1. IS SCIENCE ABLE TO BEAT XDR TB?
Francesco Blasi
Department Pathophysiology and Transplantation,
University of Milan, Italy

2. 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

3. 92 countries notified at least one case of XDR-TB
Ref: Global TB Control Report 2013
GLOBAL TB
PROGRAMME
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

4. A WORLD FREE OF TB Proposed Vision ZERO TB DEATHS ZERO TB CASES ZERO
TB SUFFERING
PROGRAMME
GLOBAL TB

5. GOAL: End the Global TB Epidemic
Proposed Goal and Targets
GOAL: End the Global TB Epidemic
2035
Target 1
95% reduction in
TB deaths (compared with 2015)
Target 2
<10/
TB incidence rate
PROGRAMME
GLOBAL TB

6. 2020 2025 2030 2035 Getting there: Milestones TARGETS TARGETS TARGETS
35% reduction in TB deaths
<85/ TB incidence rate
No affected families with catastrophic costs due to TB
TARGETS
75% reduction in TB deaths
<55/ TB incidence rate
No affected families with catastrophic costs due to TB
TARGETS
90% reduction in TB deaths
<20/ TB incidence rate
No affected families with catastrophic costs due to TB
GOAL
95% reduction in TB deaths
<10/ TB incidence rate
No affected families with catastrophic costs due to TB
Key words:
4 , four stages, movement, timeline, years, period, ahead, steps, aspects

7. Post-2015 TB Strategy Proposed Pillars and Principles
Bold policies and supportive systems
High-quality, integrated TB care and prevention
Intensified research and innovation
Government stewardship and accountability, with monitoring and evaluation
Building a strong coalition with civil society and communities
Protecting and promoting human rights, ethics and equity
Adaptation of the strategy and targets at country level, with global collaboration

8. Post-2015 TB Strategy: Pillar 1
High-quality, integrated 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, with patient-centered support 2 1
I will now go into more details on each of the 3 pillars.
The first pillar is focused on the essential components of TB care and prevention, emphasizing its universality and its quality. It incorporates all technological and system innovations that have been proven to be effective in enhancing the original DOTS and Stop TB Strategies.
In practical terms, there are 4 components of this pillar:
First, rapid diagnosis and universal drug-susceptibility testing for all cases, and systematic screening of contacts and high-risk groups.
Second, treatment to everyone and for all types of TB including drug-resistant disease, with special emphasis on the support needed for the patient.
Third, collaborative activities between TB and AIDS national programmes for TB patients living with HIV and the management of any other relevant co-morbidity.
Fourth, preventive treatment of persons at high-risk and BCG vaccination to newborns.
Preventive treatment of people at high-risk and vaccination for TB 4
Collaborative TB/HIV activities and management of co-morbidities 3
PROGRAMME
GLOBAL TB

9. Post-2015 Global TB Strategy Proposed Pillars
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

10. In turn, this requires…new tools and increased financing
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:
In turn, this requires…new tools and increased financing
(i) transmission rate, and
(ii) reactivation of latent infection among the already infected

11. What is in the pipelines for new diagnostics, drugs and vaccines in 2013?
7 new diagnostics or diagnostic methods endorsed by WHO since 2007;
6 in development;
yet no PoC test envisaged
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

12. Diagnostic development pipeline, 2013
Liquid culture + DST
Rapid speciation
LPA for MDR-TB
LPA for XDR-TB
Non-commercial
culture + DST
LPA for MDR-TB, 2nd generation
REFERENCE LEVEL
Rapid colorimetric DST
2-specimen approaches
Xpert MTB/RIF
Manual NAAT
Xpert 2nd
generation
LED microscopy
INTERMEDIATE LEVEL
VOC detection
Enzymatic detection
Ag and Ab detection
NAAT 2nd generation
PERIPHERAL LEVEL
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

13. Gene Xpert

14. Progress in the roll-out of Xpert MTB/RIF, by July 2013
Ref: Global TB Control Report 2013
GLOBAL TB
PROGRAMME

15. 20/36 HBCs* have insufficient capacity to diagnose MDR-TB≥1
Culture and DST laboratories per 5M, 2010
<1
*HBC= high-burden country
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

16. Mass vaccination with a potent vaccine:
Tools required for eradication in our lifetime – Vaccines :
Perspectives for a potent vaccine
Mass vaccination with a potent vaccine:
pre-exposure:
post-exposure:
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

