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FUTURE RESEARCH MOVEMENTFOR TUBERCULOSIS CONTROL
FUTURE RESEARCH MOVEMENTFOR TUBERCULOSIS CONTROL
A/Prof. Nguyen Viet Nhung, MD., PhDVice director, National Lung Hospital, Hanoi, Viet Nam
Deputy Manager, National Tuberculosis control ProgramVice President, Viet Nam Association against TB and Lung Diseases
Regional Green Light Committee - WHO / WPR
Looking beyond 2015:Rationale
At the 65th World Health Assembly in May 2012, Member States called upon WHO todevelop a new post-2015 TB strategy and targets and present this to Member States atthe 67th World Health Assembly in 2014. Some States also urged WHO to start theformal process through the Executive Board and World Health Assembly in 2013.
Start DevelopingDraft Global strategy
for TB prevention, treatment and carepost-2015
Dr Malgosia GrzemskaStop TB Department
World Health OrganizationTAG TB/WPRO
Phnom Penh, Cambodia, 23-25 October 2012
Moving towards a new approach:Addressing the most vulnerable
Half a million women andover 70,000 children die ofTB each year; 10 million“TB” orphans
Poor, crowded & poorly ventilatedsettings
TB linked to HIV infection, malnutrition,alcohol, drug and tobacco use, diabetes
Half a million women andover 70,000 children die ofTB each year; 10 million“TB” orphans
Migrants, prisoners, minorities,refugees face risks, discrimination& barriers to care
Moving towards a new approach:Addressing key challenges
Case detectionA third of cases notdiagnosed/reported
TB/HIV co infectionSpecial challenge in Africa
Multidrug - resistant TBSpecial challenge in Eastern
Europe
Bottlenecks for financing ofresearch and innovation
Case detectionA third of cases notdiagnosed/reported
TB/HIV co infectionSpecial challenge in Africa
Multidrug - resistant TBSpecial challenge in Eastern
Europe
Weak health policies,systems, financing, and
services
Under-engagedcommunities and
providers
The way forward:Expansion with Innovation
• Greater commitment• Active case finding• Molecular diagnosis• Treat all forms of TB• Treatment of latent TB• Research and
innovation
• Much greater engagement ofall providers and community
• Much stronger system support• Social protection• Whole-of-government
approach• Major drive for Innovation
More and BetterStop TB Strategy
• (Enhanced and)innovative TBcare/DOTS
• Bold policies andsupportive systems
• Intensified researchand innovation
• Greater commitment• Active case finding• Molecular diagnosis• Treat all forms of TB• Treatment of latent TB• Research and
innovation
More andBetter DOTS
• Much greater engagement ofall providers and community
• Much stronger system support• Social protection• Whole-of-government
approach• Major drive for Innovation
• (Enhanced and)innovative TBcare/DOTS
• Bold policies andsupportive systems
• Intensified researchand innovation
Post-2015TB Strategy
Proposed three pillarsEstablishing anew post-2015 strategy
Innovative TB Care
Boldpolicies andsupportive
systems Intensifiedresearch
andinnovation
WHO
and Partners Support to countriesSurv
eilla
nce,
Mon
itorin
g a
nd E
valu
atio
n
Intensifiedresearch
andinnovation
WHO
and Partners Support to countriesSurv
eilla
nce,
Mon
itorin
g a
nd E
valu
atio
n
Innovative TB Care Bold policies andsupportive systems Intensified Research
Vision: A world free of TB
DRAFT Post-2015 TB Strategy
CORE PRINCIPLES:Government stewardship with adequate financing
Engagement of communities and civil society; Collaboration with private sectorPromotion of human rights, ethics and equity
Adaptation of the strategy and targets at country levelMonitoring and evaluation across all strategy components
Innovative TB Care
Rapid diagnosis and systematicscreening of contacts and otherhigh-risk populations
Treatment of all forms of TB withpatient support
Management of drug-resistant TB,TB/HIV and other co-morbidities
Preventive treatment of high-riskpopulations
Bold policies andsupportive systems
Policies pursuing a system-wideapproach for integration of TB care inall health services
Universal Health Coverage with freeTB care and social protection
Regulatory framework including vitalregistration, mandatory case-notification, infection control andrational use of quality-assured drugsWhole-of-government approach toaddressing social determinants of TBincluding poverty reduction, foodsecurity, healthy living and workingconditions
Intensified Research
Discovery, development and rapiduptake of new diagnostics, drugsand vaccines
Research to optimizeimplementation and adoptinnovations
Sept 2012
Six categories ofTB Research
1. Epidemiology2. Fundamental research3. Diagnostics4. Treatment5. Vaccines6. Operational and
public health research
1. Epidemiology2. Fundamental research3. Diagnostics4. Treatment5. Vaccines6. Operational and
public health research
1. Epidemiology– Determine the burden of TB
– Understand variations in the dynamics of TB indifferent settings and identify the social andbiological drivers of M. tuberculosis transmissionat population level
2. Fundamental research– Characterize human TB by modern biochemical,
clinical and epidemiological approaches
– Better understand the host–pathogen interaction
– Use ‘discovery science’ to identify biomarkersthat can better differentiate the stages of thedisease spectrum.
