Tuberculosis is still a global threat. Approximately 1.6 million deaths were attributed to TB in 2021 globally (1). To reduce TB burden, a target of more than 90% of treatment success rate until 2025 has been suggested (2), although it remained at 86% globally in 2021 (1). For a successful treatment, maintaining adherence is essential. Poor adherence can lead to prolonged infectiousness, acquired drug resistance, relapse, and even death (3). Therefore, keeping patients’ adherence to anti-TB treatment is underscored in national TB control programs (NTP).

In South Korea, public-private mix (PPM) is a key strategy of NTP as most patients with TB in South Korea are managed in private sectors (4). PPM project was introduced in 2011 to resolve the stagnation in decline of TB incidence in early 2000’s due to a low treatment success rate in private hospitals (5). TB specialist nurses were dispatched to 184 PPM hospitals in 21 districts located all over the country to manage patients’ adherence. After implementation of the PPM project, TB incidence in South Korea has gradually decreased – from 100.8 cases per 100,000 population in 2011 to 44.6 cases per 100,000 population in 2021 (6).

In our previous study, we have reported reasons for loss to follow-up (LTFU) in TB patients in South Korea (7). Additionally, we have investigated risk factors for LTFU at the early stage of the PPM project (2011–2014) (8). However, these studies were basically cross-sectional or retrospective. In this nationwide prospective cohort study, we collected data in a time-to event form and analyzed risk factors for LTFU to identify which group we should focus on to prevent LTFU.

Among TB patients enrolled during the study period, a total of 14,942 patients were finally included (Figure 1). Of them, 356 patients had LTFU. Baseline demographic and clinical features of included patients by six treatment outcomes are presented in Table 1. Mean age of the LTFU group was 56.3 ± 18.9 years, which was lower than that of total patients (61.0 ± 19.0 years). In the LTFU group, proportion of patients who were living alone (50.6%), foreigners (21.3%), and heavy drinkers (10.7%) were higher than those in total patients. Among medical comorbidities, chronic liver disease (3.4%) and malignancy (12.1%) had higher proportions than others in total patients. Asymptomatic patients accounted for 32.3% of the LTFU group, which was not quite different from that in total patients (31.3%). As for past TB history, previous LTFU and unknown TB history accounted for 6.5 and 3.4% in the LTFU group, respectively, which were higher than those in total patients (1.2 and 1.1%, respectively). In the LTFU group, EPTB accounted for 36.3%, higher than that in total patients (23.5%). Proportion of bacteriologically confirmed TB was 64.5% in the LTFU group, which was lower than that (77.2%) in total patients.

In this study, we identified several groups showing high LTFU risk, including foreigners, patients with previous TB history reported as unfavorable outcome or those with uncertain TB history, those living alone, those with malignancy, and those who were underweight and heavy drinkers. Effect of age on LTFU was insignificant. In addition, prior treatment interruption, especially self-interruption during current TB episode, was associated with subsequent LTFU.

Previous LTFU has been found to be a significant risk factor for LTFU in previous studies (8, 16, 17), suggesting that reasons for previous LTFU are not easily improved, which might continuously affect LTFU during following treatment. We also found that a short interruption of anti-TB treatment heralded a subsequent LTFU. Directly observed treatment (DOT) is not widely implemented in South Korea due to the lack of manpower (18). Although patients with non-compliance are managed with telephone consultation and home visit, prevention of non-compliance in advance is more efficient in reducing transmission and development of drug-resistance than managing non-complaint patients which already occurred (19). Various digital adherence technologies could be applied selectively to TB patients with previous LTFU or those with short treatment interruption which can herald subsequent LTFU (Table 4).

In addition to DOT, medical or socioeconomic conditions associated with previous LTFU should be thoroughly investigated for each patient. In a previous study, adverse effects of anti-TB treatment were the most frequent causes for LTFU (7). Gastrointestinal discomfort was the most frequent adverse effect among TB patients in South Korea (20). Although there are recommendations for managing gastrointestinal discomfort in Korean guidelines for TB, such as modifying medication time after meal or before sleep, these solutions are mostly empirical. Additionally, efficacy and adequate duration of modified regimens such as rifampin-sparing regimen for patients who are not tolerable to rifampin are unknown (21). Evidence-based management of adverse effects of anti-TB treatment should be investigated and applied in clinical practice. Inadequate knowledge, attitude, and belief about TB would lead to patients’ refusal treatment (22), which is another major cause for LTFU (7). Enforced patient education and counseling program should be implemented, especially for patients with previous LTFU history and those with short treatment interruption during current TB treatment. Although rate of LTFU in each PPM hospital and each district is monitored as an key indicator for TB control in the PPM project (23), LTFU rate among patients with previous LTFU history should also be underscored.

