5/7/2012. Containment of infection: ACTIVE. Granuloma structure. TNF α TGF β. CD4 Lymphocytes. Conditions Putting Individuals at Greatest RISK

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1 Outline of Presentation Three Months of Once weekly Rifapentine and Isoniazid for LTBI: A Game Changer? Carol Dukes Hamilton, MD, MHS Senior Scientist, FHI 360 Professor of Medicine, Duke University, USA What is latent tuberculosis and why intervene? Isoniazid preventive therapy (IPT): Efficacy Toxicity and management Barriers to uptake and completion PREVENT study Hypothesis and design Results Unanswered questions Conclusions Latent TB Infection (LTBI): Basics Exposure to pulmonary TB leads to infection (LTBI) in some proportion of individuals, depending on: Intensity of exposure Vulnerability of host LTBI progresses to active TB disease in: 5 15% of healthy adults sometime over their lifetimes (even with BCG vaccine) Children 1 5 years: 24% Infants < 1 year: 40% HIV/AIDS: 10% per year Latent TB Infection (LTBI): Basics LTBI remains latent in 85 95% or more of healthy adults exposed to TB Now know that latent is an ACTIVE process Live MTB bacteria remain in granulomas, waiting for a chance to start replicating again Containment of infection: ACTIVE Conditions Putting Individuals at Greatest RISK CD8, NK Macs CD4 Lymphocytes Granuloma structure Fibrous wall TNF α TGF β Langhan s Giant cells New Engl J Med; vol 359:e19, Oct 2008 HIV/AIDS Infants Children < 5 years Silicosis Recent infection Diabetes Malnutrition/low BMI Smoking Cancer/chemotherapy Abnormal gut/absorption 1

2 CD8, NK Macs CD4 Granuloma breaks down Uncontrolled bacterial growth Fibrous wall TNF α TGF β Langhan s Giant cells Intervening: Treating LTBI A pillar of the US public health approach to TB control since mid 1960 s Isoniazid (INH) reduces the likelihood of progression to active TB disease by 70 90% Changing a 5 10% risk to a 1 3% risk for healthy population Much greater impact on high risk Lengthy Isoniazid Treatment for LTBI Treatment Regimens: How We Got There IUAT trials of 27,830 subjects with TST+ and fibrotic lesions on CXR in eastern Europe Placebo controlled randomized clinical trial (INH versus placebo) Compared 12 week to 24 weeks to 52 weeks INH/placebo Bull WHO 60: ; 1982 Bull WHO 60: ; 1982 Lengthy Isoniazid Treatment for LTBI Treatment Regimens: How We Got There Completion: Shorter is better 87% completed 12 weeks 78% completed 24 weeks 68% completed 52 weeks Efficacy: Longer is better 21% reduction in TB cases with 12 weeks treatment 65% reduction.. with 24 weeks treatment 75% reduction.. with 52 weeks treatment Bull WHO 60: ; 1982 Treatment of LTBI among HIV/AIDS patients Cohort Study in Soweto, South Africa Adults with HIV, 5 mm positive tuberculin skin test Different government policies in different clinics resulted in some getting isoniazid preventive therapy (IPT), others not Compared outcome in individuals never receiving IPT or anti retroviral therapy (ART), those receiving ART alone, those receiving IPT alone, and those who got IPT and ART (6 months IPT standard) 2

