背景
在低結核病疾病負擔國家中，依循世界衛生組織對於結核病防治指引中針對結合接觸者進行結核感染偵測以及預防性投藥可達到相當程度之結核病控制成效。然而運用此一結合防治策略於中度疾病負擔國家往往不足以達到結核病防治之預期目的。運用結核菌素皮膚檢測(tuberculin skin test, TST)以及近年來發展之丙型干擾素檢測(Interferon-gamma Release Assay, IGRA)做為篩檢工具對於一般風險民眾進行潛伏結核感染篩檢，達到早期偵測染病民眾並進行預防性投藥之疾病次段預防策略，可在族群層次降低潛伏結核感染者發病風險。由於篩檢在策略推行早期即會產生之成本，但達到後續降低結核病發生之效益卻在晚期才可顯現。如何運用經濟評估方法對於前述之結核病次段預防策略進行決策評估確鮮少被提及。
研究目的
本研究旨在對於結核菌素皮膚檢測潛伏結核篩檢、丙型干擾素檢測潛伏結核篩檢，以及結合兩種工具之潛伏結核篩檢策略相較於未有篩檢之情境，在彰化結核病防治之現況下進行效益與成本效益評估。
材料與方法
本研究首先運用彰化結核監測資料、接觸者調查資料、以及社區整合式篩檢資料在考量性別與年齡之影響下評估彰化結核疾病進展之動態變化。本研究亦運用彰化實證資料評估結核菌素皮膚檢測、丙型干擾素檢測，以及結合運用兩工具於彰化民眾對於潛伏結核感染偵測之敏感度與特異度。運用彰化地區之結核病動態參數、偵測工具特性參數，以及彰化結核防治效益參數，本研究進而運用馬可夫決策模型對不篩檢、結核菌素皮膚檢測潛伏結核篩檢、丙型干擾素檢測潛伏結核篩檢，以及結合兩種工具之潛伏結核篩檢策略進行效益與成本效益評估。本研究並運用決定性(deterministic)與機率性(probabilistic)方法評估個策略之增量成本效益比(incremental cost-effectiveness ratio，ICER)。
結果
彰化縣2016年結核病發生率為50/100,000。彰化之結合動態參數顯示，丙型干擾素檢測結果陽性相較於陰性者具有較高之結核感染率以及疾病進展速率。男性以具有較高之感染率與疾病進展速率。年長者其疾病進展速率較高，但年輕者具有較高之感染速率。彰化縣之結核病死亡率約為20%。本研究運用此彰化縣實證資料估計參數進行結核菌素皮膚檢測潛伏結核篩檢、丙型干擾素檢測潛伏結核篩檢，以及結合兩種工具之潛伏結核篩檢策略之族群結核篩檢成本效益評估。結果顯示，結合運用兩工具可達到避免較多結核個案之效益。對於避免結核個案之成本效益分析結果顯示，對於結核菌素皮膚檢測潛伏結核篩檢、丙型干擾素檢測潛伏結核篩檢，以及結合兩種工具進行平行或序列應用之潛伏結核篩檢策略之ICER分別為台幣35,966，台幣40,973，台幣45,748，以及台幣34,404元。以台幣60,000為最高願負成本(willing-to-pay)，四種策略具有成本效益之可能性分別為85.0%, 78.5%，77.0%與86.0%。對於人年之成本效益分析結果顯示，對於結核菌素皮膚檢測潛伏結核篩檢、丙型干擾素檢測潛伏結核篩檢，以及結合兩種工具進行平行或序列檢測之潛伏結核篩檢策略之ICER分別為台幣39,439，台幣44,284，台幣55,086，以及台幣37,190元。以台幣60,000為最高願負成本，四種策略具有成本效益之可能性約為60%。
結論
本研究結果顯示以結核菌素皮膚檢測潛伏結核篩檢、丙型干擾素檢測潛伏結核篩檢，以及結合兩種工具進行平行或序列檢測之潛伏結核族群篩檢策略可藉由早期偵測潛伏結核染並且以預防性投藥達到有效降低結核個案之效益。
關鍵字: 族群篩檢,潛伏結核感染,結核菌素皮膚檢測,丙型干擾素檢測,成本效益分析

Background
In contrast to the countries with low incidence of tuberculosis (TB), strategies of controlling Tuberculosis (TB) in those countries with moderate disease burden, the adoption of WHO guideline through passive case finding and chemoprevention for latent tuberculosis infection (LTBI) through active investigation for contact tracing is not sufficient to reach the goal of disease prevention. The alternative is the use of screening as a secondary prevention with the conventional Tuberculin Skin Test (TST) and the recently proposed Interferon-gamma Release Assay (IGRA) aimed at early detection and treatment of TB arising from among LTBI in average-risk population followed by the provision of chemoprophylaxis to decrease the risk of further progression to clinical TB. Given the costs incurred in screening earlier and the effectiveness of averting TB cases accrued later, economic evaluation plays an important role in decision-making for such kinds of screening strategy, which been barely addressed.
