潛伏結核全都治之介紹

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1 潛伏結核全都治 Latent TB Infection Treat for All 速克伏 3HP 短程治療處方介紹疾病管制署慢性傳染病組 1

2 Outlines Experiences of Adverse Effects with 9H in Taiwan Introduction of a Shorter Regimen for LTBI Treatment Monitor and Surveillance of Adverse Events Choosing a Regimen for Treatment of LTBI 2

3 這要從 2008 年跟我們一起一路走來的 LTBI 合作醫師說起 EXPERIENCES OF ADVERSE EFFECTS WITH 9H IN TAIWAN 3

4 2007 CI & LTBI Treatment Increase contact exam. willingness: Copayment subsidy by the TCDC People with TB Disease 2008 LTBI treatment for contacts <13 y/o Provide IGRA and LTBI treatment for contacts of all age groups (in 11 townships only) People with LTBI 2012 Expansion of LTBI treatment target : 13 y/o to birth cohort younger than 1986 in household, school & congregate settings 2015 Provide IGRA and LTBI treatment for contacts of all age groups (in 6 counties/ cities only) 4

50% 潛伏結核感染治療期間因不良反應而永久停藥比率依年齡分層, 9H HEPATITIS HEPATITIS SEVERE SKIN RASH SKIN RASH SEVERE 45% 43.3% 40% 37.9% 37.1% 35% 33.3% 30% 25% 24.8% 20% 15% 19.3% 15.5% 14.3% 18.6% 10% 5% 5.

5 50% 潛伏結核感染治療期間因不良反應而永久停藥比率依年齡分層, 9H HEPATITIS HEPATITIS SEVERE SKIN RASH SKIN RASH SEVERE 45% 43.3% 40% 37.9% 37.1% 35% 33.3% 30% 25% 24.8% 20% 15% 19.3% 15.5% 14.3% 18.6% 10% 5% 5.5% 10.0% 10.7% 9.6% 3.6% 7.1% 2.0% 0% All age < >=30 肝炎及嚴重肝炎 (ATS) 在 13 歲以上分別為 56%, 68% <13 歲則以皮膚相關癢疹為最多 (53%) 因肝炎導致住院 :0.56 (16/28,353), 沒有因不良反應導致死亡 MOHW103-CDC-C

6 70 潛伏結核感染治療期間因肝炎而永久停藥比率依年齡分層, 9H HEPATITIS(N) HEPATITIS (defined by ATS,N) HEPATITIS(%) HEPATITIS(defined by ATS,%) <10 10~19 20~29 30~39 40~49 50~59 60~69 70~79 >= 肝炎 (n=295) 在 30 歲以上會有 3-5% 的發生率, trend test: p<0.001 若為嚴重肝炎 (n=187, 即符合美國胸腔暨重症醫學會建議的肝炎標準 ), 則 <10 歲的發生率為 1,20 歲達 1%,30 歲達 2-4%, trend test: p<

7 9H vs. 3HP ( 速克伏 ) 處方 INTRODUCTION OF A SHORTER REGIMEN FOR LTBI TREATMENT 7

8 WHO Recommendation for LTBI Management 8

9 Comparison of Efficacy and Hepatotoxicity among LTBI Regimens 每種 LTBI 治療都可以有效降低 TB 發病 VS 但不同處方肝毒性的確有差異 ERJ 2015 Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries 9

10 Current Regimens for LTBI Regimen Efficacy / Effectiveness Tolerability Drug discontinue AE/ Hepatotoxicity Comments 9 INH (9H) Daily 90% / 25-88% median:60% 台灣 73 94%* 0-31% % 台灣肝炎 %* 6 and 12 months well-studied; 30-60% completion 台灣 60-80%* 3 INH + rifapentine (3HP) once-weekly 90% (estimated) 90% (estimated) 與九個月無差別 4.9% 0.4% 台灣 %, 0-1 % ** 82% completion Directly-observed 台灣 90-97%** 3 INH + rifampin % An alternative daily 41-59% 0-5.1% Hepatoxicity 4 rifampin daily % (3 months) % 0-0.7% 台灣收容人研究 *** 2-6%, 肝炎 0% An alternative When INH R, Not in HIV+ 台灣完成率 86%*** 10 Curtsey of Dr. ME Villarino/ MOHW103-CDC-C / MOHW104-CDC-C / IJTLD 2012;16(5):633-8.

