XDR-TBXDR-TBFrancesco 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

GLOBAL TB PROGRAMME

Ref: Global TB Control Report 2013

Drug Resistant TB: Development and Spread

Definitions

MDR-TB = Strains resistant to at least INH and RIF (most important 1st-line drugs)

XDR-TB = MDR TB strains with additional resistance to any fluoroquinolone and any of the 3 injectable second-line drugs (amikacin, kanamycin, capreomycin)

TDR, XXDR = Resistance to all drugs (not standardised defin)

MDR TB XDR TBTB with any drug resistance

TDR/XXDR TB

CURRENT THERAPY AND UNMET NEEDS

TB Alliance programs seek to help all TB patient populations

• There is little/no treatment for XDR-/TDR-TB

• Several new drugs with no pre-existing resistance could have promising data by 2014

– Bedaquiline, delamanid, PA-824, sutezolid, SQ109

• Proposal: initiate global study of combinations of NCEs in patients with XDR-/TDR-TB at select centers with aim of cure

– Potential collaborators: Janssen, Otsuka, TB Alliance, Pfizer, Sequella

– Help patients who would otherwise die

– Combines a “compassionate use” program with a clinical trial to advance understanding of entirely novel regimens, which can then be applied in DS- and MDR-TB

New Chemical Entities in XDR-TB

NIX-TB: “RESCUE” STUDY FOR XDR-TB

GLOBAL TB PROGRAMME

Delamanid

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

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Delamanid (ERJ 2014)

Results• Favourable outcomes were observed in 143/192 patients

(74.5%) who receiveddelamanid ≥6 months, compared to 126/229 patients (55.0%) who received delamanid for ≤2 months.

• Mortality was reduced to 1.0% among those receiving long-term delamanid, versus short-term/no delamanid (8.3%), p<0.001.

• Treatment benefit was also seen among patients with extensively drug-resistant disease.

Conclusion

Delamanid for 6 months in combination with an optimized background regimen can improve outcomes and reduce mortality among patients with both MDR- and XDR-TB.

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New drugs: Delamanid – a nitroimidazole European Medicines Agency authorized on 21-11-2013

New drugs: Bedaquiline (BDQ) – a diarylquinoline First drug developed for TB 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

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 (eg, sound protocols)2. Proper patient selection (caution: PLHIV and >65; no: children & pregnancy)3. Patient informed consent required4. Treatment design based on WHO recommendations (eg, DST, dose, never adding a single drug to a failing regimen)5. Active pharmacovigilance (esp. cardiac, liver and renal toxicities)

Urgent WHO call: acceleration of phase III trial; accurate DST; prospective collection of operational data on BDQ implementation

Bedaquiline (Bq) and PA-824

EBA at 2 w: PA-824+moxi+Z

better than: bq, bq+Z, bq+PA-824

Comparable to WHO Cat 1

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The cost (€) to treat TB and M/XDR is enormous: prevention is cost-effective

Cost per case Susceptible

MDR-TB XDR-TB

Estonia* 2,615 15,344 15,344

France 5,691

Germany 7,7,51 55,003 188.466

UK 6,234 62,343

Netherlands 8,340 46,990 148,136

Italy 9,294

Finland 8,243

Spain 9,384

AVERAGE 7,848 54,779 168,310

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Interventions over time: Interventions over time: old weapons might

be useful again to manage XDR

First sanatorium First sanatorium Germany, 1857Germany, 1857 First Dispensary, First Dispensary,

Scotland, 1897Scotland, 1897

Koch, Mtb,Koch, Mtb,18821882

Drugs, 1945-1962Drugs, 1945-1962

MMR,1950-1980MMR,1950-1980

Fox:Ambulatory treatment, 1968Fox:Ambulatory treatment, 1968

Styblo model, 1978Styblo model, 1978

DOTS, 1991DOTS, 1991

sanatoriasanatoria Outbreak Management,Outbreak Management,

Risk Group ManagementRisk Group Management

screeningscreening

BCG vaccinationBCG vaccination

drug therapydrug therapy

Socio-economic improvementSocio-economic improvement

Pneumotorax, Italy, 1907Pneumotorax, Italy, 1907

2121

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

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Pneumothorax

24

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Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB control, to prevent M/XDR-TB

2. Scale-up programmatic management and care of MDR-TB and XDR-TB

3. Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB

4. Ensure availability of quality drugs and their rational use

5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV

prevalence settings7. Mobilize urgently resources domestically and

internationally8. Promote research and development into new

diagnostics, drugs and vaccines

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Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB control, to prevent M/XDR-TB2. Scale-up programmatic management and care of

MDR-TB and XDR-TB

3. Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB

4. Ensure availability of quality drugs and their rational use

5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV

prevalence settings7. Mobilize urgently resources domestically and

internationally8. Promote research and development into new

diagnostics, drugs and vaccines

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Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB control, to prevent M/XDR-TB2. Scale-up programmatic management and care of

MDR-TB and XDR-TB 3. Strengthen laboratory services for adequate and

timely diagnosis of MDR-TB and XDR-TB

4. Ensure availability of quality drugs and their rational use

5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV

prevalence settings7. Mobilize urgently resources domestically and

internationally8. Promote research and development into new

diagnostics, drugs and vaccines

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Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB control, to prevent M/XDR-TB2. Scale-up programmatic management and care of

MDR-TB and XDR-TB 3. Strengthen laboratory services for adequate and

timely diagnosis of MDR-TB and XDR-TB4. Ensure availability of quality drugs and their

rational use5. Expand MDR-TB and XDR-TB surveillance

6. Introduce infection control, especially in high HIV prevalence settings

7. Mobilize urgently resources domestically and internationally

8. Promote research and development into new diagnostics, drugs and vaccines

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Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB control, to prevent M/XDR-TB2. Scale-up programmatic management and care of

MDR-TB and XDR-TB 3. Strengthen laboratory services for adequate and

timely diagnosis of MDR-TB and XDR-TB4. Ensure availability of quality drugs and their rational

use5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV

prevalence settings7. Mobilize urgently resources domestically and

internationally

8. Promote research and development into new diagnostics, drugs and vaccines

Conclusion• MDRTB and XDRTB are caused by humans, they don’t exist in nature. The most common causes are inappropriate treatment by the practitioner and lack of patient adherence

• That said, we desperately need newer shorter regimens. The most effective of which will be combination of new molecules

• The critical path initiative of testing several drugs in combination rather than sequentially is an effective approach

• New drugs need to be used carefully to preserve their sensitivity and effectiveness

THANK YOU FOR YOUR ATTENTION !