The 12-Dose INH-Rifapentine Once-Weekly DOT Regimen:

What Next?

CTCA Conference 2012John Jereb, FSEB, DTBE, CDCSpecial thanks to Christine Ho,

Elsa Villarino, and Andrey BorisovThe 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

• 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 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

6 INH Indef. INH 3 INH-RIF 3 INH-RPTTB 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

• 58 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 2How 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 andMonitoring

• 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

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