Achievements during the last 20 years and perspectives for elimination
Dr Mario Raviglione Director, Global TB Programme
World Health Organization, Geneva, Switzerland
Photo: Riccardo Venturi
23rd Swiss Symposium on TB 20 March 2014
Münchenwiler, Suisse
Overview
Overview of global burden of TB
Impact of interventions and progress
What future for TB control: is elimination possible in our lifetime?
Status of the R&D pipelines
What’s next?
Overview
Overview of global burden of TB
Impact of interventions and progress
What future for TB control: is elimination possible in our lifetime?
Status of the R&D pipelines
What’s next?
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)
South-East Asia 39%
Western Pacific 19%
Africa 27%
E. Mediterranean 8%
Europe 4%
Americas 3%
38% in India + China 26% in India
GLOBAL TB PROGRAMME
Ref: Global TB Control Report 2013
Estimated TB incidence rate, 2012
Percentage of new TB cases with MDR-TB Globally 3.6% (95% CI: 2.1–5.1%)
GLOBAL TB PROGRAMME
Ref: Global TB Control Report 2013
2012: Estimated number of MDR-TB cases out of notified TB cases - 80% of all cases are in 12 countries
Russian Fed.: 46,000 (15%)
India: 64,000 (21%)
China: 59,000 (20%)
Philippines: 13,000
Pakistan: 11,000
South Africa: 8,100
Ukraine: 6,800
Indonesia: 6,900
Kazakhstan: 8,800
Bangladesh: 4,200 Myanmar: 6,000
Uzbekistan: 4,000
92 countries notified at least one case of XDR-TB
GLOBAL TB PROGRAMME
Ref: Global TB Control Report 2013
Overview
Overview of global burden of TB
Impact of interventions and progress
What future for TB control: is elimination possible in our lifetime?
Status of the R&D pipelines
What’s next?
The global response: Targets, Global Plan, and Stop TB Strategy
1. Pursue high-quality DOTS expansion
2. Address TB-HIV, MDR-TB, and needs of the poor and vulnerable
3. Contribute to health system strengthening
4. Engage all care providers
5. Empower people with TB and communities
6. Enable and promote research
Goal 6: to have halted by 2015 and begun to reverse the incidence…
2015: 50% reduction in TB prevalence and deaths compared to 1990
2050: elimination (<1 case per million population)
TB cases and deaths, 1990–2012: achievements of control efforts with available tools (absolute numbers)
Mortality
Total mortality peaked early 2000s at 1.8 million 1.3 million in 2012
5
Incidence peaked at 9 million in early 2000s 8.6 million in 2012
Incidence
Ref: Global TB Control Report 2013
8.6
5.7
Global notifications Estimated incidence
The case detection/notification gap, 2012
Nearly 3 million TB cases either not notified or not
detected
NO elimination without “capturing” them
2.9 million missed
Ref: Global TB Control Report 2013
Global Progress on impact - 2012
TARGETS ON TRACK Incidence falling slowly: 2015 MDG on track
Reduction in TB mortality of 45% since 1990 22 million lives saved since 1995
87% cure rate and 56 million patients cured, 1995-2012
Ref: Global TB Control Report 2013
5 PRIORITIES FOR ACTION Reaching the “missed” cases (3 million not in the system)
Address MDR-TB as crisis
Accelerate response to TB/HIV
Increase financing to close resource gaps Ensure rapid uptake of innovations
Overview
Overview of global burden of TB
Impact of interventions and progress
What future for TB control: is elimination possible in our lifetime?
Status of the R&D pipelines
What’s next?
With current incidence decline: 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
US and Canada Eskimos, 1950s-60s: -17%/yr
Economic development: better nutrition & housing Universal health coverage & social protection TB care widely accessible to all and of high-standards Focused, high-intensity interventions 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:
This translates into…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"?
Overview
Overview of global burden of TB
Impact of interventions and progress
What future for TB control: is elimination possible in our lifetime?
Status of the R&D pipelines
What’s next?
What is in the pipelines for new diagnostics, drugs and vaccines in 2014?
