Short Course Treatment for MDR TB

Transcription

1 Objectives Short Course Treatment for MDR TB Barbara J Seaworth M.D. Medical Director Heartland National TB Center Professor of Medicine, University of Texas Health Northeast Participants will utilize newer regimens and medications which could shorten treatment for MDR TB when appropriate Recognize concerns relating to relapse with shorter regimens Identify patients likely to benefit from these shorter regimen Duration of Treatment by Drug Susceptibility, USA WHO Guidelines In MDR TB, the intensive phase should last at least 8 months In MDR TB, the total treatment duration should be at least 20 months in those with no prior MDR TB treatment Peak in cure was later for those with prior therapy months Guided by a meta-analysis from 32 studies with > 9000 treatment episodes using pooled individual patient data Ahuja et al; Plos Medicine 2012 Winston & Mitruka; EID July 2012 Treatment Outcomes Among Patients with MDR TB: Systematic Review and Meta-analysis Bayesian random-effects meta-analysis Successful treatment outcome was defined as cure or treatment completion. 34 clinical reports with a mean of 250 patients per report met the inclusion criteria. Our analysis shows that the proportion of patients treated successfully improved when treatment duration was at least 18 months, and if patients received directly observed therapy throughout treatment. Pooled success 69% if 18 months of treatment with DOT throughout Orenstein et al; Lancet Infect Dis 2009; 9: Aggressive Regimen is Associated with Improved Outcomes Individualized based on 1 st /2 nd line susceptibility test results Use of drugs with proven or likely susceptibility, including 5 drugs including an injectable for 6 months after culture conversion 4 oral drugs including a FQN which should be given for months after culture conversion Cure or completion in 66.1% of 669 patients Patients resistant to average of 5.4 drugs Only two had no prior therapy Mitnick Plos One March

2 Outcomes of MDR-TB treatment MDR-TB cohorts , global* Treatment Outcomes TB Global Report 2012 The Global TB Plan s target for 2015 of achieving at least 75% treatment success in MDR-TB patients was only reached by 30 out of a 107 countries Among a subset of 200 XDR-TB patients in 14 countries, treatment success was 33% overall and 26% died. *number of cases observed shown on the right WHO MDR Update 10/2013 Global TB report % 18% MDR treated in CDC March 2014 We Need a Cheaper and Better Treatment With less cost and resources required per treatment course more persons can be enrolled Stop transmission Decrease negative impact on patient Short, Highly Effective and Inexpensive Standardized Treatment of MDR TB Prospective cohorts treated in Bangladesh for minimum 9 months Relapse free cure 87.9% Intensive phase 4 (+) months High dose gatifloxacin (800 mg if 50 kg) Kanamycin 4 months or until sputum conversion (17% extended) Prothionamide, PZA, high dose INH (600mg), ethambutol, clofazamine INH, ethambutol, PZA given to avoid giving an expensive 2 nd line drug to complete regimen such as PAS or cycloserine Continuation phase 5 months Gatifloxacin, PZA, ethambutol, clofazamine ( mg) Van Deun, Int J Resp Crit Care Med,

3 Proportion with Successful Outcomes Short, Highly Effective, and Inexpensive Standardized Treatment of MDR TB Armand Van Deun; Am J Respir Crit Care Med Vol 182., 2010 Gatifloxacin Clofazamine throughout No INH Van Deun, Int J Resp Crit Care Med, 2010 Figure 3. Kaplan-Meier survival plot of time to adverse outcome. Adverse outcomes were failure (including one clinical failure), death, and default during treatment and relapse after treatment cessation. Outcomes of the Gatifloxacin Cohort 87.9% had successful outcome (cure and completion); 90% had at least one year of follow up 80% completed treatment within 10 months 95% completed within 12 months Results were unprecedented; regimens were not consistent with WHO guidelines Only one patient failed; isolate was susceptible to all second-line drugs and ethambutol Not able to do repeat susceptibility test or genotype due to failure of isolate to grow. QUESTIONS ABOUT THE OUTCOMES Single relapse was resistant to all four first line drugs plus ofloxacin before and after treatment Cost of the regimen was 225 Euros Bangladesh Study Observational, in hospital during intensive phase (duration of injectable), DOT throughout, meals and transportation provided. Size of cohort not defined. Standard of living increased over 12 years of various sequential cohorts INH (higher dose) and ethambutol given despite high rate of resistance Only 206 of original 1184 eligible cases given 9 month regimen Reasons for not participating unknown for most PZA not routinely tested but another study tested isolates from same area and found 50% resistant Patients had not had prior MDR treatment 3

