Download Treatment of Latent Tuberculosis Infection

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
Latent infection vs. disease
感染
發病
傳染
Class I
contact
Infectious
Class III
Infected
Class II
Disease
傳染 transmission
化學治療
Chemotherapy
結核病防治
結核病的傳染期 = 病人延遲 +
醫師延遲 +病人治療管理不當
Prophylactic
treatment
預防性
治療
Preventive
醫師延誤
病人延誤
Doctor’s delay
Patient’s delay
therapy
傳染性
結核病
接觸
Exposure
結核潛伏
感染
Subclinical
infection
Infectious TB
死亡
非傳染性
結核病
Non-Infectious
TB
BCG
vaccination
卡介苗
Source: Interventions for Tuberculosis
Control and Elimination, IUATLD 2002
Death
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)
Treatment of LTBI – Milestones
(2)
 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).
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)
Treatment of LTBI – Milestones
(4)
 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 HIVinfected patients (later changed)
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 4month regimen of RIF recommended as
options (later changed)
* MMWR June 9, 2000; 49(No. RR-6)
(5)
Treatment of LTBI – Milestones
(6)
 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
Risk Factors for Tuberculosis Following
Infection
Risk factor
Infection <1years past
Infection >7years past
HIV infection
AIDS
Fibrotic lesion
Silicosis
Jejunoileal bypass
Ca of head & neck
Hemodialysis
Immunosuppressive Tx
Gastrectomy
Diabetes
Incidence
(/1000 person-years)
10.4
0.7
79
Relative risk
170.3
2.0-13.6
30
27-63
16
10-15
11.9
5
2.0-3.6
Reider HL. Epidemiol Rev 1989;11:79-98.
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
Protection Against Tuberculosis Among Contacts
of New Cases with Isoniazid Preventive Therapy
Netherlands Navy
Kenya
USA
Japan
- 50
0
50
70
90
95
Protection (%) (log scale)
Veening GJJ. Bull Int Union Tuberc 1968;41:169-71
Egsmose T, et al. Bull World Health Organ 1965;33:419-33
Ferebee SH, et al. Am Rev Respir Dis 1962;85:490-521
Bush OB, et al. Am Rev Respir Dis 1965;92:732-40
Protection Against Tuberculosis Among Persons
with HIV Infection, with Isoniazid Preventive Therapy
Port-au-Prince
Lusaka
Kampala
New York City
Nairobi
- 50
0
50
70
90
Protection (%) (log scale)
Pape JW, et al. Lancet 1993;342:268-72
Mwinga A, et al. AIDS 1998;12:2447-57
Whalen CC, et al. N Engl J Med 1997;337:801-8
Gordin FM, et al. N Engl J Med 1997;337:315-20
Hawken MP, et al. AIDS 1997;11:875-82
Protection Against Tuberculosis with Rifampicin Preventive Therapy
3 RH - HIV, Kampala
3 RHZ - HIV, Kampala
12 wk R - Silicosis, Hongkong
12 wk RH - Silicosis, Hong Kong
3 R2Z2 - HIV, Lusaka
- 50
0
50
70
80
Protection (%) (log scale)
Whalen CC, et al. N Engl J Med 1997;337:801-8
Hong Kong Chest Service, et al. Am Rev Respir Dis 1992;145:36-41
Mwinga A, et al. AIDS 1998;12:2447-57
Reduction in diseases at 4 years (%)
Alaska Village INH Preventive Therapy
100
80
60
40
20
0
0
50
100
150
200
% of annual dose taken
Comstock GW. Am Rev Respir Dis 1970;101:780-2
IUAT Trial of INH Preventive Therapy
Reduction in disease by INH
(%)
100
80
H, 3M
H, 6M
H, 12M
60
40
20
0
<2cm
>2cm
fibrotic lesion size
Bull. WHO. 1982;60:555-64
Risk of Tuberculosis in Close Contacts:
Percentage Reduction with Isoniazid
Risk of TB (1st year) Risk of TB (10 year)
[ N (%) ]
[ N (%) ]
Induration
N
5-9mm
Placebo
1616
Isoniazid
1716
Reduction (%)
10mm
Placebo
4992
Isoniazid
4852
Reduction (%)
<5mm initially; 5mm at 1 year
Placebo
867
Isoniazid
694
Reduction (%)
(USPHS Trial)
8 (0.5)
3 (0.2)
65
31 (1.9)
18 (1.0)
45
61 (1.2)
12 (0.2)
80
147 (2.9)
57 (1.2)
60
17 (2.0)
4 (0.6)
71
32 (3.7)
10 (1.4)
61
Ferebee SH. Adv Tuberc Res 1970;17:28-106.
