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New diagnostics and drugs
for TB
Bernard Fourie PhDMedicine in Need (MEND)[email protected]
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Symptoms X-ray Smear Culture SolidCulture Liquid
DSTMolecular Probes
D e v e
l o p e
d C
o u n
t r i e s
Developing Countries
Changing Trends in TB DiagnosticsChanging Trends in TB Diagnostics
Growing Shift
Courtesy: S Sidiqui (Becton-Dickson)
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Bacteriology
Realization that culture is the only definitive diagnosisCulture is necessary for ID and ASTGoing to remain as a Gold Standard for a long timeRapid Turnaround Time is critical
More focus on liquid media
Courtesy: S Sidiqui (Becton-Dickson)
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CDC GuidelinesAFB Smear Results within 24 hours --------Culture Results report ave. 2 Weeks -------- Yes*Complete culture/Identification 3 Weeks -----Yes*Complete Culture/ID/DST in 4 weeks -------- Yes*QC, Method, Media and Reagents ------------ Yes*
*Role of BACTEC in meeting the guidelines
Courtesy: S Sidiqui (Becton-Dickson)
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FINDs Diagnostic Pipeline
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2006
ReferenceReferenceLabLab
PeripheralPeripheralLabLab
FIND Product Deliverables 2006FIND Product Deliverables 2006
--20132013
ClinicClinic
Health postHealth post
2007 2008 2009 2010 2011 2012 2013
% A
c c e s s
af t er
5 y e ar s95%
70%
10-40%
L i q u i d c
u l t u r e
M T B & D
S T
P h a g e b
a s e d
r e s i s t a n
c e t e s t
A u t o m a
t e d
N A A T
L E D F l u
o r
M i c r o s
c o p y
P O C N A A
T
U r i n a r y
A G
d e t e c t i o
n R e a d e r
b a s e d
L A T F l o
w
S p e c i a t
i o n
t e s t
U r i n a r y
N A A T
I m p r o v
e d A G / A
B
s t r i p t e
s t
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FIND/TDR Trial in Peru*
Comparison of FASTPlaque-Response test,INNO Lipa test, and direct LJ DSTGold standard: indirect DST on LJ mediumCosting sub-studyEnrolled newly diagnosed and retreatmentpatients with SS+ PTBAdditional 400 SS+ for FP sub-study
Discrepant analysis for all RIF-R tests byrepeat DST and rpo sequencing*IMT Cayetano Heredia, Inst Nat Salud, Disa Lima Norte
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FAST Plaque-Response
Specimen processing(NALC-NaOH)
Sputum collection o/n incubation rifampicin
F A S T Plaque- Response
assay procedure
Interpretation of results
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FIND/TDR Trial in PeruPreliminary Results
Performance Characteristics for RIF-R *
Test Sens Spec PPV NPVINNO 93% 99% 93% 99%FP-1 95% 96% 79% 99%
FP-2 ** 94% 100% 100% 99%D-LJ 95% 99% 95% 99%
*Subject to change pending results of discrepant analysis**Based on results 135 tests with complete results
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FIND/TDR Trial in PeruPreliminary Results
Performance Characteristics for MDR TB *
Test Sens Spec PPV NPVINNO 94% 97% 84% 99%FP-1 94% 95% 70% 99%
D-LJ 97% 98% 85% 100%
*Subject to change pending results of discrepant analysis
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Species Identification
Rapid identification needed for culture-based systems, especially broth cultureCurrent technologies, e.g., DNA probes,PCR, HPLC expensiveFIND working with TAUNS/BD to evaluateperformance of Capilia TB test in MGIT casefinding demonstration projects
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Capilia TB Assay
