MDR, XDR, TDR-TB: Treatment and Challenges

Transcription

1 MDR, XDR, TDR-TB: Treatment and Challenges Dr Rick Stapledon SA TB Services 2013 Australasian Tuberculosis Conference, Auckland, New Zealand

2 Overview Introduction Historical perspective Causes of drug resistance Definitions Treatment issues Controversies Principles of treatment Constructing a DR-TB regimen Newer drug options old & new Challenges

3 Kalyra TB Sanitorium Adelaide,

4 Artificial Pneumothorax Carlo Forlanini ( ) Courtesy: Caminero JA

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7 Tailoring a Time-bomb We are unwittingly transforming an eminently treatable condition into a life threatening disease that is exorbitantly expensive to treat. M. Iseman 1985 (Am Rev Respir Dis)

8 Launched in 2001 to draw attention to the Global threat of MDR-TB. Despite these warnings and the progress that has been made, MDR-TB has become an all consuming problem.

9 Time-line of the emergence of DR-TB Opportunities missed to control TB SHP 1950/60s SCC 1980/90s < s Drug sensitive TB MDRTB Pre- XDRTB XDRTB? TDRTB Mis-use of FLDs Mis-use of FQN (or SLI) Mis-use of SLDs More amplification

10 Causes of Drug Resistant TB Clinical and programmatic Same drugs for 40 years key issue is duration of treatment and the opportunities for interruptions & acquired resistance Inadequate or poorly administered treatment health-care providers breaking the rules patient factors non-adherence, malabsorption drug dose, quality, access & storage Short course chemotherapy amplifier effect Ongoing transmission of DR-TB HUMAN PHENOMENON

11 Pitfalls in Treatment Mahmoudi A, Iseman M (JAMA 1993;270:65-8) Review of referred TB cases for management errors error no error p No (n = 35) 28 7 Acquired resistance (%) 18/21 (86) 1/7 (14) Successful med. treatment (%) 11 (39) 7 (100) ns Mean no. medications used Hospital stay (mean days)

12 Pitfalls in Treatment Mahmoudi A, Iseman M (JAMA 1993;270:65-8) 28 patients had Rx decision errors (3.93 / patient) Most common errors adding single drug to a failing regimen failure to identify drug resistance commencing inadequate primary regimen failure to identify non adherence inappropriate use of preventive therapy

13 Random Naturally Occurring Resistance INH 1 in 10 6 RMP 1 in 10 8 EMB 1 in 10 5 STR 1 in 10 6

14 Emergence of Resistance with Single Drug Therapy of Active TB Start INH alone

15 Definitions MDR-TB Resistance to at least isoniazid and rifampicin? Rifampicin mono- or poly-resistance Importance No short course treatment regimen available Requires use of more toxic drugs for 1½ - 2 years Treatment success rates significantly lower

16 Pre-XDRTB MDR + resistance to FQN or injectable Fluoroquinolone (FQN) resistance ease of access for community acquired infections ineffective regimens for failed TB cases high rates reported in India, China, Philippines, Africa

17 Definitions XDR-TB Resistance to at least isoniazid & rifampicin + Resistance to a FQN & at least one of three injectable secondline drugs (amikacin or kanamycin or capreomycin)? should be all first line agents + all FQN s + all SLI s Importance emerging epidemic of untreatable TB Success rate ~40% very high mortality ( >25-40% )

18 ? TDR-TB Forms of DR-TB with more advanced resistance pattern than XDR-TB as currently defined Not clearly established DST for drugs beyond XDR definition are problematic total may vary in different settings (DST capacity, availability of drugs) expectation of introduction of new drugs? impact of such a label for patient, HCW

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21 Predicting MDRTB Resistance observed after Category I and II treatment regimens, Damien Foundation Bangladesh After Category I treatment 2EHRZ/6HT After Category II treatment 2SEHRZ/1EHRZ/5(HER) 3 Relapses (n=136) Failures (n=163) Relapses (n=43) Failures (n=86) Any resistance 74 (54%) 131 (82%) 35 (83%) 80 (93%) Resistance to H 69 (51%) 123 (76%) 33 (77%) 80 (93%) Resistance to H + R 8 (6%) 36 (22%) 25 (58%) 75 (87%) H = isoniazid R = rifampicin Drug resistant TB should be a laboratory based diagnosis

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23 Controversies in MDR Treatment Reliability of DST How many drugs to use Rational use of first & second line drugs Length of injectable phase Total duration of therapy Role of surgery Recommendations are based on consensus rather than data from RCTs

