Our results indicated that LTBI notifications among the foreign-born persons have continued to increase, although this is not surprising considering that the number of foreign-born persons from high TB-burden countries entering Japan have continued to increase . It is certainly possible that foreign-born LTBI patients acquired their infection after immigrating to Japan, however, a molecular-epidemiological study which examined the transmission dynamics of TB among foreign- and Japan-born patients in a large urban area in Japan has suggested otherwise, indicating that most of the foreign-born TB cases were attributable to reactivation of LTBI that were acquired in their home country . Among the Japan-born patients, the rise was mainly seen among the older persons, which can be attributable largely due to the abolition of age limit for LTBI treatment in the national guideline in 2010  and an increasing number of elderly persons being tested for and diagnosed with LTBI before being treated for other medical conditions such as rheumatoid arthritis (i.e. hence LTBI being detected “at hospital”). On the other hand, among the foreign-born persons, the LTBI notifications increased in all age groups except those aged between 0 and 14 years old, and among all modes of detection. Among the Japan-born persons, “routine” screening for LTBI has only really been conducted at selected workplaces, such as among high-risk healthcare workers – however, the constant increase in the notification of LTBI among foreign-born persons via “routine screening” may indicate that increasingly, schools and workplaces are making individual decisions to introduce LTBI screening as part of the routine health-check for foreign-born persons. Indeed, there have been sporadic reports of LTBI screening being conducted as part of medical examination upon admissions to universities [12,13]. In the absence of a clear national guideline on priorities for LTBI among foreign-born persons in Japan, rigorous studies on effectiveness and cost-effectiveness are urgently needed to determine the most appropriate intervention for case finding of LTBI targeting foreign-born persons in Japan.
The majority of the patients had started LTBI treatment with INH monotherapy. This is understandable considering that, although the WHO guideline recommends both INH monotherapy for 6 months for adults and children in countries of both low and high TB incidence, and RFP monotherapy for 3 to 4 months for both adults and children in countries with low TB incidence , the Japanese national guideline recommends INH monotherapy above RFP monotherapy . As to why a higher proportion of foreign-born patients were started with RFP monotherapy – we were unable to find an explanation from our results. We may however speculate that physicians in Japan are more inclined to RFP monotherapy because of their knowledge and awareness regarding higher prevalence of INH resistance among foreign-born TB patients .
As for the issue of treatment adherence, to our knowledge, this is the first detailed analysis of LTBI treatment outcome among foreign-born persons at a national level in Japan. Outside of Japan, several systematic reviews on adherence for and outcomes of LTBI treatment have been conducted – for example, a review that was conducted for the WHO 2015 LTBI Guideline has concluded that treatment completion rates varied across different risk groups, ranging from 6% to 94%, with lower completion rates for prisoners and immigrant . Another study which looked at studies from US and Canada has reported completion rates to be ranging between 22% and 90% , and a more recent review reported rates between 7% to 86%, both for foreign-born person . A meta-analysis that was published in 2016 has estimated the pooled treatment completion rates for migrants to be 14.3% . The studies which were included in these systematic reviews do, however, vary considerably in terms of sample size, study design, types of immigrant and treatment regimen, and hence caution is required when interpreting the results. Our study results indicate the treatment completion rate for foreign-born persons in Japan is relatively high, compared to other studies included in the abovementioned reviews, albeit not reaching the national target of 85%.
Many studies have also examined the predictors for adherence to LTBI treatment, and in general, have tended to conclude that demographic factors such as age, sex, place of birth and race do not seem to influence completion rate . In our study too, neither sex nor age were conclusive risk factors for lost to follow-up among foreign-born LTBI patients. However, as for age, although not statistically significant, there was a clear tendency for the risk to increase with age. This is quite understandable, as younger children are usually overseen by their guardians and are therefore less likely to become lost to follow-up, as well as for the fact that anti-tuberculosis drugs are unusually better tolerated at younger age. Other socio-economic factors, such as unemployment and lack of health insurance, have previously been associated with failure to complete treatment [18,19] – in our study, none of the foreign-born LTBI patients who had started treatment were reported as “non-insured”. Receiving social welfare assistance and having “others and unknown” for insurance status, which could include short-term visitors with private health insurance, were associated with elevated risk but were not statistically significant. As for job status, being employed on a daily or temporal basis, and having “others and unknown” for job status, were both associated with being lost to follow-up. Considering that LTBI treatment is publicly subsidized with minimum out-of-pocket payment, and is unlikely to place a significant financial burden for the patients, being employed on a daily or temporal basis may represent not necessarily poor economic condition but more an unstable lifestyle and greater mobility which are putting patients at risk of becoming lost to follow-up.