11 短程處方 (3HP 速克伏 ) : once weekly x 3 months = only 12 doses 潛伏結核全都治計畫 2016 年全面推行增加短程治療處方之選擇短程處方須以傳統都治方式執行 900mg Isoniazid (INH) + 900mg Rifapentine (RPT) 11

12 Priftin Taiwan Status 2016 年疾病管制署專案進口使用於非 INH 非 RMP 抗藥的傳染性肺結核病人之 LTBI(+) 接觸者 3 個月的潛伏結核感染短期治療處方 12

13 Against Mycobacteria by Inhibiting Bacterial DNA-dependent RNA Polymerase 同 C 43 H 58 N 4 O 12 RMP C 47 H 64 N 4 O 12 RPT RPT/RMP 會活化 CYP450 之 3A4 與 2C8/9, 經由 CYP450 代謝的藥物與 RPT/RMP 合併使用的話, 可能導致這些藥物的血中濃度降低, 療效減低使用 RPT/RMP, 體液或某些身體組織可能變橘紅色 RPT/RMP 抑制荷爾蒙避孕藥的效用, 建議採用其他有效避孕方式 13

14 異 RPT 跟 RMP 哪裡不一樣? RPT 半衰期比 RMP 長得多 (>12 h vs 2-3 h) RPT 與高脂餐點一起服用可增加血清濃度但 RMP 是空腹服用吸收才會好 Consumption with food (especially lipid-rich meal) increases the peak serum concentration of RPT (40-50% Cmax & AUC), in contrast to RMP that needs to be taken in a fasting state (also INH). Prifin USPI, Dec

15 NEJM 15

16 US CDC 16

17 The PREVENT TB Study (TBTC 26) -TBTC S26 Design Sterling TR et al. N Engl J Med. 2011;365: Shepardson D et al. Int J Tuberc Lung Dis. 2013;17: Morb Mort Wkly Rep 2011;60:

18 Characteristic Demographic Characteristics in mitt Populations 9H 傳統治療 (N=3,745) 3HP 短程處方 (N=3,986) Age (median,iqr) 36 (25-46) 37 (25-47) Unemployed 390 (10) 424 (11) Hx of alcohol at enrollment 1888 (50) 1929 (48) Jail/prison ever 175 (5) 221 (6) Hx of IVDU at enrollment 135 (4) 149 (4) Current smoker 1034 (28) 1112 (28) Close contact for LTBI 2609 (70) 2857 (72) HCV* 97 (3) 99 (3) * Excluded when AST >=5 x UNL HBV* 60 (2) 42 (1) 年齡較輕, 但自述有飲酒習慣偏高且靜脈毒癮者, 收容人及慢性肝病皆有收案 18

19 TBTC S26 The Prevent TB Study -Primary endpoint : TB rates by Mo33 mitt 短程處方 3HP 累積結核發生率比傳統 9H 低, 統計無顯著差異 9H (0.43%) vs. 3HP (0.19%) Log-rank P-value = 0.06 Non-inferiority demonstrated as 97.5% upper-bound of diff = 0.08% (<0.75%= NI margin) 此項臨床試驗證實, 短程處方 3HP 的療效是不輸給傳統 9H 的 Sterling TR. N Engl J Med 2011;365:

20 Tolerability in mitt Population Outcome 9H 傳統治療 (N=3,745) 3HP 短程處方 (N=3,986) P-value 勝 Treatment completion 2,585 (69.0%) 3,362(84.3%) < Permanent drug discontinue - any reason 勝 1,160 (31.0%) 624(15.7%) < Permanent drug discontinue - due to an adverse event 135 (3.6%) 188(4.7%) Death 39 (1.0%) 31 (0.8%) 0.22 使用 3HP 短程處方, 治療時間短, 完治率大幅提高 Courtesy of M. Elsa Villarino 20

21 Hepatotoxicity among persons receiving > 1 dose during treatment or within 60 days of the last dose Toxicity 9H 傳統治療 N=3,759 3HP 短程處方 N=4,040 P-value All hepatotoxicity 113 (3.0) 24 (0.6) 勝 < Related to drug 103 (2.7) 18 (0.4) 勝 < Not related 10 (0.3) 6 (0.2) 使用 3HP 短程處方, 與藥物相關之肝炎比例明顯較低 Courtesy of M. Elsa Villarino 21

22 Possible Drug Hypersensitivity 臨床試驗定義在 PREVENT trial 中, 預期會有 RMP 類的過敏反應, 其定義如下 A broad definition of was used ( 以下任一 ) a) hypotension, urticaria, angioedema, acute bronchospasm, or conjunctivitis that occurred in relation to study drug; or b) > 4 of the following (one of which had to be > grade 2) that occurred in relation to study drug: weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing, or chills. 22