Immunochromatic assay based on detection of MPB64, present in M. tb complex but not MOTT orsome BCG strainsConsists of nitrocellulose membrane with anti-MPB64mouse antibodies conjugated with colloidal goldWith antigen-antibody reaction, see red-purple bandwithin 15 minutesEvaluated for 172 mycobacterial isolates (119 M.tbcomplex): 92% sensitivity, 100% specificity*
3 false negatives with MPB64 gene mutation
*D. Hilleman, et al. IJTLD 2005;9:1409-11
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Molecular Methods
Good performance characteristicsRapidSensitive (approaching culture)Specific
Expensive and requires sophisticatedtechnologyFIND working with partners with coretechnology and platform suitable fordeveloping country use
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LAMP
Closed systemIsothermalRapidMultiprimer
Visible readout
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MTB / Rif-resistance test
Workflow sputum simple 1-step external sample prep. procedure time-to-result < 2 h throughput: > 16 tests / day / module no need for biosafety cabinet integrated controls true random access
Performance specific for MTB sensitivity better than smear, similar to culture detection of rif-resistance via rpoB gene
Product and system design test cartridges for GeneXpert System several GeneXpert modules can be combined
in 1 workstation swap replacement of detection unit ~1 day technician training for non-mycobacteriologists
cartridge
GeneXpert Systemmodule
MTB
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FIND Evaluation Studies of Interferon-gamma release assay (IGRA)
IGRAs have been shown to be as sensitiveand more specific than the TST fordiagnosis of latent TB infection (LTBI)Limited data suggest that IGRAs performwell in HIV-infected personsFIND supporting two studies nested inCREATE projects to help define role of IRGAs in diagnosing LTBI in HIV+ persons:
THRio: 3000 patients in HIV/AIDS care clinicsZAMSTAR: 10,000 HIV+/- adult TB contacts
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Interferon- based tests
Whole Blood Assay T Cell Test
QuantiFERON-TB GoldCellestis T Spot TB AssayOxford Immunotech
Whole blood exposed to
ESAT-6 and CFP-10 TB antigensInterferon- g Production Quantified
WBCs separated, Exposed to
ESAT-6 and CFP-10 antigens,Interferon-g producing cells counted
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The Interferon- Assays
Pros
Differentiates TBinfection from BCGSuitable for repeat. No
booster phenomenon Objective results, invitro procedureResults available in 24hoursNo patients second
visitSpecificity (~99%)Sensitivity (90s%)
Cons
Does not differentiatebetween latent TB andactive diseaseMultiple assays stepsBlood drawing, transport,test within 12-hoursTechnique dependentEquipment requirements(Spec. or reader,
incubator, centrifuge,pipetter)Refrigerated reagentsHigh cost
Useful in low prevalence settings and high-burden HIV
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Global TB Drug Portfolio: Sep 2005
Discovery Preclinical Clinical Testing
Dihydrolipoamide AcyltransferaseInhibitorsCornell University, NIAID
InhA InhibitorsGlaxoSmithKline, TB Alliance
Isocitrate Lyase Inhibitors (ICL)
GlaxoSmithKline, TB Alliance
MacrolidesTB Alliance, University of Illinois at Chicago
Methyltransferase Inhibitor sAnacor Pharmaceuticals
Translocase I Inhibito rs
Sequella Inc., Sankyo
Synthase Inhibitor FAS20013FASgen Inc.
MoxifloxacinBayer Pharmaceuticals, CDC TBTC, JohnsHopkins University, NIAID TBRU, TB Alliance
Diarylquinoline TMC207Johnson & Johnson
Nitroimidazo-oxazole OPC-67683
Otsuka
Natural Product s ExplorationBIOTEC, California State University, ITR, NIAID,TAACF, University of Auckland
Dipiperidines (SQ-609)Sequella Inc.
Diamine SQ-109Sequella Inc.
