IS SCIENCE ABLE TO BEAT XDR TB?
Francesco Blasi
Department Pathophysiology and Transplantation,
University of Milan, Italy
Disclosures
• I have accepted grants, speaking and conference
invitations from
Almirall, Angelini, AstraZeneca,
Bayer, Chiesi, GSK, Guidotti-Malesci, Menarini,
Novartis,
Pfizer,
and
Zambon
• I have had recent or ongoing consultancy with Almirall,
Angelini, AstraZeneca, GSK, Menarini, Mundipharma
and Novartis
92 countries notified at least one case of XDR-TB
Ref: Global TB Control Report 2013
GLOBAL TB
PROGRAMME
Proposed Vision
A WORLD FREE OF TB
ZERO
TB DEATHS
ZERO
TB CASES
ZERO
TB SUFFERING
GLOBAL TB
PROGRAMME
Proposed Goal and Targets
GOAL: End the Global TB Epidemic
2035
Target 1
95% reduction in
TB deaths (compared
with 2015)
Target 2
<10/100 000
TB incidence rate
GLOBAL TB
PROGRAMME
Getting there: Milestones
2020
TARGETS
2025
2030
2035
GOAL
TARGETS
TARGETS
• 35% reduction in
TB deaths
• 75% reduction
in TB deaths
• 90% reduction in
TB deaths
• 95% reduction
in TB deaths
• <85/100 000 TB
incidence rate
• <55/100 000 TB
incidence rate
• <20/100 000 TB
incidence rate
• <10/100 000 TB
incidence rate
• No affected
families with
catastrophic
costs due to TB
• No affected
families with
catastrophic
costs due to TB
• No affected
families with
catastrophic costs
due to TB
• No affected
families with
catastrophic
costs due to TB
GLOBAL TB
PROGRAMME
Post-2015 TB Strategy
Proposed Pillars and Principles
Highquality,
integrated
TB care
and
prevention
GLOBAL TB
PROGRAMME
Bold
policies and
supportive
systems
Intensified
research
and
innovation
Post-2015 TB Strategy: Pillar 1
Highquality,
Early diagnosis
of TB
integrated
including universal
TB care
and
drug susceptibility
prevention
testing; systematic
2
1
screening of contacts
and high-risk groups
Preventive treatment of
people at high-risk and
vaccination for TB
GLOBAL TB
PROGRAMME
GLOBAL TB
PROGRAMME
4
3
Treatment of all people with
TB including drug-resistant
TB, with patient-centered
support
Collaborative TB/HIV
activities and management
of co-morbidities
Post-2015 Global TB Strategy
Proposed Pillars
Targets: 95% reduction in deaths and 90% reduction in
incidence (< 10 cases / 100,000 population) by 2035
Integrated, patientcentered 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
GLOBAL TB
PROGRAMME
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
What is needed to accelerate incidence decline and
target "elimination"?






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:
(i) transmission rate, and
(ii) reactivation of latent infection among the already infected
In turn, this requires…new tools and increased financing
What is in the pipelines for new diagnostics,
drugs and vaccines in 2013?