23 Reported Adverse Events Among persons receiving > 1 dose During treatment or within 60 days of the last dose Accounting for attribution to study drug Toxicity 9H N=3,759 HS: hypersensitivity reaction 3HP N=4,040 注意 P-value Related to drug 206 (5.5) 332 (8.2) <0.001 Rash only 21 (0.6) 31 (0.8) 0.26 Possible HS 17 (0.5) 152 (3.8) <0.001 Other 65 (1.7) 131 (3.2) <0.001 Not related 410 (10.9) 226 (5.6) <0.001 使用短程處方較傳統 9H 多的是過敏反應和其他副作用 23

兒童的臨床試驗 A pediatric cohort nested within an openlabel RCT conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013 in 29 study sites in the United

24 兒童的臨床試驗 A pediatric cohort nested within an openlabel RCT conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013 in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of LTBI M. Elsa Villarino et al. JAMA Pediatr. 2015;169(3):

25 Tolerability and Effectiveness in Children TBTC S26 + IMPAACT Study 26 amended to enroll 352 additional children; 1,058 total & 908 for efficacy evaluation No hepatotoxicity, grade 4 events, or deaths Endpoint Treatment completion D/C adverse drug reaction 3HP N=471 勝 9H N=434 P-value 88% 81% % 0.5% 0.11 TB 0 (0%) 3 (0.78%) Upper bound of difference: 0.44% 使用 3HP 短程處方, 治療時間短, 完治率大幅提高 ; 相較於成人, 因為沒有肝炎, 副作用沒有統計顯著的差別 25

26 Discontinuation 3HP Due to AEs in 3HP 共 8 位 Children 3 influenza-like AEs (grade 2) 3 cutaneous (all with pruritic rash [2 were grade 2], 1 with oral blisters and fever [grade 3]) 2 gastrointestinal reactions (1 was grade 1 and 1 was grade 2) 9H 只有 2 位 1 cutaneous AE (grade 2) and 1 gastrointestinal reaction (grade 3) 結論是 : 9H 對兒童來說已經很安全,3HP 對兒童來說, 是一個縮短療程的 alternative 選擇 26

27 兒童注意事項 INH 的劑量 : 15 mg/kg for children 12 years old 25 mg/kg for those 2-11 years the maximum weekly dose was 900 mg RPT 的劑量 : Not adjusted for age, 請參照 a dose-per-weight band table 無法吞藥粒的兒童建議磨碎後, 與液體或半固體食物服用, 建議巧克力布丁之類的澱粉類布丁, 不建議水果口味 ( 果凍類 ) Blake MJ et al. Pharmacokinetics of rifapentine in children. Pediatr Infect Dis J. 2006;25(5): Peloquin CA et al. Stability of antituberculosis drugs mixed in food. Clin Infect Dis. 2007;45(4):

28 3HP 短程處方建議劑量 Drug Duration Dose (> 12 year-old) Frequency Total doses Isoniazid (INH) 300mg 3# 3 months 15 mg/kg rounded up to the nearest 50 or 100 mg ( 12 years old); 25 mg/kg for those 2-11 years 900 mg maximum Once weekly 12 Rifapentine (RPT) 150mg 6# 3 months kg 300 mg kg 450 mg kg 600 mg kg 750 mg 50.0 kg 900 mg maximum Once weekly 12 US CDC Latent Tuberculosis Infection: A Guide for Primary Health Care Providers 28

29 對於新藥我們用較謹慎地態度來監測非肝炎的其他副作用 MONITOR AND SURVEILLANCE OF ADVERSE EVENTS 29

全身性藥物反應 Systemic Drug Reaction Clin Infect Dis. 2015;61(4):527-35.

30 全身性藥物反應 Systemic Drug Reaction Clin Infect Dis. 2015;61(4): 因為 hypersensitivity 是 RPT 在 PREVENT Trial 中較重要的副作用, 接下來我們看看在 PREVENT Trial 與 NYC 的衛生局經驗, 了解發生的狀況和嚴重度 Clin Infect Dis. 2016; 62 (1):

31 Systemic Drug Reaction in the PREVENT Tuberculosis Study 3.5% 的 3HP (n=3893) 接受者有 systemic drug reaction (SDR) Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. 4/3893 (0.1 %) admission 13/3893 (0.3%) 有 severe reactions 8: Grade 4 toxicity (including 1 syncope) 6: hypotensive 6: syncope (no admission, 有一個有 loss consciousness) No death reported Clin Infect Dis. 2015;61(4):

32 注意 3HP 的全身性藥物反應最常見的還是 Flu-like syndrome (2.2%), 嚴重的類流感反應, 佔服藥總人數的 0.15% Clin Infect Dis Aug 15;61(4):