1. Epidemiology– Determine the burden of TB
– Understand variations in the dynamics of TB indifferent settings and identify the social andbiological drivers of M. tuberculosis transmissionat population level
2. Fundamental research– Characterize human TB by modern biochemical,
clinical and epidemiological approaches
– Better understand the host–pathogen interaction
– Use ‘discovery science’ to identify biomarkersthat can better differentiate the stages of thedisease spectrum.
3. Diagnostics– Evaluate biomarkers identified in fundamental
studies for use as diagnostic tools
– Design and validate a set of tools for diagnosis ofactive drug-sensitive and drug-resistant TB andlatent TB infection that are feasible and applicableat various health-care levels in high-burden settings
– Improve existing diagnostic tests for active drug-sensitive and drug-resistant TB and latent TBinfection at various health-care levels in high-burden settings
– Evaluate new diagnostic tools, and conductdemonstration studies, followed by evaluation ofthe programmatic impact of all diagnostic tools
3. Diagnostics– Evaluate biomarkers identified in fundamental
studies for use as diagnostic tools
– Design and validate a set of tools for diagnosis ofactive drug-sensitive and drug-resistant TB andlatent TB infection that are feasible and applicableat various health-care levels in high-burden settings
– Improve existing diagnostic tests for active drug-sensitive and drug-resistant TB and latent TBinfection at various health-care levels in high-burden settings
– Evaluate new diagnostic tools, and conductdemonstration studies, followed by evaluation ofthe programmatic impact of all diagnostic tools
4. Treatment– Develop new drugs and treatment strategies
– Develop a shorter regimen for drug-susceptible TBthat can be used in combination with HIVtreatment
– Develop a safer, more efficacious, shorter regimenfor drug-resistant TB that is compatible with HIVtreatment
– Develop safe, reliable, user-friendly drug regimenssuitable for all forms of TB in children andcompatible with HIV treatment
– Develop safer, more effective, shorter regimens forTB infected individuals
– Develop safer, shorter, highly effective regimensfor drug-susceptible and drug-resistant latent TBinfection that are compatible with HIV treatmentand suitable for children
4. Treatment– Develop new drugs and treatment strategies
– Develop a shorter regimen for drug-susceptible TBthat can be used in combination with HIVtreatment
– Develop a safer, more efficacious, shorter regimenfor drug-resistant TB that is compatible with HIVtreatment
– Develop safe, reliable, user-friendly drug regimenssuitable for all forms of TB in children andcompatible with HIV treatment
– Develop safer, more effective, shorter regimens forTB infected individuals
– Develop safer, shorter, highly effective regimensfor drug-susceptible and drug-resistant latent TBinfection that are compatible with HIV treatmentand suitable for children
5. Vaccines– Conduct fundamental research as a basis for the
development of effective TB vaccines
– Conduct research and clinical testing to betterunderstand the safety and efficacy of BCG andcandidate vaccines
– Develop standardized assays and findbiomarkers for use in clinical trials to identifycorrelates of protection
– Develop new pre- and post-exposure vaccines,new adjuvants and new delivery platforms
– Improve and standardize preclinical assays toevaluate immunogenicity and potentialprotective efficacy of new TB vaccines
– Improve and standardize testing of TB vaccinesin clinical trials
5. Vaccines– Conduct fundamental research as a basis for the
development of effective TB vaccines
– Conduct research and clinical testing to betterunderstand the safety and efficacy of BCG andcandidate vaccines
– Develop standardized assays and findbiomarkers for use in clinical trials to identifycorrelates of protection
– Develop new pre- and post-exposure vaccines,new adjuvants and new delivery platforms
– Improve and standardize preclinical assays toevaluate immunogenicity and potentialprotective efficacy of new TB vaccines
– Improve and standardize testing of TB vaccinesin clinical trials
6. Operational and public health research– Improve TB case detection and diagnosis
– Investigate methods to improve access to treatment and treatmentdelivery for drug-sensitive and drug-resistant TB
