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Treatment of MDRTB Management of Drug-resistant TB author ESCMID Courseby 27.9.19 Dr CynthiaeLibrary Chee TB Control Unit, Tan Tock Seng Hospital ESCMID © Since effective (“short-course”) chemotherapy became available in the 1970s • 1985 – 1992: Global emergence of Multidrug-resistant TB (MDR-TB) defined as TB resistant to at least Rifampicin andauthor Isoniazid by • 1993: WHO DECLARED TB “A GLOBAL EMERGENCY” • 2006 : Global emergence of Extensively drug-resistant TB (XDR-TB) defined as MDR-TB plus resistance to any fluoroquinolone and second-line injectable agent eLibrary • “Totally drug resistant TB” : resistance to all tested drugs beyond XDR- TB (yet to be defined) • 2017 : “ProgrammaticallyESCMID incurable TB” © WHO Global Tuberculosis Report 2018 author In 2017 MDR-TB / RRby-TB XDR-TB 3.5% of new cases 8.5% of MDRTB 18% of previously treated cases cases Estimated number of new cases 558,000 eLibrary(82% MDR) Number notified 160,684 8,014 Number enrolled for treatmentESCMID 139,114 8,511 * In May 2016, WHO© issued guidance that people with TB resistant to Rif, with or without resistance to other drugs, should be treated with an MDR-TB treatment regimen WHO Global Report 2018 Treatment Outcome (2015 cohort) MDR-TBauthorXDR-TB N=99,165 N=6,904 by Treatment success rate 55%* 34%* Died 15% 26% Treatment failure eLibrary8% 19% Lost to follow-up 14% 21% No outcome information 7% ESCMID • Global treatment success© rate for cases started on first-line treatment regimen in 2016 was 82% WHO MDR treatment guidelines Conventional 20-month authorKey changes to regimen based longer regimen on IPD MA of based on IPD MA 9,153 patients. by of 12,030 patients. Ahuja et al. Ahmad et al. PLOS 2012 Lancet 2018 2011 2016 2019 eLibrary MDR-TB treatment recommended for RR-TB regardless of confirmation of INH resistance Shorter 9-11 month regimen for eligible patients based on 5 observational studies [1,205 patients, success rate of ESCMIDpooled studies =84%] Medicines in longer regimen re- © grouped WHO 2011 conventional 20-month MDR-TB regimen (updated 2016) A. Fluoroquinolones Levofloxacin, Moxifloxacin, Gatifloxacin B. Second-line injectable Amikacin, Capreomycinauthor, Kanamycin agents (Streptomycin) by C. Other core second-line Ethionamide / Prothionamide agents Cycloserine / Terizidone Linezolid Clofazimine eLibrary D. Add-on agents D1 : Pyrazinamide, Ethambutol, High-dose (not part of the core MDR-TB Isoniazid regimen) D2 : Bedaquiline, Delamanid ESCMID D3 : PAS, Imipenam-cilastin, Meropenam, © Amoxycillin-clavulanate, (Thioacetazone) Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis Ahmad N et al. Lancet 2018:392:821-34 author • 12,030 patients, 25 countries, 50 studiesby • Treatment success associated with use of linezolid, levofloxacin, carbepenams, moxifloxacin, bedaquiline, clofazimine • Use of linezolid, levofloxacin,eLibrary moxifloxacin or bedaquiline associated with reduced mortality • Kanamycin and capreomycin associated with worse outcomes • Optimal numberESCMID of drugs : 5 in initial phase, 4 in continuation phase © WHO 2011 20-month regimen WHO 2019 long regimen (updated 2016) (Rapid communication Aug 2018) Group A Levofloxacin, Moxifloxacin, Levofloxacin / Moxifloxacin Gatifloxacin Bedaquiline Linezolidauthor Group B Amikacin, Capreomycin, Kanamycin, Clofazimine (Streptomycin) Cycloserineby / teridozine Group C Ethionamide / Prothionamide Ethambutol Cycloserine / Terizidone Delamanid Linezolid Pyrazinamide Clofazimine Imipenam-cilastin; meropenam Amikacin (streptomycin) eLibraryEthionamide / Prothionamide PAS Group D D1 : Pyrazinamide, Ethambutol, High-dose Isoniazid Kanamycin and capreomycin no D2 : Bedaquiline, Delamanid longer recommended D3 : PAS, Imipenam-cilastin, Meropenam,ESCMID Amoxycillin -clavulanate, (Thioacetazone)© WHO 2019 Guidelines Major Implications • Affordability of bedaquiline, linezolid to TBauthor programmes – In Singapore bedaquiline costs US$162 per tablet; linezolid costs US$36 per 600 mg tablet by • XDR- TB definition no longer relevant eLibrary • Urgent need to develop and standardise DST methods for bedaquiline, linezolid, cycloserine, clofazimine ESCMID © Bedaquiline (Sirturo) Janssen / Johnson & Johnson • Di -aryl quinoline, ATPase inhibitor; bacteriocidal andauthor sterilizing properties • Dec 2012: first new TB drug from a new drug class to receive FDA approval in 40 years by • Tiered pricing structure : US $900, $3,000 and $30,000 for low, medium and high income countries respectively • Donation programme by JansseneLibrary and USAID from 2014-2019 • Post-donation programme: US $400 per course for South Africa and through Global Drug Facility • Singapore : used in 5 patients (1 XDR-TB, 3 pre-XDRTB, and one with drug