IS SCIENCE ABLE TO BEAT XDR TB?

Francesco BlasiDepartment 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

GLOBAL TB PROGRAMME

Ref: Global TB Control Report 2013

ZERO TB DEATHS

A WORLD FREE OF TB

Proposed Vision

ZERO TB CASES

ZERO TB SUFFERINGGLOBAL TB

PROGRAMME

Proposed Goal and Targets

Target 1

95% reduction in TB deaths (compared

with 2015)

Target 2

<10/100 000 TB incidence rate

2035

GOAL: End the Global TB Epidemic

GLOBAL TB PROGRAMME

GLOBAL TB PROGRAMME

TARGETS• 35% reduction in

TB deaths

• <85/100 000 TB incidence rate

• No affected families with catastrophic costs due to TB

TARGETS• 75% reduction

in TB deaths

• <55/100 000 TB incidence rate

• No affected families with catastrophic costs due to TB

TARGETS• 90% reduction in

TB deaths

• <20/100 000 TB incidence rate

• No affected families with catastrophic costs due to TB

GOAL

• 95% reduction in TB deaths

• <10/100 000 TB incidence rate

• No affected families with catastrophic costs due to TB

20352020 20302025

Getting there: Milestones

GLOBAL TB PROGRAMME

High-quality,

integrated TB care

and preventio

n

Bold policies and supportive

systems

Intensified research

and innovation

Post-2015 TB StrategyProposed Pillars and Principles

GLOBAL TB PROGRAMME

Post-2015 TB Strategy: Pillar 1

Treatment of all people with TB including drug-resistant TB, with patient-centered support

3

Preventive treatment of people at high-risk and

vaccination for TB4

Early diagnosis of TB including universal drug susceptibility testing; systematic

screening of contacts and high-risk groups

1 2

Collaborative TB/HIV activities and management of co-morbidities

High-quality,

integrated TB care

and preventio

n

GLOBAL TB PROGRAMME

GLOBAL TB PROGRAMME

Post-2015 Global TB StrategyProposed Pillars

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

What is needed to accelerate incidence decline and target "elimination"?

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:-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

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 + DSTRapid speciationLPA 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 detectionEnzymatic detection

Ag and Ab detectionNAAT 2nd generation

2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

GLOBAL TB PROGRAMME

Gene Xpert

Progress in the roll-out of Xpert MTB/RIF, by July 2013

GLOBAL TB PROGRAMME

Ref: Global TB Control Report 2013

Culture and DST laboratories to diagnose MDR-TB, 2010

Laboratories per5M population

≥1

<1

NA

20/36 HBCs* have insufficient capacity to diagnose MDR-TB

*HBC= high-burden countryCountries = 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

Culture and DST laboratories to diagnose MDR-TB, 2010

Laboratories per5M population

≥1

<1

NA

≥1<1

Culture and DST laboratories per 5M, 2010

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

1717

Ad5 Ag85AMcMaster CanSino

VPM 1002Max Planck, VPM,

TBVI

Hybrid-I + IC31

SSI, TBVI, EDCTP,

Intercell

Immunotherapeutic:

Mycobacterial – whole cell

or extract

ID93 + GLA-SE IDRI, Aeras

Hyvac 4/ AERAS-404 + IC31

SSI, sanofi-pasteur, Aeras, Intercell

H56 + IC31SSI, Aeras, Intercell

MVA85A/AERAS-485

OETC, Aeras

AERAS-402/ Crucell Ad35Crucell, Aeras

RUTI

Archivel Farma, S.LM. Vaccae

Anhui Longcom,

China

M72 + AS01

GSK, Aeras

MTBVACTBVI, 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

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

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; 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.

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

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

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

GLOBAL TB PROGRAMME

25

Bedaquiline

Delamanid

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

Doctor

Director

Co-Director

AreaCoordinator

Expert #1

Expert #2

AreaCoordinator Doctor

Doctor submits the case

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).

(Co-)Director ask for modification

AC allocates to 2 experts

Expert #1 submits his report

Expert #2 submits his report

AC asks formodification

AC asks formodification

Validated by AC, report available

Description of the innovative platform

WHO National Representative

Eastern European doctor

EU

Doctor

Patient

Doctor, survivor, psychologist, nurse, microbiologist, rehab

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.

• The NTPR immediately receives the case in PDF, by Email

Doctor Selection of the country

Selection of the NTPR NTPR

Cross border use cases

Treating clinician NTPM Original clinician1. Creates short form

2. Allocate the case to original clinician

3. Fills the full form for the treating clinician

Source clinician NTPM Receiving clinician

1. Creates short form

2. Allocate the case to original clinician

3. Fills the full form for the receiving clinician

Treating clinician NTPM1. Creates short form, including names

1. Find the clinician who originally treated the patient:

2. Find a clinician to take care of a home country returning patient

4. Inform NTPM / Local authorities of a migrating patient relatives

THANK YOU FOR YOUR ATTENTION