Management of MDR and XDR TB Prof. Martin Boeree

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1 Management of MDR and XDR TB 1, MD, PhD Associate Professor Consultant Respiratory Medicine Department of Lung Diseases Radboud University Nijmegen Medical Centre TB Referral Hospital Dekkerswald Nijmegen, the Netherlands Dekkerswald 2 3 1

2 Management of MDR/XDR TB Introduction Epidemiology Management Drug treatment Current treatment Future treatment 4 Management of tuberculosis before the era of drug treatment Specially dedicated sanatoria, the first one opened in 1855 in Görbersdorf, Germany (current Sokołowsko, Poland) Rest, a good diet, a regular day/night rhythm, healthy air and sunlight Love, tender and care Sometimes, surgery like artificial pneumothorax to give rest to the lung 5 Sunhouses in the garden 6 2

3 Surgery for TB 7 Drug treatment was introduced from Streptomycin (1943) PAS (1948) Thiacetazone (1951) Isoniazid (1952) Pyrazinamide (1954) Cycloserine (1955) Kanamycin (1957) Ethionamide (1960) Ethambutol (1961) Capreomycin (1963) And finally rifampicin (1963) After several trials the treatment was shortened to 6 months 2HRZE/4HR The combination of isoniazid, rifampicin, pyrazinamide and ethambutol became the standard with >95% cure rate 9 3

4 Then, for 40 years no new drugs were introduced 10 Discovery of drugs for tuberculosis 11 Ma et al., Lancet, 2010 Unfortunately, TB incidence increased again The HIV epidemic Drug resistance 12 4

5 Notifications of Tuberculosis, by type of disease Tanzania mainland, TB case notifications in Malawi 14 Definitions MDR TB: resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs Pre XDR TB: resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, or to any of the three second-line injectables (amikacin, capreomycin, and kanamycin) XDR TB: resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin) TDR TB (not officially recognized): resistance to any known antituberculosis drug 15 5

6 IsemanMD, Clinical Infectious Diseases 45: , Velayati et al., CHEST 136: , 2009 Management of MDR/XDR TB Introduction Epidemiology Management Drug treatment Current treatment Future treatment 17 Notified MDR-TB cases (absolute numbers), Courtesy WHO 6

7 Notified MDR-TB cases (number per 100,000 population), Courtesy WHO Proportion of MDR among new TB cases Courtesy Stop TB Proportion of MDR among previously treated TB cases, Courtesy Stop TB 7

8 22 Outcomes of MDR-TB treatment For MDR-TB patients started on treatment in Countries that had reported at least one XDR-TB case by Oct

9 KwaZulu-Natal: 53 patients with XDR TB, of which 52 died 25 Proportion surviving March 2008: 996 XDR TB (=16% of the total MDR TB) Median survival: 16 days (range days) Days since sputum collected 26 Figure: Survival after sputum collection in patients with XDR tuberculosis with confirmed dates of death (n=42) Management of MDR/XDR TB Introduction Epidemiology Management Drug treatment Current treatment Future treatment 27 9

10 MDR and XDR TB can be cured Use at least four second-line drugs Treat at least for 8 months intensive (= use of injectable) Treat totally to 20 months or 18 months after culture conversion Globally, 48% were succesfully treated in % of all MDR TB in the world received treatment in 2011, this was only 1% in Jacobsen et al, Clin Inf. Dis Jacobsen et al, Clin Inf. Dis

11 Current recommended approach for the treatment of MDR and XDR TB Relies on drugs rejected for TB in last 50 years Uncertainty about optimal doses, durations and combinations Many of the recommendations are not based on high levels of evidence (WHO, Review by Caminero, Lancet, 2010) 31 Programmatic or individualized Programmatic approach in low and middle income countries Individualized approach in countries where all drugs and rapid diagnostic resources are available 32 After diagnosis of drug resistant tuberculosis with rapid molecular diagnostics Start according to guidelines Adjust after the definitive in vitro drug sensitivity testing Or if clinical situation allows, wait for drug sensitivity testing Then start after the definitive in vitro drug sensitivity testing 33 11

12 Classical division of anti tuberculosis drugs Groups of second-line anti-tuberculosis agents referred to in these guidelines 36 12

13 Recommendations 37 Recommendations (duration of treatment) 38 Group one: oral first-line agents (use all possible drugs) Rifampin 10 mg/kg Isoniazid 4-6 mg/kg Pyrazinamide mg/kg 39 Ethambutol mg/kg 13

14 INH may be used in higher dosages in MDR TB Prospective, double-blind trial, Kanpur India Three arms, n=123, placebo, H and H+ (16-18 mg/kg) adjuvant to standard treatment in MDR TB No second line DST H+ did better in becoming sputum-negative more rapidly (HR 2.38) and to be sputum-negative at 6 months (HR 2.37) 40 Rifabutin may be used in R resistant rifabutin susceptible organisms 15-20% of the R resistant organism are susceptible for rifabutin There is some circumstantial evidence of efficacy in patients, but low numbers DST cut off not validated, and often not available Rifabutin is expensive Therefore not recommended in programs 41 Group two: fluoroquinolones (use only one, because they share genetic targets) Moxifloxacin mg/kg or 400 mg OD (High dose) Levofloxacin 15 mg/kg mg OD Ofloxacin 15 mg/kg or mg OD Gatifloxacin Sparfloxacin 42 Ciprofloxacin 14

