Transcript TUBERCULOSIS UPDATE Diagnosis and Treatment of Latent TB

“Diagnosis and treatment of latent TB ”
Update – Internal Medicine
Dr Dick Menzies
Montreal Chest Institute
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
Overview of Talk
• LTBI diagnosis
• 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
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
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
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- 14% (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)
Interferon gamma release assays (IGRA)
• A brief introduction
TST vs IGRA: rationale
Andersen P et al, Lancet 2000
8
Genomics
Proteomics
ESAT-6
CFP-10
Cole et al, Nature 1998
9




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
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
ELISPOT (in-house)
14/1000 person-yr
Which is the best predictor of active TB?
IGRA RR= 2.4
TST 5mm RR= 2.1 TST 10mm RR=2.0
Summary: IGRA
• Good 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
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
3. If TST negative but high risk (HIV, or immune
suppressed).
Perform IGRA – to enhance sensitivity. If IGRA positive
then treat
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)
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….
THE INTERNET !! (the Online TST/IGRA interpreter)
http://www.tstin3d.com
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
17
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
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: 20-30% risk in 1 year
• Age 2-5: 15-20% risk
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!!
Individual risks of therapy
• Risks of therapy are well known for INH,
and INH hepatitis is serious
• Risks of other therapies less well known
Schematic of Risk Benefit Balance for INH
LTBI Therapy
Benefits of therapy
Risks of therapy
• Older Age
• Liver Disease
• Alcohol Use
Increased if greater
risk of disease:
HIV, diabetes,
abnormal Xray,
contact, etc
Treatment of hypertension vs LTBI
Hypertension
• Asymptomatic condition
• Very serious complications
– Death
– Major disability
• Treatment is for many years
LTBI
• Asymptomatic condition
• Very serious complications
– Death, Major disability
– AND transmission
• Treatment is 9 months
– Potential serious side effects
– Requires close monitoring and FU
– Expensive medications
– Potential serious side effects
– Requires close monitoring and FU
– Cheap medications
• BUT – no debate about Treating
• WHY the debate about Treating
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
Duration of INH Therapy and efficacy/effectiveness
Patients with Fibrotic Lesions
Population
Duration
Reduction in TB
All participants
INH 12 mo.
INH 6 mo.
INH 3 mo.
75%
65%
21%
Completer/compliers
INH 12 mo.
INH 6 mo.
INH 3 mo.
93%
69%
31%
Bull WHO 1982;555-64
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
Efficacy of therapy
• INH will reduce risk of disease by 90%
– If taken for 9 months
– If >80% of doses taken each month
Age Specific Incidence of INH hepatitis
Age
Incidence of hepatitis
0-20
21-34
35-49
49-64
65 +
< 0.1%
0.3%
1.2%
2.3%
> 5%
From USPHS Surveillance Study - probable cases ONLY, and from Arkansas nursing home
residents
Mortality from INH hepatitis
Years
Age
USPHS surveillance 1971-72
< 35
> 35
Mortality
(per 100,000)
0
98
IUAT trial
35-65
14
Study
11969-72
CDC surveillance
1972-3
1974-83
1984-8
All
All
All
54
14
6
Salpeter survey
1983-92
< 35
> 35
0.6
2.4
Problems with INH
1. Length - 9 months ideal (90% efficacy)
– Results in poor compliance - less than 50% in most
programs.
2. 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
Is a TST needed before LTBI therapy
is given?
Meta-Analysis: INH protects against TB
In HIV (+) who are TST (+)
(Pooled estimates: 0.4 (0.24-0.65))
AIDS 1999;13:501-7
Meta-Analysis: INH does not protect against TB – In
HIV (+) who are TST (-)
(Pooled estimates: 0.84 (0.54-1.30))
AIDS 1999;13:501-7
Does INH treatment of LTBI
create INH resistance?
