Evaluation Of Tuberculosis Preventive Treatment Efficacy And Identifying Of Peripheral Blood Biomarkers Reflecting Host Responses To Preventive Treatment

Background:Enlarging tuberculosis preventive treatment among at-risk populations of latent tuberculosis infection is an important method to reduce the incidence of tuberculosis and achieve the End TB Strategy targets.At present,assessing the decline of active tuberculosis incidence is a traditional way to evaluate the efficacy of preventive treatment.It usually requires a long follow-up period and huge resource inputs,which is unable to achieve individual level evaluation and not conducive to the standardization of preventive treatment.Therefore,identifying biomarkers that can be used for prognostic evaluation while evaluating the long-term protective efficacy of preventive treatment will provide technical support for further optimizing preventive treatment management.Objectives:This study relied on two randomized controlled trials targeting the population in rural China.On the basis of evaluating the five-year protective efficacy of the "isoniazid+rifapentine" combined regimen,seroepidemiology was used to screen and verify biomarkers related to the prognosis of preventive treatment.Methods:1)A randomized controlled trial conducted in middle-aged and elderly people with latent tuberculosis infection was followed up for a long time to obtain the five-year protective efficacy of a 6-week regimen based on domestic drugs(isoniazid plus rifapentine,twice a week).2)To further verify the safety and effectiveness of this innovative regimen in people with latent tuberculosis infection who have inactive tuberculosis,this study used Bio-Plex Pro Human Cytokine panels to detect the level of forty-eight cytokines in peripheral blood stimulated by mycobacteria-specific antigen before and after the preventive treatment,and screen the value of biomarkers in evaluating the efficacy of preventive treatment.Results:1)Five-year protective efficacy evaluation of 6-week twice-weekly regimen:1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis.Over a 5 years follow-up period after the intervention,for the per-protocol analysis,the incidence rate was 0.49(95%CI:0.30-0.67)per 100 person-years in the untreated control group and 0.19(95%CI:0.07-0.32)per 100 person-years in the treated group.The protection rate was 61.22%.Subgroup analysis showed that the protection rate was 76.82%in the per-protocol analysis among participants with baseline QuantiFERON-TB Gold In-Tube(QFT-GIT)interferon(IFN)-γ levels in the highest quartile(≥3.25 IU/mL).2)The relationship between the dynamic change of mycobacteria-specific antigen-induced cytokines and preventive treatment:totally,63 treated participants and 32 untreated controls were included in the study.The levels of 13 cytokines(Basic FGF,GRO-α,IL-1α,IL-1ra,IL-12(p70),SCF,TRAIL,IL-8,IFN-α2,IL-5,IL-12(p40),LIF and IL-17A)were found to be statistically different between before and after treatment in treated participants.Among these 13 cytokines,the level of IL-8 was significantly lower in QFT-GIT reversed group than in non-reversed group(p=0.028)among treated participants.Conclusion:The localized 6-week twice-weekly regimen has shown a good five-year protective efficacy,providing an appropriate means for carrying out preventive treatment for high-risk populations with latent tuberculosis infection in the elderly.The significant changes in the release level of IL-8 in peripheral blood stimulated by mycobacteria-specific antigen before and after preventive treatment suggest that it has potential application value as a biomarker for the prognosis of preventive treatment.