Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013
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Richard E. Chaisson, MD, and Maunauk Shah, MD, PhD, provide an update on epidemiology, diagnosis, and treatment. 2013

Richard E. Chaisson, MD, and Maunauk Shah, MD, PhD, provide an update on epidemiology, diagnosis, and treatment. 2013

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Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013 Presentation Transcript

  • 1. Recent Advances in Multidrug-Resistant TB This program is supported by an educational grant from
  • 2. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
  • 3. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Faculty and Disclosure Information Richard E. Chaisson, MD Professor of Medicine, Epidemiology and International Health Johns Hopkins University Director, Johns Hopkins Center for AIDS Research and Center for Tuberculosis Research Baltimore, Maryland Richard E. Chaisson, MD, has disclosed that his spouse has ownership interest in Merck. Maunank Shah, MD, has no significant financial relationships to disclose. Maunank Shah, MD Assistant Professor Department of Infectious Disease Johns Hopkins University Medical Director Tuberculosis Program Baltimore City Health Department Baltimore, Maryland
  • 4. Epidemiology of MDR-TB
  • 5. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Tuberculosis Drug Resistance: Definitions  Acquired drug resistance – Selection of resistant mutants by inadequate treatment  Primary drug resistance – Disease caused by an organism that was resistant when infection was acquired  Multidrug-resistant TB – Resistance to at least isoniazid and rifampin (and other rifamycins)  Extensively drug–resistant TB – MDR-TB plus resistance to fluoroquinolones and an injectable agent (amikacin, kanamycin, capreomycin)
  • 6. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Drug-Resistant TB: MDR and XDR  Drug-resistant TB first arises from improper treatment – Wrong selection of drugs by doctors or poor adherence to treatment by patients results in selection of naturally occurring mutants with innate resistance  Patients with acquired drug-resistant TB can spread infection to others, causing primary resistance in their contacts  In many countries, transmission of drug-resistant TB is now more common than acquired resistance[1]  The key prevention strategies for drug-resistant TB are: – Avoid creating new cases by treating TB properly and thoroughly – Prevent transmission of infection through early and proper diagnosis and infection control 1. WHO. 2013. Surveillance of drug resistance in tuberculosis.
  • 7. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB MDR-TB: Epidemiology  In 2012, an estimated 450,000 new cases of MDR-TB emerged globally[1]  Among all new cases of TB, 3.6% are estimated to have MDR- TB[1]  An estimated 20% of persons with previously treated TB have MDR-TB[1,2]  More than one half of the new MDR-TB cases occur in China, India, and the Russian Federation[1]  Mortality in MDR-TB patients usually exceeds 10%[3]  In 2012, MDR-TB caused an estimated 170,000 deaths[1] 1. WHO. 2013. Update on MDR-TB. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12. 3. Wells CD. Curr Infect Dis Rep. 2010;12:192-197.
  • 8. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB MDR-TB Among New TB Cases, 1994-2012 WHO. 2013. Surveillance of drug resistance in tuberculosis.
  • 9. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB MDR-TB Among Previously Treated TB Cases, 1994-2013 WHO. 2013. Surveillance of drug resistance in tuberculosis.
