Multidrug-resistant Tuberculosis. Charles L. Daley, MD National Jewish Health Chair, Global GLC, WHO and Stop TB Partnership

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1 Multidrug-resistant Tuberculosis Charles L. Daley, MD National Jewish Health Chair, Global GLC, WHO and Stop TB Partnership

2 Disclosures World Health Organization Chair, Global GLC Otsuka Chair, Data Monitoring Committee for clinical trials of delaminid

3 Multidrug-resistant Tuberculosis Outline Pathogenesis and Transmission of Drug Resistance Epidemiology of MDR-TB Diagnosis of MDR-TB Treatment of MDR-TB New Drugs for MDR-TB

4 Definitions for Multidrug and Extensively Drug Resistant TB 9 million TB cases Drug Susceptible Any Drug Resistance MDR-TB XDR- TB MDR-TB: Resistance to at least isoniazid and rifampin XDR-TB: MDR plus resistance to fluoroquinolones and one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin) Source: Peter Cegielski

5 Pathogenesis and Transmission of Drug-resistant TB M. tuberculosis Mutation Nature Resistant Mutants Selection Inadequate treatment Transmission Acquired Resistance Primary Resistance HIV Inadequate infection control Diagnostic delay

6 MDR-TB Notification and Enrollment Estimated MDR-TB cases among notified TB patients in 2010 No data ,000 3,001-30,000 30,001-60,000 >60,000

7 Percentage of Previously Treated TB Cases with MDR-TB

8 Countries with at Least One Case of XDR-TB by end of 2011 WHO Global TB Report, 2012

9 MDR-TB Notification and Enrollment MDR cases reported vs estimated among notified TB, 2010 WHO Region 2010 Estimated Reported Ratio African 32,000 9,504 30% American 6,200 2,158 35% East Med. 14, % European 53,000 32,616 62% S-E Asian 88,000 3,779 4% West Pacific 77,000 4,222 5% Global 290,000 53,108 18%

10 Clinical Case 57 year old Filipina woman seen in TB clinic for immigration screening 7 days after arrival to U.S. Patient had chronic cough, fatigue, anorexia, and fever for months PMH Treated for TB in PI for the past 5 years Hx of diabetes mellitus

11 Diagnostic Work-Up of TB Suspect Sputum Specimen (x2-3) AFB smear Mycobacterial Culture Solid media (4-6 wks) Liquid media (2-4 wks) Species Identification Biochemical tests (days) Molecular tests (hours) Drug Susceptibility Testing Solid media (3-4 wks) Liquid media (5-10 days) Rapid Molecular (2 hrs to 1 day)

12 Time to DST Results by Method Microscopy 24 hrs Solid Culture 6-8 wks 1 st -line DST 3-4 wks MDR-TB diagnosis after 9 to 12 weeks Microscopy 24 hrs Liquid Culture 2-3 wks 1 st -line DST 1-3 wks MDR-TB diagnosis after 3 to 5 weeks Microscopy 24 hrs LPA 24 hrs MDR-TB diagnosis after 1 to 2 days Microscopy 24 hrs Xpert 2 hrs MDR-TB diagnosis after 1 day

13 Proportion Method Agar plate is inoculated with either clinical specimen (direct) or suspension of M. tuberculosis (indirect) Anti-TB drugs added to the media as stock solutions (INH, RIF, OFL, KAN) Isolate is resistant if > 1% of the number of colonies on the control agar grow on a given drug agar plate Poor reproducibility with ethambutol and streptomycin 30/90 = 33% resistant 23/90 = 24% resistant Drug-Resistant Tuberculosis. A Survival Guide for Clinicians

14 Mutations Associated with Drug Resistance Anti-TB drug Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin Flouroquinolones Ethionamide Cycloserine PAS Gene mutation katg, inha, ahpc, KasA rpob pnca embb rpsl, rrs gyra, gyrb inha, etaa/etha alra, Ddl unknown

15 Gene Xpert Sputum Specimen (1-2) Xpert MTB/RIF Sensitivity in AFB sm +: 98% Sensitivity in AFB sm : 72% Specificity: 99.2% Culture/DST Boehme CC, et al. NEJM 2010;363:1005

16 Sensitivity and Specificity of Genotype MTBDR Assays Source: Hain Lifescience Subgroup Pooled Sensitivity Rifampin Pooled Specificity Pooled Sensitivity Isoniazid Pooled Specificity All studies MTBDRPlus Clinical specimens Ling DI, Zwerling AA, Pai M. Eur Respir J 2008;32:1165

