tb elimination and tb drugs: can we make it? · 2019. 12. 21. · review of data, assessment of...
TRANSCRIPT
TB Elimination and TB drugs: can we make it?
Dr Mario Raviglione
Director, Global TB Programme
World Health Organization, Geneva, Switzerland
Photo: Riccardo Venturi
Keynote Address, Washington, DC, 2 October 2013
GLOBAL TB PROGRAMME
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
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
1.4 million* (1.3–1.6 million)
8.7 million (8.3–9.0 million)
Up to 0.5 million
All forms of TB
Multidrug-resistant TB
HIV-associated TB 1.1 million (13%) (1.0–1.2 million)
430,000 (400,000–460,000)
Source: WHO Global Tuberculosis Report 2012 * Including deaths attributed to HIV/TB
The Global Burden of TB -2011
Unknown, but probably > 150,000
GLOBAL TB PROGRAMME
Incidence rates, 2011
Highest rates in Africa, linked to high rates of HIV infection ~80% of HIV+ TB cases in Africa
Per 100 000 population
≥300 150–299 50–149
0–24 25–49
GLOBAL TB PROGRAMME
Estimated number of MDR-TB Cases, 2011 2/3 of all cases are in 7 countries
Russian Federation 44,000
(14% of global MDR burden)
India 66,000
(21% of global MDR burden)
China 61,000
(20% of global MDR burden)
Philippines 11,000
(4% of global MDR burden)
Pakistan 10,000
(3% of global MDR burden)
South Africa 8,100
Based on old survey data
Ukraine 9,000
Based on old survey data
WHO 2012
GLOBAL TB PROGRAMME
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
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)
GLOBAL TB PROGRAMME
TB cases and deaths, 1990–2011: achievements of control efforts with available tools (absolute numbers)
Incidence Mortality
HIV-negative mortality
Mill
ion
s
Total mortality peaked early 2000s at >1.8 million 1.4 million in 2011
1.5
0 0
10
1.0
0.5
5
2.5
7.5
Peak > 9 in early 2000s 8.7 million in 2011
HIV-positive mortality
All cases
HIV-positive cases
GLOBAL TB PROGRAMME
7.8 8.7
3.7
5.8
Global notifications Estimated incidence
TB c
ase
s (m
illio
ns)
1990 2000 2010
10
5
0
The case detection/notification gap
Nearly 3 million TB cases either not notified or not
detected
NO elimination without “capturing”
them
GLOBAL TB PROGRAMME
Global Progress on impact
51 million patients cured, 1995-2011
20 million lives saved since 1995
2015 MDG and other international targets on track
BUT, TB incidence declining far too slowly, 1/3 of cases not in the system, MDR-TB un-tackled etc.
GLOBAL TB PROGRAMME
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
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
China, Cambodia -4%/yr
GLOBAL TB PROGRAMME
-3.4%/yr -5%/yr
Incidence Prevalence
-3%/yr
-7%/yr
China
Cambodia
Sustained socio-
economic development
Stop TB Strategy with adequate resources
TB care subsidized and decentralised
Decline in TB burden in China and Cambodia
Recipe:
GLOBAL TB PROGRAMME
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
W Europe after WWII -10%/yr
GLOBAL TB PROGRAMME
Nat Rev Microbiol 2012; 10: 407–16.
-10%/year Sustained socio-economic
development
Universal health coverage & social protection
TB care widely accessible Screening of high-risk groups
(but limited impact)
Infection control practices (?)
TB incidence declined 10%/year after WWII in Europe (the Netherlands)
Recipe:
GLOBAL TB PROGRAMME
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
Eskimos > 10 ; < 20
GLOBAL TB PROGRAMME
Eskimos in Alaska, NW Canada and Greenland: 15% per year incidence decline
Highly focused & high intensity interventions
Screening and massive TLTBI
TB care decentralised
BCG vaccination
Improved health access & social protection
Economic development (?)
Recipe:
-17%/year (1955-74) -8.7%/year
(1972-74)
Grzybowski S, Styblo K, Dorken E. Tuberculosis in Eskimos. Tubercle 1976; (suppl.) 57: 1-58
GLOBAL TB PROGRAMME
Can TB control among Eskimos be generalised to the world?
GLOBAL TB PROGRAMME
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
Elimination target:<1 /million/yr -20%/yr
GLOBAL TB PROGRAMME
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
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"?
