摘要：背景：截至目前為止，結核病仍是世界上最嚴重、死亡率最高的感染症．想要消滅結核病，除了要針對活動性結核病個案能夠及時診斷、治療以外，更重要的是必須能夠找出潛伏感染但仍未發病的結核接觸者，也就是所謂的潛伏結核感染者（簡稱LTBI），投予有效的治療。在過去，LTBI治療上最大的困難在於治療時間過長，需要每天服用每公斤5mg的isoniazid九個月（簡稱9H），因此大大降低了治療的完成率。所幸近年來為期12週的短程治療問世（每週口服一次每公斤15mg的長效型rifapentine以及每公斤15mg的高劑量isoniazid，共12個劑量；簡稱3HP），而且日漸成熟，目前已被世界衛生組織認定在大部分潛伏結核感染個案可用短程3HP處方取代傳統9H治療。3HP處方雖然較傳統治療方便，在肝毒性上也有較高的安全性，但卻有較高的全身過敏反應（systemic drug reaction）以及類流感症狀（flu-like symptoms），嚴重可能會低血壓、甚至休克。但由於目前對於3HP產生嚴重副作用的原因和危險因子都不清楚，再加上亞洲地區只有來自於台灣研究團隊的兩篇臨床研究資料，因此，在亞洲這個全球結核病負擔最高的地區，亟需要有更多的研究來了解3HP嚴重副作用的危險因子，進一步建構一個預測模式，儘可能在治療之前、或者是發生嚴重副作用之前（通常是第三或第四次服藥），提早偵測出可能發生嚴重副作用的個案，以提高醫師、民眾對3HP的接受度，讓接受LTBI治療者更安全。因此，我們設計了這個多醫院的前瞻性臨床試驗，分析宿主基因多型性（genetic polymorphism）、血中發炎指標以及藥物濃度，與服藥後是否發生全身性藥物反應是否相關。此外，我們也將使用過去以及未來一年研究所得資料，建構一個3HP引發全身性藥物反應的預測模式。目的：1.評估3HP治療過程中，宿主基因、發炎、藥動等生物標記與全身性藥物反應的相關性2.建構一個3HP引發全身性藥物反應的預測模式方法：在這個前瞻性、多機構的研究當中，我們將分別在臺大醫院及其新竹分院、臺北市立萬芳醫院、高雄醫學大學附設中和紀念醫院及其分院共六家醫院，針對12歲以上潛伏結核感染者，在按照衛生福利部疾病管制署公衛政策建議下接受治療的個案，邀請他們加入臨床研究，於醫療常規抽血時，檢測宿主基因多型性、血中發炎指標以及藥物濃度，同時每週詢問服藥後之臨床反應（返診面訪或電話詢問），紀錄是否發生全身性藥物反應。此外，我們也將利用過去兩年臺大醫院領導的臺灣研究團隊以及未來一年內的研究資料，利用統計方法建構一個3HP引發全身性藥物反應的預測模式。
Abstract: Background:Tuberculosis (TB) remains one of the deadliest infectious disease worldwide. Elimination of tuberculosis depend not only on rapid diagnosis and prompt treatment of active tuberculosis cases but also on the successful implement of preventive therapy for subjects with latent tuberculosis infection (LTBI). The major obstacle of traditional preventive therapy is the unacceptable long duration of daily treatment, taking isoniazid 5mg/kg for a total of 9 months (9H), thus seriously compromising its acceptability. With the introduction of 12-doses weekly high-dose (15 mg/kg) rifapentine plus isoniazid (3HP regimen), the completion rate of 3HP has be shown to b much higher than 9H. This short-course regimen has now been recommended by the World Health Organization to replace the conventional regimen for most subjects with LTBI.Though 3HP has a higher completion rate and a lower risk of hepatotoxicity than 9H, the incidences of systemic drug reaction and flu-like symptoms, even hypotension and shock, are higher. The underlying pathophysiology and risk factors for these adverse reaction are poorly understood. In addition, so far only two studies focusing on 3HP in Asia have been published, both from Taiwan. Therefore in Asia, the area of highest TB burden in the world, more studies are needed to understand the risk factors of 3HP-related systemic drug reaction and to construct a predicting algorithm to identify risk subjects prior to treatment or onset of severe advere reaction (usually occurring at the 3rd or 4th dose of 3HP), thus increasing the acceptability of 3HP and making LTBI cases safer.In this prospective, multi-center study, we will assess the association between 3HP-related systemic drug reaction and host genetic, inflammatory and pharmacokinetic biomarkers. We will also contruct a predicting algorithm for 3HP-related systemic drug reaction using the data collected in previous two and the coming one years.Objectives: 1.To explore the association between 3HP-related systemic drug reaction and host genetic, inflammatory, and pharmacokinetic biomarkers2.To construct a predicting algorithm for 3HP-related systemic drug reactionMethods:In this prospective, multi-center study conducted in the National Taiwan University Hospital and its Hsin-Chu branch, Taipei Municipal Wanfang Hospital, and Kaoshiung Medical University Chung-Ho Memorial Hospital and its branches, LTBI cases aged ≥12 will be invited to join the study. Once they receive preventive therapy according to the current public health policy, we will assay host genetic, inflammatory and pharmacokinetic biomarkers, and record clinical response and onset of systemic drug reaction after treatment under a weekly basis. Furthermore, we will construct a predicting algorithm for 3HP-related systemic drug reaction using the data collected in previous two years (2017, 2018) and the coming one year (2019).
