tb – the fight against the emerging global crisis_jennifer cohn
TRANSCRIPT
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Patient Presentation
35 yo male with HIV (CD4 ?) not on ARTp/w 1 week of cough, fevers to sub-districthospital. On levofloxacin, but noimprovement. + weight loss (cannotquantify, ? Timeline) Produces on scanty sputum Reports h/o 1 st line TB treatment 14-16
months prior. Did not bring treatment card. PE: T 39, P95, thin, lungs clear , scanty
posterior LAD
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Day 1
Levofloxacin discontinued, ceftriaxonestarted
Sputum smear negative for AFB CD4 sent CXR ordered, but patient without funds to
pay. Family member sent to get TB treatmentcard
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Barriers to Patient Careand Scale-up
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DiagnosticsCurrent
SSM over 100 yearsold and still mainstay of treatment Poor sensitivity Special populations
Less than 4% of newcases and 6% of re-treatment cases were
tested for MDR-TB GeneXpert Now about $10 per
cartridge Increases diagnosis of
MDR 3 fold Doubles HIV-TB diagnosis
Needs
POC test, ASSUREDcriteria
Special populations:children, extrapulmonary
Diagnostic that will diagnoseTB and major drugresistance patterns rapidly unified diagnostic
Competition for Xpert Open, polyvalent platforms
WHO Xpert Recommendations Feb 2013WHO Global TB Report 2012
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MSF: Xpert TB-Rif Increase lab-based diagnosis of HIV pos patients compared
to SSM (128% increase in yield- Mozambique OCB project) A 3-fold increase in the number of DR-TB cases was
observed in Zimbabwe in the 6 months following Xpert MTB
implementation. Decrease of time to diagnosis from 19 to 7 days for HIV
pos/SSM neg patients in Zim; from 65.9 days to 13.9 days for DR-TB patients in Swaziland
Issues: Not POC; Need for training; Still high inconclusiveresults (>50% of sites reporting 6% inconclusive results);Desire for additional body fluids (although improved with newWHO Recs)
Desire for additional drug testing
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Xpert MTB/RIF results: per patient analysis
1 Xperttest
Final resultsafter repeating
Xpert
SSM posivity rate 19.7%
Xpert positivity rate 22% 24%
Xpert inconclusiveresults
12% 3.6%
Relative gainXpert vs SSM
13% 23%
1 Xpert
test
Final resultsafter repeating
Xpert
SSM posivity rate 8.4%
Xpert positivity rate 14.6% 15%
Xpert inconclusiveresults 6.8% 5%
Relative gainXpert vs SSM 74% 77.5%
HIV coinfected patients
0
20
40
60
80
100
120140
160
180Sm+Xp+
Xp Inconcl
Swaziland (N=1058)
1 Xpert test Xpert repeatedin case of 1 st test inconclusive
N r o
f p a t i e n t s
N r o
f p a t i e n t s
0
10
20
30
40
50
60
70
80Sm+Xp+Xp Inconcl
Kenya (N=304)
1 Xpert test Xpert repeatedin case of 1 st test inconclusive
14
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Xpert-Rif
New WHO Guidelines (to be validated) Xpert should be used as initial test in HIV or
presumed MDR (in place of SSM) and may beused as 1 st test in all with TB suspicion (adultsand children, including gastric aspirate)
CSF, LN bx recommended as 1 st test
Implementation Infrastructure upgrade, including cold chain Lab capacity, transmission of results and
capacity for full DST
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Overview of tools for TB diagnosis: nowand in the near future
*Adapted from: G. Roscigno presentation, Global consultation on GeneXpert MTB/RIF sytem, Geneva, Dec 2010Diagnostics for tuberculosis-Global demand and market potential. WHO/TDR and FIND.2006
Integrated NAAT + 40%
/2h
Peripheralhealth clinic
Surveillance Reference methods Networks supervision
Fraction of patientsseen at given level
5%
10%
25%
60%
MicroscopyLevel
SubdistrictLevel
DistrictLevel
RegionalLabs
ReferenceLabs
DST LPA RIF/INH 2 d
Screening Passive case finding Detect and treat
Clinical Screening Primary care
Resolution Testing(screening test negiative,drug resistance)
In house DST(MODS, NRA,CRI; special settings and
conditions
?
NEXTGENERATION
NAA-BASED TEST
?
