1. “Diagnosis and treatment of latent TB ” Update – Internal Medicine
Dr Dick Menzies
Montreal Chest Institute

2. Problems with current approach to LTBI management
TST – Labour intensive, slow, non-specific
Although appears to predict benefit
Current therapy (INH)
Long duration = poor compliance - less than 50% in most programs, although can be 70%.
Serious side effects - can be fatal
Costs - close follow up necessary = expensive

3. Overview of Talk LTBI diagnosis Treatment of Latent TB
The old – Tuberculin skin test
The new – Interferon gamma release assays
Treatment of Latent TB
The current standard – 9INH
Is a TST needed before starting INH therapy?
Does INH therapy create INH resistance?
Alternatives – 4RIF and others
The 4RIF trial

4. Diagnosis - Indications for testing
Increased risk of developing TB disease
New TB infection
Increased risk of reactivation from latent TB
Increased risk of exposure
Health care workers – at hiring
Other workers with risk of exposure

5. Tools for diagnosis - TST
Strengths:
Long history: known test performance
Simple test: can be performed (almost) anywhere
Predictive ability: for benefit of treatment
Weaknesses:
Specificity: especially if BCG vaccinated
Sensitivity: especially if immune compromise
Predictive ability: <10% develop disease

6. Meta-analysis ( et al, Cochrane 2010)
Ability of TST to predict benefit of INH – in HIV infected in High incidence settings
Meta-analysis ( et al, Cochrane 2010)
12 RCT, with 5,000 subjects, mostly 6H
Risk reduction in TST+ 64% (significant)
Risk reduction in TST % (not significant)
Recent RCT in Botswana ( Lancet 2011)
1,594 subjects
Risk reduction in 400 TST+ 92% (significant)
Risk reduction in 1194 TST- 14% (not signif)

7. Interferon gamma release assays (IGRA)
A brief introduction

8. TST vs IGRA: rationale 8
Andersen P et al, Lancet 2000 8

9. The IGRAs use newly discovered antigens specific to M. tuberculosis
ESAT-6
Genomics
Proteomics
CFP-10
Cole et al, Nature 1998 9 9

10. Contains TB specific antigens - ESAT-6, CFP-10, TB7.7
QuantiFERON (QFT)
Contains TB specific antigens - ESAT-6, CFP-10, TB7.7
Incubate whole blood 16 hours, then measure IFN-γ released from sensitized lymphocytes.
Using ELISA reader
Cost – materials $20, labour $20-25,
From: Pai M, et al.,
Lancet Infect Dis 2004

11. Incidence of active TB after a positive IGRA The 5 largest studies from high burden countries
Country N
Test
Incidence of active TB in IGRA+ groups
The Gambia [Hill et al. 2008]
2348
ELISPOT (in-house)
9/1000 person-yr
Turkey [Bakir et al. 2008]
908
ELISPOT
(T-SPOT.TB)
21/1000 person-yr
S Africa [Mahomed et al. 2009]
5248
QFT
6/1000 person-yr
Colombia [del Corral et al. 2009]
2060
In-house whole-blood CFP-10 assay
11/1000 person-yr
Senegal [Lienhardt et al. PLoS One 2010]
2679
14/1000 person-yr

12. Which is the best predictor of active TB. IGRA RR= 2. 4 TST 5mm RR= 2
Which is the best predictor of active TB? IGRA RR= TST 5mm RR= 2.1 TST 10mm RR=2.0

13. Summary: IGRA Good points: Weak points:
Excellent specificity: In all situations and populations. Not affected by BCG.
Standardization: performed in clinical lab
No Bias – Less chance of bias at reading
Weak points:
Sensitivity: same as TST, especially if immune compromised
Costs – more than TST
Long term – predicting active TB – same as TST
Only 10% get disease
And still not enough experience so unknown problems

14. Choice of test to diagnose latent TB – Canadian recommendations
1. In general TST remains test of first choice
2. If TST is positive, but person is at low risk of reactivation (student or worker baseline screen):
Perform IGRA – to enhance specificity. If IGRA negative then do not treat
If TST negative but high risk (HIV, or immune suppressed).
Perform IGRA – to enhance sensitivity. If IGRA positive then treat

15. The test is positive – now what?
Medical evaluation for all – the first time a TST or IGRA is found positive
This includes symptoms, medical history
And a chest x-ray (exclude active TB)

16. No active TB is found – now what?
Decision re treatment – must balance
Risk of TB disease – test size, Chest Xray, other medical problems
Risk of adverse events
This can be complex. Takes knowledge, experience, intelligence
Or it takes….