  • 10. Diagnosis of MDR-TB
  • 11. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Diagnosis of MDR-TB  Gold-standard test: Culture of patient specimen (sputum) to assess inhibition of M tuberculosis growth in the presence of antibiotics (phenotypic assay)  Solid-media assays: Result may not be available for 3-6 wks  Automated liquid culture systems: Faster and more sensitive than solid-media cultures; results available in 1-2 wks  Rapid molecular tests can identify genotypic resistance in 1-2 days – Xpert TB/RIF identifies M tuberculosis and rifampin resistance using cartridge-based real-time PCR – Line-probe assays (eg, Hain GenoType) identify genotypic resistance to both isoniazid and rifampin 1-2 days 1-2 wks 3-6 wks 4-12 wks Average Turnaround Time for Diagnostic Tests
  • 12. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB WHO Recommendations: Diagnosis of MDR-TB  Xpert MTB/RIF should be used as the initial diagnostic test in individuals suspected of MDR-TB[1]  However, Xpert MTB/RIF does not eliminate need for conventional microscopy, culture, and DST to monitor treatment progress and to detect resistance to drugs other than rifampin[1] 1. WHO. Xpert MTB/RIF system policy statement 2011. 2. Aurum Institute. Managing TB in a new era of diagnostics. 2012. Xpert Result[2] Xpert Positive, Rifampin Susceptible Xpert Positive, Rifampin Resistant Xpert Positive, Rifampin Unsuccessful Xpert Negative Xpert Unsuccessful Interpretation Drug-sensitive TB Presumed MDR-TB Presumed drug-sensitive TB TB unlikely but further investigation necessary No diagnosis Actions Treat for drug- sensitive TB; collect sputum for microscopy and culture with DST Treat with regimen for MDR-TB; collect sputum for TB culture/DST Treat for drug- sensitive TB; collect sputum for microscopy and culture with DST Collect sputum for TB microscopy and culture to exclude TB Collect sputum for TB microscopy and culture to exclude TB
  • 13. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Performance of Xpert MTB/RIF vs Other Diagnostic Modalities Boehme C, et al. Lancet. 2011;377:1495-1505. Proportion of TB Cases and Resistance Results by Each Method in Culture-Positive Patients Liquid culture MTB/RIF test Solid culture Microscopy TBCasesDetected(%) 100 90 80 70 60 50 40 30 20 10 0 1000 20 40 60 80 Days to Detection 100% 90% 89% 67% Line-probe assay MTB/RIF test Phenotypic drug-susceptibility testing 0 20 40 60 80 100 120 140 Days to Detection 100% 94% RIFResistanceDetected(%) 100 90 80 70 60 50 40 30 20 10 0
  • 14. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Time to DST Results Halved With MDR Line Probe Assay in South Africa Time Period Median Time, Days (IQR) P Value Before LPA After LPA 1 Sputum collection to lab receipt of sample 1 (0-1) 0 (0-1) < .001 2 Lab receipt to DST testing 27 (21-34) 19 (12-31) < .001  Smear positive 26 (21-43) 13 (9-16) < .001  Smear negative 29 (22-43) 29 (22-42) .497 3 DST testing 9 (2-14) 0 (0-1) < .001 Total Sputum collection to DST results available 52 (41-77) 26 (11-52) .008 Sputum collection Lab receipt of sputum DST started DST results reported 1 2 3 Hanrahan CF, et al. PLoS One. 2012;7:e49898.
  • 15. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Time to MDR Treatment Before and After Line-Probe Assay in South Africa From initial patient sputum sample to date of appropriate MDR therapy Mos to MDR Treatment 80 2 4 6 1.00 0.75 0.50 0.25 0 CumulativeProportionon MDRTreatment After LPA Before LPA (study data) Before LPA (undetected MDR modeled) Hanrahan CF, et al. PLoS One. 2012;7:e49898.
  • 16. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Resistance at Start of Second-line TB Therapy Drug Resistance, n (%) First-line drugs  Ethambutol 826 (64.6)  Streptomycin 881 (69.0)  4 first-line drugs* 625 (49.0) Second-line drugs  Any second-line drug 559 (43.7)  At least 1 fluoroquinolone 165 (12.9) Second-line Injectable drugs  Kanamycin 237 (18.5)  Amikacin 205 (16.0)  Capreomycin 152 (12.0)  At least 1 255 (20.0)  All 134 (10.5) Other oral second-line drug  Ethionamide 249 (19.5)  Aminosalicylic acid 137 (10.7)  At least 1 346 (27.1) XDR-TB 86 (6.7) PETTS Study: Prevalence of Drug Resistance in 1278 Pts With MDR-TB  1278 pts enrolled in several countries at start of second-line TB treatment, 2005-2008  DST done centrally at CDC  High levels of resistance to second-line drugs detected – 43.7% with resistance to ≥ 1 second-line drug – 20% with resistance to ≥ 1 injectable second-line drug – 12.9% with resistance to ≥ 1 fluoroquinolone – 6.7% with XDR-TB Dalton T, et al. Lancet. 2012;380:1406-1417. *Isoniazid, rifampin, ethambutol, streptomycin.