33 Frequency of signs and symptoms in 153 cases of systemic drug reactions (SDR), stratified by arm SDR (n=153) 3HP (n=138) 9H (n=15) Signs and symptoms Number % Number % Number % Fatigue Headache Nausea Weakness Chills Myalgia (muscle pain) Fever Dizziness Joint pain Rash Abdominal Pain Flushing Conjunctivitis (red eyes) Vomiting Itching Sweats Shortness of breath Eye pain Fever: 3HP 有 2%, 9H 有 0.1%; 3HP 最常被抱怨的是疲倦, 頭痛, 噁心, 無力 ; 9H 最常被抱怨的是疹子, 癢, 疲倦 Palpitations Diarrhea Anorexia Body aches Angioedema Hypotension Tachycardia Urticaria (hives) Syncope a Chest pain Bone pain Bronchospasm

34 Natalie L. Stennis et al. Clin Infect Dis. 2016; 62 (1): 紐約市於 2013 年 1 月開始提供 3HP 當作 LTBI 治療的選擇, 但必須衛生所進行都治這個研究評估在非臨床試驗的情況下, 總共有 503 人被提供 3HP, 這個研究又助於我們了解病人的想法 34

35 Side Effects Experienced by New York City Health Department Tuberculosis Clinic Patients Treated With 3HP 注意有 32 人沒有辦法完成治療 (10.6%), 主要的副作用 : 包括噁心, 癢疹, 肚子痛和疲倦. 沒有特別觀察到 syncope 的副作用, 類流感沒有特別被整理出來, 但發燒的有 5 位, 約 1.7%. 35 Clin Infect Dis. 2016; 62 (1): 53-59

36 紐約病人拒絕 3HP 治療的理由 ( 多選 ) 不選擇 3HP 寧可選其他處方, 最常見的原因是 : 必須要到點都治, 有其他事要做很難配合, 以及 3HP 顆粒數太多不認為自己有病 / 認為自己不需要治療, 是拒絕任何 LTBI 處方最常見的原因 Natalie L. Stennis et al. Clin Infect Dis. 2016; 62 (1):

37 The Treatment Completion Rate and Side Effects of 9H and 3HP Regimens Population (courtesy of 部立彰化醫院黃伊文主任 ) 9H (n=590) 3HP (n=101) Results of treatment 勝 n % n % p value completed % % p<0.001 discontinued % % Reason of discontinued 勝 side effects % % * p<0.001 reject % 0 0 % death % 0 0 % TB % 0 0 % 3HP completion rate was significantly higher than 9H Low discontinue rate in 3HP 部立彰化醫院之 3HP 先驅計畫 37

38 Hepatotoxicity and Discontinue (courtesy of 台大醫院王振源教授 ) 勝 3HP 9H N=104 N=90 p-value Hepatotoxicity 1 (0.9%) 4 (4.3%) AST/ALT >10 ULN 0 1 AST/ALT 5~10 ULN 1 3 T-Bil >3 mg/dl 0 0 Discontinuation 11 (9.6%) 18 (20.0%) 注意 Not supervised 0 11 Due to AE 9 (8.6%) (4.4%) Tx not necessary 2 2 Family against 0 1 研究何種潛伏結核感染的治療較為安全且可達成 - 台灣的多中心隨機分派研究 MOHW103-CDC-C

39 Any AE During the treatment (courtesy of 台大醫院王振源教授 ) 3HP (n=104) 9H (n=90) p-value Any AE 48 (46.2%) 26 (28.9%) Flu-like symptoms 22 (21.2%) 16 (17.8%) 注意 Malaise 22 (21.2%) 13 (14.4%) Fever/Flush 20 (19.2%) 4 (4.4%) GI upset 14 (13.5%) 8 (8.9%) Cutaneous AE 6 (5.8%) 3 (3.3%) Blur vision 1 (1.0%) 1 (1.1%) >0.999 Irregular menstruation 1 (1.0%) 0 (0.0%) >0.999 研究何種潛伏結核感染的治療較為安全且可達成 - 台灣的多中心隨機分派研究 MOHW103-CDC-C

40 Post Marketing Surveillance by US CDC Vigilance for drug hypersensitivity reactions, particularly hypotension or thrombocytopenia No further alarm signal was detected for syncope (hypotensive in nature and suspect associated with concomitant medications HTN / CNS depressive drugs 在上市後監視發現安全性無顧慮 Curtsey of Christine S. Ho, 18th Annual Conference of the Union-NAR, th IUATLD world conference,

