Drug Resistant Tuberculosis Biology, Epidemiology and Control Dr. Christopher Dye

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1 Director of Health Information World Health Organization Geneva 1 1. Why TB patients are treated with drugs 2 Natural history and control of TB Fast 5/1 Slow 5/1 Uninfected Latent Active 1 1 infection/case infections/case Spontaneous cure 3/1 Death 5/1 3

2 Selman Waksman: streptomycin Nobel prize 1952 For his discovery of streptomycin, the first antibiotic active against tuberculosis" 4 "Hunting a beast through endless forests (Kafka d. TB 1924) Search for a TB cure yielded combination therapy 5 DOTS directly observed treatment, short-course 6

3 7 Britain beat TB in the 19th and 2th centuries? TB deaths England & Wales TB deaths/1, /yr Keats 1821 E Bronte 1848 Lawrence 193 C Bronte 1855 Mansfield 1923 Orwell 1953 Leigh How drug resistance arises 9

4 Down in the pathosphere Resistance profiling of soil bacteria D'Costa et al., 26 1 Mechanisms of resistance Isoniazid Disrupts cell wall synthesis 1s resistance mutations affecting e.g., function of katg gene involved in drug activation Rifampicin Inhibits prokaryotic RNA synthesis (Gram-stain +ve) Resistance mutations in rpob gene for RNA polymerase 11 Evolution by natural selection Heritable variation selection Before selection Ex: antibiotic resistance After selection Final population Resistance level Low High 12

5 Initial drug resistance causes treatment failure 3 treatment Percent failing drug 1 drug >1 drug Resistance background Source: Lew, Ann, Intern Med 28;149: Initial resistance to 1+ drug facilitates resistance to others 2 cquiring istance Percent ac further res drug 1 drug >1 drug Resistance background Source: Lew, Ann, Intern Med 28;149: Risk of acquiring resistance after treatment failure 1. stance nt failure Risk of resis after treatmen Isoniazid from sensitive Source: Dye & Williams 29 Rifampicin from sensitive MDR from isoniazid 15

6 MDR-TB cure rates are higher with longer treatment, supervision, and individual regimens completed (%) Cured or treatment >18 months + DOT <18 months DOT Individual regimen Type of treatment Source: Orenstein, Lancet ID 29; 9: Standard regimen 16 Superbugs: not so super Rifampin-resistant mutants of TB from lab are less fit 1.3 s of mutants Relative fitness Equal fitness.5 Gagneux, Science Resistant mutants 17 Superbugs: overcoming the handicap Some rifampin-resistant mutants from patients are not less fit mutants Relative fitness of rpob S531L mutation Other rpob mutations Equal fitness Resistant mutants Gagneux, Science 26 18

7 Relative fitness of isoniazid resistant TB and MDR-TB Isoniazid mono-resistant Isoniazid mono-resistant S315T mutation MDR Source: Gagneux Geographical distribution of drug resistant TB 2 Treatment success reaches 85% target 1 Treatment suc ccess (%) Enrolment in DOTS cohorts 21

8 Reasons for treatment failure under DOTS W Pacific SE Asia Died Failed Defaulted Transferred Not evaluated Europe E Med Americas Africa Percent of cohort 22 Falling proportion of cases seeking retreatment in China, but not in India Retreatment pro oportion India China Years of control programme 23 Cure rates are lower for MDR-TB patients 24

9 51, people developed MDR-TB in 27 Estimated number MDR-TB cases arising in 27 (1s) % 3.2% 3.8% 17.1% Africa Americas Eastern Europe Mediterranean 4.8% South-East Asia 6.3% Western Pacific 25 MDR-TB among previously treated TB patients < 6% 6 2 % 2 4% > 4 % No estimate 26 Countries that had reported at least one XDR-TB case by end March 29 27

10 4. TB drug resistance and HIV/AIDS Rapid death of XDR-TB patients at Tugela Ferry: 52/53 died, half within 16 days Proportion s urviving Days since sputum collected 3