Low BMI was associated with unfavorable outcome, especially death, in previous studies (24, 25). We found that LTFU risk was increased for TB patients who were underweight. Considering that patients with low BMI show slower gastric emptying and heightened visceral perception than those with normal or high BMI (26), the incidence of gastrointestinal discomfort during anti-TB treatment might be relatively high among TB patients who are underweight, which might have contributed to the high LTFU risk. Gastrointestinal discomfort was the most frequent adverse effect among TB patients and those who have LTFU (7, 20). Similarly, we presume that the high LTFU rate among TB patients with malignancy could be attributable to gastrointestinal discomfort which can be aggravated by anti-cancer chemotherapy. Moreover, anti-TB treatment could be easily interrupted due to minor adverse effects among TB patients with terminal cancer (7). High LTFU rate among these two groups underline the significance of managing adverse effect of anti-TB treatment and the role of medical staffs in PPM hospitals.

Foreigners showed higher LTFU rate than Korean TB patients in previous studies (8, 27). In the present study, we identified dozens of foreign TB patients who returned to their own countries without informing their attending medical staffs and reported as LTFU thereafter. As migration itself is a known risk factor for LTFU (28). Thus, thorough management during international transfer-out is needed, which requires cooperation with immigration offices. Moreover, considering that accessibility to healthcare services is often limited for immigrants due to difficulties in communication (29), effects of patient education and counseling might be insufficient for foreign patients. Burden of medical cost might also have an effect. Although all foreigners who stay in South Korea for 6 months or more are subjected to subscription to National Health Insurance (NHI) since 2019, proportion of foreigners enrolled in NHI remained at 76.8% of 1.6 million registered foreigners in 2021 (30). Since 2017, NHI has paid for full medical cost related to TB treatment (18). Considering that the role of public health centers in provision of curative services is limited in South Korea (31), medical cost could be a hurdle that limits visiting private hospitals among foreign TB patients not enrolled in NHI and undocumented foreigners with a number estimated to be 0.4 million in 2021 (32).

We identified TB patient living alone and heavy alcoholics as additional vulnerable groups for LTFU. Role of family support is crucial for patient adherence to treatment by providing emotional support, motivation and supervising patients’ medication (22, 33). However, due to rapid increase in nuclear families, the number of older adult people living alone is rising in South Korea. This leads to the lack of healthcare, poverty, social alienation, and depression among older adult population (34), which are all risk factors for non-adherence to treatment. In addition, heavy alcohol use is a well-known risk factor for LTFU (35). As in TB patients living alone, heavy alcohol use is a result of social marginalization (36), which is another major reason for LTFU (7). To tackle down these vulnerable groups, the government of South Korea has implemented enhanced case management based on vulnerability assessment since 2022 (37). In this vulnerability assessment, whether the patient has physical disability, difficulties in communication, psychological problem including substance abuse, any other comorbidities, difficulties in visiting hospitals, families living together, and adequate residence is investigated (38). For medical staff in private hospitals, these factors are difficult problems to deal with. Government’s role should be underscored in this issue. Additionally, beyond just identifying these vulnerabilities, feasible solutions should be investigated and assessed.

Interestingly, age was not associated with LTFU risk, which was discordant with results of a previous Korean study covering LTFU cases in the early period of the PPM project (2011–2014) (8). In that study, old age was associated with a high LTFU risk. Although direct comparison between the two studies is unfeasible due to different study design, decrease in LTFU between the two study periods was the most prominent among older adult TB patients. Older adult TB patients have a higher risk of adverse effects of anti-TB treatment (39). Adverse effects are known to be the most common reasons for LTFU (7). However, we presume that effects of active management of adverse effect, counseling, and patient education in PPM hospitals are the most prominent in older adult TB patient and successful implement of PPM project might in part contribute to a decrease in LTFU (40).

This study is the first prospective observational study investigating LTFU among nationwide TB patients in South Korea. However, it has several limitations. First, patients’ socioeconomic status such as income level was not investigated, although it was a significant factor for LTFU (41). Second, although a substantial proportion (11.8%) of enrolled patients were transferred out during the study period, their outcomes after transfer-out were not investigated. A previous study has shown hidden LTFU cases in South Korea during the process of inter-hospital transfer (8). However, as status of re-registration at transfer-in hospitals has been thoroughly checked by TB specialist nurses in initial hospitals since 2016, we assume that the risk of LTFU during process of transfer is insignificant as in the previous study. Third, although high-risk groups for LTFU were demonstrated in this study, the reasons and determinant factors for LTFU in detail were not covered in this study. Further studies are needed to investigate how to reduce LTFU risk among these high-risk patients by knowing reasons for LTFU.

In conclusion, previous LTFU history and brief interruption of anti-TB treatment in current treatment session are predictors for subsequent LTFU, which require enhanced case management. TB patients who were underweight and those with malignancy were high-risk groups. Thus, PPM hospitals should have an active management for adverse effects of anti-TB treatment. Foreigners, those living alone, and heavy alcoholics were vulnerable groups. For these groups, the role of government is underscored to prevent LTFU. Collaboration between private and public sectors is required.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Institutional Review Board (IRB) of Incheon St. Mary’s Hospital, the Catholic University of Korea. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because this study was observational, and no patient was at risk for personal information leakage.

JK, HK, S-SL, and JP designed the study. KP, JC, JJ, and ML contributed to data collection. HK, YK, JO, and H-KK cleaned and verified the dataset. HK did the statistical analysis and wrote the manuscript. Y-JJ, EL, and BY interpreted the results. JK and JM reviewed and edited the manuscript. JK supervised the work. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.