GLOBAL TB PROGRAMME
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 new drug submitted for approval in 2013 and rejected by EMA; -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
GLOBAL TB PROGRAMME
Diagnostic development pipeline, 2013
Source: Stop TB Partnership Working Group on New TB Diagnostics
2-specimen approaches
7 new diagnostics or diagnostic methods approved by WHO since 2007
3 diagnostics commercially available, not yet WHO-endorsed
6 diagnostics in development
LED microscopy
Xpert MTB/RIF
Liquid culture + DST
Rapid speciation
LPA for MDR-TB
Non-commercial
culture + DST
LPA for XDR-TB
LPA for MDR-TB, 2nd generation
Manual
NAAT
Xpert 2nd
generation
Rapid colorimetric DST
REFERENCE LEVEL
INTERMEDIATE LEVEL
PERIPHERAL LEVEL
VOC detection
Enzymatic detection
Ag and Ab detection
NAAT 2nd generation
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
GLOBAL TB PROGRAMME
Pipeline promising, but what do we need to eliminate TB? Potential impact of new diagnostics on TB incidence in S-E Asia
Sourc
e: L. A
bu R
addad e
t al, P
NA
S 2
009
•Led & NAAT at microscopy lab level
•Dipstick at point of care
To contribute to elimination of TB: 1.Rapid diagnostic test at point-of-care 2.Rapid drug susceptibility testing at point-of-care 3.As a result, possibility to treat with the proper regimen from day 1
GLOBAL TB PROGRAMME
Pipeline promising, but what do we need to eliminate TB? Potential impact of new tools on TB incidence in S-E Asia
Sourc
e: L. A
bu R
addad e
t al, P
NA
S 2
009
Add. Effects = effects also on latency
and infectiousness of cases in vaccinated
•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.Not just a single drugs, but… 2.Very short potent regimen for all forms of TB, and 3.Simple regimen for mass chemoprophylaxis
And/Or: Mass pre- and post-exposure vaccine
Synergy of interventions ! Action on both transmission and reactivation pathways
GLOBAL TB PROGRAMME
27 27
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 2013: good but needs to keep growing
GLOBAL TB PROGRAMME
Mass vaccination with a potent vaccine:
– pre-exposure:
– post-exposure:
Tools required for eradication in our lifetime – 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
GLOBAL TB PROGRAMME
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:
GLOBAL TB PROGRAMME
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
GLOBAL TB PROGRAMME
Ideally, we need as short a regimen as possible active against all types of TB, transforming TB into a “normal” 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 (a) treatment and (b) prevention?
GLOBAL TB PROGRAMME
New drugs: 1. Bedaquiline (BDQ) - First drug 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
GLOBAL TB PROGRAMME
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 (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 (DST, dose, never adding a single drug to a failing regimen)
5.Active pharmacovigilance (esp. cardiac, liver and renal toxicities)
GLOBAL TB PROGRAMME
Acceleration of BDQ phase III clinical trials
Development of accurate and reproducible BDQ DST method
Prospective collection of operational data on BDQ implementation
Bedaquiline: Urgent WHO call for:
GLOBAL TB PROGRAMME
New drugs: 2. Delamanid Negative opinion from European Medicines Agency
GLOBAL TB PROGRAMME
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 end 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
Re-purposed Drugs: A potent regimen for treatment
Novel regimens investigated by the TB Alliance including: PA824, Moxi, PZA, BDQ, CLO in various combinations (NC-001, NC-002, NC-003)
GLOBAL TB PROGRAMME
1. WHO recommends treatment of LTBI for: • People living with HIV (PLHIV) • Children <5 contacts of a TB case • Recent TST converters
2. IPT prevents TB with around 70% efficacy
3. Isoniazid 5 mg/kg daily (max 300 mg) for at least
6 months. Other shorter regimens efficacious (12wHP, 3HR)
4. Individual benefits clear, population level less clear (40% reported)
5. Modelling shows potential, but feasibility and scale-up remain an issue
Tools required for eradication in our lifetime: do we have a potent regimen for prevention?
GLOBAL TB PROGRAMME
Number of PLHIV on IPT increased in the past few years
But…only 450,000 started on IPT out of 3.2 million people screened for TB in HIV care settings in 2011
Completion rate in various studies varies 47-94%
Concerns by providers over side effects (real) and creation of drug resistance (not substantiated)
Implementation of IPT on a large scale is a challenge even in PLHIV
GLOBAL TB PROGRAMME
Open-label, randomized non-inferiority trial 12 weeks of 1-weekly rifapentine (P) (900 mg) + isoniazid (H) (900 mg) (DOT) vs. 9 months H
(300 mg) self-administered daily Subjects: close contacts of culture+ TB cases enrolled in USA, Canada, Brazil and Spain -
followed-up for 33 months
Active TB: 7/3986 in the 12wPH group (cumulative rate, 0.19%) vs. 15/3745 in the H group (cumulative rate, 0.43%), (rate difference: 0.24%)
PREVENT-TB Study: Methods & Outcomes
Sterling et al, NEJM, 2011
GLOBAL TB PROGRAMME
Treatment completion rates: 82.1% in the 12wPH group vs. 69.0% in the H group (P<0.001)
Permanent drug discontinuation owing to an adverse event: 4.9% in the 12wPH group vs. 3.7% in the H group (P = 0.009)
Rates of investigator-assessed drug-related hepatotoxicity: 0.4% and 2.7%, respectively (P<0.001)
PREVENT-TB Study: Methods & Outcomes
GLOBAL TB PROGRAMME
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
GLOBAL TB PROGRAMME
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
1. Enhance strategy and approach to TB care, control and research
2. Mobilize resources for research
3. Build full commitment
What can be done?