24 Changes in recommendations on regimen composition between the 2008 and 2011 updates of the guidelines

25 Recommendations 8 and 9 In the treatment of patients with MDR-TB, an intensive phase of at least 8 months duration is recommended In the treatment of patients with MDR-TB, a total treatment duration of at least 20 months is recommended in patients without any previous MDR- TB treatment (conditional recommendations / very low quality evidence)

26 Treatment Principles MDR-TB WHO 2008 Treatment selection based on history of previous therapy & reliable DST results should not base regimen on DST results of E, S or group 4/5 drugs Use at least 4 drugs to which the organism has not been previously exposed Initial injectable phase should be for a minimum 8 months (2011 update) Total duration should be a minimum 20 months (at least 12 months after culture conversion) Use ART in HIV positive cases All treatment daily DOT

27 WHO TB Drug Classification Group Group1 - First line (oral) Group 2 - Injectable agents Drugs Isoniazid, Rifampicin, Ethambutol, Pyrazinamide Capreomycin, Kanamycin, Amikacin, Streptomycin Group 3 Fluoroquinolones Group 4 - Other second line agents (bacteriostatic) Ofloxacin, Levofloxacin, Moxifloxacin, Gatifloxacin Ethionamide, Protionamide, Cycloserine, Para- aminosalicylic acid, Group 5 Third line agents of uncertain efficacy (not routinely recommended) Clofazimine, Linezolid, Amoxicillinclavulanate, Imipenem, Clarithromycin, high dose isoniazid

28 Developing a Treatment Regimen for MDR-TB Step 1 First Line Agents Injectable Agents Fluoroquinolones Pyrazinamide Ethambutol Capreomycin Kanamycin Amikacin Streptomycin Levofloxacin Moxifloxacin Gatifloxacin Not considered core drugs Begin with any first-line agents to which the isolate is susceptible. Add an injectable drug and a FQN based on DST results use only 1 from each group due to shared genetic targets

29 Developing a Treatment Regimen for MDR-TB Step 2 Oral Second line Drugs Use at least 2 depending on whether previous SLD use or not, to give 4 core drugs. Protionamide or Ethionamide Cycloserine PAS

30 Developing a Treatment Regimen for MDR-TB Step 3 Consider as necessary limited clinical experience if not at least 4 core drugs from previous groups needs careful consultation with MDR expert Third Line Drugs Clofazimine Linezolid Amoxicillin/clavulanate Imipenem High dose isoniazid (10-15 mg/kg) Clarithromycin Bedaquiline

31 Treatment Principles XDR-TB WHO 2008 Any FLD that may be susceptible Injectable agent to which organism is susceptible consider 12 mths or more If all resistant use one not used previously Use a later generation FQN Use all group 4 drugs not previously used Use 2 or more group 5 drugs Duration - 18 months after culture conversion Consider adjuvant surgery for localised disease

32 Treatment Principles XDR-TB WHO 2008 Ensure strong Infection Control measures Treat HIV Provide comprehensive monitoring & patient support All treatment daily DOT

33 Anti-TB Drug Cross Resistance Drug Rifampicin Cross Resistance High level cross resistance with other rifamycins Fluoroquinolones Variable cross-resistance Some newer generation drugs remain susceptible despite earlier generation drugs being resistant Aminoglycosides and polypeptides Amikacin and kanamycin; variable crossresistance Isolates resistant to amikacin are usually resistant to kanamycin & capreomycin Capreomycin & viomycin; high cross-resistance

34 Management Approach Case management team to develop patient care plan design treatment regimen where to manage home, hospital isolation, IC Ensure treatment completion Daily DOT (not intermittent) patient centred approach eg incentives monitor, manage adverse effects promptly Education patient, family, staff Patient support measures Actions if patient defaults

35 Bangladesh Study Short, Highly Effective and Inexpensive Standardised Treatment of Multidrug-resistant Tuberculosis Van Deun et al Am J Respir Crit Care 2010;182: KPHGECZ 5 GEZC G Gatifloxacin (high dose) E Ethambutol Z Pyrazinamide C Clofazimine K Kanamycin P Protionamide H Isoniazid (high dose)

36 Outcome of treatment of multidrug-resistant tuberculosis, by grouped regimen category, Bangladesh Damien Foundation Projects