17. THE INTERNET !! (the Online TST/IGRA interpreter)
On-line resource for
interpreting TST or IGRA
Incorporates test result, clinical history,
& other biologic risk
factors to estimate
composite risk.
Uses age to estimate risk of hepatotoxicity with INH

18. Considerations for therapy
Individual benefit: Primary consideration is the balance of risk of INH therapy vs benefit in terms of likelihood of TB prevention
Public health benefit: Reduction of transmission through prevention of cases vs cost and feasibility

19. Risk of active TB disease
Lifetime risks with Latent TB infection:
Young healthy adult: 5-10%
HIV infected: >50%
Diabetic: 3-4X relative risk = 20-40%
Very young child:
Age <1: 50% risk in 1 year
Age 1-2: % risk in 1 year
Age 2-5: % risk

20. Consequences of active TB
Mortality:
Undiagnosed Smear positive: 33%/year
Diagnosed and treated: 4% - 7%
Long term disability following active TB
Surprisingly little data.
US study – average 20% loss of lung function
From Canada – 24% reduction in QALY
Data needed!!

21. Individual risks of therapy
Risks of therapy are well known for INH, and INH hepatitis is serious
Risks of other therapies less well known

22. Schematic of Risk Benefit Balance for INH LTBI Therapy
Benefits of therapy
Increased if greater risk of disease:
HIV, diabetes, abnormal Xray, contact, etc
Risks of therapy
Older Age
Liver Disease
Alcohol Use

23. Treatment of hypertension vs LTBI
Asymptomatic condition
Very serious complications
Death
Major disability
Treatment is for many years
Potential serious side effects
Requires close monitoring and FU
Expensive medications
BUT – no debate about Treating
Asymptomatic condition
Very serious complications
Death, Major disability
AND transmission
Treatment is 9 months
Potential serious side effects
Requires close monitoring and FU
Cheap medications
WHY the debate about Treating

24. LTBI treatment – what are the options?
6-9 months of INH
2 months RIF-PZA
3-4 months INH-RIF
3 months once weekly INH& Rifapentine
4 months RIFampin

25. Population Duration Reduction in TB
Duration of INH Therapy and efficacy/effectiveness Patients with Fibrotic Lesions
Population Duration Reduction in TB
All participants INH 12 mo. 75%
INH 6 mo. 65%
INH 3 mo. 21%
Completer/compliers INH 12 mo. 93%
INH 6 mo. 69%
INH 3 mo. 31%
Bull WHO 1982;555-64

26. How Much Isoniazid Is Needed for the Prevention of Tuberculosis?
Longer durations of therapy up to 9 months, corresponded to lower TB rates
No extra increase in protection among those who took >9 months
Comstock GW, 1998

27. Efficacy of therapy INH will reduce risk of disease by 90%
If taken for 9 months
If >80% of doses taken each month

28. Age Specific Incidence of INH hepatitis

29. Mortality from INH hepatitis

30. Problems with INH 1. Length - 9 months ideal (90% efficacy)
Results in poor compliance - less than 50% in most programs.
Drug induced hepatitis -
- Less common now, but deaths still occur.
Also rash, neuropathies
3. Costs - INH is cheap but close follow up is necessary. This is expensive

31. Is a TST needed before LTBI therapy is given?

32. Meta-Analysis: INH protects against TB
In HIV (+) who are TST (+)
(Pooled estimates: 0.4 ( ))
AIDS 1999;13:501-7

33. (Pooled estimates: 0.84 (0.54-1.30))
Meta-Analysis: INH does not protect against TB – In HIV (+) who are TST (-)
(Pooled estimates: 0.84 ( ))
AIDS 1999;13:501-7