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
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
Experimental Study of Short-Course
Preventive Therapy in Mice – the start of 2RIF-PZA
Lecour HF, et.al. Am Rev Respir Dis 1989:140:1189-93
International Study of 12INH vs 2RIF-PZA in
HIV Infected patients - OUTCOMES
Regimen
2 RIF/PZA
12 INH
No. enrolled
791
790
Confirmed TB
Conf/Probable TB
Death
19
28
139
26
29
159
RR (CI)
0.7 (.4,1.2)
0.95 (.6,1.2)
0.9 (.7,1.1)
Completion of therapy – 6 INH vs 2RZ
(From Gao et al, IJTLD; 2006:10:1080-1090)
Author
Location
6 INH
2 RZ
Halsey
Haiti
55%
74%
Mwinga
Zambia
66%
75%
Jasmer
USA
57%
61%
Leung
Hong Kong
89%
83%
Tortajada
Spain
77%
82%
Serious Adverse Events – 6INH vs 2RZ
(From Gao et al, IJTLD; 2006:10:1080-1090)
Author
Mean Age
6-12 INH
2 RZ
Halsey
31
0
0
Mwinga
31
3%
4%
Jasmer
37
3%
9%
Leung
60
6%
35%
Tortajada
nr
4%
12%
2 months Rifampin and PZA
•
•
•
•
•
In 1989 – 2 mos RIF&PZA – effective in mice
1990-2000 – several trials – all in HIV infected
2000 – Strong recommendations – to use this
2000-2001 – Reports of severe hepatitis
2001 – recommendation withdrawn
• DO NOT USE 2 RIF-PZA
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
3-4 mos Rifampin-INH vs 6-12 mos INH
A meta-analysis of 5 RCT’s
Occurrence of active TB
(Ena & Valls, Clin Inf Dis; 2005; 40: 670-676)
INH
INH/RIF
(Diff. %)
Hong Kong (silicotics)
25/173
26/167
(+1.1%)
Martinez (Spain – HIV)
0/98
1/98
(+1.0%)
Martinez (Spain - HIV)
4/64
2/69
(- 3.3%)
Rivero (Spain – HIV)
3/83
3/82
(+0.1%)
Whalen (Uganda – HIV)
7/536
9/556
(+0.3%)
Pooled estimates
39/954
41/972
(+0.1%)
3-4 mos Rifampin-INH vs 6-12 mos INH
A meta-analysis of 5 RCT’s
Serious Adverse Events
(Ena & Valls, Clin Inf Dis; 2005; 40: 670-676)
INH
INH/RIF
(Diff. %)
Hong Kong (silicotics)
13/173
8/167
(- 2.7%)
Martinez (Spain – HIV)
9/98
7/98
(- 2.0%)
Martinez (Spain - HIV)
15/64
5/69
(- 16%)
Rivero (Spain – HIV)
6/83
15/82
(+11%)
Whalen (Uganda – HIV)
3/536
13/556
(+1.7%)
Pooled estimates
46/954
48/972
(+0.1%)
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
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
3 months once weekly INH & Rifapentine –
Incidence of active TB
Randomized
Completed
TB Disease - All patients
- Completed
9INH
3HP
3649
3895
2536 (69%)
3190 (82%)
12 (0.4%)
7 (0.2%)
5 (0.2%)
4 (0.1%)
3 months once weekly INH & Rifapentine –
Adverse events
9INH
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%
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
Experimental Study of Short-Course
Preventive Therapy in Mice – what about RIF?
Lecour HF, et.al. Am Rev Respir Dis 1989:140:1189-93
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
6 Months Rifampin Mono-Therapy
(For contacts of INH resistant cases)
(Polesky et al., AJRCCM; 1996: 155: 1735-38
•
•
•
•
•
•
•
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
Program Experience with 4RIF and 9INH
Maryland 1999-2004
Page et al. Archives Internal Med. 2006: 166; 1863-70
• Patients offered 4 RIF or 9 INH by provider
• Concurrent study but non-randomized
Number Starting
Completing Therapy
Grade 3 to 4 Hepatitis
4 RIF
9 INH
1,379
770
987 (72%)
405 (52%)
1 (0.1%)
12 (2%)
Program Experience with 4RIF and 9INH
New Jersey 1999-2004
Lardizabal et al. Chest, 2006: 130;1712-16
Non-concurrent and non-randomized study
Number Starting
Completing Therapy
Grade 3 to 4 SAE
Hepatitis
4 RIF
9 INH
261
213
210 (81%)
113 (53%)
8 (3%)
13 (6%)
0
3
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
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
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
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
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 followup visit
• Study staff to have as little direct involvement as
possible
– Minimize ‘study effect’
– Estimate effectiveness under ‘routine’ conditions
RCT of 9 INH vs. 4 RIF –
Phase 1
Completion of therapy among randomized participants
9 INH
(N=58)
4 RIF
(N=58)
Completed Rx good compliance, N(%)
36 (62%) 1
50 (86%)
Completed Rx poor compliance, N(%)
8 (14%)
3 (5%)
14 (24%) 1
4 (7%) 1
MD stopped b/o Side effects N(%)
8 (14%)
2 (3%)
< 90% of doses correct at 1 month, N(%)
20 (34%)
12 (21)
Did not complete Rx, N(%)
1
P-value = 0.01
1
RCT of 4RIF vs. 9INH for LTBI – Phase 1
Phase 1: Side effects associated with the 2
regimens
9 INH
4 RIF
Major – hepatitis, N
4
0
Major – other, N
2
2
14% 1
27% 1
Minor, %
1
P-value = <0.001
RCT of 4RIF vs. 9INH for LTBI – Phase 2
Completion of Phase 2 Study
4 RIF
(N=420)
Completed Therapy N (%)
Patient Non-compliant (Total)
- Drop-out
- Intolerance
MD Non-compliant
9 INH
(N=427)
339 (81%) 259 (69%)
61 (14%)
117 (27%)
52 (12%)
3 (1%)
82 (20%)
23 (5%)
6 (1%)
12 (3%)
P-value
<.0001
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%)
17 (4.0%)
16 (3.8%)
1
1
1
1
0
0
.02
.003
-
Grade 1 to 2 - Total
- Rash
- GI intolerance
- Hematologic
11 (2.0%)
8
1
2
7 (1.6%)
4
2
0
NS
NS
-
* Severity,
type + relationship to study drug by independent blinded 3-member panel
RCT of 4RIF vs. 9INH for LTBI – Phase 2
Therapy Stopped Permanently but Not Related to Study Drug*
4 RIF
(N=420)
9 INH
(N=427)
Death
0
1
Pregnancy
2
3
* The
P-value
severity, type and relationship to study drug judged by
independent three-member panel blinded to patient allocation.
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
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
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!!)
Thank - you