Doing the Math: The Dilemma of Drug Resistant Tuberculosis. Frances Jamieson, MD, FRCPC PHO Rounds, April 17 th, 2012

Transcription

1 Doing the Math: The Dilemma of Drug Resistant Tuberculosis Frances Jamieson, MD, FRCPC PHO Rounds, April 17 th, 2012

2 Tuberculosis : A Global Problem WHO Estimates (2010 data): 8.8 million New Infections 1.1 million Deaths

3 TB by the numbers One third of the world s population is infected with M. tuberculosis 5-10% will develop active disease Almost 2 million persons die annually almost 5,000 every day It is estimated that each case left untreated can infect an average of persons annually before death

4 Drug Resistant Tuberculosis: Definitions * Multi-drug Resistant Tuberculosis: MDRTB -resistant to isoniazid (INH) and rifampin (RMP) Extensively-drug Resistant Tuberculosis: XDRTB -resistant to INH, RMP (ie MDRTB) PLUS any of the fluoroquinolones (e.g levofloxacin, moxifloxacin or gatifloxacin) and at least one of the 3 injectable drugs (capreomycin, kanamycin, amikacin) *MMWR November 3 rd,2006

5 The global TB situation Estimated number of cases, 2010 Estimated number of deaths, 2010 All forms of TB 8.8 million ( million) 1.1 million* ( million) HIV-associated TB Multidrugresistant TB 1.1 million ( million) ~ 650,000 out of 12 million (11-14 million) prevalent TB cases 350,000 (320, ,000) Source: WHO Global Tuberculosis Control Report 2011 ( * Excluding deaths attributed to HIV/TB

6 Time trends in MDR-TB Available data from 74 countries and territories with measurements for at least two years could not answer the question of whether the proportion of previously untreated TB cases with MDR was increasing, decreasing or stable over time at a global or regional level.

7 Global Tuberculosis Control: WHO report 2011

8 Public Health Agency of Canada: Tuberculosis in Canada 2007

9 Public Health Agency of Canada: Tuberculosis in Canada 2007

10 No one is spared John Keats George Orwell

11 Davies RPO et al, Int J Tuberc Lung Dis 1999;3(12):

12 Rate per 100,000 population Number of Cases Tuberculosis incidence rate and counts Canada: ,000 2, Cases 2,000 5 Rate 1,500 1, Public Health Agency of Canada 0

13 Pathogenesis of Tuberculosis Stuart GR et al, Nature Rev Microbiol 2003;1:97-100

14 Chest X-Ray with Cavity in Tuberculosis 14

15 Biology of M. tuberculosis Very long generation time approx hours Can remain dormant in cells (inactive, low metabolic activity) Cavitary lesions form with large numbers of organisms

16 M. tuberculosis isn t like other bacteria M. tuberculosis (Mtb) infection usually acquired early in life; organisms enter latency (metabolically inactive) Mtb organisms do not interact and exchange genetic information (unlike other bacteria, e.g. S. aureus colonizing the nasopharynx) Resistance can only occur through chromosomal mutation Mutation rate for individual genes varies between and within genes

17 Doing the Math: The Development of Drug Resistance in M. tuberculosis Risk of drug resistant mutants emerging in a patient depends on the product of the risks of mutation for each agent and the size of the bacterial population within compartments (e.g. lung cavities): P = 1 - (1 r) n where P = probability of drug resistance emerging; r is the mutation rate, and n is the number of bacilli in a lesion (usually estimated at 10 8 ) Gillespie SH, Antimicrob Agents and Chemotherapy, 2002

18 Doing a lot more math Emergence of mono-resistance before treatment: Emergence of multi-drug resistance before treatment: Emergence of multi-drug resistance during treatment: Colijn C et al, Plos ONE 2011;6(3):e

19 Doing the Math risk of drug resistance Single drug therapy with a risk of mutation of 10-6 : Probability = 100% Two drug therapy with combined risks of mutation of : Probability = 0.01% Above two drug therapy with a bacterial population in a lesion of : Probability = 1.0%

20 Spontaneous mutation rates for first-line TB drug therapy Rifampin: 3.32 X 10-9 Isoniazid: 2.56 X 10-8 Ethambutol: 1.0 X 10-7 [Streptomycin: 2.29 X 10-8 ]