34. Does INH treatment of LTBI create INH resistance?

35. INH treatment and INH resistance
This was assessed in a large cohort of SE Asian refugees who were screened and treated after arrival in the US.
No difference in rates of INH Resistant TB in persons who took INH, vs those who took nothing
Meta-analysis (Godfrey-Fausett et al)
Reviewed placebo controlled RCT of INH
Small, but non-significant increase

37. LTBI treatment – what are the options?
6-9 months of INH
2 months RIF-PZA
3-4 months INH-RIF
3 months once weekly INH& Rifapentine
4 months RIFampin

38. Experimental Study of Short-Course Preventive Therapy in Mice – the start of 2RIF-PZA
Lecour HF, et.al. Am Rev Respir Dis 1989:140:

39. International Study of 12INH vs 2RIF-PZA in HIV Infected patients - OUTCOMES
Regimen 2 RIF/PZA 12 INH RR (CI)
No. enrolled
Confirmed TB (.4,1.2)
Conf/Probable TB (.6,1.2)
Death (.7,1.1)

40. Completion of therapy – 6 INH vs 2RZ (From Gao et al, IJTLD; 2006:10:1080-1090)
Author Location INH 2 RZ
Halsey Haiti 55% 74%
Mwinga Zambia 66% 75%
Jasmer USA 57% 61%
Leung Hong Kong 89% 83%
Tortajada Spain 77% 82%

41. Serious Adverse Events – 6INH vs 2RZ (From Gao et al, IJTLD; 2006:10:1080-1090)
Author Mean Age INH 2 RZ
Halsey
Mwinga % 4%
Jasmer % 9%
Leung % 35%
Tortajada nr 4% 12%

42. 2 months Rifampin and PZA
In 1989 – 2 mos RIF&PZA – effective in mice
– several trials – all in HIV infected
2000 – Strong recommendations – to use this
– Reports of severe hepatitis
2001 – recommendation withdrawn
DO NOT USE 2 RIF-PZA

43. LTBI treatment – what are the options?
6-9 months of INH
2 months RIF-PZA
3-4 months INH-RIF
3 months once weekly INH& Rifapentine
4 months RIFampin

44. 3-4 mos Rifampin-INH vs mos INH A meta-analysis of 5 RCT’s Occurrence of active TB (Ena & Valls, Clin Inf Dis; 2005; 40: )
(+0.1%)
41/972
39/954
Pooled estimates
(+0.3%)
9/556
7/536
Whalen (Uganda – HIV)
3/82
3/83
Rivero (Spain – HIV)
(- 3.3%)
2/69
4/64
Martinez (Spain - HIV)
(+1.0%)
1/98
0/98
Martinez (Spain – HIV)
(+1.1%)
26/167
25/173
Hong Kong (silicotics)
(Diff. %)
INH/RIF
INH

45. 3-4 mos Rifampin-INH vs mos INH A meta-analysis of 5 RCT’s Serious Adverse Events (Ena & Valls, Clin Inf Dis; 2005; 40: )
(+0.1%)
48/972
46/954
Pooled estimates
(+1.7%)
13/556
3/536
Whalen (Uganda – HIV)
(+11%)
15/82
6/83
Rivero (Spain – HIV)
(- 16%)
5/69
15/64
Martinez (Spain - HIV)
(- 2.0%)
7/98
9/98
Martinez (Spain – HIV)
(- 2.7%)
8/167
13/173
Hong Kong (silicotics)
(Diff. %)
INH/RIF
INH

46. LTBI treatment – what are the options?
6-9 months of INH
2 months RIF-PZA
3-4 months INH-RIF
3 months once weekly INH& Rifapentine
4 months RIFampin

47. 3 months INH & Rifapentine (3HP)
Large scale trial – just completed
96% HIV negative
US, Canada, Spain and Brazil
9 months daily INH vs 3 months INH/RPT once weekly
12 doses – directly observed
More than 8,000 enrolled