41 使用速克伏需要做哪些監測速克伏短程治療處方 (3HP) 較 9H 更少發生藥物性肝炎, 肝功能檢查 (ALT, total bilirubin) 原則上比照 9H 處方的肝炎監測建議與 9H 不同的地方是, 在肝病或者有其他醫療的考慮 ( 貧血或血小板相關的疾病 ) 時, 需要抽驗 CBC/DC 的基礎值, 再決定追蹤的頻率治療期間仍然要每月回診 41

42 停藥的標準全身性過敏反應 ( 立刻 ) 肝炎的原則如 9H 其餘非過敏反應的副作用, 視臨床需要給予支持療法, 停藥與否視個別病人是否能耐受, 及臨床嚴重度而決定 42

43 建議處置原則若遇到發燒的 flu-like syndrome, 經驗上可先確認病人是否在服藥後幾小時發生, 一天內即緩解, 那表示藥物相關的機會最大 ; 若非上述之典型症狀, 鑑別診斷是否有其他發燒的疾病, 例如流感泌尿道感染等, 再依各疾病對症治療預先讓病人知道可能的 flu-like syndrome, 開立解熱鎮痛劑 ( 例如普拿疼 ), 讓病人碰到發燒先觀察反應, 而不是跑急診部分病人噁心嘔吐厲害, 可使用服藥前止吐劑, 來緩解服藥當下的不適若遇到肝炎, 依 9H 停藥標準處理, 原則上不再 re-challenge 同樣的處方其他的副作用, 可考慮 re-challenge, 若失敗亦可考慮轉換成 9H 43

44 治療前確認個案是否有以下狀況 : 肝硬化慢性肝炎或肝病變酒癮靜脈毒癮者 HIV 陽性病人孕婦及產後 3 個月內的婦女 yes no 結核病診治指引第五版檢驗肝功能基礎值 * >=35 歲 <35 歲協助相關疾病檢查和評估, 治療過程中, 每月回診評估前 2 個月每月檢驗肝功能後續每月回診評估, 視臨床情況進行抽血檢查若病人肝功能狀況達肝炎 ** 定義, 則建議停藥檢驗 : 肝功能基礎值 * HBsAg, anti-hcv Ab HIV ELISA/Combo Ag+Ab 任一異常均無異常 * 肝功能基礎值 : ALT (GPT), Total bilirubin ** 肝炎定義 : 若治療前肝功能 < 正常值 2X: ALT (GPT) > 正常值 5X 或臨床有肝炎症狀且 ALT (GPT) > 正常值 3X 或 Total bilirubin >3mg/dL 若治療前肝功能正常值 2X: 肝功能超過治療前基礎值 2X 治療過程中, 每月回診評估倘若病人有肝炎症狀, 或醫師認為有需要, 則予以檢驗肝功能 ; 若達肝炎 ** 定義, 則建議停藥 44

45 使用速克伏短程治療處方應注意什麼 I 因 RPT 為專案進口, 故使用速克伏前, 須簽署同意書使用速克伏者均應加入 DOPT 醫師處方後, 請病人與公共衛生聯繫, 討論每次服藥時間, 以利病人預先規劃其個人行程已知紫質症 (porphyria) 的病人, RMP 使用會使疾病本身惡化, 故避免開立 RPT RPT 抑制荷爾蒙避孕藥的效用, 請提醒病人改用其他非荷爾蒙避孕法, 例如保險套等 45

46 使用速克伏短程治療處方應注意什麼 II RPT 會活化 CYP450 之 3A4 與 2C8/9, 經由 CYP450 代謝的藥物與 RPT 合併使用的話, 可能導致這些藥物的血中濃度降低, 療效減低 RPT 誘導的酶活性在首次投予後 4 天發生, 酶活性在停止使用 RPT 之後 14 天恢復比較重要會因交互作用而被降低濃度的藥物, 例如 : coumadin, methadone, phenytoin 以及治療愛滋病藥物 protease inhibitors, 或 NRTIs 等對於 Azole 類抗黴菌藥物, 中樞神經抑制藥物或三環抗憂鬱劑, 及免疫抑制劑也常有交互作用需知會處方之臨床醫師, 以利病人其他疾病的控制和生活品質 46