3 Soweto Results TB incidence (per 100 person years) No IPT or ART 7.1 ( CI) Reference Adjusted hazard rate (95% CI) IPT 5.2 ( ) 0.36 ( ) ART 4.6 ( ) 0.87 ( ) IPT & ART 1.1 ( ) 0.11 ( ). 6 9 months INH: Perfection? Inexpensive Effective Experience Completion rates for self administered therapy in the US ~ 53% Does NOT consider those who never agree to start! Adverse events common 18% in one study in San Diego* *LoBue, Moser; AJRCCM 168; 443 7; 2003 Shorter Treatment for LTBI? Rifampin and pyrazinamide Efficacy similar to INH; toxicity too high INH and rifampin for 3 months 5 trials, total of 1,926 adults (meta analysis)* Hong Kong, Spain, Uganda Estimated similar efficacy and safety Rifampin for 3 months One study (silicosis + TST+) showed 63% efficacy Studies in INH resistant exposures shows reasonable efficacy Less toxicity than INH *Ena, Valls; CID 40:670 6; 2005 Shorter Treatment for LTBI? HIV+ Trial Population Regimen Length Intermittency Result Soweto HIV + H 6 months Daily, SA All better H/RPT 3 months Once weekly DOT than expected TB H/RIF 3 months Twice weekly DOT in pop; No difference H continuous >2 years Daily, SA between regimens Botswana HIV + H 6 months then placebo Daily, SA H 36 months Daily, SA Longer therapy HR.57 (.33.99); Benefit seen almost entirely in TST+ INH = H; Rifapentine = RPT; Rifampin = RIF, SA = self administered; DOT = directly observed Dilemma: Efficacy Effec veness Completion Efficacy Toxicity Effectiveness [AKA Study 26 and The PREVENT TB Study] Need data to support a new approach 3

4 PREVENT TB Study Background Funded by CDC with support by sanofi aventis who supplied rifapentine Presenting on behalf of the CDC funded TB Trials Consortium and protocol team, including co chairs Tim Sterling and Elsa Villarino 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 Study Design Study Design Randomized clinical trial of high risk clients Not placebo controlled All subjects were followed for 33 months from date of enrollment 9H Arm 3HP Arm INH + RPT DOT Weekly, 12 doses INH Self administered Daily, 9 months, 270 doses Non inferiority study design, margin (delta) 0.75% Needed 3200 evaluable persons per arm to have > 80% power to show that 3HP not inferior to 9H 3HP once weekly dose Rifapentine 900 mg max Graduated dosing for persons <50 kg INH mg/kg; 900 mg max 9H daily dose INH 5 15 mg/kg; 300 mg max. Inclusion Criteria Primary Aim Persons > 2 years old who were: Tuberculin skin test (TST) positive close contacts of a culture confirmed TB case TST converters Documented negative positive within 2 years HIV infected with Positive TST Close contact to TB case regardless of TST TST positive, fibrosis on chest radiograph consistent with prior untreated TB Children 2 4 years old with + TST or close contact with a culture confirmed TB case Evaluate the effectiveness of weekly 3HP by DOT vs. daily 9H self administered (SA) Primary endpoint: Culture confirmed TB in persons >18 y.o and cultureconfirmed or clinical TB in persons < 18 y.o. 4

5 Exclusion Criteria Confirmed or suspected TB TB resistant to INH or rifampin in source case History of treatment with > 14 consecutive days with a rifamycin > 30 days with INH Prior treatment of TB or M. tuberculosis infection in HIV uninfected persons Intolerance to INH or rifamycins Aspartate aminotransferase (AST) > 5x upper limit if AST determined Pregnant or lactating females HIV 1 antiretroviral therapy within 90 days of enrollment Weight < 10 kg Results: Adults only (few HIV+) Enrollment began June 2001 Enrollment ended February 15, 2008 Follow up ended September 30, 2010 Proportion of subjects completing 33 months of follow up 86% (H) and 88% (HP) Analysis Populations Intention to treat (ITT) All persons enrolled in the study Modified intention to treat (MITT) EFFECTIVENESS Enrolled in the study Eligible Per protocol (PP) EFFICACY All persons enrolled in the study who were eligible Completed study drug within targeted time period Or developed TB or died but completed > 75% of expected doses prior to event All follow up time counted; did not require reaching 33 months Primary Endpoint: Modified Intention to Treat Adults, HIV sero-negative Difference in TB rates between the 2 study arms, and non-inferiority delta Modified Intention to Treat Population at 33 months follow up Event rate estimates and the non inferiority test at 33 months follow up Arm N # TB cases TB per 100 p-y Cumulative TB rate (%) Difference in cumulative TB rate Upper bound of 95% CI of difference in cumulative TB rates* Below the 0.00% line favors RPT/INH 9H 3, HP 3, * non-inferiority margin (delta) = 0.75% 5

