Elizabeth A. Talbot MD Assoc Professor, ID and Int l Health Deputy State Epidemiologist, NH GEISELMED.DARTMOUTH.EDU GEISELMED.DARTMOUTH.

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1 The image part with relationship ID rid2 was not found in the file. MDR TB Management Review of the Evolution (or Revolution?) Elizabeth A. Talbot MD Assoc Professor, ID and Int l Health Deputy State Epidemiologist, NH Good News Toward Ending TB Global MDR TB 9.6M new cases (133/100k) Incidence decreasing 1.5% each year since 2000 First case increase since % increase from India Doubled in Indonesia! 1.5M deaths (4,400/day) 47% decrease since 1990 Stable MDR with increasing proportion on treatment MDR or RR TB Only 8.5% of new TB cases and 17% of confirmed retreatment cases received drug sensitivity testing (DST) Culture, Xpert, Line Probe Assay (LPA) Estimated 480,000 developed MDR Only 136,000 were detected WHO/HTM/TB/ ; Image reproduced with permission. *MDR=resistance to >H+R. % of New Cases with MDR-TB % of Previously Treated with MDR-TB 1

2 92 Countries Reported >1 XDR-TB MDR TB plus resistance to any fluoroquinolone and >1 of the 3 injectable 2 nd -line drugs, capreomycin, kanamycin or amikacin 2012: TDR-TB in India WHO Treatment Recommendations Direct costs, mostly covered by the public sector $134,000 per MDR TB patient (average) $430,000 per XDR TB patient (average) $17,000 per non-mdr TB patient Marks SM, et al. EID 2014;20(5): World Health Organization, Dr. Richard Menzies of Montreal Chest Institute Guidelines for the programmatic management of drug-resistant TB,

3 The image part with relationship ID rid2 was not found in the file. The image part with relationship ID rid2 was not found in the file. The image part with relationship ID rid2 was not found in the file. Basis for Guideline Development Main Changes in 2016 Recommendations Expert meeting Nov 2015 Data review Meta-analysis that included data on 9,153 patients through 2011 who were nearly all adults Additional evidence published until Aug 2015 Data on 974 children in cohorts and studies published up until September 2014 Approached high priority questions MDR-TB treatment recommended for all patients with rifampicin-resistant tuberculosis, regardless if isoniazid resistance is confirmed or not Evidence-informed recommendations on role of surgery included Medicines used in design of individualized MDR-TB treatment regimens are regrouped differently based on current evidence on effectiveness and safety The Bangladesh Regimen Big Change SHORTER STANDARDIZED TREATMENT FOR MDR TB Results of 9-m Regimen in Bangladesh Francophone Africa Cohort Published cohort (206 pts) Cure 82.5% Completion 5.3% Default 5.8% Death 5.3% Failure 0.5% Relapse 0.5% Overall success rate: 87.9% (95% CI 82.7, 92.6) Cohort update (515 pts) 81.2% 3.3% 7.8% 5.6% 1.4% 0.8% Overall success rate: 84.5% (95% CI 0.81, 0.88) Am J Respir Crit Care Med Vol , 2010 Aung et all, IJTLD 18(10): , 2014 Introdion Objectif Méthodes Conclusion Benin, Burkina-Faso, Burundi, Cameroon, Côte d Ivoire, CAR, Niger, DRC and Rwanda Similarly high success rates 82.1% Preliminary data, to be completed end 2016 >20 country programs using regimen in operational research 3

4 The image part with relationship ID rid2 was not found in the file. The image part with relationship ID rid2 was not found in the file. Data Summary 7-drug standardized regimen showed efficacy similar to outcomes reported for drug sensitive TB Hopes for Shorter Standard Regimen Programmatic use is feasible in most settings worldwide Complete in 9-12 months Compares with ~24 m <US$ 1000 drug cost per patient Compares with 3k Expected to improve outcomes and potentially decrease deaths due to better adherence and reduced loss to follow-up Short Course Recommendation Short course indicated conditionally* Rifampin resistant and MDR pulmonary Not previously treated with second line drugs Resistance to FQs and second line injectables excluded or very unlikely All ages Nonpregnant +/- HIV Must monitor for effectiveness, harms and relapse, with patient-centered care and social support to enable adherence *Conditional recommendation, very low certainty in the evidence STREAM One to watch STREAM TO PROVIDE MORE EVIDENCE On-going STREAM trial (Standardised Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB) Multi-center randomized control trial To eliminate risk that patient selection biased results obtained from cohort studies To assess 9-month regimen in variety of settings including high levels of HIV-coinfection 4

