Transcript Interim Guidelines: The 12-Dose INH-Rifapentine Once

The 12-Dose INH-Rifapentine
Once-Weekly DOT Regimen:
What Next?
CTCA Conference 2012
John Jereb, FSEB, DTBE, CDC
Special thanks to Christine Ho,
Elsa Villarino, and Andrey Borisov
The findings and conclusions in this presentation are those of the
presenter and do not necessarily represent the views of CDC.
Disclosures and Disclaimer
• No financial conflicts of interest
• Experimental treatment regimens
• Off-label usage of FDA-approved
•
medications
The findings and conclusions in this
presentation are those of the presenter and
do not necessarily represent the views of
CDC.
Public Health Motivation
• The global burden of latent M.
tuberculosis infection is enormous.
– More than 2 billion people infected
•
Raviglione MD. JAMA 1995;273:220-6.
• From this reservoir, millions of people
will develop active tuberculosis (TB) in
coming decades
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
• Origins of current INH-RPT guidelines
• Summary of current guidelines
• Project for post-marketing surveillance
• Study of self-supervised INH-RPT
• Plans for additional guidelines
Methods for Guidelines
• Review of evidence: three Tx trials
• Expert consultation: five questions
• Synthesis
– Evidence
– Expert opinion
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
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– 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
• Sterling TR. NEJM 2011
• Largest trial (8000 participants)
• Longest enrollment period
• Children age ≥2 yr
• Spectrum of “high-risk” predicates
• 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
Expert Consultants
*Nisha Ahamed, MPH
Bob Belknap, MD
Marcos Burgos, MD
Kim W. Field, RN, PHN, MSN
*Jennifer M. Flood, MD, MPH
James M. Holcombe, MPPA,
CPM
David P. Holland, MD, MHS
*C. Robert Horsburgh, MD, MUS
Steven Kyong Won Hwang, MD
Chrispin Kambili, MD
Michael Lauzardo, MD, MSc
Cynthia Lee, MA, CHES
Mark N. Lobato, MD
Bonita T. Mangura, MD, FACP,
FCCP
*Masa Narita, MD
*Charles Nolan, MD
Max Salfinger, MD
Barbara J. Seaworth, MD
*Gary L. Simpson, MD, PhD
Jeffrey R. Starke, MD
Timothy R. Sterling, MD
Claire R. Wingfield, MPH
Ed L. Zuroweste, MD
Question 1
Should CDC issue interim
recommendations for the 12-dose,
once-weekly, combination IsoniazidRifapentine regimen (3HP) for treating
latent TB infection?
Question 2
How should other groups not well represented in
Study 26 be included in the guidelines?
– Persons who are diagnosed during targeted testing
outside of contact investigations (e.g., screenings
at homeless shelters, testing of immigrants)
– Persons with HIV infection
– Children
– Persons at risk for TB because of medical
immunosuppression.
Question 3
How should patients under treatment be
monitored for safety from adverse
affects?
Question 4
Should 3HP be administered DOT only?
For which situations or patients would
self-supervised therapy be acceptable
or recommendable?
Question 5
What are the priorities for further research
with this regimen?
CDC Guidelines for Weekly
INH-RPT DOT, 12 Doses
• Equal alternative for 9 mo INH
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– Otherwise healthy persons with LTBI
and factors predicting progression
– Age ≥12 yr
Consideration for other patients if
feasibility favors INH-RPT
Did I mention “DOT”?
MMWR 2011; 60: 1650–1653
CDC Guidelines for Weekly
INH-RPT DOT, 12 Doses,
Children 2–11 Years Old
• Small numbers in treatment trials
• No pediatric formulation of RPT
• Recommended if
– Notable risk of TB
– Unlikely to complete 9 mo INH
MMWR 2011; 60: 1650–1653
Not Recommended for
• 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
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– “Class IV” (old, healed pulmonary TB)
– HIV infection (i.e., not being treated)
Drug-drug interactions with rifamycins
DOT
Completion of Therapy
• No evidence basis for any criteria
• No definition in CDC guidelines
• 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
– Vigilance for hypersensivity
• Thrombocytopenia
• Hypotension
– Hepatotoxicity
• Baseline ALT for few conditions
–HIV infection
–Post-partum period
–Liver disease; alcohol usage
Adverse Effects:
What’s Coming
• PreventTB (Study 26) analysis: ongoing
• INH-RPT Post-Marketing Surveillance
Project (observational prospective)
– 18 sites
– Denominator data
– Endpoints: COT; adverse effects, including
• Breakthrough TB
• Drug resistance
– Costs and operational details
Project Sites (Provisional)
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Arkansas
Arizona – Pima
Bureau of Prisons
California
Georgia
Illinois – Kane
Kansas
Michigan
Mississippi
New Mexico
Nevada
New York
North Dakota
Ohio – Columbus
Oregon
South Carolina
Tennessee
Virginia – Alexandria
Wisconsin
TBTC Study 33:
iAdhere
• Comparison of DOT and SAT INH-RPT
• Sub-study with Short Messaging Service
• Open label
• Randomized by household group
• Primary endpoint: Tx completion
• MEMS caps monitoring for SAT
• 1000 patients, age >18 yr
Guidelines:
What’s Coming
• New Targeted Testing Guidelines
• ATS, IDSA, CDC collaboration
• AAP participation
• Evidenced-based structure
• Due out in summer 2013
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