4 Predictors of Poor Outcome for MDR Patients Bangladesh Independent predictors of death and failure: Rare HIV positive Mean BMI 16.8 WHO DOTS Plus Projects Independent predictors of death and failure: HIV positive Low BMI Short Course MDR TB Treatment Outcomes in Other Countries Cameroon, Benin, Niger and others not as part of study report: 83.8% good outcomes (cure or treatment completion) Only 1 st line treatment, little 2 nd line resistance 10% ofloxacin resistant, no XDR 85% bilateral disease on CXR 17 % Positive smear at 4 months culture results not reported Prior treatment, more resistance Extensive disease, positive smear Positive culture after 3 months of treatment Kurbatova et al. Tuberculosis, % failure 0.6% relapse The Union to Test MDR TB Regimen that Shortens Treatment by Half A clinical trial testing a new MDR-TB regimen that shortens the treatment time by more than half will begin enrolling patients in four countries in early Sponsored by the International Union Against Tuberculosis and Lung Disease (The Union), the trial will compare the 9-month regimen with existing standardized treatment in four countries that will be selected later this year. The shorter regimen demonstrated cure rates exceeding 80% in a pilot program. STREAM Randomized to Study Regimen versus WHO Standard Study regimen: 9 months supplemented by kanamycin, INH, and prothionamide in the 4 month intensive phase. All daily (7 days/week) except for kanamycin given 3 x/ week after 12 weeks. Kanamycin: 15 mg/kg body weight (maximum 1 g) Isoniazid: 300 mg (< 33 kg), 400 mg (33-50 kg) or 600 mg (> 50 kg) Prothionamide: 250 mg (< 33 kg), 500 mg (33-50 kg) or 750 mg (> 50 kg) Clofazimine: 50 mg (< 33 kg), 100 mg (33-50 kg) or 100 mg (> 50 kg) Moxifloxacin: 400 mg (< 33 kg), 600 mg (33-50 kg) or 800 mg (> 50 kg) Ethambutol: 800 mg (< 33 kg), 800 mg (33-50 kg) or 1200 mg > 50kg) PZA: 1000 mg (< 33 kg), 1500 mg (33-50 kg) or 2000 mg (> 50 kg) STREAM to be Modified to Include 2 Bedaquiline Arms Original Union study was to evaluate the short course Bangladesh regimen for MDR TB; to determine non inferiority Arm A : Standard of care WHO regimen. Arm B: Modified Bangladesh with high dose moxifloxacin instead of gatifloxacin New partnership of UNION, MRC and Janssen adds two new arms as part of Stage 2 Arm C* will compare BDQ as part of an all oral 9 month regimen to Modified Bangladesh Arm D* 6 month BDQ containing kanamycin 2 months to modified Bangladesh *No longer comparing to WHO Standard of Care regimen 4

5 4/25/14 MARVEL ATCG A5913 Fool s Errand: The Sloppy Science of the MDR-TB STREAM Trial Confirming the efficacy and safety of bedaquilineinclusive regimens is a priority. Comparing them to unvalidated MDR-TB drug combinations in the planned STREAM study is not the way to go about it Phase 2 in development for MDR TB 6 month regimen Bedaquiline PA 824 PZA Levofloxacin or Linezolid tagline Vol. 21, No. 1, April 2014; Mike Frick The medicine and syringes to treat one MDRTB patient for one year. Patients need to undergo treatment from 1824 months Staggering Medication Burden New Drugs New Shorter Regimens How Can We Best Get There? IDSA fact sheet Sustainable TB Drug Development Wallis CID, January 2013 Wallis CID, January 2013 Relationship between required duration of treatment and relapse rate is based on 2 month sputum culture status: Based on: Analysis of 5561 patients in 4 global regimens showed highly significant relationship between 2 month culture status and relapse rate A new regimen with a conversion rate of 95% (2 months) is predicted to result in a 5% relapse rate 5

6 Short Course Treatment for MDR TB Moving in the right direction but there are still as many questions as answers What about populations with 2 nd line drug exposure? What about special populations? Children, HIV? What about XDR TB? What about new drug combinations? Conclusions Robust research is needed to identify better ways to care for patients with MDR-TB Safety of new drugs must be established New drugs must be affordable New drugs must be available to populations that bore the risk of treatment trials New regimens should be studied based on the standard of care WHO Regimen -New drugs should be tested against an aggressive regimen to best identify efficacy Only ~15 % of MDR is diagnosed with DST Only ~ 18 % MDR treated according to WHO standards 2011 (~25% in 2013) 6