin for 4 months [28] and 12 weeks of weekly isoniazid and rifapentine [29] were not inferior to 9 months of isoniazid for the prevention of active TB. Both regimens also showed better completion rates and fewer serious adverse events, especially hepatitis. Another much shorter regimen, one month of daily isoniazid and rifapentine [30], was not inferior to 9 months of isoniazid with a higher completion rate. Shorter rifamycin-based regimens may replace 6-9 months of isoniazid, considering better safety and adherence [31].

However, a recent Korean study of a treatment regimen using 12-week of weekly isoniazid and rifapentine showed a higher rate of flu-like symptoms and a 1.8% rate of anaphylaxis, despite a higher completion rate and lesser hepatotoxicity than 3 months of isoniazid and rifampicin [32]. These findings raise concerns that this regimen might not be appropriate for LTBI regimen for the general population in South Korea.

Therapeutic vaccination is a new and promising approach for LTBI treatment. In a phase IIb trial, a candidate vaccine, M72/AS01_E, reduced the risk of developing active TB in human immunodeficiency virus (HIV)-negative people with LTBI by 49.7% for 3 years [33]. The overall efficacy of 49.7% is low compared with that of most established vaccines in the treatment of other diseases. However, considering the high prevalence of LTBI worldwide and the limitations of current preventive chemotherapy, a vaccine could have a great impact on TB control. In addition, the vaccine can be expected to work in patients with drug-resistant TB who show the limited effect of preventive chemotherapy.

The prevalence of LTBI in Korea has gradually decreased in accordance with a decrease in the prevalence of TB. According to the National Tuberculosis Prevalence Survey, which was conducted every 5 years from 1965 to 1995, the LTBI prevalence in general population decreased from 64.2% in 1965 to 59.3% in 1975 then to 44.4% in 1990 (Fig. 1) [34]. In 2016, the Korea National Health and Nutrition Examination Survey showed an LTBI prevalence of 33.2% [35].

One of the key changes in the LTBI prevalence is its remarkable decrease in the younger population. The LTBI prevalence among those aged < 30 years was 44.5% in 1965, which was decreased to 15.5% in 1995 [36]. Recent studies showed further decrease in the rate of LTBI in the younger population (Table 1). In the 2016 surveillance using TST, the LTBI prevalence was 6.5% and 10.9% in the ages 10 to 19 and 20 to 29, respectively [35], and which was further decreased 2.0% and 3.4%, respectively, in the 2018 surveillance using IGRA [37].

In contrast, the prevalence of LTBI in the elderly population is still high. Many studies in various settings have shown that age is the most important predictor of LTBI [37-39]. To implement and scale up the programmatic management of LTBI in South Korea, the age differences of the LTBI prevalence should be considered.

In South Korea, the National Tuberculosis Control policies have focused on early diagnosis and appropriate treatment of patients with active TB [34]. Recently LTBI management has been expanded and integrated into key elements of the National Tuberculosis Control program [34,40]. An LTBI program was started for HIV-infected persons and household contacts under 6 years of age in 2004 [40]. Contact investigation programs were expanded to close contacts under 18 years of age in 2008, and to all age groups in 2011. In 2013, a TB epidemiologic investigation team was established, and active contact investigation was expanded to close contact in congregate settings. In 2016, the Tuberculosis Prevention Act was amended, making TB and latent TB screening mandatory for community workers in congregate settings. By the Tuberculosis Prevention Act, systematic LTBI screening and treatment were conducted for about 1.2 million individuals in congregated settings in 2017 [38].

LTBI management has been recommended as an independent chapter in the 2011 Korean TB guidelines [41]. In the updated 2017 Korean TB guidelines, the age limit for LTBI treatment among close contacts was extended from 35 to 65 years [41]. In addition, screening for and treatment of LTBI in healthcare workers was first recommended.

In the past decade, the LTBI program has been expanded and progressed under the vision of ‘TB Free Society, Healthy Country.’ It is time to take a step forward to implement and scale-up programmatic LTBI management. For a programmatic approach, the following challenges need to be addressed; target group selection, treatment-related interventions, monitoring and surveillance system, and an extension plan for vulnerable and hard-to-reach groups.

Prioritization of the target population should be the first step in a national plan for programmatic management of LTBI [8,42]. The most important benefit of LTBI treatment is ‘individual-level benefit,’ which reduces the risk of developing TB in high-risk individuals. Another key benefit is ‘public health-level benefit’ which could reduce further transmission of TB in the community [43]. This is an important reason for offering LTBI screening and treatment to workers in congregated settings, including healthcare workers. To achieve TB elimination, a public health approach in LTBI management will be necessary. However, this approach has concerns about increasing the individual risk of harm from unnecessary treatment. In addition, the impact of this approach on overall TB control should be carefully assessed to optimize the allocation of available resources. In 2017, there was a debate about the plan of LTBI mass screening for adults aged 40 and first-grade high school students [44]. The Korean government conducted the proactive LTBI screening and treatment among workers in congregate settings for about 1.2 million individuals in 2017 and 0.5 million individuals in 2018 [37,38]. This project includes several groups not recommended for high-risk groups by the WHO [8]. The achievement and limitation of this project should be carefully reviewed to develop strategies that are optimized for the Korean situation.

Proper management of those identified as LTBI cases is also important. Low acceptance and poor completion rate are the major barriers to implementing programmatic LTBI management [26,27]. In order to increase adherence to LTBI treatment, treatment-related interventions should be accompanied, such as case management, education, and counselling. Appropriate recording, reporting, and monitoring systems should be established.

In addition, plans for vulnerable and hard-to-reach groups (i.e., elderly individuals, foreigners residing in Korea [45], North Korean defectors [46], and the homeless) should be explored [47,48]. TB among the elderly population is becoming a major problem in TB control, which accounts for approximately 40% of new TB cases and 78% of TB-related deaths in South Korea. The number of new TB cases in ≥ 65 years of age has increased consistently with time (Fig. 2). In this group, reactivation from past infection is the major mechanism of developing active TB rather than recent transmission. Despite its theoretical benefit, providing LTBI treatment to individuals ≥ 65 years is a clinical challenge because of the high risk of age-related adverse events such as hepatotoxicity. Therefore, a tailored approach to LTBI treatment in the elderly population is needed. Active case finding through systemic screening is another approach to managing TB in the elderly [49]. Recently, a pilot project of systematic TB screening in the elderly showed a high rate of TB detection [50].