Discussion
TB, infection, liver dysfunction
ADVERSE REACTIONS, EVENTS, DISEASE, INFECTION
To the best of our knowledge, this is the first RCT on LTBI testing and treatment in populations with radiographically inactive TB and without history of TB treatment in rural China. This study showed a high burden of radiographically inactive TB among the study participants (6.84%, 2,988/43,670), and the prevalence of LTBI was as high as 28.61% (855/2,988) among these participants. Unfortunately, the studied six-week regimen for LTBI treatment did not show significant protective effect in the total study population. Subsequent exploratory subgroup analyses observed a positive protective effect among the participants with fibrotic lesions (55.42%) and among those aged ≥60 years (80.17%), but it did not reach statistical significance.Our results suggested that there was a certain proportion of the general population in rural China who might have been infected with MTB and left inactive TB lesions after self-cured. Additionally, the prevalence of LTBI was much higher among individuals with radiographically inactive TB (28.61%, 855/2,988) than that among the general rural adults from the same study site (19.0%, 801/4,223) [To improve the guarantee on safety, we adapted the frequency of active side-effects monitoring by revising it from once monthly to twice monthly based on previous research. Therefore, some adverse reactions were handled in time at the initial stage. On the other hand, the participants also received more care, which improved their compliance. During the intervention implementation, only two participants showed moderate liver dysfunction, which was significantly lower than the findings in our previous trial that performed among middle-aged and elderly individuals with LTBI (1.17%) [Consistent with the recommendation by guidelines from America and Canada, we excluded participants with anti-TB treatment history because there was insufficient evidence to include them as preventive treatment targets. However, some evidence still suggested that this population was at a higher risk of developing disease in high-burden settings [Our study has several limitations. First, some TB cases especially subclinical TB cases might have been under-diagnosed because only participants with suspected TB were transferred for further microbiological tests. The unexpected lower incidence of active disease limited us to detect expected treatment effects and get a conclusive finding, considering the current sample size. Although not reaching statistical significance, a positive protective effect was observed among the subgroups with fibrotic lesion and among those aged ≥60 years, further studies with sufficient outcome events from larger sample size are needed to verify our results as calculated in Supplementary Table S13. Second, participants in this trial were not blinded because an untreated control group was used. To reduce the risk of potential bias, the panel members for evaluation and diagnosis of the active TB were fully unaware of the trial-group assignments. In addition, AE evaluation was mainly based on laboratory measurements and graded using a standardized, widely used CTC-AE. Third, as there is no gold standard for LTBI testing, infection status and time of infection acquisition were not known with certainty. There is a need to further explore whether these factors would influence treatment effectiveness.In conclusion, a high burden of radiographically inactive TB without anti-TB treatment history was identified in rural China. No significant efficacy of the six-week regimen was observed for TB preventive treatment among this key population, which might have been influenced by ages and the type of radiological lesion. A more precise definition of radiographically inactive TB is needed to verify our preliminary findings and to explore precise context-specific intervention for this population in future.