Presentation on theme: "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,"— Presentation transcript:
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: From this reservoir, millions of people will develop active tuberculosis (TB) in coming decades
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 Public Health Motivation
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 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 6 INHIndef. INH3 INH-RIF3 INH-RPT TB per 100 P-Y AE per 100 P-Y TB cases overall No TB difference by regimen Death rate 5.7/100 P-Y
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 Isoniazid- Rifapentine 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 –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 –“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) 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