17. Global TB Vaccine Pipeline 2014: good but needs to keep growing
Phase II
Phase III
Phase IIb
Phase I
Ad5 Ag85A
McMaster CanSino
VPM Max Planck, VPM, TBVI
MVA85A/AERAS OETC, Aeras
ID93 + GLA-SE
IDRI, Aeras
Hyvac 4/ AERAS IC31 SSI, sanofi-pasteur, Aeras, Intercell
H56 + IC31 SSI, Aeras, Intercell
Hybrid-I + IC31 SSI, TBVI, EDCTP, Intercell
AERAS-402/ Crucell Ad35 Crucell, Aeras
rBCG
Viral vector
Protein/adjuvant
Attenuated M.tb
RUTI Archivel Farma, S.L
M72 + AS01 GSK, Aeras
M. Vaccae
Anhui Longcom, China
MTBVAC
TBVI, Zaragoza, Biofabri
Immunotherapeutic: Mycobacterial – whole cell or extract
Hybrid-I + CAF01
SSI, TBVI
GLOBAL TB
PROGRAMME 17 17

18. Reality check about vaccines
BCG evidence and MVA85A phase 2b trial results
BCG: efficacy in disseminated pediatric forms proven. Efficacy against adult contagious forms variable. Revaccination efficacy nihil or dubious
MVA85A:
Reality check about vaccines
Today we do not have a potent pre- and post-exposure vaccine, we have BCG
Today we do not have yet clarity about correlates of immunity and bio-markers
Today, we do not fully understand pathogenesis and immunity
Safe
Showing it is feasible to test vaccine candidates in large trials, but… No detectable efficacy
GLOBAL TB
PROGRAMME

19. 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)

20. XDR-TB treatment: what's left?
Aminoglycosides
Amikacin, Kanamycin
Polypeptides
Capreomycin
First line drugs
Fluoroquinolones
Ciprofloxacin, Ofloxacin, etc. +
Thioamides
Ethionamide, Prothionamide
It is important to understand the treatment of MDR TB in order to understand the definitions used in this study. The second-line drugs used for the treatment of MDR TB are divided into 6 main classes which are shown in the blue boxes on this slide. These include: aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine, and para-aminosalicylic acid, or PAS. Examples of commonly used drugs in each class are shown to the right of each box with more than 1 drug in its class.
In designing a treatment regimen for patients with MDR TB, a clinician needs to select at least 4-6 drugs from separate classes to which the organism is susceptible. If the infecting organism is resistant to multiple drug classes, it is very difficult to design a treatment regimen with enough drugs that are known to be effective against TB.
Serine analogues
Cycloserine
PAS

21. 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; use of one that the patient has not previously received is recommended.a
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.
5. Add bedaquiline and one or more of the following drugsb: 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.

22. Reality check about treatment and chemoprophylaxis
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
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
Today we do not have a test capable of identifying who will progress to active TB among the ?2 billion infected
GLOBAL TB
PROGRAMME

23. A potent regimen for treatment
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 month arm did not work
Three trials have investigated the performance of treatment regimen including a third-generation fluoroquinolone and the possibility to shorten treatment of drug-susceptible TB to 4 months. R
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

24. GLOBAL TB
PROGRAMME

25. Bedaquiline
Delamanid

26. Building an MDR-TB Regimen

28. Delamanid

35. Delamanid
Delamanid added to a background MDR-TB regimen improves significantly SS-C conversion at month 2 (45.4 vs 29.6%)

40. 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.

41. 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

42. Now operational at www.tbconsilium.org
E-platform
Now operational at
>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

43. Doctor, survivor, psychologist, nurse, microbiologist, rehab
Description of the innovative platform
Doctor, survivor, psychologist, nurse, microbiologist, rehab EU
WHO National Representative
Eastern
European
doctor
Doctor
Patient

44. The platform principles: Case creation
Any physician can create an account and submit a case, through a 10 steps web form
Estimated time: min. Upload of pictures, scans, etc possible.

45. The platform principles: Case creation

46. The platform principles: dashboards (example in Russian)

48. Selection of the country
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.
The NTPR immediately receives the case in PDF, by
Selection of the country
Selection of the NTPR
Doctor
NTPR

49. 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
2. Allocate the case to original clinician
Receiving clinician
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

51. Clinical question to the expert Time necessary to load (minutes)
Country requesting
Country of birth
Sex
Age
Clinical question to the expert
Time necessary to load (minutes)
Response time (hours)
Susceptibility
of the strain
P/EP
Italy
Moldova F 29
Treatment regimen (after 9 months, still bacteriologically positive, when to stop it) 20 24
Susceptible P
Vietnam 14
Treatment regimen (drug choice)
MDR M 34
Treatment regimen drug (drug choice)
XDR
India 12
Pre-XDR
P/EP (lymph node) UK 19
Treatment regimen (drug choice )
EP (cervical and mediastinal lymphnode)
Romania 36
Treatment regimen and drug interactions 28
Treatment duration and drug choice
Somalia 40
Treatment regimen, advice for monitoring the response and when to stop treatment
144
Expert # 1 took 6 days to respond
EP (Mediastinal lymphadenopathy) 35
Advices for management of cachexia, muscle wasting and possible surgery. Confirmation of MDR treatment plan. 48 32
Treatment regimen, advice for surgery, advice for PET
EP ( Chronic abscess left thigh)

55. THANK YOU FOR YOUR ATTENTION