  • 17. Principles of MDR-TB Treatment
  • 18. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB MDR-TB General Principles  An individualized approach should be undertaken – Guided by drug susceptibility testing when available – Assessment of comorbidities that may affect therapy should be undertaken before therapy  Never add a single drug to a failing regimen  Use at least 3-5 previously unused drugs to which an isolate has in vitro susceptibility  Supervise treatment to ensure adherence  Continue treatment for at least 18-24 mos after culture conversion WHO. Guidelines for programmatic management of drug-resistant TB. 2011. Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.
  • 19. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Drugs for MDR-TB Group 1: First-line oral drugs Ethambutol Pyrazinamide High-dose isoniazid Group 2: Fluoroquinolones Levofloxacin Moxifloxacin Gatifloxacin Ofloxacin Group 3: Injectable drugs Kanamycin Amikacin Capreomycin Streptomycin Group 4: Oral bacteriostatic second-line drugs Ethionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid Group 5: Drugs of unclear efficacy Clofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanate Thioridazine *Other newer drugs Adapted from: Chang KC, et al. Respirology. 2013;18:8-21. *Newer drugs will be discussed later in the educational activity.
  • 20. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Building a Treatment Regimen for MDR-TB Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians. Chang KC, et al. Respirology. 2013;18:8-21. Step 1: Include any first-line drugs to which the isolate is susceptible Injectables Kanamycin Amikacin Capreomycin Streptomycin Step 2: Add a fluoroquinolone Fluoroquinolone Levofloxacin Moxifloxacin Gatifloxacin First-line Drugs Ethambutol Pyrazinamide Step 3: Include an injectable agent Oral Second-line Drugs Ethionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid Third-line Drugs Clofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanate Thioridazine Other new drugs Step 4: Include second-line drugs until you have 4-6 drugs to which the isolate is susceptible Consider third-line drugs if there are not 4-6 drugs to which the isolate is susceptible
  • 21. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Treatment Regimens for MDR-TB Resistance Pattern Regimen Comments INH and RIF Strept PZA + EMB + FQN + injectable (for ≥ 6 mos) + second-line agent if extensive disease Treat 18-24 mos following conversion INH, RIF + (PZA or EMB) (PZA or EMB) + FQN + 2 second- line agents + injectable agent (for first 6 mos) Treat 18-24 mos following conversion; consider additional agents, high-dose INH INH, RIF, PZA, EMB FQN + 3 second-line agents + injectable drug for first 6-12 mos Treat 18-24 mos following conversion INH, RIF, PZA, EMB, FQN Injectable + 3 second-line agents + third-line agents Treat 24 mos following conversion; consider high-dose INH, Surgery INH, RIF, PZA, EMB, injectables FQN + all available second-line agents; consider any third-line agents if susceptible Treat 24 mos following conversion; consider surgery Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.
