Economic urgency and the pathway to eliminate TB Dr Mario Raviglione Director, Global TB Programme World Health Organization, Geneva, Switzerland Photo: Riccardo Venturi

Overview Quick overview of global burden of TB Impact of interventions and progress Is elimination possible in our lifetime? What is needed to accelerate incidence decline? What can be done today?

Overview Quick overview of global burden of TB Impact of interventions and progress Is elimination possible in our lifetime? What is needed to accelerate incidence decline? What can be done today? GLOBAL TB PROGRAMME

Estimated number of cases Estimated number of deaths 1.3 ( ) million* in children in women 8.6 ( ) million 0.5 m in children 2.9 m in women (300k-600k) All forms of TB Multidrug-resistant TB HIV-associated TB 1.1 ( ) million (13%) 320,000 (300k-340k) Source: WHO Global Tuberculosis Report 2013 * Including deaths attributed to HIV/TB The Global Burden of TB ,000 (102k-242k)

Overview Quick overview of global burden of TB Impact of interventions and progress Is elimination possible in our lifetime? What is needed to accelerate incidence decline? What can be done today?

Global Progress on impact MDG on track and reduction in TB mortality of 45% since million patients cured, million lives saved since 1995 BUT, TB incidence declining too slowly, 1/3 of cases not in the system, MDR-TB challenge not yet properly addressed Ref: Global TB Control Report 2013

Overview Quick overview of global burden of TB Impact of interventions and progress Is elimination possible in our lifetime? What is needed to accelerate incidence decline? What can be done today?

Full implementation of Global Plan: 2015 MDG target reached but TB not eliminated by 2050 Current rate of decline -2%/yr W Europe after WWII -10%/yr China, Cambodia -4%/yr Elimination target:<1 / million / yr -20%/yr

Overview Quick overview of global burden of TB Impact of interventions and progress Is elimination possible in our lifetime? What is needed to accelerate incidence decline? What can be done today?

Economic development: better nutrition & housing Universal health coverage & social protection TB care widely accessible to all and of high-standards Focused, high-intensity interventions, including BCG in children Screening of high-risk groups and mass TLTBI Infection control practices However… while incidence decline can accelerate, “elimination” is another story, as it requires major reduction of: In turn, this requires…new tools and increased financing (i) transmission rate, and (ii) reactivation of latent infection among the already infected What is needed to accelerate incidence decline and target "elimination"?

What is in the pipelines for new diagnostics, drugs and vaccines in 2013? Diagnostics: ₋7 new diagnostics or diagnostic methods endorsed by WHO since 2007; ₋6 in development; ₋yet no PoC test envisaged Drugs: -1 new drug approved in late 2012, but probably little impact on epidemiology; -1 expected to be approved in 2013; -a regimen and other 2-3 drugs likely to be introduced in the next 4-7 years Vaccines: ₋11 vaccines in advanced phases of ₋development; ₋1 just reported with no detectable efficacy

Pipeline promising, but what do we need to eliminate TB? Potential impact of new tools on TB incidence in S-E Asia Source: L. Abu Raddad et al, PNAS 2009 Add. Effects = effects also on latency and infectiousness of cases in vaccinated Led & NAAT at microscopy lab level Dipstick at point of care Regimen 1 = 4-month, no effect on DR Regimen 2 = 2-month, 90% effective in M/XDR Regimen 3 = 10-day, 90% effective in M/XDR To eliminate TB: 1.Very short potent regimen for all forms, and 2.Simple regimen for mass chemoprophylaxis Or: Mass pre- and post-exposure vaccine Synergy of interventions ! Action on both transmission and reactivation pathways

Ideally, we need as short a regimen as possible active against all types of TB, transforming TB into a common infectious disease. However, we only have “short-course chemotherapy” Ideally, we need mass chemoprophylaxis (TLTBI), as TLTBI prevents reactivation with up to 70% efficacy. However: Safety issue on a mass scale: fatal hepatitis 4.13 (95% CI ) Risk Ratio (vs placebo) (Cochrane Review, 2010); 4-7/100,000 incidence (Millard PS et al. West J Med. 1996;164: ) Single dose treatment not available: no existing drug kills intracellular bacteria (such as M. tuberculosis) in a non-replicative state Screening of truly infected or at real risk not available: no “IGRA-plus” Tools required for eradication in our lifetime (drugs ): Do we have potent regimen for treatment and prevention?