6 Difference in TB rates between the 2 study arms, and non-inferiority delta Difference in TB rates between the 2 study arms, and non-inferiority delta Modified Intention to Treat Population at 33 months follow up Per Protocol Population at 33 months follow up Cumulative TB Rate 33 months from enrollment MITT Tolerability: MITT population Outcome Treatment completion Permanent drug d/cany reason 9H N=3,745 3HP N=3,986 P-value 2,585 (69.0%) 3,362 (82.0%) < ,160 (31.0%) 624 (18.0%) < Permanent drug d/cdue to an adverse 135 (3.6%) 188 (4.7%) event Death 39 (1.0%) 31 (0.8%) 0.22 Log-rank P-value: 0.06 Reported Adverse Events Among persons receiving >1 dose During treatment or within 60 days of the last dose Regardless of attribution to study drug Reported Adverse Events Among persons receiving >1 dose During treatment or within 60 days of the last dose Accounting for attribution to study drug Toxicity 9H N=3,759 3HP N=4,040 P value Grade (9.7%) 325 (8.0%) 0.01 Grade (5.2%) 181 (4.5%) 0.16 Grade 4 39 (1.0%) 34 (0.8%) 0.37 Toxicity 9H N=3,759 3HP N=4,040 P value Related to drug 206 (5.5) 328 (8.1) < Rash only 17 (0.5) 35 (0.9) 0.02 Possible HS 15 (0.4) 158 (3.9) < Other 71 (2.0) 122 (3.0) Not related 399 (10.3) 220 (5.5) < HS: hypersensitivity reaction 6

7 Hepatotoxicity Among persons receiving >1 dose During treatment or within 60 days of the last dose Toxicity All hepatotoxicity 9H N=3,759 3HP N=4,040 P value 113 (3.0) 24 (0.6) < Related to drug 103 (2.7) 18 (0.5) < Limitations Few HIV infected participants Enrollment of this population was extended to December 2010 Tolerability and effectiveness data pending Complete tolerability assessment in young children also pending Enrollment of children 2 11 years old extended to December 2010 Not related 13 (0.4) 6 (0.2) H Arm Conclusions: PREVENT TB INH Self administered Daily, 9 months INH + RPT 3HP Arm DOT Weekly, 3 months 3HP by DOT was at least as effective as 9H by self administration The 3HP TB rate was approximately half that of 9H The 3HP completion rate was significantly higher than 9H 82% vs. 69% 3HP was safe relative to 9H Lower rates of any adverse event, and less hepatotoxicity attributable to study drug CDC Recommendations for Treatment of LTBI CDC convened a panel of experts to review data Noted non inferiority of 12 dose, once weekly regimen Higher completion rates Less hepatotoxicity Apparent overall fewer adverse events CDC Recommendations for Treatment of LTBI 7

8 CDC Recommendations for Treatment of LTBI Pending.. TBTC PREVENT TB: Children and HIV+ Results late 2012/early 2013 DOT versus self administered effectiveness TBTC iadhere study starting 2012 Effectiveness and safety when given on large scale in program settings will be assessed by CDC Updated LTBI Guidelines 2013 Conclusions A regimen of 12 once weekly doses of INH + RPT by DOT is as effective as 9 months of INH self admin Recommended for adults by CDC ATS/CDC/IDSA LTBI treatment guideline update in progress Data in children and PLWHA pending Offering 12 weeks of therapy may increase uptake and completion of an effective regimen Acknowledgements CDC Division of TB Elimination, supporting TB Trials Consortium since 1995 Members of the TB Control community across the US, Canada, Brazil & Spain Key partners in patient identification, recruitment, follow up TBTC PREVENT TB Study team And all participating TBTC study coordinators, site investigators Our patients who participated, on behalf of those who we hope will benefit 8