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Treatment of Latent Tuberculosis Infection 索任 醫師 社團法人中華民國防癆協會 第一胸腔病防治所

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Presentation on theme: "Treatment of Latent Tuberculosis Infection 索任 醫師 社團法人中華民國防癆協會 第一胸腔病防治所"— Presentation transcript:

1 Treatment of Latent Tuberculosis Infection 索任 醫師 社團法人中華民國防癆協會 第一胸腔病防治所 http://www.tb.org.tw

2 Latent infection vs. disease 感染發病

3 Infectious Infected Class II Disease Class III contact Class I 傳染

4 結核病防治 結核潛伏 感染 傳染性 結核病 非傳染性 結核病 Prophylactic treatment 預防性 治療 化學治療 卡介苗 接種 病人延誤 醫師延誤 傳染 transmission 死亡 接觸 Source: Interventions for Tuberculosis Control and Elimination, IUATLD 2002 Preventive therapy Doctor’s delay Patient’s delay Infectious TB Non-Infectious TB Subclinical infection Exposure BCG vaccination Death Chemotherapy 結核病的傳染期 = 病人延遲 + 醫師延遲 + 病人治療管理不當

5 Treatment of LTBI – Milestones For more than 3 decades, an essential component of TB prevention and control in the U.S. has been the treatment of persons with LTBI to prevent TB disease. (1)(1)

6 Treatment of LTBI – Milestones 1965: American Thoracic Society (ATS) recommends treatment of LTBI for those with previously untreated TB, tuberculin skin test (TST) converters, and young children. 1967: Recommendations expanded to include all TST positive reactors (  10 mm). (2)(2)

7 Treatment of LTBI – Milestones 1974: CDC and ATS guidelines established for pretreatment screening to decrease risk of hepatitis associated with treatment Treatment recommended for persons ≤ 35 years of age (3)(3)

8 Treatment of LTBI – Milestones 1983: CDC recommends clinical and laboratory monitoring of persons  35 who require treatment for LTBI 1998: CDC recommends 2 months of rifampin (RIF) plus pyrazinamide (PZA) as an option for HIV-infected patients (later changed) (4)(4)

9 Treatment of LTBI – Milestones 2000: CDC and ATS issue updated guidelines for targeted testing and LTBI treatment * 9-month regimen of isoniazid (INH) is preferred 2-month regimen of RIF and PZA and a 4- month regimen of RIF recommended as options (later changed) * MMWR June 9, 2000; 49(No. RR-6) (5)(5)

10 Treatment of LTBI – Milestones 2001: Owing to liver injury and death associated with 2-month regimen of RIF and PZA, use of this option de-emphasized in favor of other regimens ** 2003: 2-month regimen of RIZ and PZA generally not recommended — to be used only if the potential benefits outweigh the risk of severe liver injury and death *** ** MMWR August 31, 2001; 50(34): 733-735 *** MMWR August 8, 2003; 52(31): 735-739 (6)

11 Risk Factors for Tuberculosis Following Infection Reider HL. Epidemiol Rev 1989;11:79-98.

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13 Persons at Risk for Developing TB Disease Persons at high risk for developing TB disease fall into 2 categories Those who have been recently infected Those with clinical conditions that increase their risk of progressing from LTBI to TB disease HIV-infected persons Those with a history of prior, untreated TB or fibrotic lesions on chest radiograph Persons with certain medical conditions

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17 Alaska Village INH Preventive Therapy Comstock GW. Am Rev Respir Dis 1970;101:780-2

18 IUAT Trial of INH Preventive Therapy Bull. WHO. 1982;60:555-64

19 Risk of Tuberculosis in Close Contacts: Percentage Reduction with Isoniazid Ferebee SH. Adv Tuberc Res 1970;17:28-106. (USPHS Trial)

20 新城鄉、秀林鄉及南澳鄉 結核菌素反應陽性之學齡前兒童結核病發病情形 追蹤期間: 4.75  0.54 年 索任. 衛生行政學刊 1992;12:67-72.

21 Limitations of Preventive Therapy for Tuberculosis Toxicity Compliance Drug resistance Reinfection Feasibility PPD Burden Cost

22 Isoniazid-related Hepatitis Probable isoniazid-related cases of hepatitis SGOT  250 Karmen units, or SGOT < 250 Karmen units, but SGPT  SGOT, and Negative HBsAg (if done), and Other causes of hepatitis not apparent Possible isoniazid-related cases of hepatitis SGOT < 250 Karmen units, or SGOT  250, in the presence of other causes of liver disease, or SGOT  250, but lacking other biochemical tests Kopanoff DE et al. Am Rev Respir Dis 1978;117:991-1001.

23 Isoniazid-related Hepatitis Kopanoff DE et al. Am Rev Respir Dis 1978;117:991-1001.

24 Cumulative Percentage of Isoniazid-related Hepatitis Cases by Month of Occurrence Kopanoff DE et al. Am Rev Respir Dis 1978;117:991-1001.