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
計
發生率
結核菌素反應
10-14mm
15-19mm
20+mm
INH 預防性治療
有
無
原住民
是
否
有卡介苗疤
5/271 (1.8%)
1.6/1000 人年
無卡介苗疤
4/16 (25.0%)
33.1/1000 人年
2/84 (2.4%)
3/121 (2.5%)
0/66 (0)
2/4 (50.0%)
1/5 (20.0%)
1/7 (14.3%)
1/181 (0.6%)
4/90 (4.4%)
2/13 (15.4%)
2/3 (66.7%)
5/212 (2.4%)
0/59 (0)
4/15 (26.7%)
0/1 (0)
追蹤期間：4.750.54年
索任. 衛生行政學刊 1992;12:67-72.
Limitations of
Preventive Therapy for Tuberculosis
 Toxicity
 Compliance
 Drug resistance
 Reinfection
 Feasibility



PPD
Burden
Cost
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.
Isoniazid-related Hepatitis
Case Rate (/1000)
25
20
Probable
Possible
15
10
5
0
< 20
20-34
35-49
50-64
> 64
Age Group (yr)
Kopanoff DE et al. Am Rev Respir Dis 1978;117:991-1001.
Cumulative Percentage of Isoniazid-related
Hepatitis Cases by Month of Occurrence
Cumulative Percentage of Cases
100
Probable (n=92)
Possible (n=82)
Both (n=174)
80
60
40
20
0
0
2
4
6
8
10
12
Month of Occurrence
Kopanoff DE et al. Am Rev Respir Dis 1978;117:991-1001.
Death Rate by Year Among Persons Started
on INH Preventive Therapy
Year
1972
1973-74
1975-76
1977-78
1979-80
1981-82
1983-84
1985-86
1987-88
Total
No. of
Deaths
21
19
12
30
10
26
16
6
12
152
No. Started on
Preventive Therapy
39115
52397
89250
116272
139218
162901
153386
144680
187541
1084760
Death Rate
(/100,000)
53.7
36.3
13.4
25.8
7.2
16.0
10.4
4.1
6.4
14.0
Snider DE et al. Am Rev Respir Dis 1992;145:494-7.
Limitations of
Preventive Therapy for Tuberculosis
 Toxicity
 Compliance
 Drug resistance
 Reinfection
 Feasibility



PPD
Burden
Cost
Percent of Available INH Doses Taken During
the First 4 Monthly Medication Orders
INH Order
n
Mean (%)
SD
1
74
37.0
35.2
2
50
35.5
32.6
3
26
28.1
23.9
4
15
32.3
34.2
Total
34.8
Alcabes P et al. Compliance with isoniazid prophylaxis in jail.
Am Rev Respir Dis 1989;140:1194-97.
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.
Limitations of
Preventive Therapy for Tuberculosis
 Toxicity
 Compliance
 Drug resistance
 Reinfection
 Feasibility



PPD
Burden
Cost
Summary of Studies on Primary Anti-TB Drug
Resistance Among M. Tuberculosis in Asia
*
% resistant to single drug*
% resistant to
multiple drugs
INH
RMP
SM
EMB
INH & >=2
RMP drugs**
Location
Year
No. of
isolates
tested
Istanbul, Turkey
1992
525
1.0
2.7
12.2
0.6
3.0
7.2
Nepal
1986-91
160
4.4
0
4.4
0
2.5
1.2
Kamataka, India
1985-89
880
16.9
1.4
1.5
0
2.0
3.5
North Arcot, India
1985-89
2779
12.7
0.1
3.7
…
1.6
7.0
Karachi, Pakistan***
1990-92
123
11.3
3.2
8.9
2.4
…
6.5
Beijing, China
1978-92
1309
4.91.7
0.30.8
Korea
1980-90
396
25.012.6
0-0
4.67.1
5.61.6
0-0
6.5-7.1
Malaysia
1984-87
856
4.2
1.0
7.6
1.4
0
2.0
Taiwan***
1990-95
1935
9.2
1.5
5.7
0.7
1.2
Monoresistant
**
excluding both H&R
***
6.6-4.2 0-0.8
0.4-0 4.1-10.0
cumulative % for single drug, not mutually exclusive
Cohn DL et al. Clin Infect Dis 1997;24(suppl 1):s121-30.