Diagnostics: ₋7 new diagnostics or diagnostic methods endorsed by WHO since 2007; ₋6 in development; Drugs: -2 new drugs approved in 2012 & 2013 for MDR-TB; -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 reported in 2013 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 2.Simple regimen for mass chemoprophylaxis 3.Not a single drug or two…
Or: Mass pre- and post-exposure vaccine
Synergy of interventions ! Action on both transmission and reactivation pathways
Time-to-result: 1 h 45 min
GeneXpert
DNA molecules are mixed with dry PCR reagents
Sample is automatically filtered & washed
Ultrasonic lysis of filter-captured organisms to release DNA
Semi-nested real-time amplification & detection in
integrated reaction tube
4
5
6
Concentrates bacilli & removes inhibitors
1
2
Sputum liquefaction & inactivation with 2:1 SR
Transfer of 2 ml after 15 min
3 End of hands on work
Printable test result
A new test: Xpert MTB/RIF
Xpert: updated WHO Recommendations, 2013
1. Xpert MTB/RIF should be used as the initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated TB. (Strong recommendation)
2. Xpert MTB/RIF may be considered as a follow-on test to microscopy in settings where MDR-TB or HIV is of lesser concern, especially in further testing of smear-negative specimens. (Conditional recommendation acknowledging major resource implications)
3. Xpert MTB/RIF use also expanded to for use in childhood TB and extrapulmonary TB
New drugs: Bedaquiline (BDQ) – a diarylquinoline First drug develooped for TB in forty years
Only data from Phase IIb trials available , further efficacy and safety data needed from rigorously conducted Phase III trials
On December 28, 2012, the U.S. FDA approved BDQ
In early 2013, WHO commissioned independent review of data, assessment of validity of surrogate markers for MDR-TB outcome, and cost-effectiveness study
In January 2013, WHO held an Expert Committee meeting to get advice
In June 2013, after STAG-TB endorsement and through publication of interim guidelines, WHO recommended BDQ use for MDR-TB under five strict conditions
WHO has disseminated its guidelines to all Member States and is working on operational manual and other guidance
Bedaquiline: Interim WHO policy guidance
BDQ may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB, under five specific conditions (conditional recommendation, very low confidence in estimates of effect): 1. Treatment under close monitoring (eg, sound protocols) 2. Proper patient selection (caution: PLHIV and >65; no: children & pregnancy) 3. Patient informed consent required 4. Treatment design based on WHO recommendations (eg, DST, dose, never adding a single drug to a failing regimen) 5. Active pharmacovigilance (esp. cardiac, liver and renal toxicities) Urgent WHO call: acceleration of phase III trial; accurate DST; prospective collection of operational data on BDQ implementation
New drugs: Delamanid – a nitroimidazole European Medicines Agency authorized on 21-11-2013
1. Today we have two new drugs for MDR-TB, but 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 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 dubious
• MVA85A:
28 28
Ad5 Ag85A McMaster CanSino
VPM 1002 Max Planck, VPM,
TBVI
Hybrid-I + IC31 SSI, TBVI, EDCTP,
Intercell
Phase II Phase III Phase IIb
Immunotherapeutic: Mycobacterial – whole cell
or extract
ID93 + GLA-SE IDRI, Aeras
Hyvac 4/ AERAS-404 + 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 2014: 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
Assessment of new tools – 2014 Good pipelines, but no revolution yet
Diagnostics: ₋7 new diagnostics or diagnostic methods endorsed by WHO since 2007; ₋6 in development;
₋yet no PoC test Drugs: -2 new drugs approved in 2012 & 2013 for MDR-TB : little impact on epidemiology; -a regimen and other 2-3 drugs likely to be introduced in the next 4-7 years
-Yet no new regimen for all forms Vaccines: ₋11 vaccines in advanced phases of ₋development; ₋1 reported in 2013 with no detectable efficacy
₋Yet no new vaccine
Overview
Overview of global burden of TB
Impact of interventions and progress
What future for TB control: is elimination possible in our lifetime?
Status of the R&D pipelines
What’s next?
Vision, goal and targets
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) No affected families face catastrophic costs due to TB
75% reduction in TB deaths (compared with 2015) 50% reduction in TB incidence rate (compared with 2015) (< 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
Early diagnosis of TB including universal drug-susceptibility testing ; systematic screening of contacts and high-risk groups
Treatment of all people with TB including drug -resistant TB; and patient support
Collaborative TB/HIV activities and management of co-morbidities
Preventive treatment for persons at high-risk; and vaccination against tuberculosis
Bold policies and supportive systems
Political commitment with adequate resources for TB care and prevention
Engagement of communities , civil society organizations, and all public and private care providers
Universal health coverage policy; and regulatory framework for case notification, vital registration, quality and rational use of medicines, and infection control
Social protection, poverty alleviation, and actions on other determinants of TB
Intensified Research and Innovation
Discovery, development and rapid uptake of new tools, interventions and strategies
Research to optimize implementation and impact, and promote innovations
Targets: 95% reduction in deaths and 90% reduction in incidence (< 10 cases / 100,000 population) by 2035
Post-2015 Global TB Strategy Proposed Pillars
1. The world is on track to achieve the 2015 target of incidence reduction, and current measures can reduce deaths and cure patients, but they cannot eliminate TB
2. For elimination one would need potent short treatments, mass TLTBI, and potent pre- and post-exposure vaccines. None is available today . Basic research is fundamental to gain further knowledge and fill the R&D pipelines
3. MDR-TB challenge: a real public health crisis in some countries. Urgent measures needed: increase access to care, ensure rapid diagnosis, procure and ensure second-line medicines, support patients, continue R&D. Above all: prevent MDR-TB!
4. 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) much intensified research efforts
Conclusions
…grazie, merci, danke, thank you