1.Today we do not have a potent treatment regimen that lasts <2 months and treats TB and M/XDR-TB. It will probably not be available for at least 5-10 years 2.Today we do have a treatment for latent TB infection that is 70% efficacious, but difficult to scale-up to whole population (? 2 billion infected) or even to high-risk groups 3.Today we do not have a test capable of identifying who will progress to active TB among the ?2 billion infected Reality check about treatment and chemoprophylaxis

BCG evidence and MVA85A phase 2b trial results Safe Showing it is feasible to test vaccine candidates in large trials, but… No detectable efficacy BCG: efficacy in disseminated pediatric forms proven. Efficacy against adult contagious forms variable. Revaccination efficacy nihil or dubious MVA85A:

16 Ad5 Ag85A McMaster CanSino VPM 1002 Max Planck, VPM, TBVI Hybrid-I + IC31 SSI, TBVI, EDCTP, Intercell Phase IIPhase IIIPhase IIb Immunotherapeutic: Mycobacterial – whole cell or extract ID93 + GLA-SE IDRI, Aeras Hyvac 4/ AERAS IC31 SSI, sanofi-pasteur, Aeras, Intercell H56 + IC31 SSI, Aeras, Intercell MVA85A/AERAS- 485 OETC, Aeras AERAS-402/ Crucell Ad35 Crucell, Aeras RUTI Archivel Farma, S.L M. Vaccae Anhui Longcom, China M72 + AS01 GSK, Aeras MTBVAC TBVI, Zaragoza, Biofabri rBCG Viral vector Protein/adjuvant Attenuated M.tb Hybrid-I + CAF01 SSI, TBVI Global TB Vaccine Pipeline 2013: good but needs to keep growing Reality check about vaccines 1.Today we do not have a potent pre- and post-exposure vaccine, we have BCG 2.Today we do not have yet clarity about correlates of immunity and bio-markers 3.Today, we do not fully understand pathogenesis and immunity

Overview Quick overview of global burden of TB Impact of interventions and progress Is elimination possible in our lifetime? What is needed to accelerate incidence decline? What can be done today?

1.Enhance strategy and approach to TB care, control and research 2.Mobilize resources for research What can be done?

DRAFT Post-2015 TB Strategy at a glance  A WORLD FREE OF TB Zero deaths, disease and suffering due to TB  End the Global TB Epidemic  95% reduction in TB deaths (compared with 2015)  90% reduction in TB incidence rate (<10/100,000)  75% reduction in TB deaths (compared with 2015)  50% reduction in TB incidence rate (< than 55/100,000)  No affected families face catastrophic costs due to TB VISION: GOAL: TARGETS FOR 2035: MILESTONES FOR 2025:

Projected acceleration of TB incidence decline to target levels Optimize current tools, pursue universal health coverage and social protection Introduce new vaccine, new prophylaxis Average -10%/year -5%/year Current global trend: -2%/year Average -17%/year

Integrated, patient- centered TB care and prevention Bold policies and supportive systems Intensified research and innovation Post-2015 Global TB Strategy Proposed Pillars and Principles

Targets: 95% reduction in deaths and 90% reduction in incidence (< 10 cases / 100,000 population) by 2035 Post-2015 Global TB Strategy Proposed Pillars

This is what is necessary: Vaccine blueprint – but do we have enough funding for it? Five keys to progress: Creativity in research and discovery Correlates of immunity and biomarkers for TB vaccines Clinical trials: harmonization & cooperation Rational selection of TB vaccine candidates The critical need for advocacy, community acceptance and funding