Aims
This thesis aimed at assessing the efficacy and cost-effectiveness of applying Tuberculin Skin Test (TST), IGRA, and the combination of the two compared with no screen together with the consideration of current context of TB prevention strategy in Changhua.
Material and Methods
The forces of natural evolution of tuberculosis from susceptible, LTBI, reinfection, clinical TB resulting from exogenous and endogenous sources, to TB death was first derived from the empirical data of TB surveillance registry, contact investigation registry, and community-based screening samples with the consideration of the effect of age, sex. The diagnostic characteristics of TST, IGRA, and the combination of the two were derived by using the data from Changhua integrated community-based screening. Based on the parameters of TB evolution, the effectiveness and cost-effectiveness for the four scenarios of no screen, TST screening, IGRA screening, and screening by using TST combined with IGRA were assessed by using Markov decision tree under the context of TB prevention in Changhua. The incremental cost-effectiveness ratios (ICERs) with deterministic and probabilistic approach were estimated.
Results
The incidence of TB in 2016 was 50 per 100,000. Regarding the force of TB infection rate and conversion rate, subjects with positive IGRA had higher risks on both rates. Male also had higher risk in these two rates. While the elderly had a higher risk for the progression to clinical TB from LTBI, the risk of LTBI was higher for the young. The case-fatality rate of TB in Changhua was around 20%. By using the parameters derived from the empirical data in Changhua, the cost-effectiveness of the population-based screening strategies using TST and IGRA were assessed. The combination uses of TST and IGRA provides a higher efficacy in averting TB cases compared with no screen. Regarding the cost-effectiveness of TB case averted, the ICER for prevention one TB case was estimated as NT 35,966, NT 40,973, NT 45,748, and NT 34,404 for the screening strategy using TST, IGRA, the combination of the two in parallel and that in serial, respectively with the probability of being cost effective of 85.0%, 78.5%, 77.0%, and 86.0%, respectively, based on the NT 60,000 threshold value of wiliness-to-pay. The ICER for life-years gain was NT 39,439, NT 44,284, NT 55,086, and NT 37,190 for TST screen, IGRA screen, the screen with the combination of TST and IGRA in parallel, and that in serial, respectively. The NT 60,000 willing-to-pay threshold gives the probability of being cost-effective around 60% for the four strategies compared with no screen.
Conclusion
The strategy of screening for LTBI in an average-risk population by using TST, IGRA and TST combined IGRA is effective in averting TB cases through the early identification of LTBI subjects followed by the chemoprophylaxis of INH.

Keywords: population-based screen, LTBI, TST, IGRA (QFT-GIT), cost-effectiveness analysis

Contents
誌謝………………………………………………………………………………. i
中文摘要…………………………………………………………………………. ii
英文摘要…………………………………………………………………………. iv
Chapter 1 Introduction…………………………………………………………… 1
Chapter 2 Literature review……………………………………………………… 4
2.1 Background………………………………………………...……….. 4
2.1.1 Goble Burden of Tuberculosis………………………………..… 4
2.1.2 Epidemiology of Tuberculosis in Taiwan…………………….... 5
2.2 Screening for LTBI………………………………………..........…... 6
2.3 Cost-effectiveness analysis of LTBI Screening……………………. 9
Chapter 3 Material & Method………………………………………………….. 13
3.1 Empirical Data on the evaluation of tuberculosis prevention in Changhua………………………………………………………….……... 13
3.1.1 Data on the tuberculosis evolution…………………………….... 13
3.1.2 Empirical data on assessing the diagnostic characteristics on TST and IGRA………………………………………………………………….. 14
3.2 Strategies for TB Screening and Intervention………………………... 15
3.3 Decision Analysis for TB screening strategies with Markov decision tree………………………………………………………..………………. 16
3.3.1 Markov decision model………………………………...……….. 16
3.3.2 Evaluation of TB screening with probability cost-effectiveness analysis……………………………………………………………….. 18