歷年新病人結核菌抗藥性情形
抗
作者/年代
菌株數
藥
性
菌
株
比
例
(%)
任何藥
INH
SM
EMB
RMP
INH+RMP
星/1960
162
22.2
13.4
11.7
-
-
朱/1962
154
14.3
8.4
7.8
-
-
吳/1971-72
557
30.7
22.6
15.4
-
-
張/1979-82
1914
17.9
8.4
9.2
0.1
0
羅/1984-88
1924
9.9
6.8
5.0
0.4
0.2
余/1990-95
1935
12.3
9.2
5.7
0.7
1.5
1.2
姜/1996
249
16.1
12.0
4.8
0.8
2.8
1.6
吳&許
/1997-2000
817
18.1
11.4
8.4
2.3
2.4
2.1
台灣省慢性病防治局台北示範中心
Limitations of
Preventive Therapy for Tuberculosis
 Toxicity
 Compliance
 Drug resistance
 Reinfection
 Feasibility



PPD
Burden
Cost
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.
Limitations of
Preventive Therapy for Tuberculosis
 Toxicity
 Compliance
 Drug resistance
 Reinfection
 Feasibility



PPD
Burden
Cost
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.
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.
Effect of BCG Vaccination on
Tuberculin Reactivity
16
Percent with reaction
14
Never BCG
BCG in Pre-school
BCG in Infancy
BCG at older age
12
10
8
6
4
2
0
5-9
Quebec, Canada
10-14
15+
Size of tuberculin reaction in mm
Menzies R et al. Am Rev Respir Dis 1992;145:621-25.
Effect of Age and BCG Status on
Tuberculin Reactions
Vaccination
status
Never
vaccinated
Vaccinated in
infancy
Vaccinated
when older
Age Group: Mean Age
Grade 6:
Grade 10:
Young adults:
11.1
16.2
22.5
1.5%
2.7%
4.1%
4.9%
7.5%
10.3%
12.5%
16.7%
25.5%
Induration  10mm
Menzies R et al. Am Rev Respir Dis 1992;145:621-25.
Influence of BCG Vaccination on
PPD Reaction
Induration  6mm by PPD RT23 2tu
Non-BCG-vaccinated
85/2819 (3%)
BCG-vaccinated
80/164 (49%)
BCG in infancy
23/57 (40%)
BCG after 1 yr of age
31/50 (62%)
Swedish schoolchildren, 8-9 years of age
Larsson LO et al. Eur Respir J 1992;5:584-6.
Distribution of Tuberculin Reactivity
for Children  14 Years of Age, Chile
70
No BCG scar
60
1 BCG scar
2 BCG scars
Percent
50
40
30
20
10
0
0
1-4
5-9
10-14
15+
Tuberculin Reaction Size (mm)
Sepulveda RL et al. Am J Respir Crit Care Med 1994;149:620-4.
Comparison of Subjects Vaccinated at Birth With
Non-vaccinated Subjects of the Same Age
Tuberculin tested 20-25 years after BCG vaccination, Spain
TT result BCG-vaccinated Non-BCG-vaccinated
N=887
N=446
5 mm
237 (53.1%)
154 (17.4%)
10mm
130 (29.1%)
106 (12.0%)
15mm
40 (9.0%)
46 (5.2%)
Miret-Cuadras P et al. Tuberc Lung Dis 1996;77:52-8.