17 Laboratory Diagnosis of TB with Xpert MTB/RIF TB suspect Xpert MTB/RIF Sensitivity AFB + 98% AFB - 72% Specificity 99% TB +, RIF + TB +, RIF - TB -, RIF - Hain Sensitivity RIF 98% INH 85% Culture DST Culture DST Culture DST

18 Designing a Treatment Regimen General Principles Regimens should be based on: the history of drugs taken by the patient drugs and regimens used in the country and the prevalence of resistance When possible, once daily dosing is recommended however Ethionamide/Prothionamide, PAS and Cycloserine are often split dosed Drug dosages should be determined by body weight WHO. Guidelines for the programmatic management of drug-resistant TB, 2008

19 Designing a Treatment Regimen General Principles Treatment of adverse drug effects should be immediate and adequate Each dose should be given by DOT and preferably by a health care worker DST, when available and from a reliable laboratory, should be used to guide therapy (INH, Rifampin, injectables, fluoroquinolone) WHO. Guidelines for the programmatic management of drug-resistant TB, 2008

20 Antituberculosis Drugs Group 1 Isoniazid Ethambutol Rifampin/Rifabutin Pyrazinamide Group 2 Group 3 Group 4 Group 5 Streptomycin Kanamycin Amikacin Capreomycin Viomycin Levofloxacin Moxifloxacin Ofloxacin Ethionamide Protionamide Cycloserine Terizidone P-aminosalicylic acid Clofazimine Imipenem Thioacetazone Amoxacillin/Clavulanate Macrolides Linezolid High-dose INH

21 Building a Treatment Regimen Step 1 Group 1 Ethambutol Pyrazinamide 4 likely effective drugs plus PZA Step 2 Group 2 Streptomycin Kanamycin Amikacin Capreomycin Step 3 Group 3 Levofloxacin Ofloxacin Moxifloxacin Step 4 Group 4 Ethionamide Protionamide Cycloserine Terizidone P-aminosalicylic acid Step 5 Group 5 Clofazimine Imipemen Amoxacillin/Clavulanate Macrolides Linezolid Thioacetzone High-dose INH

22 2011 Updated PMDT Guidelines The Guidelines were based on the results of a meta-analysis that included 32 studies and >9000 patients (XDR-TB patients were excluded) For each recommendation, the strength of the recommendation and quality of the evidence were provided

23 Designing a Treatment Regimen Composition of the Regimen Recommendations Four second-line drugs likely to be effective (including a parenteral agent) as well as PZA, should be used in the intensive phase (conditional recommendation/very low quality of evidence) Regimens should include at least PZA, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide) and either cycloserine or PAS, if cycloserine cannot be used (conditional recommendation/very low quality of evidence) WHO 2011 Update

24 Duration of Therapy

25 Duration of Therapy Recommended in 2011 Update Recommendations: An intensive phase of at least 8 months duration is recommended (conditional recommendation, very low quality of evidence) A total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (conditional recommendation, very low quality of evidence) WHO 2011 Update

26 Case A 66 year old man presents with chronic cough and weight loss He has been on and off antituberculosis therapy for the past 10 years Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin and kanamycin He has diabetes mellitus but no other co-morbidities AFB smear is positive, culture is growing M. tuberculosis and DST demonstrates in vitro resistance to INH, rifampin, and kanamycin and susceptible to ofloxacin

27 Building a Treatment Regimen Step 1 Group 1 Ethambutol Pyrazinamide 4 likely effective drugs plus PZA Step 2 Group 2 Streptomycin Kanamycin Amikacin Capreomycin Step 3 Group 3 Levofloxacin Ofloxacin Moxifloxacin Step 4 Group 4 Ethionamide Protionamide Cycloserine Terizidone P-aminosalicylic acid Step 5 Group 5 Clofazimine Imipemen Amoxacillin/Clavulanate Macrolides Linezolid Thioacetzone High-dose INH

28 Odds Ratios of Treatment Success by Duration of Intensive Phase and Total Treatment WHO 2011 Update

29 Treatment Outcomes of MDR-TB: 2 Systematic Reviews and Meta-analyses Orenstein et al, Lancet Infect Dis studies Pooled treatment success of 62% (individualized 64% vs standardized 54%, p = NS) Treatment outcomes were better when: Duration of treatment was at least 18 months Patients received DOT Johnston et al PLoS ONE studies Pooled treatment success of 62% Treatment outcomes were better when: surgical resection no previous treatment fluoroquinolone use