47 可能與 RPT 有藥物交互作用的藥單藥物分類 Antiarrhythmics Antibiotics Oral Anticoagulants Anticonvulsants Antimalarials Azole Antifungals Antipsychotics Barbiturates Benzodiazepines Beta-Blockers Calcium Channel Blockers Cardiac Glycoside Preparations Corticosteroids Fibrates Oral Hypoglycemics Hormonal Contraceptives/ Progestins Immunosuppressants Methylxanthines Narcotic analgesics Phophodiesterase-5 (PDE-5) Inhibitors Thyroid preparations Tricyclic antidepressants Examples of Drugs Within Class Disopyramide, mexiletine, quinidine, tocainide Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin) Warfarin Phenytoin Quinine Fluconazole, itraconazole, ketoconazole Haloperidol Phenobarbital Diazepam Propanolol Diltiazem, nifedipine, verapamil Digoxin Prednisone Clofibrate Sulfonylureas (e.g., glyburide, glipizide) Ethinyl estradiol, levonorgestrel Cyclosporine, tacrolimus Theophylline Methadone Sildenafil Levothyroxine Amitriptyline, nortriptyline 47

48 病人臨時無法於約定日服藥, 可以提前或延後嗎? 考慮速克伏短程治療處方藥物半衰期, 及配合實務上都治計畫可能面臨爽約之情形, 爽約後的第二天, 儘快目視服藥, 總之越快越好依據美國 CDC 的建議, 若欲提早或延後, 兩個劑量間, 間隔須大於 72 小時, 並於下個劑量回到原來的每七天服藥週期,28 天內不超過 5 個劑量來給予為原則 Sterling TR. N Engl J Med 2011;365: (supplementary protocol) 48

49 轉換藥物後使用時間的建議以下為專家意見原則上 3HP 與 9H 如果病人無法耐受副作用, 可嘗試互換若服用 3HP 後碰到無法忍耐的副作用, 或者有具體實驗值不宜繼續時, 服用過 4 doses 3HP + 6H 可完成治療 49

50 計畫成效評估與監測 TB or Not TB? 治療效益分析副作用監測抗藥性監測 50

51 副作用的經驗分享成立諮詢醫師專線, 可透過 1922 反映, 本署防疫醫師會主動與您聯繫, 協助解決相關問題建立合作醫師電子郵件群組, 定期發送相關訊息計畫初期, 定期舉辦電話會議, 邀請專家們列席, 讓醫師及個管師自由參加提問討論鼓勵臨床醫師向全國不良反應通報中心通報 51

52 沒有藥證就沒有藥害救濟怎麼辦? 在病人選擇使用 3HP 時, 簽署的速克伏同意書上, 已向民眾敘明因為是專案進口藥物, 故發生藥害時無法申請藥害救濟故若民眾服用速克伏後, 產生需要申請藥害救濟之副作用時, 將由廠商投保之產品責任保險來負擔如出現嚴重副作用, 將由公衛護士比照預防接種受害救濟申請方式, 與廠商聯繫 52

53 若發生嚴重不良反應產生嚴重副作用 : 住院或者死亡倘服用速克伏至少一劑後, 產生嚴重副作用 ( 住院或者死亡 ), 請透過 1922 進線, 通報嚴重不良反應給疾病管制署本署將派員儘速至醫院陪同診治醫師了解嚴重不良反應, 是否與藥物安全性有關 53

54 Choosing a Regimen for Treatment of LTBI Factors to Consider Likelihood of completion Appropriate for age, exposure, other issues <2, 2 11 years, 12 years + Human immunodeficiency virus (HIV)+ and Antiretroviral therapy Co morbidities, pregnancy, drug interactions Social concerns: homelessness, drug and alcohol use, mental health issues, etc. Drug resistance 54

55 Choosing a Regimen for Treatment of LTBI Factors to Consider Efficacy Patient preference Possible side effects Cost Drug (s) Directly observed therapy (DOT) costs, if any Staff time Monitoring DOT access / availability 55

56 Choosing a regimen for LTBI contacts HIV + pregnant woman Quiz Homeless, alcohol-using man 8 month-old girl, contact of her mother An 11 y/o boy, failed INH after 2 months of self administration, living in a remote village 56

57 3HP 短程處方不同年齡層使用建議 12 歲 ( 含 ) 以上 9H 及 3HP 為 INH susceptible (9H) 及 INH & RMP susceptible (3HP) 的建議處方 2-11 歲以 9H 為 INH susceptible 的建議處方未滿 2 歲不建議 3HP, 只有 9H 為 INH susceptible 的建議處方 US CDC Latent Tuberculosis Infection: A Guide for Primary Health Care Providers 57

resistant 未滿 2 歲之兒童 < 2 years of age 接受 ARTs 治療之 HIV 感染者 (protease inhibitors

58 不適用 3HP 處方者 Ineligible Patients 孕婦 ( 或準備懷孕的婦女 Pregnant and those expecting to become pregnant during treatment 指標個案為 INH 或 RMP 抗藥 Source case is INH or RMP resistant 未滿 2 歲之兒童 < 2 years of age 接受 ARTs 治療之 HIV 感染者 (protease inhibitors 的濃度會被影響 ) 2-11 歲兒童 ( 建議處方為 9H, 欲使用 3HP 請參考劑量建議 ) 正在使用 coumadin, methadone, phenytoin 58