Comparison of Subjects Vaccinated at 6-14 Years
With Non-vaccinated Subjects of the Same Age
Tuberculin tested 20-25 years after BCG vaccination, Spain
TT result BCG-vaccinated Non-BCG-vaccinated
N=1978
N=1948
5 mm
1252 (63.3%)
451 (23.2%)
10mm
683 (34.5%)
323 (16.6%)
15mm
217 (11.0%)
157 (8.1%)
Miret-Cuadras P et al. Tuberc Lung Dis 1996;77:52-8.
PPD skin test
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.
Results of Second Tuberculin Test
4.78 Years After Previous Negative Test
TT result
BCG-vaccinated Non-BCG-vaccinated
5 mm
87 (70.2%)
64 (24.9%)
6mm
77 (62.1%)
52 (20.2%)
10mm
40 (32.3%)
31 (12.1%)
15mm
14 (11.3%)
9 (3.5%)
Miret-Cuadras P et al. Tuberc Lung Dis 1996;77:52-8.
PPD skin test
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
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).
Tuberculin Reaction Size in Children
Aged 6 in Taiwan, 1996-1997
PPD RT23 1tu/0.1ml
70
60
BCG(+)
BCG(-)
50
%
40
30
20
10
0
BCG(+) 39680 tested; ≧ 10 mm: 5424 (13.7%); ≧ 15 mm: 894(2.3%)
BCG(-) 8640 tested; ≧ 10 mm: 291 (3.37%)
28-29
26-27
24-25
22-23
20-21
18-19
16-17
14-15
12-13
10-11
8-9
6-7
4-5
2-3
0-1
Induration (mm)
Summary of Costs and Health Benefits of INH
Preventive Therapy or 12, 24 and 52 Weeks’
Duration*
Treatment duration, wk
Direct cost of program, $(+)
Cost for adverse reactions, $(+)
Savings from cases prevented
(discounted), $(-)
Net costs, $
Cases prevented (discounted)
Cost per case prevented, $
QALYs gained (discounted) +
Cost per QALY gained, $
*
+
12
62,200
1,772
16,453
24
122,400
2,396
49,838
52
244,800
3,287
55,929
47,519
3.28
14,488
5.21
9,121
74,958
10.54
7,112
17.22
4,353
192,128
11.99
16,024
19.48
9,863
For a cohort of 1,000 persons (base case estimates, 5% discount rate).
QALY indicates quality-adjusted life years.
Snider DE. JAMA 1986;255:1579-83.
Factors Determining Effectiveness of
Preventive Chemotherapy
 Risk of tuberculosis given infection
 Efficacy of regimen
 Adherence to treatment
Interventions for Tuberculosis Control and Elimination, IUATLD 2002
Effectiveness of Preventive Chemotherapy
Risk of
tuberculosis
Efficacy of
regimen
Adherence to
treatment
Overall
effectiveness
Number to treat to
prevent 1 case
0.05
0.60
0.30
0.009
111
0.10
0.60
0.30
0.018
56
0.30
0.60
0.30
0.054
19
0.30
0.90
0.30
0.081
12
0.30
0.90
0.50
0.135
7
0.30
0.90
0.80
0.216
5
Interventions for Tuberculosis Control and Elimination, IUATLD 2002
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
Interventions for Tuberculosis Control and Elimination, IUATLD 2002
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
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
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
潛伏感染治療舉例
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
TB TB 何時了 – Non compliant
910529
940909
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
傳染 transmission
化學治療
Chemotherapy
結核病防治
結核病的傳染期 = 病人延遲 +
醫師延遲 +病人治療管理不當
Prophylactic
treatment
預防性
治療
Preventive
醫師延誤
病人延誤
Doctor’s delay
Patient’s delay
therapy
傳染性
結核病
接觸
Exposure
結核潛伏
感染
Subclinical
infection
Infectious TB
死亡
非傳染性
結核病
Non-Infectious
TB
BCG
vaccination
卡介苗
Source: Interventions for Tuberculosis
Control and Elimination, IUATLD 2002
Death
Treatment of Latent TB Infection (LTBI)
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
Epidemiologic Basis of TB Control, IUATLD, 1999