30 Weighted Proportion of Favorable Outcomes in XDR-TB Studies (N=13) Later generation FQN used in: at least 50% of patients 59% less than 50% of patients 31% P = % Jacobson KR et al. Clin Infect Dis 2010;51:5-14

31 History of Thoracic Surgery in TB Hippocrates is credited with performing the first drainage of a tuberculous empyema

32 Plombage and Thoracoplasty Oleothorax Lucite balls Thoracoplasty Sputum negative in 30-60% Closure of cavity in 80%; mortality 10%

33 Surgical Resection Indications: Persistently positive smear or sputum culture for AFB despite aggressive chemotherapy High risk for failure/relapse based on drug resistance profile and extent of disease Complications of TB including, empyema, bronchopleural fistula, hemoptysis Contraindications Pulmonary hypertension Predicted inadequate post-operative pulmonary reserves Other severe morbidities

34 Effect of Surgery in 8 Cohort Studies in Patients with MDR/XDR-TB Reference Country Years N Surgery n (%) Rx success Effect of Surgical Resection- MV Odds (CI) Jeon S. Korea (9) 18% 0.18 ( )* Kwon S. Korea (23) 66% ( ) Keshavjee Russia (9) 66% NS Kim S. Korea (4) 45% 3.87 ( ) Kim S. Korea (30) 63% NS Torun Turkey (26) 77% 1.5 ( ) Leimane Latvia (9) 66% NS Chan USA (63) 75% 4.23 ( ) *predictor of unfavorable outcome Kemplar RR, et al. Lancet Infect Dis 2012;12;

35 18 Retrospective Case Series of Surgery for MDR-XDR-TB 964 patients (895 MDR, 69 XDR-TB) > 95% treatment failure or high likelihood of failure/ relapse At least 2 months of culture negativity required in all but one study ( mos) Pre-operative culture status ranged: % (median 53%) Outcomes Range (median) Postoperative culture conversion % (92.5%) Perioperative morbidity 0-39% (23%) Perioperative mortality 0-5 (1.3%) Kemplar RR, et al. Lancet Infect Dis 2012;12;

36 Common Drug Side Effects Side Effects Drug G.I. effects Ethionamide PAS Quinolones Clofazimine Aminoglycosides Rifabutin Headache Quinolones INH Cycloserine Ethambutol Ethionamide Skin problems Clofazimine Cycloserine INH Rifabutin PAS Ethionamide Ethambutol Photosensitivity Clofazimine Quinolones Hepatotoxicity INH Pyrazinamide Rifabutin Behavioral changes Ethionamide PAS Quinolones Cycloserine INH Quinolones Ethionamide

37 Common Drug Side Effects Side Effects Drug Musculoskeletal/joint Pyrazinamide Quinolones Rifabutin Visual changes, eye pain Hearing loss, tinnitus, loss of balance Rifampin INH Ethambutol Rifabutin Clofazimine INH (high-dose) Linezolid Aminoglycosides Capreomycin Dizziness Aminoglycosides/capreomycin Cycloserine Quinolones Peripheral neuropathy INH Ethionamide Cycloserine Ethambutol Hypothyroidism Ethionamide PAS Hypokalemia/hypomag Aminoglycoside/capreomycin

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39 Bedaquiline (TMC207) for MDR-TB Phase 2, randomized, controlled trial 47 patients with MDR-TB randomized to TMC207 or placebo plus standard fivedrug regimen Results Reduced time to conversion Increased proportion that converted (48% vs 9%) Mild to moderate AEs with nausea more common with TMC207 (26% vs4%) Diacon AH, et al. NEJM 2009;360:2397

40 Delamanid for MDR-TB Phase 2 randomized, placebo-controlled trial 481 MDR-TB patients were randomized to delamanid or placebo plus WHO regimen Results Increased proportion that converted by 2 months 100 mg 45.4% 200 mg 41.9% Placebo 29.6% AEs evenly distributed QT prolongation more common with delamanid Gler MT, et al. NEJM 2012;366:2151

41 Summary MDR-TB should be treated with at least 4 drugs likely to be effective plus PZA The regimen should include an injectable agent, late-generation fluoroquinolone, ethionamide, PZA plus cycloserine (or PAS) The intensive phase should last at least 8 months and the continuation phase at least 20 months Treatment outcomes remain suboptimal

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