Investments in TB R&D by Research Category: For vaccines: no increase $225,000,000 $75,000,000 $0 DrugsBasic Science Infrastructure/ Unspecified Operational Research $150,000, $114,862,738 Vaccines $32,170,084 $144,336,532$76,555,111$30,194,127 $170,233,497$73,225,383$33,967,288 $174,178,052$109,337,224$34,411,742 $191,483,304$110,133,485$49,536,760 $230,540,443$78,446,298$60,895,355 Diagnostics $81,892,167 $91,643,009 $113,325,202 $98,728,019 $172,447,841 $129,008,413 $40,741,527 $43,205,600 $40,734,199 $25,032,930 $56,686,918 $83,145,063 $19,408,124 $31,890,329 $42,435,113 $49,788,950 $38,921,229 $48,410,889 $68,351, $250,038,877$95,446,326$84,140,175$120,361,419$44,617,845$55,043,541

Conclusions and call to action 1.The world is on track to achieve the (un-ambitious) 2015 target of incidence reduction, and current measures can reduce deaths and cure patients, but they cannot eliminate TB 2.Three pillars will be the basis to accelerate incidence decline: (i) universal access to quality TB care and control, (ii) bold health system policies, and (iii) intensified research efforts 3.For elimination one would need potent short treatments, mass TLTBI and potent pre- and post-exposure vaccines. None is available today 4.Basic research is fundamental to gain further knowledge and R&D pipelines must be expanded, nurtured and well-financed. 5.Increased financial resources for TB Vaccine development: we need a new global TB vaccine “partnership” of all engaged developers, investors, donors so that efforts are synergised and synchronised. This is not a job for one agency only!

Eradication of tuberculosis: Will it be feasible? I bet you: a potent vaccine will do! …Merci beaucoup!

Assessment of fluoroquinolone trials in early 2014 Three trials: OFLOTUB/Gatifloxacin for TB Phase III trial: gatifloxacin substituted for ethambutol – 4 months Rx - results expected second half 2013 ReMox: moxifloxacin substituted for ethambutol or isoniazid – 4 months Rx - results expected early 2014 Rifaquin trial: moxifloxacin substituted for ethambutol (intensive phase), associated with rifapentine once weekly in continuation phase – presentation at CROI month arm did not work Tools required for eradication in our lifetime: (1a) A potent regimen for treatment NC-001 regimen: PA-824, pyrazinamide, moxifloxacin

1.IPT prevents TB with around 70% efficacy, individual benefits clear, population level less clear (40% reported). 2.WHO recommends treatment of LTBI for: People living with HIV (PLHIV) Children <5 contacts of a TB case Recent TST converters 3.Isoniazid 5 mg/kg daily (max 300 mg) for at least 6 months, but shorter regimens also efficacious (12wHP, 3HR) 4.Fatal hepatitis: 2010 Cochrane review 4.3 RR (0.5-34); incidence 4-7/100,000 (Millard 1996) 5.Modelling shows potential, but feasibility and scale-up remain an issue. No predictive test Tools required for eradication in our lifetime: a potent regimen for prevention/ treatment of latent infection?

Mass vaccination with a potent vaccine: –pre-exposure: –post-exposure: Tools required for eradication in our lifetime (2: Vaccines): Perspectives for a potent vaccine would prevent infection to occur, and therefore disease, but impact would take a long time to appear would prevent “reactivation”, and would have impact on transmission as new cases will not emerge any longer out of the pool of already infected. However, it would not prevent new infection

Enhanced TB Strategy Post-2015 (draft) Targets: 95% reduction of deaths and < 10 cases / 100,000 population by 2035

Annual Global Plan Research Funding Targets vs Investments: for vaccines, ¼ available $800,000,000 $600,000,000 $400,000,000 $200,000,000 $0 Fundamental research New diagnostics New drugsNew vaccines $420,000,000 $340,000,000 $740,000,000 $380,000,000 $80,000,000 Operational research Global Plan Annual Targets2011 Investments $120,361,419 $55,043,541 $95,446,326 $84,140,175 $250,038,877