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Economic urgency and the pathway to eliminate TB
Dr Mario RaviglioneDirector, 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?
Estimated number of cases
Estimated number of deaths
1.3 (1.0-1.6) million*•74.000 in children•410.000 in women
8.6 (8.3-9.0) million•0.5 m in children•2.9 m in women
450.000 (300k-600k)
All forms of TB
Multidrug-resistant TB
HIV-associated TB 1.1 (1.0-1.2) million (13%)
320,000 (300k-340k)
Source: WHO Global Tuberculosis Report 2013 * Including deaths attributed to HIV/TB
The Global Burden of TB -2012
170,000 (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 - 2012
2015 MDG on track and reduction in TB mortality of 45% since 1990
56 million patients cured, 1995-2012
22 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 MDGtarget 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
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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 0.5-34) Risk Ratio (vs placebo) (Cochrane Review, 2010); • 4-7/100,000 incidence (Millard PS et al. West J Med. 1996;164:486-91.)
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:
1616
Ad5 Ag85AMcMaster CanSino
VPM 1002Max Planck, VPM,
TBVI
Hybrid-I + IC31
SSI, TBVI, EDCTP, Intercell
Immunotherapeutic:
Mycobacterial – whole cell
or extract
ID93 + GLA-SE IDRI, Aeras
Hyvac 4/ AERAS-404 + IC31
SSI, sanofi-pasteur, Aeras, Intercell
H56 + IC31SSI, Aeras, Intercell
MVA85A/AERAS-485
OETC, Aeras
AERAS-402/ Crucell Ad35Crucell, Aeras
RUTI
Archivel Farma, S.L
M. Vaccae
Anhui Longcom, China
M72 + AS01
GSK, Aeras
MTBVACTBVI, 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 StrategyProposed Pillars and Principles
Post-2015 Global TB StrategyProposed 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: 2005-2011. For vaccines: no increase
$225,000,000
$75,000,000
$0 Drugs Basic Science Infrastructure/Unspecified
OperationalResearch
$150,000,000
2005
2006
2007
2008
2009
2010
$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
$68,351,530
2011 $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 2013. 4-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)
Annual Global Plan Research Funding Targets vs. 2011 Investments: for vaccines, ¼ available$800,000,000
$600,000,000
$400,000,000
$200,000,000
$0Fundamental
researchNew
diagnosticsNew drugs New
vaccines
$420,000,000
$340,000,000
$740,000,000
$380,000,000
$80,000,000
Operationalresearch
Global Plan Annual Targets 2011 Investments
$120,361,419
$55,043,541$95,446,326 $84,140,175
$250,038,877