update diagnosis and treatment of 结核的诊断与治疗的更新课件

“Diagnosis and treatment of latent TB ” Update Internal Medicine Dr Dick Menzies Montreal Chest Institute Problems with current approach to LTBI management TST Labour intensive, slow, non-specific Although appears to predict benefit Current therapy (INH) Long duration = poor compliance - less than 50% in most programs, although can be 70%. Serious side effects - can be fatal Costs - close follow up necessary = expensive Overview of Talk LTBI diagnosis The old Tuberculin skin test The new Interferon gamma release assays Treatment of Latent TB The current standard 9INH Is a TST needed before starting INH therapy? Does INH therapy create INH resistance? Alternatives 4RIF and others The 4RIF trial Diagnosis - Indications for testing Increased risk of developing TB disease New TB infection Increased risk of reactivation from latent TB Increased risk of exposure Health care workers at hiring Other workers with risk of exposure Tools for diagnosis - TST Strengths: Long history: known test performance Simple test: can be performed (almost) anywhere Predictive ability: for benefit of treatment Weaknesses: Specificity: especially if BCG vaccinated Sensitivity: especially if immune compromise Predictive ability: 50% Diabetic: 3-4X relative risk = 20-40% Very young child: Age 9 months Comstock GW, 1998 Efficacy of therapy INH will reduce risk of disease by 90% If taken for 9 months If 80% of doses taken each month Age Specific Incidence of INH hepatitis Mortality from INH hepatitis Problems with INH 1. Length - 9 months ideal (90% efficacy) Results in poor compliance - less than 50% in most programs. 2. Drug induced hepatitis - - Less common now, but deaths still occur. Also rash, neuropathies 3. Costs - INH is cheap but close follow up is necessary. This is expensive Is a TST needed before LTBI therapy is given? Meta-Analysis: INH protects against TB Meta-Analysis: INH protects against TB In HIV (+) who are TST (+)In HIV (+) who are TST (+) (Pooled estimates: 0.4 (0.24-0.65)(Pooled estimates: 0.4 (0.24-0.65) AIDS 1999;13:501-7 AIDS 1999;13:501-7 Meta-Analysis: INH does not protect against TB In Meta-Analysis: INH does not protect against TB In HIV (+) who are TST (-)HIV (+) who are TST (-) (Pooled estimates: 0.84 (0.54-1.30)(Pooled estimates: 0.84 (0.54-1.30) Does INH treatment of LTBI create INH resistance? INH treatment and INH resistance This was assessed in a large cohort of SE Asian refugees who were screened and treated after arrival in the US. No difference in rates of INH Resistant TB in persons who took INH, vs those who took nothing Meta-analysis (Godfrey-Fausett et al) Reviewed placebo controlled RCT of INH Small, but non-significant increase LTBI treatment what are the options? 6-9 months of INH 2 months RIF-PZA 3-4 months INH-RIF 3 months once weekly INH 2006:10:1080-1090) Author Location 6 INH2 RZ Halsey Haiti55%74% Mwinga Zambia66%75% Jasmer USA57%61% Leung Hong Kong89%83% Tortajada Spain77%82% Serious Adverse Events 6INH vs 2RZ (From Gao et al, IJTLD; 2006:10:1080-1090) Author Mean Age 6-12 INH2 RZ Halsey3100 Mwinga313%4% Jasmer373%9% Leung606%35% Tortajadanr4%12% 2 months Rifampin and PZA In 1989 2 mos RIF 2005; 40: 670-676)(Ena 2005; 40: 670-676) (+0.1%)41/97239/954Pooled estimates (+0.3%)9/5567/536Whalen (Uganda HIV) (+0.1%)3/823/83Rivero (Spain HIV) (- 3.3%)2/694/64Martinez (Spain - HIV) (+1.0%)1/980/98Martinez (Spain HIV) (+1.1%) 26/16725/173Hong Kong (silicotics) (Diff. %)INH/RIF INH 3-4 mos Rifampin-INH vs 6-12 mos INH 3-4 mos Rifampin-INH vs 6-12 mos INH A meta-analysis of 5 RCTs A meta-analysis of 5 RCTs Serious Adverse EventsSerious Adverse Events (Ena 2005; 40: 670-676)(Ena 2005; 40: 670-676) (+0.1%)48/97246/954Pooled estimates (+1.7%)13/5563/536Whalen (Uganda HIV) (+11%)15/826/83Rivero (Spain HIV) (- 16%)5/6915/64Martinez (Spain - HIV) (- 2.0%)7/989/98Martinez (Spain HIV) (- 2.7%)8/16713/173Hong Kong (silicotics) (Diff. %)INH/RIF INH LTBI treatment what are the options? 