25 Death Rate by Year Among Persons Started on INH Preventive Therapy Snider DE et al. Am Rev Respir Dis 1992;145:494-7.

26 Limitations of Preventive Therapy for Tuberculosis Toxicity Compliance Drug resistance Reinfection Feasibility PPD Burden Cost

27 Percent of Available INH Doses Taken During the First 4 Monthly Medication Orders Alcabes P et al. Compliance with isoniazid prophylaxis in jail. Am Rev Respir Dis 1989;140:1194-97.

28 Results of a Directly Observed Intermittent Isoniazid Preventive Therapy Program in a Shelter for Homeless Men 47 (73%) of 64 men recommended to take preventive regimens began therapy. 23/47 (49%) completed the 6- to 12-month regimen. Men who failed to complete therapy received a median of 11 biweekly doses over a median of 9 weeks. The most common reason for incomplete treatment was that the men no longer frequented the shelter. Out-of-state location of personal contacts in case of emergency was strongly associated with noncompliance. Mazar-Stewart V et al. Am Rev Respir Dis 1992;146:57-60.

29 Limitations of Preventive Therapy for Tuberculosis Toxicity Compliance Drug resistance Reinfection Feasibility PPD Burden Cost

30 Summary of Studies on Primary Anti-TB Drug Resistance Among M. Tuberculosis in Asia Cohn DL et al. Clin Infect Dis 1997;24(suppl 1):s121-30.

31 歷年新病人結核菌抗藥性情形 台灣省慢性病防治局台北示範中心

32 Limitations of Preventive Therapy for Tuberculosis Toxicity Compliance Drug resistance Reinfection Feasibility PPD Burden Cost

33 Tuberculosis Results From Recent Transmission The minimum percentage of cases due to primary tuberculosis in the urban homeless in central Los Angeles was estimated to be 53%. Barnes PF et al. JAMA 1996;275:305-7. Nearly 1/3 of new cases of tuberculosis in San Francisco are the result of recent infection. Small PM et al. N Engl J Med 1994;330:1703-9. In the inner-city of New York, recently transmitted tuberculosis accounts for 40% of the incident cases and almost 2/3 of drug-resistant cases. Alland D et al. N Engl J Med 1994;330:1710-6.

34 Limitations of Preventive Therapy for Tuberculosis Toxicity Compliance Drug resistance Reinfection Feasibility PPD Burden Cost

35 Factors Causing Decreased Ability to Respond to Tuberculin (1) Factors related to the person being tested Infections Viral (measles, mumps, chicken pox) Bacterial (typhoid fever, brucellosis, typhus, leprosy, pertussis, overwhelming tuberculosis, tuberculous pleurisy) Fungal (South American blastomycosis) Live virus vaccinations (measles, mumps, chicken pox) Metabolic derangements (chronic renal failure) Nutritional factors (severe protein depletion) Diseases affecting lymphoid organs (Hodgkin’s disease, lymphoma, chronic lymphocytic leukemia, sarcoidosis) Drugs (corticosteroids and other immunosuppressive agents) Age (newborns, elderly patients with “waned” sensitivity) Recent or overwhelming infection with M. tuberculosis Stress (surgery, burns, mental illness, graft-versus-host reactions) ATS. Am Rev Respir dis 1990;142:725-35.

36 Factors Causing Decreased Ability to Respond to Tuberculin (2) Factors related to the tuberculin used Improper storage (exposure to light and heat) Improper dilution Chemical denaturation Adsorption (partially controlled by adding Tween  80) Factors related to method of administration Injection of too little antigen Delayed administration after drawing into syringe Injection too deep Factors related to reading the test and recording results Inexperienced reader Conscious or unconscious bias Error in recording ATS. Am Rev Respir dis 1990;142:725-35.

37 Effect of BCG Vaccination on Tuberculin Reactivity Menzies R et al. Am Rev Respir Dis 1992;145:621-25. Quebec, Canada

38 Effect of Age and BCG Status on Tuberculin Reactions Induration  10mm Menzies R et al. Am Rev Respir Dis 1992;145:621-25.

39 Influence of BCG Vaccination on PPD Reaction Swedish schoolchildren, 8-9 years of age Larsson LO et al. Eur Respir J 1992;5:584-6.

40 Distribution of Tuberculin Reactivity for Children  14 Years of Age, Chile Sepulveda RL et al. Am J Respir Crit Care Med 1994;149:620-4.

41 Comparison of Subjects Vaccinated at Birth With Non-vaccinated Subjects of the Same Age Miret-Cuadras P et al. Tuberc Lung Dis 1996;77:52-8. Tuberculin tested 20-25 years after BCG vaccination, Spain

42 Comparison of Subjects Vaccinated at 6-14 Years With Non-vaccinated Subjects of the Same Age Miret-Cuadras P et al. Tuberc Lung Dis 1996;77:52-8. Tuberculin tested 20-25 years after BCG vaccination, Spain

43 Boosting Some people with LTBI may have a negative skin test reaction when tested years after infection because of a waning response. An initial skin test may stimulate (boost) the ability to react to tuberculin. Positive reactions to subsequent tests may be misinterpreted as new infections rather than “boosted” reactions. PPD skin test

44 Results of Second Tuberculin Test 4.78 Years After Previous Negative Test Miret-Cuadras P et al. Tuberc Lung Dis 1996;77:52-8.