Diagnostics:
₋7 new diagnostics or diagnostic
endorsed by WHO since 2007;
₋6 in development;
₋yet no PoC test envisaged
methods
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
Vaccines:
₋11 vaccines in advanced phases of
₋development;
₋1 reported in 2012 with no detectable
efficacy
Diagnostic development pipeline, 2013
Liquid culture + DST
Rapid speciation
LPA for MDR-TB
Non-commercial
culture + DST
LPA for XDR-TB
LPA for MDR-TB, 2nd generation
REFERENCE LEVEL
Rapid colorimetric DST
2-specimen approaches Xpert MTB/RIF
LED microscopy
INTERMEDIATE LEVEL
Xpert 2nd
generation
Manual
NAAT
VOC detection
Enzymatic detection
Ag and Ab detection
NAAT 2nd generation
PERIPHERAL LEVEL
2007
2008
2009
2010
2011
2012
2013
2014
2015
7 new diagnostics or diagnostic methods approved by WHO since 2007
3 diagnostics commercially available, not yet WHO-endorsed
6 diagnostics in development
GLOBAL TB
PROGRAMME
Source: Stop TB Partnership Working Group on New TB Diagnostics
2016
Gene Xpert
Progress in the roll-out of Xpert MTB/RIF, by July 2013
Ref: Global TB Control Report 2013
GLOBAL TB
PROGRAMME
ulture and DST laboratories to diagnose MDR-TB, 2010
20/36 HBCs* have insufficient capacity
to diagnose MDR-TB
Culture and DST laboratories to diagnose MDR-TB, 2010
Laboratories per
5M population
≥1
≥1
Culture and DST
<1
<1 laboratories per 5M, 2010
*HBC= high-burden country
NA
Countries = Afghanistan, Armenia, Azerbaijan, Bangladesh, Belarus, Brazil, Bulgaria, Cambodia, China, DR Congo, Estonia, Ethiopia, Georgia, India,
Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Latvia, Lithuania, Mozambique, Myanmar, Nigeria, Pakistan, Philippines, Republic of Moldova, Russian
Federation, South Africa, Tajikistan, Tanzania, Thailand, Uganda, Ukraine, Uzbekistan, Viet Nam, Zimbabwe
Tools required for eradication in our lifetime – Vaccines :
Perspectives for a potent vaccine
Mass vaccination with a potent vaccine:
– pre-exposure:
would prevent infection to occur, and therefore disease,
but impact would take a long time to appear
– post-exposure:
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
Global TB Vaccine Pipeline 2014:
good but needs to keep growing
Phase II
Ad5 Ag85A
McMaster CanSino
ID93 + GLA-SE
IDRI, Aeras
Hyvac 4/ AERAS-404
+ IC31
SSI, sanofi-pasteur,
Aeras, Intercell
H56 + IC31
SSI, Aeras, Intercell
MTBVAC
TBVI, Zaragoza,
Biofabri
Hybrid-I + CAF01
SSI, TBVI
GLOBAL TB
PROGRAMME
VPM 1002
Max Planck, VPM,
TBVI
Hybrid-I + IC31
SSI, TBVI, EDCTP,
Intercell
RUTI
Archivel Farma, S.L
Phase IIb
Phase III
MVA85A/AERAS485
OETC, Aeras
AERAS-402/ Crucell
Ad35
Crucell, Aeras
M72 + AS01
GSK, Aeras
M. Vaccae
Anhui Longcom,
China
Viral vector
rBCG
Protein/adjuvant
Attenuated M.tb
Immunotherapeutic:
Mycobacterial – whole cell
or extract
17
BCG evidence and MVA85A phase 2b trial results
• BCG: efficacy in disseminated pediatric forms proven. Efficacy against adult
Reality check about vaccines
contagious forms variable. Revaccination efficacy nihil or dubious
• MVA85A:
1.Today we do not have a potent pre- and postexposure 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
Safe
pathogenesis and immunity

 Showing it is feasible to test vaccine candidates in large trials, but…
No detectable efficacy
GLOBAL TB
PROGRAMME
Latest recommendations for MDR-TB treatment – 2011
 A fluoroquinolone, preferably later-generation, and
ethionamide should be used
 4 second-line drugs likely to be effective including a
parenteral agent and pyrazinamide should be used in
the intensive phase
 Regimens should include at least pyrazinamide, a FQ, a
parenteral agent, ethionamide (or prothionamide), and
either cycloserine or PAS (p-aminosalicylic acid) if
cycloserine cannot be used
 Duration: at least 8 months for the intensive phase and
at least 20 months in total
Evidence: meta-analysis of >9000 individual MDR-TB patient data from 32 published observational
studies, none being randomised controlled trials (RCTs)
Management of Patients With Documented or Strongly
Suspected XDR-TB – Harrison’s Principles of Internal Medicine
1. Use pyrazinamide and any first-line oral agents that may be effective.
2. Use an injectable agent to which the strain is susceptible, and consider an extended duration of use
(12 months or possibly the whole treatment period). If the strain is resistant to all injectable agents;
a
use of one that the patient has not previously received is recommended.
3. Use a later-generation fluoroquinolone, such as moxifloxacin, levofloxacin or, possibly, gatifloxacin.
4. Use all second-line oral bacteriostatic agents (para-aminosalicylic acid, cycloserine, and ethionamide
or prothionamide) that have not been used extensively in a previous regimen or that are likely to be
effective.
b
5. Add bedaquiline and one or more of the following drugs : clofazimine, linezolid,
amoxicillin/clavulanic acid, clarithromycin, and carbapenems such as imipenem/cilastatin and
meropenem. If bedaquiline is not available, add linezolid plus two or more from the same list of drugs.