11 Drug resistant TB is linked to HIV coinfection in some places e.g., Latvia TB patients MDR Any resistance Unknown HIV status (%) 765/5162 (14.8) 1782/5162 (34.5) HIV-positive (%) 39/148 (26.4) 66/148 (44.6) Odds ratio (95%CL) 2.1 (1.4-3.) 1.5 ( ) p-value <.1 < Reversing the spread of drug resistant TB 32 /yr New cases/1, TB case rate stable or falling after epidemics peak in Africa and Europe Europe Going up Africa /yr 25 2 Going down SE Asia 1 E Med 2 World Americas 34% TB 66% TB New cases/1, 15 W Pacific 33

12 Stop production of resistant cases Benign epidemic R sensitive > 1 R resistant < 1 Index case Resistant Sensitive 34 Stop production and reproduction of resistant cases Severe epidemic R sensitive > 1 R resistant > 1 Index case Resistant Sensitive 35 United States r resistant /yr INH sensitive or cases/1, INH sensitive INH resistant MDR MDR cases/1,/yr

13 Hong Kong r resistant /yr INH sensitive or cases/1, INH sensitive INH resistant MDR ,/yr MDR cases/ Estonia r resistant /yr INH sensitive or cases/1, INH sensitive INH resistant MDR ,/yr MDR cases/ Russia (Orel, Tomsk) r resistant /yr INH sensitive or cases/1, INH sensitive INH resistant MDR ,/yr MDR cases/

14 In 9/1 sites, all TB strains are on a slow path to elimination ion number Case reproducti Severe epidemic Benign epidemic INH sensitive INH resistant Multidrug resistant 4 Reversing the spread of MDR-TB possible now, but will not eliminate TB by 25 Treat drug-sensitive TB to maximize fall in incidence 9 w TB cases/1,/yr New other countries 2 1 Benign drug sensitive TB Treat MDR-TB to interrupt self-sustaining transmission 4 35 Severe MDR-TB New TB cases/1,/yr other countries Spread of Beijing strains in Cape Town, South Africa Case s Beijing drug sensitive Beijing drug resistant Spread of Beijing strains in Cape Town, South Africa Year Source: van der Spuy, Tuberculosis (Edinb) 28 42

15 Drug resistant tuberculosis biology, epidemiology and control Drugs are needed until a better vaccine is made Drug resistance arises because:» Combinations of 1 st line drugs are not effectively used to treat sensitive strains of TB» Resistant strains not identified and treated with appropriate drugs Patients carrying resistant strains have a lower chance of cure and survival 43 References 1. World Health Organization, Global Tuberculosis Control: Epidemiology, Strategy, Financing. WHO report , World Health Organization: Geneva. p D'Costa, V.M., et al., Sampling the antibiotic resistome, Science, : p Lew, W., Pai, M, Oxlade, O, Martin, D, and Menzies, D, Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis, Annals of Internal Medicine, : p Dye, C. and B.G. Williams, Eliminating multidrug resistant tuberculosis slowly; Submitted 5. Orenstein, E.W., et al., Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis, Lancet Infectious Diseases, 29. 9: p Gagneux, S., et al., The competitive cost of antibiotic resistance in Mycobacterium tuberculosis, Science, : p Gagneux, S., Infectiousness of drug-resistant Mycobacterium tuberculosis, International Journal of Tuberculosis and Lung Disease, In press 8. Jassal, M. and W.R. Bishai, Extensively drug-resistant tuberculosis, Lancet Infectious Diseases, 29. 9: p van der Spuy, G.D., et al., Changing Mycobacterium tuberculosis population highlights clade-specific pathogenic characteristics, Tuberculosis (Edinb), Dye, C., et al., Erasing the world's slow stain: strategies to beat multidrug-resistant tuberculosis, Science, : p World Health Organization, Anti-Tuberculosis Drug Resistance in the World. Fourth Global Report. 28, World Health Organization: Geneva 44 45