59 歡迎成為短程處方 LTBI 治療合作醫師! 2016 年我們徵求願意一起使用 3HP 短程處方 12 劑的 LTBI 治療合作醫師療效確定, 不輸給 9H 較高的完成率 84% vs. 69% 較低的肝毒性 0.6% vs. 3% 在台灣應該會有同樣的結果在 4R vs. 6H 的收容人治療方案已經注意到由公共衛生都治團隊 (DOPT) 100% 與您一起照顧潛伏結核感染的病人! Chan PC, et al. Int J Tuberc Lung Dis. 2012;16(5): Sterling TR, et al. N Engl J Med 2011;365: Clin Infect Dis. 2015;61(4):

60 詹珮君李品慧 60

61 Case presentation of severe systemic drug reaction A 37-year-old female developed anaphylaxis 6 hours after receiving the fourth dose. Signs and symptoms associated with this reaction included pruritic rash, blood pressure of 85/45 mmhg, dizziness, weakness, fatigue, nausea, subjective fever, flushing, muscle pain, and headache. The event did not require hospitalization and the patient completely recovered within 48 hours. Clin Infect Dis. 2015;61(4):

62 Case presentations of thrombocytopenia, anemia, or leukopenia that were reported in relation to study drug Laboratory values at enrollment and during treatment of were evaluated, looking for values of hemoglobin < 10.0 g/dl, platelets < 100,000/mm 3, and white blood cell count (WBC) < 3x10 3 /mm 3. Study participants did not undergo routine laboratory monitoring, nor were lab values a study exclusion criterion. Study investigators had the option of performing laboratory testing if the study participant developed clinical evidence of anemia or thrombocytopenia. Clin Infect Dis. 2015;61(4):

63 Thrombocytopenia A 21 year old female developed a systemic drug reaction / serious adverse event (SAE) after the third dose of 3HP. platelet count of 8,000 /mm 3 The next day the platelet count was 191,000 / mm 3, suggesting that the initial result may have been lab error. No manifestations of bleeding were reported. She was HIV-seronegative and there was no history of hepatitis B, hepatitis C, alcohol abuse, or cirrhosis. The WBC was 1.99x10 3 /mm 3. She was receiving no concomitant medications. Clin Infect Dis. 2015;61(4):

64 Anemia a HIV-seronegative 39 year old was reported to develop a systemic drug reaction after receiving four 3HP doses. There was no report of jaundice or dark urine; the hemoglobin was 8.7 mg/dl. Clin Infect Dis. 2015;61(4):

65 Leukopenia with fever a 21 year old developed a systemic drug reaction / serious adverse event (SAE) after the third 3HP dose. The event started 4 hours after study drug ingestion. Signs and symptoms included conjunctivitis, rash, pruritus, and facial erythema. Also fatigue, headache, fever (102.1 F), myalgias, arthralgias, flushing, chills, palpitations, and shortness of breath. She was found to have elevated ALT/AST, thrombocytopenia, and a WBC of 1.3x10 3 /mm 3. She reported no concomitant medications. The event resolved within 48 hours. Clin Infect Dis. 2015;61(4):

66 發燒 20 歲女性, 抱怨服第二次 3HP 後自覺發燒確實超過 38 C, 但除了 Flu-like illness 之外並沒有嚴重不適感, 服退燒藥會診抽血沒有 sepsis 的跡象, 也沒有臨床其他感染的情況再服藥依然微燒, 並不需要退燒藥, 自退完成 12 doses 3HP MOHW103-CDC-C

67 基礎值直接型黃疸 23 歲男性, 無特殊病史個案肝功能正常, 但基礎值黃疸異常 (1.3mg/dL) 服藥中每月抽血並無肝功能異常, 發現為直接型黃疸, 臨床無黃疸症狀無特殊用藥史完成 12 doses 3HP MOHW103-CDC-C

68 Flow chart for LTBI study regimen 3HP re-challenge (re-challenge doses given at least 24 hours apart) Modified by supp of Clin Infect Dis. 2015;61(4):

69 Guidelines for drug re-challenge Do not re-challenge if patient does not want to rechallenge Never re-challenge if grade 4 toxicity and no other likely cause of the toxicity Consider re-challenge if grade 3 toxicity Recommend re-challenge if grade 1-2 toxicity (though not mandated) For serious manifestations of presumed rifamycinassociated hypersensitivity reactions (acute renal failure, hemolytic anemia, thrombocytopenia, anaphylaxis including wheezing and/or dyspnea), the patient should not be re-challenged with rifamycin. Supp of Clin Infect Dis. 2015;61(4):