Monitor patients closely for linezolid-induced side effects such as myelosuppression and peripheral
neuropathy.
6. The introduction of delamanid into clinical use will provide further options. The association with
bedaquiline is, however, not recommended at the moment in view of the current lack of information
on potential additive cardiac toxicity.
7. Consider treatment with high-dose isoniazid if low-level resistance to this drug is documented.
8. Consider adjuvant surgery if there is localized disease.
9. Enforce strong infection-control measures.
10. Implement strict directly observed therapy and full adherence support as well as comprehensive
bacteriologic and clinical monitoring.
Reality check about treatment and chemoprophylaxis
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
GLOBAL TB
PROGRAMME
Re-purposed Drugs:
A potent regimen for treatment
 Assessment of fluoroquinolone trials in early 2014
 Three trials:
 OFLOTUB/Gatifloxacin for TB Phase III trial: gatifloxacin substituted for ethambutol – 4
months Rx - results in late 2013 failed to show non-inferiority. However, gatifloxacin was safe
 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
 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
GLOBAL TB
PROGRAMME
Bedaquiline
Delamanid
25
Building an MDR-TB Regimen
Delamanid
DELAMANID
Delamanid added to a background
MDR-TB regimen improves
significantly SS-C conversion at
month 2 (45.4 vs 29.6%)
35
ERS PHARMA EVENT - ROME
A symposium was organized by ERS with
the participation of supranational
agencies such as WHO and ECDC.
The aim of the event was to bring
together industry and key TB
stakeholders to discuss and agree on
common principles of rational
introduction and responsible use of new
TB tools.
ERS/WHO Consilium for M/XDR-TB
 Objectives:
 To allow a European clinician, free
cost, to load patient’s data and
receive in 1 working day
suggestions by 2 experts on how
to manage a difficult-to treat TB
case
 To support follow-up of TB
patients travelling within Europe
 Web-based regional platform
 Specialized team able to cover
several perspectives:(clinical for
both adults and children, surgical,
radiological, public health,
psychological, nursing, etc.
 Managed by ERS, in collaboration
with WHO Europe (formal agreement)
and ECDC
E-platform
Now operational at www.tbconsilium.org
• >50 International Experts selected by ERS/WHO/ECDC panel
• Legal issues tackled according to Swiss and European regulations
• Available in : English, Spanish, Portuguese and Russian
•Transborder migration component under development
Description of the innovative platform
Doctor, survivor, psychologist,
nurse, microbiologist, rehab
AC asks for
modification
(Co-)Director ask
for modification
Director
Doctor
Doctor submits
the case
Area
Coordinator
Co-Director
EU
AC allocates to 2
experts
Expert #1
Expert #1 submits
his report
Area
Coordinator
Expert #2
One of the 2 directors either ask for
more info, or allocate to an AC. Both
directors have the same rights (but 2
different accounts).
Validated by AC,
report available
Expert #2 submits
his report
AC asks for
modification
WHO National
Representative
Doctor
Patient
Eastern
European
doctor
Doctor
The platform principles: Case creation
• Any physician can create an account and submit a case,
through a 10 steps web form
• Estimated time: 20-45 min. Upload of pictures, scans, etc
possible.
The platform principles: Case creation
The platform principles: dashboards (example in Russian)
www.tbconsilium.org
The platform principles: Trans-border cases
• As of today, the system is limited to the creation of a case and
selection of a National TB Project Representative in the
country the patient is moving to.
Doctor
Selection of
the country
Selection of
the NTPR
NTPR
• The NTPR immediately receives the case in PDF, by
Email
Cross border use cases
1. Find the clinician who originally treated the patient:
Treating clinician
1. Creates
short form
NTPM
2. Allocate
the case to
original
clinician
Original clinician
3. Fills the full form for the treating clinician
2. Find a clinician to take care of a home country returning patient
Source clinician
1. Creates
short form
NTPM
3. Fills the full form for the receiving clinician
4. Inform NTPM / Local authorities of a migrating patient relatives
Treating clinician
1. Creates
short form,
including
names
NTPM
2. Allocate
the case to
original
clinician
Receiving
clinician
THANK YOU FOR YOUR ATTENTION