Transcript Presentazione di PowerPoint

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
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)
TB with any
MDR TB
drug
resistance
TDR/XXDR TB
XDR TB
CURRENT THERAPY AND UNMET NEEDS
TB Alliance programs seek to help all TB patient populations
Unmet
Needs
Current
Therapy
Drug
M(XDR)-TB
Sensitive TB
TB/HIV coinfection
Latent TB
Infection
Pediatric TB
4 drugs taken
for 6 or more
months
Injections and
drugs taken for
more than 2
years, poorly
tolerated
Drug-drug
interactions
with ARVs
9 months of
isoniazid
No adequate
dosing
formulations
Shorter,
simpler
therapy
More effective,
shorter, safer
simpler
regimens
Coadministration
with ARVs
Shorter, more
easily tolerated
therapy
Adequate
dosing
regimens and
formulations
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
GLOBAL TB
PROGRAMME
Delamanid
Delamanid added to a background MDRTB regimen improves significantly SS-C
conversion at month 2 (45.4 vs 29.6%)
11
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.
12
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.
2.
3.
4.
5.
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
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
16
The cost (€) to treat TB and M/XDR is enormous:
prevention is cost-effective
Cost per case
Susceptibl
e
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
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, 1945-1962
Koch, Mtb,
1882
MMR,1950-1980
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
Outbreak Management,
sanatoria
Risk Group Management
screening
drug therapy
Socio-economic improvement
20
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
21
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
Pneumothorax
23
24
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
8.
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
25
Global Policy: MDR-TB and XDR-TB
1.
2.
Strengthen basic TB control, to prevent M/XDR-TB
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
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
5.
6.
7.
8.
26
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
8.
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
1.
2.
3.
4.
5.
6.
7.
8.
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
1.
2.
3.
4.
5.
6.
7.
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
8. Promote research and development
into new diagnostics, drugs and
vaccines
29
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 !