  • 22. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB “Bangladesh” Regimen: Experimental Short-Course Treatment for MDR-TB  Controlled trial under way to confirm the efficacy of this regimen van Deun A, et al. Am J Respir Crit Care Med. 2010;182:684-692. *Resistance likely for many MDR patients. Phase Drugs 4-mo intensive phase High-dose INH* Prothionamide* Kanamycin Gatifloxacin Ethambutol* Pyrazinamide* Clofazimine 5-mo continuation phase Gatifloxacin Ethambutol* Pyrazinamide* Clofazimine
  • 23. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Potency and Tolerability of Existing TB Drugs Dorman SE, et al. Nat Med. 2007;13:295-298. Increasing potency, reliability, reproducibility of susceptibility testing Decreasing tolerability First-line Drugs Second-line Drugs Rifampin Isoniazid Pyrazinamide Ethambutol Fluoroquinolones (moxifloxacin, gatifloxacin, levofloxacin) Injectable agents Aminoglycosides (streptomycin, amikacin, kanamycin) Polypeptides (capreomycin) Oral bacteriostatic agents (ethionamide, protionamide, cycloserine/ terizidone, p-aminosalicylic acid, thiacetazone) Agents with unclear efficacy (clofazimine, amoxicillin-clavulanate, clarithromycin, linezolid)
  • 24. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Adverse Effects of MDR-TB Drugs Drug Toxicities and Adverse Effects Ethambutol Visual acuity, color vision Pyrazinamide Hepatotoxicity Isoniazid Neurologic effects, hepatotoxicity Injectables Vestibular, renal toxicity, hearing loss Fluoroquinolones GI, CNS, cardiac toxicities, tendinopathy Cycloserine/terizidone CNS toxicity, behavioral changes Ethionamide GI toxicity, hypothyroidism PAS GI toxicity, hypothyroidism, osteoarticular pain. Clofazimine Changes in skin and ocular pigmentation, GI effects Linezolid Thrombocytopenia, neutropenia, neuropathy, metallic taste Aurum Institute. Managing TB in a new era of diagnostics. 2012.
  • 25. Newer Drugs for MDR-TB Prevention Strategies
  • 26. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Bedaquiline  Oral diarylquinoline  Target: ATP synthase – Activity specific to mycobacteria  Bactericidal activity comparable to RIF-INH-PZA in mice  Sterilizing activity comparable to rifampin in mice  Synergy with PZA  No cross-resistance with other antimycobacterial drugs (INH, RIF, EMB, PZA, streptomycin, amikacin, or moxifloxacin) Andreas K, et al. Science. 2005;307:223-227. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12. Br N O (S) H O(R) N
  • 27. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB C208: Phase II Trial of Bedaquiline for MDR-TB  Stage I study: 47 pts with newly diagnosed pulmonary MDR-TB randomized to bedaquiline or placebo in combination with 5-drug second-line TB regimen – BDQ dose: 400 mg QD for 2 wks, then 200 mg TIW for 6 wks  BL resistance: pyrazinamide, 65%; ethambutol, 59%; kanamycin, 8%; ofloxacin, 8%; ethionamide, 8%  BDQ reduced time to culture conversion (HR: 11.8; 95% CI: 2.3-61.3; P = .003)  Incidence of AEs similar between arms – Nausea more frequent in BDQ vs placebo: 26% vs 4% (P = .04).Diacon AH, et al. N Engl J Med. 2009;360:2397. 0 0.2 0.4 0.6 0.8 1.0 0 7 42 Culture-PositivePatients(%) 14 21 28 35 49 56 Placebo (n = 24) Bedaquiline (n = 23) Days 52% 91%
  • 28. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB C208: Phase II Trial of Bedaquiline for MDR-TB  Stage II study: 15 sites in Brazil, India, Latvia, Peru, Philippines, Russia, South Africa, Thailand  Pts randomized to receive BDQ (n = 67) vs placebo (n = 66) for 24 wks with 5-drug BR – BDQ dose: 400 mg QD for 2 wks, then 200 mg TIW for 22 wks  After Wk 24, both groups continued the 5-drug BR to total of 96 wks  Culture conversion at Wk 24 significantly higher with bedaquiline vs placebo  Cure rate also significantly higher WHO. The use of BDQ in treatment of MDR-TB—interim policy guidance. 2013. Outcome BDQ Placebo P Value Median time to sputum conversion, days (95% CI) 83 (56-97) 125 (98-168) < .0001 Pts with culture conversion, %  Wk 24  Wk 72  Wk 120 78.8 71.2 62.1 57.6 56.1 43.9 .008 .069 .035 Proportion cured, % 57.6 31.8 .003
  • 29. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB FDA Bedaquiline Indication  Approved by FDA in 2012 as part of combination therapy in adults with pulmonary MDR-TB – Should be used only when an effective treatment regimen cannot otherwise be provided[1]  Recommended dose: 400 mg PO QD for 2 wks, then 200 mg PO TIW, for a total duration of 24 wks  First drug with novel mechanism approved by FDA for TB since 1971 Bedaquiline [package insert].