37 Treatment Outcomes among Patients with Extensively Drug-Resistant Tuberculosis: Systematic Review and Meta-Analysis K Jacobson et al CID 2010; 51: 6-14 Study Characteristics (no of studies) Favourable Outcomes P Improvement % (95% CI) HIV prevalence % (13) Mean Age, years (13) Percent Female (12) Mean no. of drugs in regimen (10) Mean no of likely active drugs (10) Percent who received FQN (10) Percent who received linezolid (10) Percent who underwent surgery (10) 0.27 ( ) (-35 to -3.8) (-3 to 8.8) (-14.9 to 15.3) (-8.6 to 20) (1.1 to 6.4) (-3.9 to 6.4) (-4.9 to 8.7) 65 Reported 13 studies on 560 patients: Weighted favourable outcome 43.7% (95% CI %) Weighted proportion who died 20.9% (95% CI %) ~4% improved outcome with later generation FQN Younger mean age predicted better outcome

38 Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. (M Gopal et al Int J Tuberc Lung Dis 2013; 17: ) Reviewed 599 patients with DR-TB Overall favourable effect 65% (95% CI 54-76) MDR-TB (6 studies, 531) 65% (CI 52-79) XDR-TB (4 studies, 68) 66% (CI 42-89) Discussion In vitro & animal studies suggest a measurable anti-tb effect? improved killing of persisters? prevents amplification of resistance Bangladesh study used throughout;? effect in successful shortening

39 Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. H Cox et al Int J Tuberc Lung Dis 2012; 16: Reviewed 11 studies 148/218 who received linezolid had evaluable outcomes Pooled Treatment success 67.99% (95% CI ) Culture conversion 97.86% 95% CI ) Adverse events (mean duration 7 months) Frequency: Range 30.63% (95% CI ) 79.32% (95% CI ) Dose 600mg 34.4%, 600mg 49.85% Neuropathies 36.12% (CI ) Bone marrow suppression 28.47% (CI ) Treatment stopped: pooled rate 36.2% (R %) Conclusions Potentially useful drug but needs to be used with caution Cost a significant limiting factor

40 Role of Surgery Consider cultures remain positive after 4-6 months the pattern of drug resistance is extensive and cure with therapy alone is unlikely complications of disease eg haemoptysis, empyema Success depends on: localised disease sufficient pulmonary reserve

41 Surgical Interventions for drug-resistant tuberculosis: a systematic review and meta-analysis. M T Marrone Int J Tuberc Lung Dis 2013; 17:6-16 Conclusions Surgery has a role to play in the treatment of MDR and XDR-TB but Insufficient evidence to determine the utility of surgery combined with anti-tb treatment in treatment of MDR-TB

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43 Bedaquiline (TMC 207) WHO approval for use in MDR/XDR-TB cases Concerns regarding increased risk of cardiac arrythmias especially when used in combination with FQNs, clofazimine Action Kills by inhibiting ATP synthase in cell wall Prevents upkeep of the cell membrane No cross-resistance with existing drugs May be best used as additional drug for first line treatment (drug susceptible cases)

44 Shortened time to culture conversion (12 v 18 wks) & improved rate of conversion

45 Bedaquiline (TMC 207) WHO Interim Recommendations (conditional, very low confidence in estimates of effects) An effective MDR regimen (core 4 drugs + PZA in IP) cannot be designed Proven resistance is shown to any FQN or SLI in addition to MDR (pre-xdr) In XDRTB, may be used instead of a group 5 agent Use: Maximum duration 6 mths 400mg daily first 2 wks, 200mg 3x /wk next 22 wks Should not be added alone to a failing regimen

46 Treatment failure Evidence for treatment failure treatment compliance good unsatisfactory clinical response persistent +ve cultures > 8 months no satisfactory treatment options left Management? stop due to risk of breeding pan-drug resistant strain? salvage treatment options for compassionate use? use of new investigational drugs eg bedaquiline need to ensure regulatory process in place for access & to prevent further resistance from mis-use team approach to decision making patient & family support need policy for managing infection risk

47 MDR-TB the challenges Resource intensive prolonged monitoring required (2 years +) large cost incurred (drugs, hospitalization, prolonged isolation, DOT, lab testing) drugs alone $$$$ times drug susceptible case Social & economic impact to individual Management of treatment failures when to stop treatment to prevent pan-drug resistance? risk of further resistance from use of compassionate TB drug where to house the untreatable to prevent transmission Pool of clinical expertise diminishing in low prevalence countries No proven therapy for infected contacts