– Institute sustainable collaboration with all private and publicproviders of TB care and control
– Address priority operational research questions at global, regional ornational level to improve implementation of collaborative TB andHIV activities, and also in respect of other diseases or conditions inwhich the risk for TB is increased
– Design collaborative activities in other disease programmes orsituations in which TB risk is increased
– Investigate methods to encourage community participation, toincrease the effectiveness of all interventions (e.g. case-finding,access to treatment and care delivery)
– Optimize infection control to reduce TB transmission
– Improve measurement of disease burden by effective surveillance,monitoring and evaluation of TB programmes
– Ensure that countries have the capacity to perform TB-relatedoperational research to improve TB programme performance
6. Operational and public health research– Improve TB case detection and diagnosis
– Investigate methods to improve access to treatment and treatmentdelivery for drug-sensitive and drug-resistant TB
– Institute sustainable collaboration with all private and publicproviders of TB care and control
– Address priority operational research questions at global, regional ornational level to improve implementation of collaborative TB andHIV activities, and also in respect of other diseases or conditions inwhich the risk for TB is increased
– Design collaborative activities in other disease programmes orsituations in which TB risk is increased
– Investigate methods to encourage community participation, toincrease the effectiveness of all interventions (e.g. case-finding,access to treatment and care delivery)
– Optimize infection control to reduce TB transmission
– Improve measurement of disease burden by effective surveillance,monitoring and evaluation of TB programmes
– Ensure that countries have the capacity to perform TB-relatedoperational research to improve TB programme performance
Five priority areas1. Access, screening and
diagnosis of TB;
2. Sustainable collaboration withall care-providers for TBcontrol;
3. Prevention of TB in peopleliving with HIV, and jointtreatment of HIV and TB;
4. Access to and delivery oftreatment for drug-susceptibleand M/XDR-TB;
5. Capacity-building foroperational research.
1. Access, screening anddiagnosis of TB;
2. Sustainable collaboration withall care-providers for TBcontrol;
3. Prevention of TB in peopleliving with HIV, and jointtreatment of HIV and TB;
4. Access to and delivery oftreatment for drug-susceptibleand M/XDR-TB;
5. Capacity-building foroperational research.
KEY FACTS AND MESSAGES ON FUTURE TB RESEARCHGlobal TB Report 2012 - WHO
• Develop new TB diagnostics, drugs, and vaccines
• WHO has endorsed several new diagnostic tests
or methods since 2007, including Xpert
MTB/RIF that has the potential to transform TB
care. Other new tests, including point- of- care
tests, are in development.
• 11 vaccine candidates for TB prevention in
Phase I or Phase II trials and one
immunotherapeutic vaccine in a Phase III trial. It
is hoped that one or two of the candidates in a
Phase II trial will enter a Phase III trial in the
next 2–3 years, with the possibility of licensing at
least one new vaccine by 2020.
• Develop new TB diagnostics, drugs, and vaccines
• WHO has endorsed several new diagnostic tests
or methods since 2007, including Xpert
MTB/RIF that has the potential to transform TB
care. Other new tests, including point- of- care
tests, are in development.
• 11 vaccine candidates for TB prevention in
Phase I or Phase II trials and one
immunotherapeutic vaccine in a Phase III trial. It
is hoped that one or two of the candidates in a
Phase II trial will enter a Phase III trial in the
next 2–3 years, with the possibility of licensing at
least one new vaccine by 2020.
• 11 new or repurposed anti-TB drugs in clinical trials.– Phase III trials of 4-month regimens for the treatment of drug-
susceptible TB are expected in 2013.
– 2 new compounds are being evaluated for use as an adjunct tocurrent optimized regimens for MDR-TB; one compound recentlymoved to a Phase III trial and the other is expected to do so beforethe end of 2012.
– A new three - drug combination regimen that could be used totreat both drug-sensitive TB and MDR-TB and shortentreatment duration has been tested in a Phase II study of earlybactericidal activity, with encouraging results.