48. 3 months once weekly INH & Rifapentine –Incidence of active TB
3HP
Randomized
3649
3895
Completed
2536 (69%)
3190 (82%)
TB Disease - All patients
12 (0.4%)
7 (0.2%)
- Completed
5 (0.2%)
4 (0.1%)

49. 3 months once weekly INH & Rifapentine – Adverse events
3HP
Randomized
3649
3895
Total- Grade 3-4 AE
7.4%
6.0%
Drugs stopped for AE
3.6%
5.0%
Hepatotoxicity
2.8%
0.5%
Hypersensitivity
0.8%
4.0%

50. LTBI treatment – what are the options?
6-9 months of INH
2 months RIF-PZA
3-4 months INH-RIF
3 months once weekly INH & Rifapentine
4 months RIFampin

51. Experimental Study of Short-Course Preventive Therapy in Mice – what about RIF?
Lecour HF, et.al. Am Rev Respir Dis 1989:140:

52. Efficacy of 3 months of Rifampin for the Prevention of TB Patients with Silicosis
Hong Kong Chest Service. Am Rev Respir Dis 1992;145:36-41

53. 6 Months Rifampin Mono-Therapy (For contacts of INH resistant cases) (Polesky et al., AJRCCM; 1996: 155:
Homeless persons in Boston, screened in shelters
Extended Outbreak of INH resistant TB
204 Exposed persons with documented TST conversion
Therapy of LTBI was not randomized
71 no therapy – 8.6% active TB
38 given INH – 7.9% active TB (all were INH Resistant)
86 RIF or INH/RIF – 0 active TB
49 Rifampin only – no hepatitis or increased LFT’s

54. Program Experience with 4RIF and 9INH Maryland 1999-2004 Page et al
Program Experience with 4RIF and 9INH Maryland Page et al. Archives Internal Med. 2006: 166;
Patients offered 4 RIF or 9 INH by provider
Concurrent study but non-randomized
4 RIF
9 INH
Number Starting
1,379
770
Completing Therapy
987 (72%)
405 (52%)
Grade 3 to 4 Hepatitis
1 (0.1%)
12 (2%)

55. Program Experience with 4RIF and 9INH New Jersey Lardizabal et al. Chest, 2006: 130;
Non-concurrent and non-randomized study
4 RIF
9 INH
Number Starting
261
213
Completing Therapy
210 (81%)
113 (53%)
Grade 3 to 4 SAE
8 (3%)
13 (6%)
Hepatitis 3

56. A randomized trial to compare 4 months Rifampin vs 9 months INH for the treatment of LTBI
Phase 1: Compliance and completion
Completed in 2003
Phase 2 – Adverse events and costs
Completed in 2007
Phase 3: Efficacy and effectiveness

57. RCT of 9 INH vs. 4 RIF for LTBI Study design
Design - open label randomized trial
Positive control = 9INH
Not placebo as INH of proven benefit

58. RCT of 4RIF vs 9INH for LTBI Study Population – Inclusion Criteria
Positive TST, high risk - prescribed LTBI treatment.
Highest risk reactors – Risk of reactivation >1% per year
Close contact, TST conversion, HIV (+), apical fibronodular disease
Moderate Risk (risk of 0.5% - 1% per year)
Diabetes, renal failure, immuno-compromise
Casual contacts, TST conversion in 2-5years
Or two of the following three:
Arrival in the past two years from TB endemic country
Less than 90% ideal body weight
Granulomas, calcified nodes
TST > 15mm

59. RCT of 4RIF vs 9INH for LTBI Study Population – Exclusion Criteria
Exclude as few as possible
Essential exclusion criteria:
Contacts of INH or RIF resistant (or MDR) index cases
High potential for drug interactions (Certain HIV therapy, or oral contraceptives)
Known INH or RIF allergy
All other patients eligible if LTBI therapy prescribed
Regardless of age, or other risk factors for SAE

