TB – the fight against the emerging global crisis_Jennifer Cohn

7/28/2019 TB the fight against the emerging global crisis_Jennifer Cohn

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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!

Documents

TB – the fight against the emerging global crisis_Jennifer Cohn