70 Modified Naranjo adverse drug reaction probability scale Yes N Do Not Score o Know 1. Are there previous conclusive reports on this reaction? a (Do not know) 2. Did the adverse event appear 24 hours after the suspected drug was administered? 3. Did the adverse reaction improve or resolve when the drug was discontinued? 4. Did the adverse reaction reappear when the study drug(s) , -1, or 0 was/were readministered (as a re-challenge or as a full dose)? b 5. Are there alternative causes (other than the drug), such as concomitant drugs and other diseases, that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo (vitamin B6) was given? c 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? a (Do not know) 8. Was the adverse reaction more severe with a re-challenge or full dose? d or 0 9. Did the patient have a similar reaction to the same or similar (no) drugs in any previous exposure? a 10. Was the adverse event confirmed by any objective evidence? e Total Score To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score. Total Score ADR Probability Classification >9 Highly Probable 5-8 Probable 1-4 Possible Supp of Clin Infect Dis. 2015;61(4): Doubtful 70

71 Doses of Rifapentine mg/kg 71

72 The PREVENT TB Study (TBTC 26) Summary 8,053 persons, 2 y/o, enrolled United States, Canada, Brazil, Spain June 2001-February months of follow-up Pre-defined non-inferiority margin: 0.75% 7,731 in modified intention-to-treat (MITT) Enrolled in the study, and eligible Tuberculosis risk (cumulative) 3HP: 7 / 3,986 (0.19%) -> DOPT 9H: 15 / 3,745 (0.43%) -> self administration Rate difference: -0.24% Upper limit of 95% CI of difference: 0.01%. Sterling TR. N Engl J Med 2011;365:

73 Cumulative Tuberculosis Event Rates 短程處方 3HP 累積結核發生率比傳統 9H 低, 統計無顯著差異 Log-rank P-value =

74 Difference in Rates of Tuberculosis MITT Analysis 此項臨床試驗證實, 短程處方 3HP 的療效是不輸給傳統 9H 的 74 Sterling TR. N Engl J Med 2011;365:

75 Interferon-Gamma Release Assay (IGRA) 感染結核菌者, 其 T cell 與 M. tuberculosis 之抗原反應會產生 interferon-gamma 因此可以抽取病人血液中 T cell 與結核菌的特異性抗原 (ESAT-6, CFP-10,TB7.7) 於體外反應, 觀察是否產生足夠的 interferongamma 減少了卡介苗的干擾提高特異性, 且使用 T cell 體外測試的方式, 病人不須再次就診以判讀結核菌素測驗結果目前在台灣核准使用的有 QuantiFERON-TB 與 T-SPOT.TB 75

76 結果判讀檢驗方法結果不確定 (indeterminate) 陽性陰性臨界值 * TB 抗原減 Nil QFT-GIT Enzyme-linked immunosorbent assay mitogen < 0.5 IU/ml 或 Nil > 8.0 T-SPOT Enzyme-linked immunospot 0.35 IU/ml 且 25% Nil 值 * >8 spots < 0.35 IU/ml*, 或 0.35 IU/ml 且 < 25% Nil 值 * > 10 spots in Nil 或 < 20 (spot forming unit, SFU) mitogen < 4 spots 5, 6, or 7 spots 不確定的 QFT 結果, 可能是採檢操作問題或與病人的免疫功能低下有關 1. 考慮重新採檢 2. 免疫低下則如同 TST 可能出現偽陰性建議臨床給予預防性投藥以減低未來發病的風險 76

擔費用外, 另可額外申請三項新增給付項目 ( 即套裝給付 ), 分別是 : 1. E4003C 結核病接觸者檢查衛教諮詢及抽血 100 點 2. E4004C 丙型干擾素釋放詴驗 IGRA 檢驗 ( 不含詴

擔費用外, 另可額外申請三項新增給付項目 ( 即套裝給付 ), 分別是 : 1. E4003C 結核病接觸者檢查衛教諮詢及抽血 100 點 2. E4004C 丙型干擾素釋放詴驗 IGRA 檢驗 ( 不含詴 105 年潛伏結核全都治 - 醫院版 Q&A 醫院版本 Q&A 內容提及之專有名詞說明 ( 依字母順序 ): 專有名詞說明 3HP 速克伏短程治療處方, 為 isoniazid 900mg 合併 rifapentine 900mg, 每週 1 次, 服用 3 個月共 12 個劑量之短程治療處方