Disclosures. Public Health Motivation 6/6/2012. The 12-Dose INH-Rifapentine Once-Weekly DOT Regimen: What Next?

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1 The 12-Dose INH-Rifapentine Once-Weekly DOT Regimen: What Next? NTCA Conference June 14, 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 No financial conflicts of interest Experimental treatment regimens Off-label usage of FDA-approved medications 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 1

2 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 33: self-supervised INH-RPT Plans for additional guidelines Methods for Guidelines Review of evidence: three Tx trials Expert consultation: five basic questions Synthesis Evidence Expert opinion 2

3 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 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 AE per 100 P-Y

4 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 4

5 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 5

6 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? 6

7 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: 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 both Notable risk of TB Unlikely to complete 9 mo INH MMWR 2011; 60: Not Recommended for Children <2 yr old Patients taking anti-retrovirals for HIV Women who are pregnant Patients with INH- or RIF-resistant LTBI 7

8 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 definition 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 recommendations Vigilance for hypersensivity Thrombocytopenia Hypotension Hepatotoxicity Baseline ALT for few conditions HIV infection Post-partum period Liver disease; alcohol usage 8

9 Adverse Effects: Ongoing Developments PreventTB (Study 26) analysis of AEs INH-RPT Post-Marketing Surveillance Project (observational prospective) 18 volunteer sites Denominator data Endpoints: COT; adverse effects, including Breakthrough TB Drug resistance Costs and operational details 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