Chapter 4 Results………………………………………………………….… 20
4.1 Disease burden and chronological trend of TB………………...… 20
4.2 Characteristics of TB evolution………………………………..… 20
4.3 The efficacy of DOTs for TB control……………………………. 21
4.4 Diagnostic characteristics of TST and IGRA for LTBI………..… 22
4.5 Case-fatality of TB in Changhua………………………………… 22
4.6 Parameters for the evaluation of TB screening strategies in Changhua………………………………………………………….... 23
4.7 Cost-effectiveness analysis for TB screening strategies and DOTs 24
4.8 Probabilistic approach for assessing the cost-effectiveness of screening strategies for TB…………………………………………………..... 26
Chapter 5 Discussions………………………………………………….…... 29
5.1 Cost-effectiveness of the screening strategies for TB prevention.. 29
5.2 Diagnostic characteristics of TST and IGRA………………….... 30
5.3 Limitations…………………………………………………….... 31
5.4 Conclusion…………………………………………………….... 33
Chapter 6 References……………………………………….…………...… 34





Table list
Table 1. Characteristics of TB cases in Changhua from 1991 to 2016………….. 38
Table 2. Natural progression of TB in Changhua by IGRA result………..……... 39
Table 3. Characteristics of Tuberculosis recurrence cases…………...…….......... 40
Table 4. Estimated results on DOTs efficacy for the prevention of TB recurrence 41
Table 5. Characteristics of subject for the evaluation of diagnostics characteristics for TST and IGRA…………………………………………………………………... 42
Table 6. Estimated results on the diagnostic characteristics of TST and IGRA… 43
Table 7. Annual TB case-fatality in Changhua……………………………….…. 44
Table 8. Parameters of TB screening in Changhua………………………........... 45
(a) TB evolution……………………………………………………….... 45
(b) Characteristics of screening tools…………………………………… 47
(c) Efficacy of chemoprophylaxis and BCG……………………………. 48
(d) Cost…………………………………………………………………. 49
Table 9. Cost-effectiveness analysis using life-years gained as efficacy…….… 50
Table 10. Cost-effectiveness analysis using TB cases averted as efficacy…….. 51
Table 11. Sensitivity analysis for ICER with discount rate ranged between 0.01 and 0.05…………………………………………………………………………….. 52
Figure list
Figure 1. Decision Analysis for TB screening strategies with Markov decision tree………………………………………………………………...…………….. 53
Figure 2. Chronological trend of TB incidence and intervention strategies in Changhua……………………………………………………………………….. 58
Figure 3. Chronological trend of TB incidence by types (pulmonary, extra-pulmonary, and mixed types) in Changhua………………………………………………….. 59
Figure 4. Chronological trend of TB incidence by sex in Changhua………….... 60
Figure 5. TB incidence by age groups in Changhua……………………………. 61
Figure 6. TB incidence by age groups and sex in Changhua…………………… 62
Figure 7. Annual trend of TB case-fatality in Changhua……………………….. 63
Figure 8. Results of probabilistic approach of cost-effectiveness analysis for four screening strategies and no screen for life-years gained……………..………… 64
Figure 9. Acceptability curves for four screening strategy compared with no screen in terms of life-years gained…………………………………………………….… 69
Figure 10 Results of probabilistic approach of cost-effectiveness analysis for four screening strategies and no screen for TB cases averted…………………….…. 73
Figure 11 Acceptability curves for four screening strategy compared with no screen in terms of TB cases averted…………………………………………………....... 78
Figure 12 Sensitivity analysis for ICER with discount rate raged between 0.01 and 0.05…………………………………………………………………………….. 82

Auguste P, Tsertsvadze A, Pink J, Court R, Seedat F, Gurung T, Freeman K, Taylor-Phillips S, Walker C, Madan J, Kandala NB, Clarke A, Sutcliffe P. Accurate diagnosis of latent tuberculosis in children, people who are immunocompromised or at risk from immunosuppression and recent arrivals from countries with a high incidence of tuberculosis: systematic review and economic evaluation. Health technology assessment (Winchester, England). 2016;20:1-678.
CDC (1996). "The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices." MMWR Recomm Rep 45(RR-4): 1-18.
Centers for Disease, C. (1983). "Tuberculosis in a nursing care facility--Washington." MMWR Morb Mortal Wkly Rep 32(9): 121-122, 128.