GatifloxacinOFLOTUB Consortium, Lupin, NIAID TBRU,Tuberculosis Research Centre, WHO TDR
Cell Wall Inhibitor sColorado State University, NIAID
Novel Antibiotic ClassGlaxoSmithKline, TB Alliance
Picolinamide ImidazolesNIAID, TAACF )
Pleuromutilins
GlaxoSmithKline, TB Alliance
QuinolonesKRICT/ Yonsei University, NIAID,TAACF, TB Alliance
Screening and Target IdentificationAstraZeneca
Thiolactomycin AnalogsNIAID, NIH
Nitroimidazole AnalogsNIAID, Novartis Institute for Tropical Diseases,TB Alliance
NitrofuranylamidesNIAID, University of Tennessee
Pyrrole LL-3858Lupin Limited
Nitroimidazole PA-824Chiron Corporation, TB Alliance
Non-Fluorinated QuinoloneTaiGen
CarboxylatesTB Alliance, Wellesley College
Nitroimidazo-oxazole Back-upOtsuka
STOP TB New Drugs Working Group
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Clinical Development Pipeline
Lupin Ltd.Phase ILL-3858
TB AlliancePhase IPA-824
Otsuka Pharmaceutical Co., Ltd.Early Bactericidal ActivityOPC-67683
Johnson & Johnson (Tibotec)Early Bactericidal ActivityTMC 207
Bayer; TB Alliance; CDC ;University College of London;Johns Hopkins UniversityPhase II / IIImoxifloxacin
EC / OFLOTUB Consortium;IRD * ; WHO TDR ; Lupin Ltd.Phase IIIgatifloxacin
Sponsor / CoordinatorDevelopment StageCompound
* Institut de Recherche pour le Developement World Health Organization, Tropical Disease Research Centers for Disease Control and Prevention
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Pipeline Compounds
2005 2006 2007 2008 2009 2010 2011 2012
Mox i f lox ac in I I I I I NDAGat i f lox ac in I I I I I NDAJ & J I /I I I I I NDA
Ot suk a I I /I I I I /I I I NDALupin I I /I I I I /I I I NDAPA-824 I I I I /I I I NDASequel la I I I I /I I I NDA
Identify and develop best combination regimen(s)
2013
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Short-/Medium-term prospectsMore potent fluoroquinolones
MoxifloxacinGatifloxcinLevofloxacin
CapreomycinInjectable(Inhaled dry-powder formulation in advanced development)
PASTabletsGranular with acid-resistant outer coating
Clofazimine
Capsules(Liposomal)(Other members of class high potency against MDR)
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Ratio C max on MIC 90 of the mainfluoroquinolones
Drug (mg) C max (g/ml)
MIC90 Cmax /MIC90
Ciprofloxacin 500 1-2 1.0 1-2Ofloxacin 400 4 2.0 2Levofloxacin 500 5-7 1.0 5-7Sparfloxacin 200 1.1 0.5 2Moxifloxacin 400 4-5 0.5 8-10
Ref. : Hooper etRef. : Hooper et WolfsonWolfson AAC 1985 ; 28 : 716 AAC 1985 ; 28 : 716 --721 ; Hooper721 ; Hooper ClinClin. Inf. Dis. 2000 ; 30 : 243. Inf. Dis. 2000 ; 30 : 243 --254 ;254 ; LubaschLubasch et al., AAC 2000 ; 44 : 2600et al., AAC 2000 ; 44 : 2600 --26032603
23
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Moxifloxacin in treatment of MDRTB*
Activity of the OFX-containing third-line regimenagainst M. tuberculosis was rather weak in vivo,whereas when OFX was replaced by MXF, 9months of treatment with a modified third-lineregimen (MXF/AMK/ETH/PZA) displayed
bactericidal activity comparable to that of 6months of treatment with the standard regimen inmice
*Veziris N et al. Antimicrob Agents Chemother. 2003 Oct;47(10):3117-22
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Gatifloxacin, moxifloxacin or ofloxacin replacing
ethambutol in conventional HRZE regimen Conversion of sputum during 1 st two months*
Log rank test
2 (3)=10.69
p= 0.0136
*Preliminary data presented at IUATLD Conference, Paris 2005Oflotub Consortium Study supported by EC and WHO/TDR
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Survival of HIV-associated MDRTB NYC Treatment(Turret, NEJM 1995)
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