October 2012
John Jereb, Sundari Mase, FSEB, DTBE, CDC
Special thanks to Christine Ho
and Andrey Borisov
The findings and conclusions in this presentation are those of the
presenter and do not necessarily represent the views of CDC.
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of Tuberculosis Elimination
Disclosures
• No financial conflicts of interest
• Experimental treatment regimens
• Off-label usage of FDA-approved
medications
Public Health Motivation
• Treatment of latent M. tuberculosis infection
is a key component of TB prevention and
elimination.
• 9 months of isoniazid (INH) is highly
efficacious, but effectiveness is diminished
by low completion rates (30–60%).
• A shorter regimen is needed.
– High completion rates, effectiveness, and tolerability
Outline
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Origins of current INH-RPT guidelines
Summary of current guidelines
Project for post-marketing surveillance
Study 33: self-supervised INH-RPT
Plans for additional guidelines
Treatment Trial, Brazil
• Schechter M. AJRCCM 2006
• Household contacts to AFB+
– 399 TST+ adults (age ≥ 18 yr)
• 2 mo. daily RIF-PZA self-sup.
– 20/193 grade 3 or 4 hepatitis
– 1 TB case
• 3 mo. DOT weekly INH-RTP
– 2/206 grade 3 or 4 hepatitis
– 3 TB cases
Treatment Trial, RSA
• Martinson NA. NEJM 2011
• 1148 HIV-infected, TST+; no HIV Tx
– 6 mo. INH daily self-supervised
– Indefinite INH daily self-supervised
– 3 mo. INH-RIF twice weekly DOT
– 3 mo. INH-RPT weekly DOT
• Endpoint: TB-free survival
• Followed up to 6 yr
RSA Trial, Results
• 58 TB cases overall
• No TB difference by regimen
• Death rate 5.7/100 P-Y
6 INH
Indef. INH
3 INH-RIF
3 INH-RPT
TB per 100 P-Y
3.6
2.7
2.9
3.1
AE per 100 P-Y
15.4
18.4
10.6
8.7
Treatment Trial, Brazil, Canada,
Spain, and the United States
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Sterling TR. NEJM 2011
Largest trial (almost 8000 participants)
Longest enrollment period
Children age ≥2 yr
Spectrum of “high-risk” predictors
Both effectiveness and efficacy
Difference in TB rates between the 2 study arms, and non-inferiority “delta”
Modified Intention to Treat Population; A33 analysis
Difference in TB rates between the 2 study arms, and non-inferiority “delta”
Per Protocol Population; A33 analysis
Reported Adverse Events
Among persons receiving > 1 dose
During treatment or within 60 days of the last dose
Regardless of attribution to study drug
3HP
N=4,040
325 (8.0%)
P-value
Grade 1-2
9H
N=3,759
364 (9.7%)
Grade 3
194 (5.2%)
181 (4.5%)
0.16
Grade 4
39 (1.0%)
34 (0.8%)
0.37
Toxicity
0.01
Reported Adverse Events
Among persons receiving > 1 dose
During treatment or within 60 days of the last dose
Accounting for attribution to study drug
Related to drug
Rash only
Possible HS
9H
N=3,759
206 (5.5)
17 (0.5)
15 (0.4)
3HP
N=4,040
328 (8.1)
35 (0.9)
158 (3.9)
<0.0001
0.02
<0.0001
Other
Not related
71 (2.0)
399 (10.3)
122 (3.0)
220 (5.5)
0.001
<0.0001
Toxicity
HS: hypersensitivity reaction
P-value
Hepatotoxicity
Among persons receiving > 1 dose
During treatment or within 60 days of the last dose
9H
N=3,759
113 (3.0)
3HP
N=4,040
24 (0.6)
<0.0001
Related to drug
103 (2.7)
18 (0.5)
<0.0001
Not related
13 (0.4)
6 (0.2)
0.08
Toxicity
All
hepatotoxicity
P-value
MMWR 2011; 60: 1650–1653
CDC Guidelines for Weekly
INH-RPT DOT, 12 Doses
• Equal alternative for 9 mo INH
– Otherwise healthy persons with LTBI and
factors predicting progression
– Age ≥12 yr
• Consideration for other patients if
feasibility favors INH-RPT
• DOT
MMWR 2011; 60: 1650–1653
INH and RPT Dosages
CDC Guidelines for Weekly
INH-RPT DOT, 12 Doses,
Children 2–11 Years Old
• Small numbers in treatment trials
• No pediatric formulation of RPT
• INH-RPT recommended if both
– Notable risk of TB
– Unlikely to complete 9 mo INH
MMWR 2011; 60: 1650–1653
Not Recommended for
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Children <2 yr old
Patients taking anti-retrovirals for HIV
Women who are pregnant
Patients with INH- or RIF-resistant LTBI
Precautions
• Exclude TB disease carefully if
– “Class IV” (old, healed pulmonary TB)
– HIV infection (i.e., not being treated)
• Drug-drug interactions with rifamycins
• DOT
Completion of Therapy
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No evidence basis for definition criteria
No consensus definition of completion
No CDC guidance for interruptions
PreventTB (Study 26) definition
– 11 or 12 doses
– Doses separated by >72 hr
– Within 16 weeks
Adverse Effects and
Monitoring
• Few problems in the treatment trials
• Monitoring recommendations
– Vigilance for hypersensivity
• Thrombocytopenia
• Hypotension
– Hepatotoxicity
• Baseline ALT for few conditions
–HIV infection
–Post-partum period
–Liver disease; alcohol usage
National Surveillance for
Severe Adverse Effects
• Since 2004, at DTBE
• “Severe” = death, or hospital admission
• LTBI treatment
– Any regimen
– At least one dose
• Forms available by contacting
LTBIdrugevents@cdc.gov
• On-site CDC investigations, on request
Adverse Effects in Study 26:
Work in Progress
• Hypersensitivity syndrome
– Panel of immunologists
– Working definition
– One scientific abstract, submitted
• Methadone interactions
– Mainly, withdrawal
– Preliminary findings in early 2013
Adverse Effects in Study 26:
Work in Progress
• Adverse effects trends analysis
– Total AEs decreased over time
– Most decrease: HS reactions
– Findings in 2013
• Hepatitis sub-study
– Matched case-control design
– Focus on viral hepatitis infections
– Findings in 2013
Adverse Effects in Study 26:
Work in Progress
• HIV extended enrollment
• Pediatric extended enrollment
• Focus on INH-RPT safety
– 60 day monitoring is complete
– Data collection is complete
• 33-month monitoring is ongoing
Post-implementation
INH/Rifapentine Project
Takin’ It To the Streets…
(And Keeping it Safe)
Sundari Mase, M.D., M.P.H.
