The challenges of eliminating tuberculosis

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1 The challenges of eliminating tuberculosis Christopher Dye World Health Organization

2 Pre 2015: dynamics and control of TB Drug resistance as part of the TB challenge Post 2015: TB elimination and sustainable development

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4 Pre 2015: dynamics and control of TB

5 TB deaths/100,000/yr Britain beat TB in the 19th and 20th centuries? Much of the (slow) decline preceded drugs Keats 1821 E Bronte 1848 Lawrence 1930 C Bronte 1855 Mansfield 1923 Orwell 1953 Leigh

6 BCG: the jab since 1921 ~100M doses to infants annually in >150 countries with vaccination policy protects children from meningeal and disseminated TB, not adults from pulmonary TB 100 High BCG coverage across all WHO regions 80 Percent coverage 60 Africa Americas 40 E Mediterranean Europe 20 Global SE Asia W Pacific WHO/UNICEF data

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8 Cases or deaths/100k population/year Tuberculosis in Alaskan Eskimos Grzybowski et al 1976 "greatest contribution intensive case finding and treatment" Cases 13%/year t 1/2 5.3 years Deaths 30%/years t 1/2 2.3 years

9 Global burden of TB 4-5% 20%

10 TB case rate stable or falling after epidemics peak in Africa and Europe TB cases/100,000/yr A Resurgent, stabilizing 30% Driven by HIV Linked to drug resistance S&E Africa C&W Africa World E Europe Year TB cases/100,000/yr B Stable or falling slowly 70% C Europe Despite drug treatment High income Year SE Asia World W Pacific E Mediterranean Latin America

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12 TB MDGs by 2015? Stop TB targets: falling incidence, halve prevalence and death rates Incidence Prevalence Mortality HIV+ All regions WHO Global tuberculosis report 2014 Not Africa, E Med, Europe Not Africa, E Med, Europe

13 Dynamics of drug resistant TB

14 MDR-TB AND XDR-TB Multidrug-resistant tuberculosis MDR-TB Resistant to at least isoniazid and rifampicin Extensively drug-resistant TB XDR-TB Resistant to isoniazid and rifampin, plus any fluoroquinolone and at least 1 of 3 injectable second-line drugs (amikacin, kanamycin or capreomycin) Totally drug-resistant TB TDR-TB Informal, undefined by susceptibility tests

15 Drug resistant TB worldwide >50% cases of MDR-TB in China, India, Russia 480,000 cases MDR-TB in % new cases, 20% recurrent cases

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17 >85 countries by 2014

18 of 480,000 detected Only 10% of MDR- TB cases known to be successfully treated diagnosed treated Poor practice promotes the evolution of resistance? cured

19 Six criteria govern long-term dynamics of drug-sensitive and drugresistant TB, based on case reproduction numbers Condition on R 0S Condition on R 0R Outcomes Number of cases < 1 < R 0S Extinction of S and R > R 0S Extinction of S and R > 1 Extinction of S; R persists in selfsustaining transmission cycles > 1 > R 0S Extinction of S; R persists in selfsustaining transmission cycles < R 0S Persistence of S and R < 1 Extinction of S, persistence of R Fraction new cases resistant Falling Rising Rising to fixation Rising to fixation Rising then steady Rising then steady but low Dye (2015) The Population Biology of Tuberculosis (Princeton UP)

20 Stop production of resistant cases Benign epidemic R 0 sensitive > 1 R 0 resistant < 1 Index case Resistant Sensitive

21 Stop production and reproduction of resistant cases Severe epidemic R 0 sensitive > 1 R 0 resistant > 1 Index case Resistant Sensitive

22 Two factors that determine the evolution of drug resistant TB strains 5 Treatment Rx failure Resistance after Rx failure Relative risk of treatment failure Risk of resistance after failure Isoniazid vs sensitive MDR vs isoniazid 0.0 Isoniazid from sensitive MDR from isoniazid Data pooled from 138 surveys in 118 countries

23 MDR-TB half as fit as drug susceptible TB in Peruvian households Hazard ratio MDR-TB 0.56 ( ) Grandjean et al 2015 PLoS Med (June 23)

24 Relative fitness of MDR-TB strains: not just biology Odds ratio resistant:sensitive Based on studies of case clusters (Dye 2015) Study number

25 80 Beware preconceptions: MDR-TB in Cape Town Beijing drug sensitive Beijing drug resistant 60 MDR-TB cases Years van der Spuy 2008

26 MDR new TB cases (%) Forecasting the future of MDR-TB 15 years ago Isoniazid + Rifampicin since early 1970s Years of drug use range of results from 47 areas Dye & Espinal 2001

27 Estonia Contrasting dynamics of resistance: E Europe 0.3 Estonia 60 Reported cases/100,000/yr %/yr Proportion new cases MDR %/yr Year Russia Year 0.4 Russia Reported cases/100,000/yr %/yr Year Proportion new cases MDR Archangelsk 5%/yr Ivanovo 9%/yr 0.1 Tomsk 7%/yr Orel 9%/yr Year

28 8 Contrasting dynamics of resistance: low incidence United States United States Reported cases/100,000/yr %/yr Proportion new cases MDR %/yr Year United Kingdom Year United Kingdom Reported cases/100,000/yr %/yr Proportion new cases MDR %/yr Year Year

29 Case reproduction number Case reproduction numbers for sensitive and resistant TB mostly < 1 INH sensitive INH resistant Multidrug resistant 0.0

30 Reversing the spread of MDR-TB possible now, but will not eliminate TB by 2050 New TB cases/100,000/yr Treat drug-sensitive TB to maximize fall in incidence other countries Benign drug sensitive TB New TB cases/100,000/yr Treat MDR-TB to interrupt self-sustaining transmission Severe MDR-TB 9 other countries

31 After 2015: Sustainable Development Goals

32 2010 MDG Summit 2012 Rio+20 Post-2015 Development Agenda Mandate for the SDGs SUSTAINABLE DEVELEOPMENT GOALS Environment, poverty, health on same agenda 17 PROPOSED GOALS AND TARGETS 3. Attain healthy life for all at all ages By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.

33 10000 TB cases: elimination by 2050? TB cases/million/year Up to 10%/yr with current technology Beyond current technology 2%/yr 10%/yr Elimination <1/M 20%/yr Year

34 United States of America Europe

35 USA: eliminate TB by Total Cases/million/yr 10 US born Not on course for elimination: needs boost from IPT for HIV- IPT HIV - Base On course for elimination

36 TB deaths/100,000/yr Britain beat TB in the 19th and 20th centuries? Much of the (slow) decline preceded drugs Keats 1821 E Bronte 1848 Lawrence 1930 C Bronte 1855 Mansfield 1923 Orwell 1953 Leigh

37 Three times the risk of TB in poorest Peruvian households Hazard ratio lowest 3rd 2.86 ( ) Grandjean et al 2015 PLoS Med (June 23)

38 TB, universal health coverage and sustainable development UHC

39 The challenges of eliminating tuberculosis The epidemic 9 million new cases in 2014 Falling 1-2%/yr << 20%/yr needed for elimination No country on course to elimination target Drug resistance 0.5M new cases MDR-TB each year - stable XDR-TB in 85+ countries trends unknown Spread of drug resistance resistance is preventable and (slowly) reversible DR-TB not the main obstacle to TB elimination Elimination integrating social wisdom into biotechnology (cf Dubos)

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