  • 30. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB CDC Provisional Guidance on Bedaquiline  BDQ may be used as a component of TB therapy when an effective treatment regimen cannot otherwise be provided – Administer by DOT for 24 wks with food in adults with laboratory-confirmed pulmonary MDR-TB – Use on case-by-case basis in children, HIV-positive pts, pregnant women, pts with extrapulmonary MDR-TB, and pts with comorbid conditions on concomitant medications – Use on case-by-case basis for durations > 24 wks CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
  • 31. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB WHO Interim Guidance on Use of Bedaquiline  BDQ may be added to a WHO-recommended regimen in adult MDR-TB patients under following conditions: – When an effective treatment regimen containing 4 second- line drugs in addition to PZA, according to WHO recommendations, cannot be designed – When there is documented resistance to any fluoroquinolone in addition to MDR – Recommended for adults older than 18 yrs of age under carefully monitored conditions WHO. Bedaquiline for MDR-TB. 2013.
  • 32. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Bedaquiline Safety Concerns  Black box warning: increase in all-cause mortality and prolongation of QT interval—monitor EKGs[1] – 30 deaths occurred in the clinical trial program in patients receiving BDQ vs 6 on placebo[2]  BDQ should be used with caution with other drugs that can cause QT interval prolongation and EKGs should be monitored more often[1] – Includes clofazimine and fluoroquinolones  BDQ should not be used with rifampin or rifapentine, which are strong inducers of CYP3A4[1] 1. Bedaquiline [package insert]. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
  • 33. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Bedaquiline Monitoring  All patients should be monitored wkly for adverse effects  EKGs should be monitored at baseline and at least 2, 12, and 24 wks after starting treatment  Serum potassium, calcium, and magnesium should be measured at baseline and whenever clinically indicated, especially if QT interval prolongation is detected  All patients started should be included in a registry for ongoing monitoring  Additional notes: – Bedaquiline should never be used as a single drug – Bedaquiline has a long terminal half-life of 4-5 mos; should be discontinued before other drugs in regimen – Rifamycins and other CYP3A4 inducers reduce bedaquiline concentrations – Bioavailability is significantly affected by food CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
  • 34. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Delamanid (OPC-67683)  Nitro-dihydro-imidazooxazole  Derivative of metronidazole  Inhibits mycolic acid synthesis  Potent preclinical in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of TB Skripconoka V, et al. Eur Respir J. 2013;41:1393-1400. N O O F F FO OO O N+ N N
  • 35. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Delamanid: Phase II Trial vs Placebo  Multinational trial of pts with pulmonary MDR-TB  Pts randomized to 2 mos of – Delamanid 100 mg (n = 161) – Delamanid 200 mg (n = 160) – Placebo (n = 160) – Each with WHO BR  Primary endpoint: sputum culture conversion at 2 mos  Delamanid significantly increased rate of sputum conversion vs placebo after 2 mos of treatment  QT prolongation reported significantly more frequently with delamanid  All other AEs mild to moderate and similar among groupsGler MT, et al. N Engl J Med. 2012;366:2151-2163. Patients(%) 41.9 29.6 45.4 100 80 60 40 20 0 Delamanid 200 mg Delamanid 100 mg Placebo 57/136 37/12564/141 P = .04 P = .008 n/N = Mycobacterial Growth Indicator Tube Culture Conversion at Day 57
  • 36. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB EMEA Delamanid Recommendation  In November 2013, the European Committee for Medicinal Products for Human Use recommended granting a conditional marketing authorization for delamanid for the treatment of MDR-TB  Recommended indication: – Use as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability EMEA. Marketing authorization for delamanid. November 2013.