As for the length of treatment regimen, while the WHO 2015 Guideline has concluded that longer treatment duration was detrimental to treatment completion, a systematic review that was published a year later has concluded that study results were inconclusive, with some showing better treatment outcomes for shorter regimens using rifampicin, pyrazinamide, rifabutin and/or INH, than the standard regimen (6 or 9 months of INH) while others showing similar completion rates, and also that the studies themselves were too heterogeneous to conduct pooled analysis . In our study, the proportion of lost to follow-up was bigger among those who have started treatment with INH than those with RFP monotherapy (12.3% vs. 6.4%), however, the difference was shown not to be significant in the logistic regression analysis (p=0.12). There could also be various cofounding factors, and a separate survey may be necessary before conclusions can be drawn. It must also be noted that the information regarding treatment regimen is only of that upon notification – in reality, regimen can and do change during the course of the treatment , however, neither the change nor the new regimen after change is captured in the JTBS.
It has been reported that one of the major challenges in ensuring adherence especially for LTBI treatment is to overcome the psychological resistance held by patients to take drugs for a non-contagious and non-symptomatic infection that may never develop into active disease, but which could cause potential adverse effects, and convince them of the potential benefits of prevention . This could be challenging especially when targeting patients who come from culture that is unfamiliar with the concept of screening and prevention . For example, a prospective study that has examined the predictors for non-completion of LTBI treatment has concluded that a perceived risk of progression to active TB is strongly associated with better adherence . However, discussions regarding which factors may influence the construction of such perceived risk and benefit are still inconclusive. One possible factor is the status of being a contact of an active TB patient, and having a close experience with the disease. Indeed, some studies have indicated that contacts tended to have higher completion rates than other population groups [22, 23, 24]. In our study, whether or not the patient was a contact of a TB case could be identified from the variable “mode of detection” – those who were detected by contact investigation are obviously case contacts, however, our results indicated that being a contact was not associated with better treatment adherence. This may suggest that being a contact of a TB case alone is a weak motivating factor to adhere to and complete LTBI treatment, at least among foreign-born persons in Japan.
Another potential factor is patient education and counselling – for example, studies from prison have indicated that those who have received education sessions about LTBI prior to being released had higher treatment completion rates post-release, than those who did not . Several studies have shown that well-designed educational intervention using culturally and socially sensitive languages can assist patients make better-informed decisions about the potential risks and benefits of LTBI treatment [26, 27]. We were unable to assess the possible impact of education as such is not collected in the JTBS. However, numerous studies on adherence support to foreign-born active TB patients in Japan have pointed to the challenge of language [28, 29]. Even today, Japan continues to be a largely mono-cultural society and it is quite common that local healthcare workers only speak Japanese. There is an increasing awareness of the need to improve the language capacity of health services, against the rising number of foreign-born patients in Japan – however, the resources are still very much limited. Under such situation, it is not difficult to imagine that foreign-born patients in Japan are not receiving the appropriate and adequate information that they need to make informed decisions about LTBI and treatment. Studies are needed to explore the most effective information, education, and communication for foreign-born patients regarding LTBI.
Finally, we considered the time between entry to Japan and diagnosis of LTBI as a potential risk factor for lost to follow-up. Compared with those who had been diagnosed within 2 years of arriving to Japan, those who had been in Japan for more than 2 years but less than 5 years had a slightly raised risk of becoming lost to follow-up (adjusted odds ratio 1.69, 95% confidence interval 1.00-2.87). The risk probably reflects the risk of transferring-out of Japan, rather than becoming lost to follow-up in Japan, as the proportion of international transfer-out was the highest among those who had been in Japan for more than 2 years but less than 5 years (n=15/222, 6.7%). The reasons are not clear, though this may be related to the duration of permit to stay, which majority of foreign-born students and workers are requested to apply when staying in Japan. The duration of stay depends on the type of permit, however, and it is usually 1 year, 3 years or 5 years. In other words, those who are transferring out of Japan may simply be doing so, because their permit to stay is expiring. This brings up another important issue surrounding the continuum of care for LTBI patients across national borders, but the discussions are beyond the scope of this study.
Our study is not without limitations. Firstly, as our sole source of data was the JTBS, we were unable to examine the effects of variables which were not collected in the JTBS, such as frequency of side-effect [30,31], and alcohol and/or drug dependence [28, 32], which have previously been identified as being potentially detrimental to treatment adherence. Secondly, our study did not take into account those who have become lost to follow-up at various stages in the cascade of care in diagnosis and treatment of LTBI, including those who, despite being eligible, were not tested for LTBI and those, after being diagnosed as LTBI, did not initiate treatment. For example, the previously mentioned meta-analysis has concluded that screening completion rates was the lowest among the migrants (43%), compared with other populations such as medical personnel (86.1%), marginalized persons (83.3%) and contacts of active case (79.3%) . A separate study is probably required to examine the entire cascade of care for LTBI among foreign-born persons in Japan.