5 The image part with relationship ID rid2 was not found in the file. The image part with relationship ID rid4 was not found in the file. The image part with relationship ID rid6 was not found in the file. The image part with relationship ID rid5 was not found in the file. STREAM Stage 1 Design STREAM 9-month Regimen (B) Non-inferiority design Control regimen (A) is locally used WHO recommended regimen Study regimen (B) similar to Bangladesh regimen with exception that high dose moxifloxacin replaces high dose gatifloxacin >18 years old, smear-pos pulmonary tuberculosis If HIV positive may be smear negative Initial resistance to rifampin on LPA, Xpert or other DST No evidence of initial resistance to fluoroquinolone or 2 nd -line injectables on LPA Weeks Drug doses by weight group Drug < 33 kg kg > 50 kg Kanamycin* mg/kg body weight Isoniazid (H) mg 400 mg 600 mg Prothionamide mg 500 mg 750 mg Clofazimine mg 100 mg 100 mg Moxifloxacin mg 600 mg 800 mg Ethambutol mg 800 mg 1200 mg Pyrazinamide mg 1500 mg 2000 mg Kanamycin 3 times/week after week 12 The intensive phase may be extended by 4 or 8 weeks if smear conversion has not occurred by 16 or 20 weeks 25 STREAM Stage 1 Status Enrolment commenced July 2012 Sites: Ethiopia (2), South Africa (3), Vietnam and Mongolia 424 of initial target of 400 patients enrolled Intake closed June 30th 2015 Primary endpoint at 30 months Last patient visit: Q Results from Stage 1 expected: Q1/ STREAM Stage 2 Adding an all oral and a 6 month regimen Primary objectives: To assess whether the proportion of patients with favorable efficacy outcome on Regimen C, the fully oral regimen, is as effective as Regimen B at 76 weeks (18 months) To assess whether proportion of patients with favorable efficacy outcome on Regimen D, the 6-month regimen, is as effective as Regimen B at 76 weeks (18 months) Regimens for STREAM Stage 2 Also a big change APPROACH TO INDIVIDUALIZED REGIMEN 5

6 The image part with relationship ID rid2 was not found in the file. New Drug Groupings Composing Individualized Regimen Clofazimine and linezolid are core second-line medicines p-aminosalicylic acid is an Add-on agent Macrolides no longer included No change in role of bedaquiline and delamanid Assigned to specific subgroup of Add-on agents; no pediatric recommendation Create regimen with >5 effective drugs during intensive phase Include PZA and 4 core second-line TB medicines 1 from group A, 1 from group B, and >2 from group C If minimum cannot be composed as above, an agent from group D2 and other agents from D3 may be added to bring total to 5 Further strengthen regimen with high-dose isoniazid and/or ethambutol Group A=Levofloxacin; Moxifloxacin; Gatifloxacin; Group B=Amikacin, Capreomycin, Kanamycin, (Streptomycin); Group C= Ethionamide (or Prothionamide), Cycloserine (or Terizidone), Linezolid, Clofazimine; Group D2=Bedaquiline, Delamanid; Group D3=p-aminosalicylic acid, Imipenem-cilastatin, Meropenem, Amoxicillin-clavulanate, Thioacetazone *Conditional recommendation, very low certainty in the evidence Pediatric Regimen Mostly identical to those of adults If mild disease, harms associated with group B meds (second-line injectable agents) outweigh benefits and therefore group B medications may be excluded Treatment success in children with clinically-diagnosed disease was high and not significantly different in patients treated with and without group B medication (93.5% vs. 98.1% respectively; n=219) No new data for bedaquiline and delamanid so no recommendation for use of D2 agents in children Indications for Surgery Per WHO: In patients with rifampicin-resistant or multidrug-resistant TB, elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen (conditional recommendation, very low certainty in the evidence) Typical recommendations: Adequate 1 st and 2 nd -line regimens of anti-tb medications have failed to cure or cause M. tb cultures to convert to negative within 4 to 6 months Sufficient medications available to treat postoperatively Disease is sufficiently localized to allow lobectomy or pneumonectomy Remaining lung tissue is relatively free of disease Other Indications for Surgery Acceptable surgical risk, with sufficient pulmonary reserve to tolerate the resection Additional possible indications for surgery: Major bronchial obstruction Severe hemoptysis Bronchopleural fistula Surgery for MDR TB Patients Even after lung resection, the patient must complete a full course of treatment (i.e., months after culture conversion) with medications to which the M.tb strain is susceptible If patient is culture negative after surgery, then surgery is considered the conversion episode 6

7 The image part with relationship ID rid2 was not found in the file. Patients with MDRTB Need: Thank you! Accurate and prompt diagnosis Notification Appropriate case management Appropriate treatment based on drug susceptibility test results Appropriate infection control measures Treatment of Contacts to Drug Resistant TB Persons exposed to INH-resistant TB: - Rifampin: 4 months adults 6 months children Persons likely infected with MDR TB: months PZA and EMB, or PZA and FQ (i.e., 2 drugs to which organism is susceptible) Limited experience with FQ as single agent Detecting MDR TB Monitoring Serum Drug Levels Method Description Advantages Disadvantages Sens/Spec Time Proportion method MGIT DST MODS GeneXpert MTB/RIF Line Probe Assay (Hain, INNO LiPA) Solid (agar) culture Liquid culture DST Microtiter plate using liquid media Automated modular PCR Molecular probes for detection of DR mutations Conventional Expertise, BSL3, time (Reference) 68d Automated or manual Direct testing, relatively inexpensive Fast, simple, safe, multiple diseases Relatively simple, fast, accurate, cost less than MGIT DST Expertise, BSL3, time, cost, contamination (10%) Complex, biohazard, contamination Cost (16k platform, 10 cartridge), only RIF Expertise, culture isolate or smear positive sputum, lab space, still need culture capacity 100/99 22d 92/96 7d TB: 88/98 RIF: 94/98 RIF 98/99 INH 84/99 90min 6h Serum drug level monitoring should be considered in patients with the following medical conditions: HIV positive/aids Diabetes Malabsorption syndromes Renal failure Failure to improve on treatment/relapse MDR TB 7

8 DOT for MDR TB Essential that MDR TB patients be treated with Directly Observed Therapy (DOT) Improved overall cure rates Reduction in community prevalence of MDR Intermittent regimens should not be used All 2 nd -line agents must be administered daily Twice/day DOT should be used when feasible, and more frequent dosing than twice daily should be avoided All doses must be observed 8