  • 37. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Linezolid  Oxazolidinone, approved to treat drug-resistant, Gram-positive bacteria  Good activity against MDR-TB in vitro and in animal studies  Use in TB often limited due to long-term toxicities (bone marrow suppression, neuropathy)  However, retrospective chart review (2003-2007) of 30 pts (29 with pulmonary TB) who received linezolid 600 mg QD (plus vitamin B6) as part of a regimen for MDR-TB concluded[1]: – Culture conversion occurred in all pulmonary cases at median of 7 wks – AEs occurred in only 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea – Only 3 patients stopped linezolid treatment because of AEs 1. Schecter GF, et al. Clin Infect Dis. 2010;50:49-55. F O N N O O O N H
  • 38. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Linezolid 600 mg QD immediately* Linezolid 600 mg QD delayed by 2 mos* Pts with sputum- culture–positive XDR- TB (no response to any TB drugs in previous 6 mos) (N = 41) Smear conversion or 4 mos *All pts remained on background regimen of drugs they were taking before study entry. Second randomization continued at least 18 mos after smear conversion or after 4 mos on first regimen. Linezolid 600 mg QD 22 mos Linezolid 300 mg QD Lee M, et al. N Engl J Med 2012;367:1508-1518. Phase II Trial of Linezolid in Patients With XDR-TB  Phase II trial in South Korea  Primary endpoint: time to sputum-culture conversion on solid medium (data censored 4 mos after study entry) Linezolid 600 mg QD Linezolid 300 mg QD
  • 39. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Phase II Trial of Linezolid in Patients With XDR-TB  Culture conversion at 4 mos: – 79% (15/19) in immediate arm vs 35% (7/20) in delayed arm (P = .001)  87% (34/39) with negative sputum culture within 6 mos  31 pts (82%) with clinically significant AEs related to LZD – 3 pts d/c therapy  Pts on LZD 300 mg on second randomization had fewer AEs  13 pts completed therapy without relapse  4 pts acquired LZD resistance Lee M, et al. N Engl J Med. 2012;367:1508-1518. 1.0 0.8 0.6 0.4 0.2 0 0 30 60 90 120 150 180 Days Since Start of LZDCumulativeProbability ofConversion Conversion Probability According to Time on Treatment
  • 40. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Sutezolid (PNU-100480)  Oxazolidinone, related to linezolid  MOA: protein synthesis inhibition[1]  Like LZD, has a high barrier to resistance  More potent than LZD in mice, whole blood culture  Efficacy in mice similar to isoniazid and/or rifampin and may be synergistic with other first-line drugs  May be safer than LZD S N F O N O OH N H CH3 1. Alffenaar JW, et al. Antimicrob Agents Chemother. 2011;55:1287-1289.
  • 41. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Early Bactericidal Activity of Sutezolid in HIV+/- Pts With Drug-Susceptible TB  Significant log CFU reductions with both sutezolid regimens during the 14-day treatment period – 600 mg BID: -0.09 log/day (90% CI: -0.06 to -0.11) – 1200 mg QD: -0.07 log/day (90% CI: -0.04 to -0.09) – Trend toward superior response with BID dosing  Both dosing schedules generally safe and relatively well tolerated – 7/50 sutezolid-treated pts experienced ALT increases to 2-3 x ULN, which were asymptomatic and resolved spontaneously Wallis RS, et al. AIDS 2012. Abstract THLBB02. Graphic used with permission. 0 -1 -2 -3 140 2 4 6 8 10 12 Day ChangeinlogCFU 1200 QD 600 BID HREZ
  • 42. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB PA-824  PA-824: nitroimidazole-oxazine – Active in vitro and in mouse models  Cross-resistant with delamanid  High protein binding may render PA-824 less accessible in cavities of pulmonary TB  May be useful in combination regimens; synergistic with other drugs F F F O O O O ON N+
  • 43. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Novel Drug Combinations With PA-824 Show Promise in Mouse Models  PA-824 with moxifloxacin and pyrazinamide cures TB more rapidly than the first-line regimen in mice[1]  Bedaquiline + PA-824 + sutezolid may provide a novel 3-drug backbone for a universally active short-course regimen[2] Regimen (Duration) Mice Cured, % (n/N) 4 Mos 5 Mos 6 Mos RIF-INH-PZA (2 mos) + RIF-INH (4 mos) 50 (10/20) 100 (20/20) 100 (20/20) RIF-MXF-PZA (2 mos) + RIF-MXF (3 mos) 95 (19/20) 100 (20/20) 100 (20/20) Pa-MXF-PZA (2 mos) + Pa-MXF (4 mos) 100 (20/20) 100 (20/20) 100 (20/20) Regimen Relapse, % (n/N) After Tx for 2 Mos 3 Mos 4 Mos RIF + PZA + INH ND 100 (15/15) 64 (9/14) BDQ + SUT + CFZ + Pa 93 (14/15) 13 (2/15) 7 (1/15) BDQ + SUT + CFZ 87 (13/15) 27 (4/15) 7 (1/14) BDQ + SUT + Pa 100 (15/15) 43 (6/14) 0 (0/15) BDQ + CFZ + Pa 100 (15/15) 60 (9/15) 33 (5/15) SUT + CFZ + Pa 100 (15/15) 100 (15/15) 100 (15/15) 1. Nuermberger EL, et al. Antimicrob Agents Chemother. 2008;52:1522-1524. 2. Williams K, et al. Antimicrob Agents Chemother. 2012;56:3114-3120.
