1. 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

4. 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

5. Drug Resistant TB: Development and Spread7

6. Causes of MDR
Patient mismanagement

7. Definitions TB with any drug resistance MDR TB
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)
TDR/XXDR TB
TB with any
drug resistance
MDR TB
XDR TB

8. Current Therapy and Unmet Needs
TB Alliance programs seek to help all TB patient populations
Drug Sensitive TB
4 drugs taken for 6 or more months
Shorter, simpler therapy
M(XDR)-TB
Injections and drugs taken for more than 2 years, poorly tolerated
More effective, shorter, safer simpler regimens
TB/HIV co-infection
Drug-drug interactions with ARVs
Co-administration with ARVs
Latent TB Infection
9 months of isoniazid
Shorter, more easily tolerated therapy
Pediatric TB
No adequate dosing formulations
Adequate dosing regimens and formulations
Current Therapy
Unmet
Needs

9. NIX-TB: “RESCUE” STUDY FOR XDR-TB
New Chemical Entities in XDR-TB
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
Reactive:
Only slated for XDR – not expanding to MDR-TB or DS-TB; this is for patients with no other options. Drugs have not been tested together previously so unethical to attempt to treat patients for which approved cures currently exist, i.e. DS-TB MDR-TB

10. GLOBAL TB
PROGRAMME

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

12. 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.

13. New drugs: Delamanid – a nitroimidazole
European Medicines Agency authorized on

14. 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

15. 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):
Treatment under close monitoring (eg, sound protocols)
Proper patient selection (caution: PLHIV and >65; no: children & pregnancy)
Patient informed consent required
Treatment design based on WHO recommendations (eg, DST, dose, never adding a single drug to a failing regimen)
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

16. 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

18. EBA (Early Bactericidal Activity) studies
For reasons of shortening time, improving evaluation efficiency and reducing cost of lengthy evaluation, clinical trials now test new combinations in randomised, 14 day EBA studies involving pulmonary TB patients with drug susceptible disease
As judged by two different microbiological endpoints, 2-3 new regimens are compared vs standard regimen on their effectiveness to reduce the number of culturable M. tuberculosis bacilli in sputum

19. 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
France
5,691
Germany
7,7,51
55,003 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

20. Interventions over time: old weapons might be useful again to manage XDR
First sanatorium Germany, 1857
First Dispensary, Scotland, 1897
BCG vaccination
Pneumotorax, Italy, 1907
Drugs,
MMR,
Koch, Mtb,
1882
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
sanatoria
Outbreak Management,
Risk Group Management
screening
drug therapy
Socio-economic improvement

21. 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 21 21

22. 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

23. Pneumothorax

25. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

26. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

27. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

28. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

29. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

30. 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

31. THANK YOU FOR YOUR ATTENTION !