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Day 3 Results and clinical
progression Still febrile despite
ceftriaxone CD4 80 AFB x 2 negative CXR
Familycommunications: TBtreatment card: RHZE(defaulter) and
RHZES (defaulted)
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Treatment Costs
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Funding and Political Will 86% funding domestic Global Fund issues growing grants ($130 mn)
GF provides 82% of international funding for TB, 91%for MDRTB
GF funding threatened GF reforms threaten access to grants for high burden
countries Funding for Dx and Rx of MDR-TB is only
$0.7billion in 2013 (Drug costs are $0.3 billion) Funding gap of 94 million in high burden
countries expected
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R&D Investment
TAG. 2012 TB R&DReport.
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MSF Access Campaign
Where to now?
What
s the way forward?
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Overarching Goal Advocate for a package of care that
includes diagnosis, treatment and modelsof care that leads to improved health and
survival for those living with MDRTB andcontrol in communities Simple, rapid, affordable and universal diagnostics Sustainable access to quality DR-TB medications at
the right price Enabling environment for scale up Support for MSF activities
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Better Diagnostics Scaling up
Xpert use and other new diagnostictools late in pipeline.
Survey of current guidelines andimplementation key countries
Affordable prices Hain Xpert follow ons
Pipeline advocacy Need POC TB diagnostic Expanded sample types Improved sensitivity in peds and
HIV positive
Improved DST TPP for pipeline
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The TB diagnostics pipeline
Peripherallevel
Feasibilityand proof of
principle
Developmentoptimization(design lock)
Evaluationstudies
ColorimetricTLA (DST)
Referencelevel
District,Subdistrict,microscopy
Demonstrationstudies
POLI
C Y
Antibodydetection (MBio)
Beta-lactamaseassay (GlobalBio
Diagnostics)
TREK Sensititre
Epistem Genedrive
FIND is a co-sponsor
BD Max NAAT
NAA based assays Alere QTwist Dx; IonianTechn;Biohelix Techn; Enigma;Wave 80; NorthWesternUniv.; Daktari
AlereDetermine LAM(completed)
Hain GenotypeMTBDR sl
VOC based assays
Abbott NAAT
TrueNAT MTB
TB-LAMP (completed)
Seek TB
NAA based test
Qiagen (China)
Ustar BiotechnologiesEasyNatTB
NIPRO (LPA)
Culture based test
Fast Follower technologies for NAA based test
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Fast-Follower technologies for NAA-based test
Adapted from :TB Diagnostic Technology Landscape. Semiannual Update. UNITAID. December 2012
+
+
+?
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NCEs for MDR-TB Access including compassionate use
(pre-registration), cost, access plan, IPand potential for generic production (e.g.PO, MPP, VL), registration in countries
Rapid and appropriate guideline change Bold study design
Data needed Additional data needed in special populations
(e.g peds) Shorter duration? Need data on NCE combinations
Caution with scale up Safety data Key sub-populations e.g. underlying liver
disease? Combination with other QTc prolonging agents
Antibiotic stewardship
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Repurposed Drugs
Current Barriers Lack of approved indication for TB Need for clear guidance on data
required for approval/dossier submission (WHO new drugstaskforce)
Access (price or supplyrestrictions)
Drug not registered in countries
Innovation Needed Growing evidence for importance
of repurposed drugs inconstructing potent all-oralregimens with NCEs
Identify gaps in information necessary for TB indication
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Drugs Advocacy Goals
Guidelines andimplementation WHO GLs, country GLs WHO new drugs taskforce esp
guidance on repurposed EML Dashboard
Access and affordability Company advocacy Incentivize generics (including
VL/MPP) Tech transfer Simplify production UNITAID etc
Communications and reports
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TB Trial Principals: An Ideal Regimen
1. Contain at least one new class of drug2. Be broadly applicable for use against MDR and XDR strain3. Contain 3 to 5 effective drugs (not have more than 5 drugs)4. Not combining drugs of same class5. Be an oral regimen (will not utilize an injectable agent)6. Have a simple dosing schedule7. Have a good side effect profile with limited monitoring8. Be of a short duration of 6 months or less9. Have minimal interactions with anti-retrovirals
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Trial and Trial Support
Goals To develop one or several MDRTB or potentially global TB
regimens in 5 years Demonstrate efficacy/indication of repurposed drugs Demonstrate utility of FQ in setting of new oral drugs Combine new classes (and assess safety/efficacy)
Support Negotiate for trial access Post-trial access Civil society and other stakeholder awareness/support Internal and external communications (jointly)
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Thank you!