  • 44. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB HIV-negative or HIV-positive pts* with newly diagnosed pulmonary smear and culture-positive drug- sensitive TB (N = 83) Day 14 Early Bactericidal Activity of Novel Combinations of TB Drugs  Phase II trial in TB-infected pts Diacon AH, et al. Lancet. 2012;380:986-993. Bedaquiline + Pyrazinamide (n = 15) Bedaquiline + PA-824 (n = 15) PA-824 + Pyrazinamide (n = 15) Rifampin/Isoniazid/Ethambutol/Pyrazinamide (n = 8) Bedaquiline (n = 15) PA-824 + Pyrazinamide + Moxifloxacin (n = 15) *6 HIV-positive subjects.
  • 45. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Early Bactericidal Activity of Novel TB Regimens 0.5 0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 0 142 4 6 8 10 12 Day LogCFUChangeFromBaseline Bedaquiline Bedaquiline + PZA Bedaquiline + PA-824 RHEZ PA-824 + PZA PA-824 + PZA + moxifloxacin Diacon AH, et al. Lancet. 2012;380:986-993. Standard-of- care regimen Novel PA-824/ PZA/moxifloxacin regimen
  • 46. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Prevention of MDR-TB  Prevention of MDR-TB involves adequate, proper treatment of initial disease to prevent selection of resistance – Prompt diagnosis with adequate TB treatment under DOT – Rapid identification of MDR-TB and use of appropriate second-line regimens – Avoid further evolution of resistance – Airborne infection control – Preventive treatment of TB/HIV coinfection with optimal use of ART  Management strategies for established cases mainly rely on specific alternative treatment regimens complemented with surgery in carefully selected cases
  • 47. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Preventive Therapy in Contacts of Pts With MDR-TB in Micronesia  232 contacts of 5 pts with 2 different MDR-TB strains  105 with positive TST received preventive therapy  Strain A: resistant to isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin – Contacts offered fluoroquinolone alone or in combination with ethionamide  Strain B: resistant to isoniazid, rifampin, and ethionamide – Contacts offered fluoroquinolone with ethambutol  No cases of MDR-TB developed in those treated – 28 untreated contacts developed MDR-TB ECDC. Management of contacts of MDR TB and XDR TB patients. 2012.
  • 48. clinicaloptions.com/hiv Recent Advances in Multidrug-Resistant TB Conclusions  Current approaches to MDR-TB therapy are long, with much toxicity  Bedaquiline is the first drug with a novel mechanism of action to be approved by FDA for MDR-TB since 1971  Delamanid recently approved by European Medicines Agency – Both agents indicated only when an effective regimen cannot otherwise be provided  Multiple new drugs are in the pipeline  Successful eradication of MDR-TB will require new drug regimens with novel drug combinations
  • 49. Go Online for More CCO Educational Content on Multidrug- Resistant TB! Interactive Virtual Presentation featuring streaming narration of these slides by expert faculty Richard E. Chaisson, MD, and Maunank Shah, MD clinicaloptions.com/hiv