15 Group two: fluoroquinolones The use of high dose levofloxacin or moxifloxacin is preferred above ofloxacin or gatifloxacin Now phase III trials in drug sensitive TB: moxifloxacin (REMox) A recent presentation at the union meeting in Paris (October 2013) showed that 4 months of gatifloxacin in combination with HRZ was inferior to the 6 months standard regimen (Oflotub) 43 Group three: injectables (use only one, because they share similar genetic targets) Amikacin mg/kg Kanamycin mg/kg Capreomycin mg/kg 44 Streptomycin mg/kg Group three: injectables Guidelines: each member of the aminoglycoside family is equally effective, except for streptomycin Kanamycin generally cheapest Capreomycin generally less ototoxic 45 15

16 Group four: less-effective anti-tb drugs (use all possible drugs if necessary) Ethionamide/prothionamide mg/kg or mg BD Cycloserin/terizodone 15 mg/kg or mg BD P-aminosalicylic acid (PAS) 150 mg/kg or 8 12 g BD 46 Group five: less-effective anti-tb drugs or where clinical data are sparse (use all possible drugs if there are less than four from the other groups) Clofazimine 100 mg OD Amoxycillin with clavulanate 875/125 BID Linezolid 600 mg OD Imipemen mg QID Clarithromycin 500 mg BID 47 High dose isoniazid mg/kg Thiocetazone 150 mg Changes to the recommendations on regimen composition between the 2008 and 2011 updates of the guidelines 48 16

17 Management of MDR/XDR TB Introduction Epidemiology Management Drug treatment Current treatment Future treatment 49 New compounds Will also be reviewed in another presentation for HST in the series on respiratory infections 50 TB drug development pipeline Develop effective animal models, surrogate markers etc. Discovery Early Discovery Hit to Lead Lead to Preclinical Candidate Preclinical Development Phase I Phase II Phase III Combination Trials Identify Possible Combinations Combination Trials Combination Trials 51 17

18 Budget needed for Global TB drug pipeline 54 18

19 Novel compounds to treat active TB disease 55 Bedaquiline (TMC207) 56 Mechanism: inhibits F0 subunit of the mycobacterial ATP synthase proton pump Possible use: Shorter treatment (especially in mice together with PZA strong effect) (Shorter) treatment of MDR/XDR TB FDA approved bedaquiline (Sirturo ) for MDR TB treatment In 2013 black box alert : unexplained surplus of deaths in bedaquiline group in follow up 57 19

20 The nitroimidazoles PA 824 (Chiron, now Novartis) OPC (Otsuka): delamanid Derivatives from metronidazol Mechanism of action (several): intracellular NO production, lipid and protein synthesis Use for shorter treatment in DS and DR TB (Also) for latent TB Delamanid has an MIC 10x lower than PA Nov. 2013, EMA approved the drug: Deltyba 50 mg 59 Source: EMA/CHMP/713909/2013 Committee for Medicinal Products for Human Use (CHMP) PA-824 Now evaluated in combinations by the Global Alliance 60 20

21 SQ 109 (Sequella) An effluxpump inhibitor Also exhibits activity on the cell wall synthesis In phase 2 (in PanACEA) 61 Oxazolidinones: inhibit protein synthesis Linezolid: many side effects, use now in MDR/XDR TB, in MDR trial with OBT design PNU : sutezolid (Pfizer). More potent than linezolid in in vitro, ex vivo and murine models. Phase IIa eba study just ended (BID 600 mg vs. OD 1200 mg) results to follow AZD5847 (AstraZeneca): two phase I studies, no safety problems BID 1200 mg. Phase II study planned Three more compounds to be evaluated by GATB 62 The quinolones: in phase III Mechanism of action: inhibit DNA gyrasis Moxifloxacin (Bayer): ReMOX, Rifaquin Gatifloxacin: Oflotob Consortium 63 21

22 Phase III trials recently presented October 2013 in Paris RIFAQUIN 2EMRZ/2M2P2 2EMRZ/4M1P1 Standard control regimen 2HRZE/4HR OFLOTUB 2HRZG/2HRG Standard control regimen 2HRZE/4HR Both studies: 4 months inferior 64 Thioridazine Used in psychiatry for depressive psychosis Shown to have anti TB activity Used on compassionate basis in XDR TB patients, and will be evaluated in clinical trials in the PanACEA consortium 65 H37Rv Control infection (A) Extensive lung consolidation (arrows) is visible in control animals after 120 days of infection by drugsensitive control Strain H37Rv. MDR Control Infection (C) Control mice after 120 days of infection with MDR strain show extensive pneumonic areas (arrow) H37Rv Infection Plus Thioridazine (B) In contrast, less pneumonia (arrow) is seen in the lung of Mice treated with Thioridazine 32 mg/kg daily by intragastric cannula MDR Infection Plus Thioridazine In comparison, less lung consolidation (arrow) is seen in the lung of mice infected by the MDR-TB strain and treated daily during two months with 70 mg/kg of thioridazine 66 22

23 Global Alliance: a series of trials, NC (new combinations) NC-001 NC-006 Will start in 2014 NC-006 phase III: 3PaMZ vs. 2HRZE/4HR 67 NC-001: Test regimens with EBA? PA-824, moxifloxacine, PZA 68 Lancet,2012 So what will we see in the future? dreams and realities In the next decades TB treatment will change Shorter treatment both for DS as for DR TB 4 months 3 months 2 weeks when I am retired + individualized treatment With combinations of strongly sterilizing compounds 69 High dose rifampicine (Higher dose) of pyrazinamide Bedaquiline Moxifloxacine PA-824/delamanid Sutezolid Clofazimine 23

24 Thank you