6-9 months of INH 2 months RIF-PZA 3-4 months INH-RIF 3 months once weekly INH145:36-41 6 Months Rifampin Mono-Therapy (For contacts of INH resistant cases) (Polesky et al., AJRCCM; 1996: 155: 1735-38 Homeless persons in Boston, screened in shelters Extended Outbreak of INH resistant TB 204 Exposed persons with documented TST conversion Therapy of LTBI was not randomized 71 no therapy 8.6% active TB 38 given INH 7.9% active TB (all were INH Resistant) 86 RIF or INH/RIF 0 active TB 49 Rifampin only no hepatitis or increased LFTs Program Experience with 4RIF and 9INH Maryland 1999-2004 Page et al. Archives Internal Med. 2006: 166; 1863-70 Patients offered 4 RIF or 9 INH by provider Concurrent study but non-randomized 4 RIF9 INH Number Starting 1,379770 Completing Therapy 987 (72%)405 (52%) Grade 3 to 4 Hepatitis 1 (0.1%)12 (2%) Program Experience with 4RIF and 9INH New Jersey 1999-2004 Lardizabal et al. Chest, 2006: 130;1712-16 4 RIF9 INH Number Starting261213 Completing Therapy210 (81%)113 (53%) Grade 3 to 4 SAE8 (3%)13 (6%) Hepatitis03 Non-concurrent and non-randomized study A randomized trial to compare 4 months Rifampin vs 9 months INH for the treatment of LTBI Phase 1: Compliance and completion Completed in 2003 Phase 2 Adverse events and costs Completed in 2007 Phase 3: Efficacy and effectiveness RCT of 9 INH vs. 4 RIF for LTBI Study design Design - open label randomized trial Positive control = 9INH Not placebo as INH of proven benefit RCT of 4RIF vs 9INH for LTBI Study Population Inclusion Criteria Positive TST, high risk - prescribed LTBI treatment. Highest risk reactors Risk of reactivation 1% per year Close contact, TST conversion, HIV (+), apical fibronodular disease Moderate Risk (risk of 0.5% - 1% per year) Diabetes, renal failure, immuno-compromise Casual contacts, TST conversion in 2-5years Or two of the following three: Arrival in the past two years from TB endemic country Less than 90% ideal body weight Granulomas, calcified nodes TST 15mm RCT of 4RIF vs 9INH for LTBI Study Population Exclusion Criteria Exclude as few as possible Essential exclusion criteria: Contacts of INH or RIF resistant (or MDR) index cases High potential for drug interactions (Certain HIV therapy, or oral contraceptives) Known INH or RIF allergy All other patients eligible if LTBI therapy prescribed Regardless of age, or other risk factors for SAE RCT of 4RIF vs 9INH for LTBI Data Gathering in treatment phase Pragmatic trial As little impact on follow-up as possible, i.e. routine follow-up Follow-up visits will be monthly for first 2 months, or more often per physician CBC, liver transaminases at baseline and first follow- up visit Study staff to have as little direct involvement as possible Minimize study effect Estimate effectiveness under routine conditions RCT of 9 INH vs. 4 RIF Phase 1 Completion of therapy among randomized participants 3 (5%) 8 (14%) Completed Rx poor compliance, N(%) 2 (3%)8 (14%)MD stopped b/o Side effects N(%) 12 (21)20 (34%) 90% of doses correct at 1 month, N(%) 4 (7%) 114 (24%) 1Did not complete Rx, N(%) 50 (86%) 1 36 (62%) 1Completed Rx good compliance, N(%) 4 RIF (N=58) 9 INH (N=58) 1 P-value = 0.01 RCT of 4RIF vs. 9INH for LTBI Phase 1 Phase 1: Side effects associated with the 2 regimens 27% 114% 1Minor, % 22Major other, N 04Major hepatitis, N 4 RIF 9 INH 1 P-value = 0.001 RCT of 4RIF vs. 9INH for LTBI Phase 2 Completion of Phase 2 Study 4 RIF (N=420) 9 INH (N=427) P-value Completed Therapy N (%) 339 (81%) 259 (69%) .0001 Patient Non-compliant (Total) - Drop-out - Intolerance 61 (14%) 52 (12%) 3 (1%) 117 (27%) 82 (20%) 23 (5%) MD Non-compliant6 (1%)12 (3%) RCT of 4RIF vs. 9INH for LTBI Phase 2 Serious Drug Related Adverse Events 4 RIF (N=420) 9 INH (N=427) P-value All Grades Total (%) *16 (3.8%)24 (5.6%)NS Grade 3 to 4 - Total - Hepato-toxicity - Hematologic - Drug Interaction - Rash 6 (1.5%) 3 (0.7%) 1 1 1 17 (4.0%) 16 (3.8%) 1 0 0 .02 .003 - - - Grade 1 to 2 - Total - Rash - GI intolerance - Hematologic 11 (2.0%) 8 1 2 7 (1.6%) 4 2 0 NS NS - - * Severity, type + relationship to study drug by independent blinded 3-member panel RCT of 4RIF vs. 9INH for LTBI Phase 2 Therapy Stopped Permanently but Not Related to Study Drug* 4 RIF (N=420) 9 INH (N=427) P-value Death01 Pregnancy23 * The severity, type and relationship to study drug judged by independent three-member panel blinded to patient allocation. Serious adverse events significantly less than 9INH Particularly for gr