FSEB/DTBE/CDC
LTBI Treatment and a History of
Adverse Events
“Those who do not remember the
past are condemned to repeat it…..”
– Santayana
Learning from History
This CDC-funded project will use the
experience of the field to conduct postimplementation surveillance to inform national
TB program activities
• Actively monitor for adverse effects of the
new 12 weekly dose INH-RPT regimen
through TB programs
• Collect information on programmatic issues
• Treatment trials are not good predictors of
program experience
Objectives
• Assess the use of INH-RPT in non-research
settings for adverse effects
– Collect ‘denominator data’ prospectively
– Note if certain populations, risk factors or settings
are more often associated with adverse effects
• Assess adherence and treatment completion
• Assess impact of INH-RPT on programs
– Staffing
– Costs
• Match patients with TB registry at 2 years
Program requirements
• Use of INH-RPT regardless of project
participation
• Able to track and evaluate patients for adverse
events
• Able to notify CDC contact of adverse events
within 1 day
• Able to collect basic demographic information,
number of people started and completed on
regimen, and symptom review checklist from
each weekly dosing visit
INH-RPT Project Sites
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Arkansas
Arizona – Pima
Bureau of Prisons
California
Georgia
Hawaii
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Illinois – Kane
Kansas
Mississippi
Minnesota
New Mexico
Nevada
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New York
North Dakota
Ohio – Columbus
Oregon
South Carolina
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Seattle WA
Tennessee
Virginia
Wisconsin
Information To Be Collected
• Ideally would want the same information collected across
sites and populations to promote comparability
• Essential data- core set of variables needed for
assessment
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Number of patients started and completed on regimen
Weekly screening for symptoms and adverse effects
Demographics in aggregate form
Notification of adverse events
• Full complement – ideal set of variables for assessment
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Individual demographics
Epidemiological risk factors (homeless, correctional)
Medical risk factors (diabetes, HIV, smoking)
Medications
Timing of doses
Program Evaluation
• Effectiveness
– Adherence
– Medication procurement
• Feasibility
– DOT
– Staffing
– Cost
Adverse Events
• Key person for each project site and CDC
contact person for adverse effects
• All adverse events reviewed at DTBE
• Conference calls (monthly) and transmission of
information (quarterly) at set frequency
– Ensure needed modifications are made
– Share patterns of adverse events across sites
• TB registry match at 2 years (or later)
• Coalesce and report information
Adverse Events
• Approximately 650 patients started on INHRPT
• Seven hospitalizations reported to CDC
• Six out of seven have been investigated by
CDC; the seventh investigation this week
• Not all hospitalizations will be attributable
to INH-RPT
Take Home Messages
• INH/Rifapentine has only been studied in
treatment trials and the surveillance
project tracks what is happening in the
real world
• CDC recommendation is to only give
INH-RPT by DOT
• Any SAE should be reported to Public
Health
• Important to track SAEs systematically, in
real time
Thank You!
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Field Services and Evaluation Branch
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Clinical Research Branch
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Terry Chorba
John Jereb
Sundari Mase
Mark Lobato
Neha Shah
Field Medical Officer Team
Evaluation Team
Program Consultants and Public Health Advisors
Andy Vernon
Elsa Villarino
Andre Borisoff
Stefan Goldberg
Surveillance, Epidemiology and Outbreak Branch
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Tom Navin
Krista Powell
TBTC Study 33:
iAdhere
• Comparison of DOT, SAT INH-RPT, and
Short Messaging Service (SMS)
• Open label
• Randomized by household group
• Primary endpoint: Tx completion
• MEMS caps monitoring for SAT
• 1000 patients, age >18 yr
TBTC Study 33:
iAdhere
• Opened for enrollment September 18
• 2 of 13 sites
• Phased in, site by site
FDA Review for
LTBI Indication
• Meeting with Sanofi Aventis, September 4
• Study 26 data from CDC
• No foreseeable timetable
Guidelines:
What’s Coming
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New Targeted Testing Guidelines
ATS, IDSA, CDC collaboration
AAP participation
Evidenced-based structure
Forecast: summer 2013