21 Ghandi NR et al, Lancet 2010; May 19 epub

22 Acquired and Primary Drug Resistance: Zhang Y et al, Int J Tuberc Lung Dis 2009;13(11):

23 Treatment of Tuberculosis 23

24 Ma Z et al, Lancet; May epub

25 What is a First-line drug? Canadian Tuberculosis Standards, 6 th Edition, 2007

26 Drug Susceptibility Testing of MTB - Determining Resistance All first isolates of MTB from patients are tested for susceptibility to the first line panel of drugs : Isoniazid ( INH) Rifampin ( RIF) Ethambutol (EMB) Pyrazinamide) ( PZA) Testing is by MGIT/BT 960 method

27 First-line drug therapy for fully-susceptible TB National Institute of Allergy and Infectious Diseases

28 Drug Resistant Tuberculosis: Definitions * Multi-drug Resistant Tuberculosis: MDRTB -resistant to isoniazid (INH) and rifampin (RMP) Extensively-drug Resistant Tuberculosis: XDRTB -resistant to INH, RMP (ie MDRTB) PLUS any of the fluoroquinolones (e.g levofloxacin, moxifloxacin or gatifloxacin) and at least one of the 3 injectable drugs (capreomycin, kanamycin, amikacin) *MMWR November 3 rd,2006

29 MDRTB requires treatment with second-line drugs 29

30 Drug Susceptibility Testing of MtbC: Second-line* Drug Name Critical Concentration mg/ml Amikacin 1.0 Capreomycin 2.5 Ethionamide 5.0 Kanamycin 2.5 Linezolid 1.0 Moxifloxacin 0.25 Ofloxacin (for Ciprofloxacin) 2.0 PAS 4.0 Rifabutin 0.5 Streptomycin 1.0 *Using MGIT/960 as of October 1 st, 2010

31 MDRTB and possible effective treatments National Institute of Allergy and Infectious Diseases

32 Proportion of MDR among new TB cases Latest available data, <3 3-<6 6-<12 12-<18 >18 No data available Subnational data only The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO All rights reserved

33 Proportion of MDR among previously treated TB cases Latest available data, <6 6-<12 12-<30 30-<50 >50 No data available Subnational data only The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO All rights reserved

34 Ontario Ontario Public Health Agency of Canada: Tuberculosis: Drug Resistance in Canada Public Health Agency of Canada: Tuberculosis: Drug Resistance in Canada

35 XDR-TB Public Health Agency of Canada: Tuberculosis: Drug Resistance in Canada

36 Countries Reporting at Least One Case of XDRTB by October 2011 Argentina Burkina Faso Estonia Japan Namibia Republic of Korea The Former Yugoslav Republic of Macedonia Armenia Bhutan France Kazakhstan Nepal Republic of Moldova Togo Australia Cambodia Georgia Kenya Netherlands Romania Tunisia Austria Canada Germany Kyrgyzstan Niger Russian Federation Turkey Azerbaijan Chile Greece Latvia Norway Slovenia Ukraine Bangladesh China India Lesotho Pakistan South Africa United Arab Emirates Belarus Colombia Indonesia Lithuania Peru Spain United Kingdom Belgium Czech Republic Iran (Islamic Rep. of) Mexico Philippines Swaziland United Republic of Tanzania Benin Dominican Republic Ireland Mongolia Poland Sweden United States of America Botswana Ecuador Israel Mozambique Portugal Tajikistan Uzbekistan Brazil Egypt Italy Myanmar Qatar Thailand Viet Nam WHO 2011

37 Is there Totally Drug Resistant TB (TDR)? After reports from Iran in 2009 of Extremely Drug Resistant (XXDR-TB), and more recently from India of Totally Drug Resistant (TDR-TB), WHO convened an expert panel on March nd, 2012: Cannot validate new definitions of TDR or XXDR due to technical challenges with drug susceptibility testing of many second-line anti-tb drugs DST for drugs used to define MDRTB and XDRTB are accurate and reproducible 37

38 XDRTB and diminishing options for therapy National Institute of Allergy and Infectious Diseases

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40 New drug therapies on the horizon National Institute of Allergy and Infectious Diseases

41 Tuberculosis and Drug Resistance: A Global Problem

42 Thank-you!