The challenges of eliminating tuberculosis

The challenges of eliminating tuberculosis Christopher Dye World Health Organization

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

Pre 2015: dynamics and control of TB

TB deaths/100,000/yr Britain beat TB in the 19th and 20th centuries? 300 250 200 150 100 50 Much of the (slow) decline preceded drugs Keats 1821 E Bronte 1848 Lawrence 1930 C Bronte 1855 Mansfield 1923 Orwell 1953 Leigh 1967 0 1820 1840 1860 1880 1900 1920 1940 1960 1980 2000

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 0 1980 1985 1990 1995 2000 2005 2010 WHO/UNICEF data

Cases or deaths/100k population/year 1000 100 10 1 0.1 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 1950 1955 1960 1965 1970 1975

Global burden of TB 4-5% 20%

TB case rate stable or falling after epidemics peak in Africa and Europe TB cases/100,000/yr 350 300 250 200 150 100 50 A Resurgent, stabilizing 30% Driven by HIV Linked to drug resistance S&E Africa C&W Africa World E Europe 0 1990 1995 2000 2005 2010 Year TB cases/100,000/yr 250 200 150 100 50 B Stable or falling slowly 70% C Europe Despite drug treatment High income 0 1990 2000 2010 Year SE Asia World W Pacific E Mediterranean Latin America

TB MDGs by 2015? Stop TB targets: falling incidence, halve prevalence and death rates 1990-2015 Incidence Prevalence Mortality HIV+ All regions WHO Global tuberculosis report 2014 Not Africa, E Med, Europe Not Africa, E Med, Europe

Dynamics of drug resistant TB

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

Drug resistant TB worldwide >50% cases of MDR-TB in China, India, Russia 480,000 cases MDR-TB in 2013 4-5% new cases, 20% recurrent cases

>85 countries by 2014

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

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)

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

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

Two factors that determine the evolution of drug resistant TB strains 5 Treatment Rx failure Resistance after Rx failure Relative risk of treatment failure 4 3 2 1 Risk of resistance after failure 0.8 0.6 0.4 0.2 0 Isoniazid vs sensitive MDR vs isoniazid 0.0 Isoniazid from sensitive MDR from isoniazid Data pooled from 138 surveys in 118 countries

MDR-TB half as fit as drug susceptible TB in Peruvian households Hazard ratio MDR-TB 0.56 (0.34-0.90) Grandjean et al 2015 PLoS Med (June 23)

Relative fitness of MDR-TB strains: not just biology Odds ratio resistant:sensitive 10.0 1.0 0.1 Based on studies of case clusters (Dye 2015) 1 2 3 4 5 6 7 8 9 10 11 Study number

80 Beware preconceptions: MDR-TB in Cape Town Beijing drug sensitive Beijing drug resistant 60 MDR-TB cases 40 20 0 0 2 4 6 8 10 12 Years van der Spuy 2008

MDR new TB cases (%) 14 12 10 8 6 4 2 0 Forecasting the future of MDR-TB 15 years ago Isoniazid + Rifampicin since early 1970s 0 10 20 30 Years of drug use range of results from 47 areas Dye & Espinal 2001

Estonia Contrasting dynamics of resistance: E Europe 0.3 Estonia 60 Reported cases/100,000/yr 40 20-7.9%/yr Proportion new cases MDR 0.2 0.1 2.8%/yr 120 0 1997 2000 2003 2006 2009 2012 Year Russia 0.0 1997 2000 2003 2006 2009 2012 Year 0.4 Russia Reported cases/100,000/yr 100 80 60-1.2%/yr 40 20 0 1998 2001 2004 2007 2010 2013 Year Proportion new cases MDR Archangelsk 5%/yr 0.3 0.2 Ivanovo 9%/yr 0.1 Tomsk 7%/yr Orel 9%/yr 0.0 1996 2001 2006 2011 Year

8 Contrasting dynamics of resistance: low incidence United States United States 0.015 Reported cases/100,000/yr 6 4 2-4.9%/yr Proportion new cases MDR 0.01 0.005 1.1%/yr 0 1997 2000 2003 2006 2009 2012 Year United Kingdom 16 0 1997 2002 2007 2012 Year United Kingdom 0.015 Reported cases/100,000/yr 12 8 4 0.87%/yr Proportion new cases MDR 0.01 0.005 5.2%/yr 0 2000 2003 2006 2009 2012 Year 0 1998 2003 2008 2013 Year

Case reproduction number 2.0 1.5 1.0 0.5 Case reproduction numbers for sensitive and resistant TB mostly < 1 INH sensitive INH resistant Multidrug resistant 0.0

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 90 80 70 60 50 40 9 other countries 30 20 10 Benign drug sensitive TB 0 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 2020 New TB cases/100,000/yr 40 35 30 25 20 15 10 5 0 Treat MDR-TB to interrupt self-sustaining transmission Severe MDR-TB 9 other countries 1996 1998 2000 2002 2004 2006 20082010 2012 2014 2016 2018 2020

After 2015: Sustainable Development Goals

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.

10000 TB cases: elimination by 2050? TB cases/million/year 1000 100 10 Up to 10%/yr with current technology Beyond current technology 2%/yr 10%/yr Elimination <1/M 20%/yr 1 1990 2000 2010 2020 2030 2040 2050 Year

United States of America Europe

USA: eliminate TB by 2050 100 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 1 1990 2000 2010 2020 2030 2040 2050

TB deaths/100,000/yr Britain beat TB in the 19th and 20th centuries? 300 250 200 150 100 50 Much of the (slow) decline preceded drugs Keats 1821 E Bronte 1848 Lawrence 1930 C Bronte 1855 Mansfield 1923 Orwell 1953 Leigh 1967 0 1820 1840 1860 1880 1900 1920 1940 1960 1980 2000

Three times the risk of TB in poorest Peruvian households Hazard ratio lowest 3rd 2.86 (1.60-4.76) Grandjean et al 2015 PLoS Med (June 23)

TB, universal health coverage and sustainable development UHC

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)