45 Two-Step Testing (1) A strategy to determine the difference between boosted reactions and reactions due to recent infection. If first TST is positive, consider the person infected If first TST is negative, give second TST 1–3 weeks later If second TST is positive, consider the person infected If second TST is negative, consider the person uninfected at baseline PPD skin test

46 Two-Step Testing (2) Use two-step tests for initial baseline skin testing of adults who will be retested periodically (e.g., health care workers). PPD skin test

47 Tuberculin Reaction Size in Children Aged 6 in Taiwan, 1996-1997 BCG(+) 39680 tested; ≧ 10 mm: 5424 (13.7%); ≧ 15 mm: 894(2.3%) BCG(-) 8640 tested; ≧ 10 mm: 291 (3.37%) PPD RT23 1tu/0.1ml

48 Summary of Costs and Health Benefits of INH Preventive Therapy or 12, 24 and 52 Weeks ’ Duration* Snider DE. JAMA 1986;255:1579-83.

49 Interventions for Tuberculosis Control and Elimination, IUATLD 2002 Factors Determining Effectiveness of Preventive Chemotherapy Risk of tuberculosis given infection Efficacy of regimen Adherence to treatment

50 Effectiveness of Preventive Chemotherapy Risk of tuberculosis Efficacy of regimen Adherence to treatment Overall effectiveness Number to treat to prevent 1 case 0.050.600.300.009111 0.100.600.300.01856 0.300.600.300.05419 0.300.900.300.08112 0.300.900.500.1357 0.300.900.800.2165 Interventions for Tuberculosis Control and Elimination, IUATLD 2002

51 Problems with Preventive Chemotherapy Difficulties in ensuring adherence Efficacious but inefficient Rare adverse drug events Ensuring certainty to exclude active tuberculosis Interventions for Tuberculosis Control and Elimination, IUATLD 2002

52 Considerations in the Use of Preventive Therapy Logistic and material feasibility and ease: Household contacts > persons with risk factors > risk groups > general population Drug costs: isoniazid << rifampicin, pyrazinamide Risk perception  adherence Interventions for Tuberculosis Control and Elimination, IUATLD 2002

53 Indications for Preventive Therapy In industrialized countries: Young persons with tuberculous infection Persons with risk factors In low-income countries: Children < 5-yr-old, free of disease living with a sputum smear-positive case Interventions for Tuberculosis Control and Elimination, IUATLD 2002

54 預防性治療在台灣的應用 符合以下所有 4 條件者建議投予 9 個月的 INH 預 防性治療: 12 歲以下兒童。 曾與無 INH 抗藥性証據的傳染性結核病人密切接 觸。 結核菌素皮膚試驗反應陽性( PPD RT23 +Tween80 2TU/0.1ml Mantoux 試驗 72 小時後 反應硬結:無 BCG 疤者 ≥10mm ;有 BCG 疤者 ≥18mm )。 無臨床結核病証據。 結核病診治指引, 衛生署疾病管制局, 2004

55 媽媽:柯 X X 27 歲 女性 咳嗽喀痰 6 個月 痰塗片 AFB +++ 初治: 2HERZ/4HER 女兒: 3 歲 女性 PPD +21v 胸部 X 光正常 預防性治療: INH 9 個月 潛伏感染治療舉例

56 TB TB 何時了 – Non compliant 910529940909

57 Preventing TB infection Prompt and effective treatment of the most infectious cases (smear positive) 儘早有效治癒塗陽病人 即是最有效的預防

58 結核病防治 結核潛伏 感染 傳染性 結核病 非傳染性 結核病 Prophylactic treatment 預防性 治療 化學治療 卡介苗 接種 病人延誤 醫師延誤 傳染 transmission 死亡 接觸 Source: Interventions for Tuberculosis Control and Elimination, IUATLD 2002 Preventive therapy Doctor’s delay Patient’s delay Infectious TB Non-Infectious TB Subclinical infection Exposure BCG vaccination Death Chemotherapy 結核病的傳染期 = 病人延遲 + 醫師延遲 + 病人治療管理不當

59 Treatment of Latent TB Infection (LTBI)

60 Treatment of Latent TB Infection Current Recommendations in Taiwan Isoniazid 10-15 mg/kg daily for 9 months Recommended for children those fulfill the following criteria <= 12 y/o History of contact with TB patient that has no evidence of INH resistance PPD positive (RT23 2tu/0.1ml) (>=10mm if BCG-, >=18mm if BCG+) No evidence of clinical disease 結核病診治指引, 衛生署疾病管制局, 2004

61 Epidemiologic Basis of TB Control, IUATLD, 1999


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