• Funding for TB research and development has increased inrecent years, but stagnated between 2009 and 2010. At US$630 million in 2010, funding falls far short of the annualtarget of US$ 2 billion specified in the Global Plan to StopTB 2011–2015.
• 11 new or repurposed anti-TB drugs in clinical trials.– Phase III trials of 4-month regimens for the treatment of drug-
susceptible TB are expected in 2013.
– 2 new compounds are being evaluated for use as an adjunct tocurrent optimized regimens for MDR-TB; one compound recentlymoved to a Phase III trial and the other is expected to do so beforethe end of 2012.
– A new three - drug combination regimen that could be used totreat both drug-sensitive TB and MDR-TB and shortentreatment duration has been tested in a Phase II study of earlybactericidal activity, with encouraging results.
• Funding for TB research and development has increased inrecent years, but stagnated between 2009 and 2010. At US$630 million in 2010, funding falls far short of the annualtarget of US$ 2 billion specified in the Global Plan to StopTB 2011–2015.
Lead Optimization PreclinicalDevelopment
GLPTox. Phase I Phase II Phase III
Delamanid (OPC-67683)GatifloxacinMoxifloxacinRifapentine
AZD5847Bedaquiline (TMC-207)LinezolidNovel Regimens2
PA-824RifapentineSQ-109Sutezolid (PNU-100480)
CPZEN-45DC-159aQ201SQ609SQ641
Preclinical DevelopmentDiscovery1 Clinical Development
DiarylquinolineDprE InhibitorsGyrB inhibitorsInhA InhibitorsLeuRS InhibitorsMGyrX1 inhibitorsMycobacterial Gyrase
InhibitorsPyrazinamide AnalogsRiminophenazinesRuthenium (II) complexesSpectinamidesTranslocase-1 Inhibitors
Global TB Drug Pipeline
BTZ043TBA-354
AZD5847Bedaquiline (TMC-207)LinezolidNovel Regimens2
PA-824RifapentineSQ-109Sutezolid (PNU-100480)
CPZEN-45DC-159aQ201SQ609SQ641
DiarylquinolineDprE InhibitorsGyrB inhibitorsInhA InhibitorsLeuRS InhibitorsMGyrX1 inhibitorsMycobacterial Gyrase
InhibitorsPyrazinamide AnalogsRiminophenazinesRuthenium (II) complexesSpectinamidesTranslocase-1 Inhibitors
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone1 Ongoing projects without a lead compound series can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.2 Combination regimens: first clinical trial (NC001) of a novel TB drug regimen testing the three drug combination of PA-824,moxifloxacin, and pyrazinamide was initiated November 2010 and completed in 2011 with promising results. The secondclinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitiveand multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide andclofazimine in combinations and is scheduled to begin September 2012.
Updated: June 18, 2012
www.newtbdrugs.org
4 Repurposed Drugs6 New Drugs3 New Classes
Drugs currently in the regulatoryreview processDrugs currently in the regulatoryreview process
• TB Diagnosis– Techniques– Approach
• Treatment– Drugs / Regimens– Delivery Management
• Prevention– Infection control– Vaccination– Preventive therapy
• Specific categories– Smear negative– TB/HIV– Pediatric TB– M/XDR TB
• Research Partnership
• TB Diagnosis– Techniques– Approach
• Treatment– Drugs / Regimens– Delivery Management
• Prevention– Infection control– Vaccination– Preventive therapy
• Specific categories– Smear negative– TB/HIV– Pediatric TB– M/XDR TB
• Research Partnership
Acknowledgements• WHO/Stop TB Department:
• Diana Elizabeth Weil, Malgosia Grzemska, Mukund Waman Uplekar
and group for developing a New TB control Strategy post 2015
• Christian Lienhardt and GROUP in development of the “AnInternational Roadmap for Tuberculosis Research” and “Prioritiesin Operational Research to Improve Tuberculosis Care and Control”
• WHO/WPRO: Catharina Van Weezenbeek
• NTP Viet Nam: Dinh Ngoc Sy and staff
• WHO/Stop TB Department:• Diana Elizabeth Weil, Malgosia Grzemska, Mukund Waman Uplekar
and group for developing a New TB control Strategy post 2015
• Christian Lienhardt and GROUP in development of the “AnInternational Roadmap for Tuberculosis Research” and “Prioritiesin Operational Research to Improve Tuberculosis Care and Control”
• WHO/WPRO: Catharina Van Weezenbeek
• NTP Viet Nam: Dinh Ngoc Sy and staff