60. As little impact on follow-up as possible, i.e. routine follow-up
RCT of 4RIF vs 9INH for LTBI Data Gathering in treatment phase – Pragmatic trial
As little impact on follow-up as possible, i.e. routine follow-up
Follow-up visits will be monthly for first 2 months, or more often per physician
CBC, liver transaminases at baseline and first follow-up visit
Study staff to have as little direct involvement as possible
Minimize ‘study effect’
Estimate effectiveness under ‘routine’ conditions

61. RCT of 9 INH vs. 4 RIF – Phase 1 Completion of therapy among randomized participants
3 (5%)
8 (14%)
Completed Rx poor compliance, N(%)
2 (3%)
MD stopped b/o Side effects N(%)
12 (21)
20 (34%)
< 90% of doses correct at 1 month, N(%)
4 (7%) 1
14 (24%) 1
Did not complete Rx, N(%)
50 (86%) 1
36 (62%) 1
Completed Rx good compliance, N(%)
4 RIF (N=58)
9 INH (N=58)
For RIF 3 were drop out (2 lost of FU, 1 refused TX), 2 had side effects (2 other than hepatitis). For INH, 7 were drop out (2 lost of FU, 3 no compliance, 1 other medical problem, 1 refused to continue therapy), 6 had side effects (4 were hepatitis, 2 others)
1 P-value = 0.01

62. 27% 1 14% 1 Minor, % 2 Major – other, N 4 Major – hepatitis, N 4 RIF
RCT of 4RIF vs. 9INH for LTBI – Phase 1 Phase 1: Side effects associated with the 2 regimens
27% 1
14% 1
Minor, % 2
Major – other, N 4
Major – hepatitis, N
4 RIF
9 INH
1 P-value = <0.001

63. RCT of 4RIF vs. 9INH for LTBI – Phase 2 Completion of Phase 2 Study
P-value
Completed Therapy N (%)
339 (81%)
259 (69%)
<.0001
Patient Non-compliant (Total)
- Drop-out
- Intolerance
61 (14%)
52 (12%)
3 (1%)
117 (27%)
82 (20%)
23 (5%)
MD Non-compliant
6 (1%)
12 (3%)

64. 6 (1.5%) 3 (0.7%) 17 (4.0%) Grade 3 to 4 - Total - Hepato-toxicity
RCT of 4RIF vs. 9INH for LTBI – Phase 2 Serious Drug Related Adverse Events
4 RIF
(N=420)
9 INH
(N=427)
P-value
All Grades – Total (%) *
16 (3.8%)
24 (5.6%) NS
Grade 3 to 4 - Total
- Hepato-toxicity
- Hematologic
- Drug Interaction
- Rash
6 (1.5%)
3 (0.7%) 1
17 (4.0%)
.02
.003 -
Grade 1 to 2 - Total
- GI intolerance
11 (2.0%) 8 2
7 (1.6%) 4
* Severity, type + relationship to study drug by independent blinded 3-member panel

65. RCT of 4RIF vs. 9INH for LTBI – Phase 2 Therapy Stopped Permanently but Not Related to Study Drug*
P-value
Death 1
Pregnancy 2 3
* The severity, type and relationship to study drug judged by independent three-member panel blinded to patient allocation.

66. Conclusions – 4RIF Serious adverse events significantly less than 9INH
Particularly for grade 3 to 4 hepatitis
The most important/lethal complication
Completion significantly better with 4RIF than 9INH
Both in Phase 2 and in Phase 1
Overall costs lower with 4RIF
Despite high RIF costs in Canada

67. RCT of 4RIF vs 9INH for LTBI – Phase 3 Objectives of Phase 3
Primary objective (effectiveness)
Compare incidence of confirmed active TB in all randomized in the 28 months post-randomization
“Pragmatic” trial – estimate under programme conditions.
Secondary objectives
Compare incidence of confirmed active TB in those who took at least 80% of doses within maximum allowed time (efficacy)
Compare incidence of confirmed plus clinical active TB in all randomized
Compare serious adverse events

68. RCT of 4RIF vs 9INH for LTBI – Timelines of Phase 3
Planned enrolment is almost 6,000 persons
Enrolment to end in 2013
Last follow-up will end in 2015
Publication in 2016!!
Wish me luck
(even just to last that long!!)

69. Thank - you