GLOBAL TB PROGRAMME
INTEGRATED, PATIENT-CENTRED CARE AND
PREVENTION
BOLD POLICIES
AND SUPPORTIVE
SYSTEMS
INTENSIFIED RESEARCH
AND INNOVATION
Post-2015 Global TB Strategy Proposed Pillars and Principles
GLOBAL TB PROGRAMME
INTEGRATED, PATIENT-CENTRED 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 with patient support
Collaborative TB/HIV activities; and management of co-morbidities
Preventive treatment of persons at high-risk and vaccination for TB
BOLD POLICIES AND SUPPORTIVE SYSTEMS
Political commitment with adequate resources for TB care and prevention
Engagement of communities, civil society organizations, and public and private care providers
Universal Health Coverage policy; and regulatory frameworks for case notification, vital registration, drug quality and rational use, and infection control
Social protection, poverty alleviation and actions on other TB determinants
INTENSIFIED RESEARCH AND INNOVATION
Discovery, development and rapid uptake of new tools, interventions, and strategies
Research to optimize implementation and impact, and promote innovations
VISION: A WORLD FREE OF TB – ZERO DEATHS, DISEASE AND SUFFERING DUE TO TB
Post-2015 Global TB Strategy
PRINCIPLES Government stewardship and accountability, with monitoring and evaluation
Strong coalition with civil society and communities Protection and promotion of human rights, ethics and equity
Adaptation of the strategy and targets at country level, with global collaboration
GLOBAL TB PROGRAMME
GLOBAL TB PROGRAMME
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) Less than 10 cases per 100,000 population
75% reduction in TB deaths (compared with 2015) TB cases reduced to less than 50 per 100,000 population No affected families face catastrophic costs due to TB
VISION:
GOAL:
TARGETS FOR 2035:
MILESTONES FOR 2025:
TB deaths TB incidence
Mill
ion
s
Rat
e p
er
10
0,0
00
po
pu
lati
on
Proposed targets Goal: End the global TB epidemic
Existing tools + UHC/SP
New tools results of R&D
-75%
-95%
Existing tools + UHC/SP
New tools results of R&D
GLOBAL TB PROGRAMME
2011 TB R&D investments witnessed an 82% increase over 2005 levels, but only 3% growth since 2010.
Total TB R&D Funding: 2005-2011: ¼ of the need
$700,000,000
$525,000,000
$350,000,000
$175,000,000
$0
2005 2006 2007 2008 2009 2010
$357,426,170
$417,824,708
$473,920,682 $491,476,917
$619,209,536 $630,446,462
2011
$649,648,183
GLOBAL TB PROGRAMME
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
$0
Fundamental research
New diagnostics
New drugs New vaccines
$420,000,000
$340,000,000
$740,000,000
$380,000,000
$80,000,000
Operational research
Global Plan Annual Targets 2011 Investments
$120,361,419
$55,043,541 $95,446,326 $84,140,175
$250,038,877
GLOBAL TB PROGRAMME
Investments in TB R&D 2005-2011. For drugs: the highest increase but enough?
$225,000,000
$75,000,000
$0 Drugs Basic Science Infrastructure/
Unspecified Operational
Research
$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
GLOBAL TB PROGRAMME
Top priority: commitment must change
"…
…"
GLOBAL TB PROGRAMME
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. For elimination one would need potent short treatments, mass TLTBI and potent pre- and post-exposure vaccines. None is available today
3. 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
4. Basic research is fundamental to gain further knowledge
5. R&D pipelines must be expanded , nurtured and well-financed. Development of a new regimen, shorter, simpler and cheaper, must be the ultimate aim
6. Increased financial resources for research: the TB community must keep working united to provide the right messages to investors and pursue progress
Conclusions and call to action
GLOBAL TB PROGRAMME
Eradication of tuberculosis: Will it be feasible?
" …there are three major weapons which can be
used in a policy of eradication: chemotherapy, vaccination, and chemoprophylaxis
GLOBAL TB PROGRAMME
…many thanks to all
Acknowledgments: Dr C. Lienhardt, Dr P. Glaziou, H. Getahun and our GTB teams
GLOBAL TB PROGRAMME