hypersensitivity reactionESCMID to second -line drugs) © WHO 2019 Updated Guidelines (Rapid Communication Aug 2018) Group A Regimen to comprise all Gp A Medicines to be Levofloxacin / Moxifloxacin and at least one Gp B agent prioritized Bedaquiline (at leastauthor 4 drugs) Linezolid Must include at least 3 drugs byfor rest of regimen after Bdq Group B is stopped after 6 months Medicines to be Clofazimine added next Cycloserine / teridozine If one or two drugs in Gp A used, both Gp B drugs must Group C eLibrary be included Medicines to be Ethambutol Delamanid included to Gp C drugs to be used when complete the Pyrazinamide regimens when Imipenam-cilastin; meropenam an effective regimen cannot agents from Gps Amikacin (streptomycin) be constituted using Gp A and A and B cannot EthionamideESCMID/ Prothionamide Gp B drugs be used PAS © Duration: 18-20 months WHO shorter standardized MDR treatment regimen 2016 update for pulmonary TB, regardless of age or HIV status Intensive phase author 4 – 6 months Gatifloxacin (or Moxifloxacin) Clofazimine by Extended to up to 6 months in Pyrazinamide cases of lack of sputum smear Ethambutol conversion at 4 months Kanamycin Prothionamide HigheLibrary-dose isoniazid Continuation phase Gatifloxacin (or moxifloxacin) 5 months Clofazimine ESCMID Pyrazinamide © Ethambutol WHO 9-11 month MDR-TB Regimen Exclusion criteria • Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid) author • Exposure to ≥1 second-line medicines in theby shorter MDR-TB regimen • Intolerance to ≥1 medicines in the shorter MDR-TB regimen or risk of toxicity (eg. drug-drug interaction) • Pregnancy • Extrapulmonary TB (2019 - DisseminatedeLibrary or CNS TB; all PLHIV with extrapulmonary disease) • At least one medicine in the shorter MDR-TB regimen not available in the programme ESCMID © WHO 9-11 month MDR-TB regimen Drug dosages Drug < 30 kg 30-50 kg author> 50 kg by Gatifloxacin 400 mg 600 mg 800 mg Moxifloxacin 400 mg 600 mg 800 mg Clofazimine 50 mg 100 mg 100 mg Ethambutol 800 mg 800 mg 1200 mg Pyrazinamide 1000 mg eLibrary1500 mg 2000 mg Isoniazid 300 mg 400 mg 600 mg Prothionamide 250 mg 500 mg 750 mg Kanamycin + 15 mg / kg body weight (max 1 kg) ESCMID + : for adults ©> 59 years of age, dose reduced to 10 mg/kg (max 750 mg) A Trial of a Shorter Regimen for Rifampicin-Resistant Tuberculosis (STREAM study) Nunn AJ et al. N Engl J Med March 28 2019 • 424 participants with Rif Resistant TB (5.8% INH-susceptible) without resistance to FQ and SLI randomized in 2:1 ratio to short regimen (9-11 month)author or long WHO 2011 (20- month) regimen by • Primary efficacy outcome was favourable status at 132 weeks: – Cultures that were negative at 132 weeks after randomization and at one previous occasion during the trial period, with no intervening positive culture or unfavourable outcome • Non inferiority of short regimen demonstrated – Favourable status at 132 weeks : 78.8% in short regimen group vs 79.8% in long regimen group – Death : 8.5% vs 6.4% eLibrary – Acquired resistance to FQ or SLI : 3.3% vs 2.3% – Unfavourable bacteriologic outcomes : 10.6% vs 5.6% • Safety – AE of grade 3 or higher in 48.2% vs 45.4% – QT prolongation to 500 msec 11% vs 6.4% – Hepatobiliary disordersESCMID 8.9% vs 5.7% © WHO 2019 Guidelines Shorter MDR-TB regimen • Based on STREAM study and IPD MA: author – Higher risk of treatment failure and relapse in patients with baseline resistance to PZA and ethionamide by • Recommendations: – Emphasis on DST for FQ and SLI, as well as other drugs in regimen (eg PZA, mutations associated with INH and ethionamide resistance) before start of RxeLibrary – Contraindicated if resistant mutations to FQs or SLI on MTBDRsl, presence of both inhA and katG mutations on MTBDRplus; resistance to PZA – KanamycinESCMID should be replaced by amikacin © Eligibility for WHO shorter regimen Patients from SE Asia – Singapore sample, 2002-2016 Country of birth No of cases Resistance to at least one of the 6 drugs in WHO regimen excludingauthor INH Bangladesh 4 3by (75%) China 37 23 (62.2%) India 7 6 (87.5%) Indonesia 76 57 (75%) Myanmar eLibrary56 40 (71.4%) Philippines 18 10 (55.6%) Vietnam 15 12 (80%) Singapore/Malaysia 54 39 (72.2%) ESCMID Overall © 267 190 (71.2%) Eur Resp J 2017 Singapore experience WHO Shorter 9-11 month regimen author • 8 patients commenced by – All had GI symptoms; hypokalemia – 3 had Hepatotoxicity – 3 had prolonged QTc – 2 had rash eLibrary • Poorly tolerated • 3 patients completed Rx, 3 left country, 2 had to convert to long regimen (renal impairment, hepatoxicity) ESCMID © MDRTB Treatment Outcome Singapore citizens/PRs 2007-2017 author 14 Treatmentby N=63 12 Outcome 10 Success 56 (89%) 8 Died 5 (8%) 6 eLibraryLost to follow- 2 (3%)
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