Comstock, G. W. (1999). "How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults?" Int J Tuberc Lung Dis 3(10): 847-850.
Dion MJ, Tousignant P, Bourbeau J, Menzies D, Schwartzman K. Measurement of health preferences among patients with tuberculous infection and disease. Medical decision making : an international journal of the Society for Medical Decision Making. 2002;22:S102-114.
Dion MJ, Tousignant P, Bourbeau J, Menzies D, Schwartzman K. Feasibility and reliability of health-related quality of life measurements among tuberculosis patients. Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation. 2004;13:653-665.
Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2006;10:1192-1204.
Houben, R. M. and P. J. Dodd (2016). "The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling." PLoS Med 13(10): e1002152.
Kang YA, Lee HW, Yoon HI, Cho B, Han SK, Shim YS, Yim JJ. Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. Jama. 2005;293:2756-2761.
Lai CC, Hsu CY, Hsieh YC, Yeh YP, Chen HH. The effect of combining QuantiFERON-TB Gold In-Tube test with tuberculin skin test on the detection of active tuberculosis. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2018;112:245-251.
Linas BP, Wong AY, Freedberg KA, Horsburgh CR, Jr. Priorities for screening and treatment of latent tuberculosis infection in the United States. American journal of respiratory and critical care medicine. 2011;184:590-601.
Lobue, P. and D. Menzies (2010). "Treatment of latent tuberculosis infection: An update." Respirology 15(4): 603-622.
Marra CA, Marra F, Colley L, Moadebi S, Elwood RK, Fitzgerald JM. Health-related quality of life trajectories among adults with tuberculosis: differences between latent and active infection. Chest. 2008;133:396-403.
Nienhaus A, Schablon A, Costa JT, Diel R. Systematic review of cost and cost-effectiveness of different TB-screening strategies. BMC health services research. 2011;11:247.
Pease C, Hutton B, Yazdi F, Wolfe D, Hamel C, Quach P, Skidmore B, Moher D, Alvarez GG. Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses. BMC infectious diseases. 2017;17:265.
Pooran A, Booth H, Miller RF, Scott G, Badri M, Huggett JF, Rook G, Zumla A, Dheda K. Different screening strategies (single or dual) for the diagnosis of suspected latent tuberculosis: a cost effectiveness analysis. BMC pulmonary medicine. 2010;10:7.
Steffen RE, Caetano R, Pinto M, Chaves D, Ferrari R, Bastos M, de Abreu ST, Menzies D, Trajman A. Cost-effectiveness of Quantiferon(R)-TB Gold-in-Tube versus tuberculin skin testing for contact screening and treatment of latent tuberculosis infection in Brazil. PloS one. 2013;8:e59546.
Taiwan CDC. Taiwan Tuberculosis Control Report 2017. 2018.
Tasillo A, Salomon JA, Trikalinos TA, Horsburgh CR, Jr., Marks SM, Linas BP. Cost-effectiveness of Testing and Treatment for Latent Tuberculosis Infection in Residents Born Outside the United States With and Without Medical Comorbidities in a Simulation Model. JAMA internal medicine. 2017;177:1755-1764
The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 1996;45:1-18.
Vynnycky E, Fine PE. The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiology and infection. 1997;119:183-201.
Wang PD. Assessment of the need for universal BCG vaccination of children in Taipei. Public health. 2009;123:74-77.
WHO. Global tuberculosis report 2018. 2018.
Yeh YP, Luh DL, Chang SH, Suo J, Chang HJ, Chen TH. Tuberculin reactivity in adults after 50 years of universal bacille Calmette-Guerin vaccination in Taiwan. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2005;99:509-516.
林名男: 結核病自然病史與結核病預防性治療成本效益之電腦模擬模式分析. in 流行病學研究所. 台北市, 國立臺灣大學; 2001. pp. 56. (Lin, 2001)
許辰陽: 廣義線性隨機過程於傳染病之應用. in 流行病學與預防醫學研究所, 臺灣大學; 2014. pp. 1-312. (Hsu, 2014)
賴昭智: 隨機過程在肺結核及嚴重急性呼吸道症候群傳染病之運用. in 流行病學與預防醫學研究所, 臺灣大學; 2015. pp. 1-207. (Lai, 2015)
謝孟蓁: 中度結核盛行地區潛伏結核感染之社區性研究─應用丙型干擾素分泌檢測與結核菌素測驗. in 流行病學與預防醫學研究所, 臺灣大學; 2013. pp. 1-104. (Hsieh, 2013)