TB the fight against the emerging global crisis

Credit: Elizabeth Griot

Dr Jennifer Cohn Medical Coordinator Mdecins Sans Frontires Access Campaign

MSF Access Campaign

Patient Presentation
35 yo male with HIV (CD4 ?) not on ART p/w 1 week of cough, fevers to sub-district hospital. On levofloxacin, but no improvement. + weight loss (cannot quantify, ? Timeline)
Produces on scanty sputum Reports h/o 1st line TB treatment 14-16 months prior. Did not bring treatment card. PE: T 39, P95, thin, lungs clear, scanty posterior LAD

Day 1
Levofloxacin discontinued, ceftriaxone started Sputum smear negative for AFB CD4 sent CXR ordered, but patient without funds to pay. Family member sent to get TB treatment card

Barriers to Patient Care and Scale-up

Diagnostics
Current Needs POC test, ASSURED criteria Special populations: children, extrapulmonary Diagnostic that will diagnose TB and major drug resistance patterns rapidly unified diagnostic Competition for Xpert Open, polyvalent platforms
WHO Xpert Recommendations Feb 2013 WHO Global TB Report 2012

SSM over 100 years old and still mainstay of treatment

Poor sensitivity Special populations

Less than 4% of new cases and 6% of retreatment cases were tested for MDR-TB GeneXpert
Now about $10 per cartridge Increases diagnosis of MDR 3 fold Doubles HIV-TB diagnosis

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 inconclusive results (>50% of sites reporting 6% inconclusive results); Desire for additional body fluids (although improved with new WHO Recs) Desire for additional drug testing

Xpert MTB/RIF results: per patient analysis

HIV coinfected patients
Kenya (N=304)
80 Sm+

14

70
60

Xp+ Xp Inconcl

1 Xpert test SSM posivity rate Xpert positivity rate 19.7% 22% 12% 13%

Nr of patients

Final results after repeating Xpert

24% 3.6% 23%

50
40 30 20 10 0

Xpert inconclusive results

1 Xpert test Xpert repeated in case of 1st test inconclusive

Relative gain Xpert vs SSM

Swaziland (N=1058)
180 160 Sm+ Xp+ Xp Inconcl

Nr of patients

140 120 100 80 60 40 20 0

1 Xpert test SSM posivity rate Xpert positivity rate Xpert inconclusive results 8.4% 14.6% 6.8% 74%

Final results after repeating Xpert

15% 5% 77.5%

1 Xpert test

Xpert repeated in case of 1st test inconclusive

Relative gain Xpert vs SSM

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 be used as 1st test in all with TB suspicion (adults and children, including gastric aspirate) CSF, LN bx recommended as 1st test

Implementation
Infrastructure upgrade, including cold chain Lab capacity, transmission of results and capacity for full DST

Xpert MTB/RIF : considerations for scale up

Cost and cost effectiveness study:
Brazil preliminary data on cost of diagnosis: SSM US$ 7.20 (US$ 14.40 on 2 samples as per WHO guidelines) Xpert MTB/RIF US$ 17.80 MSF cost-effectiveness study and based on data from the HIV/AIDS/TB programme in Buhera district- preliminary results: - price of an Xpert cartridge $11.70 (= UNITAID negotiated price + freight) - post-Xpert intervention for TB diagnosis (i.e. Xpert MTB used as the initial test on TB suspects) more cost-effective than the pre-Xpert intervention (i.e. SSM as initial test and no Xpert MTB available) Affordability (Pantoja et al 2012) -Use of Xpert MTB/RIF as first-line diagnostic test for all TB suspects is affordable in middle income countries -Use of Xpert MTB/RIF as a first line test in low-income countries will require substantial increase in funding for TB control and/or further reduction in price/test

Overview of tools for TB diagnosis: now and in the near future

Fraction of patients seen at given level
Surveillance Reference methods Networks supervision Resolution Testing (screening test negiative, drug resistance) Reference Labs Regional Labs
In house DST (MODS, NRA,CRI; special settings and conditions

5%

DST LPA RIF/INH 2 d

District Level Screening Passive case finding Detect and treat

Integrated

10%

Subdistrict Level

NAAT + 40% /2h

25%
Microscopy Level

?
?

NEXT GENERATION NAA-BASED TEST

Clinical Screening Primary care

Peripheral health clinic

60%

from: G. Roscigno presentation, Global consultation on GeneXpert MTB/RIF sytem, Geneva, Dec 2010 * Adapted Diagnostics for tuberculosis-Global demand and market potential. WHO/TDR and FIND.2006

Day 3
Results and clinical progression
Still febrile despite ceftriaxone CD4 80 AFB x 2 negative CXR

Family communications: TB treatment card: RHZE (defaulter) and RHZES (defaulted)

The issues - DRTB treatment

Old last approved new drug was 50 years ago
Long Treatment takes two years Complex multiple tablets, 8 months of injectable agents, needs tailored to individual resistance patterns. Hard to scale-up Expensive Can cost up to $4500 in drug costs alone

Toxic Side effects range from hearing loss to intractable nausea to psychosis
Inadequate high default rates, low cure rates, generates further resistance, no paediatric FDC Unproven No RCT or prospective trials exist for the current regimen.
MSF Access Campaign

Current Treatment

Treatment Costs

Procurement and Forecasting

Fragmented market
Public and private Small orders, poor forecasting Lack of coordination of orders, underuse of GDF

Lack of country registration Lack of clarity on guidelines (capreomycin vs other injectable; ethionamide vs prothionamide etc) Uncertain supply and stock outs
30% of meds rely on single supplier API vulnerable: kanamycin, amikacin, prothionamide, clofazamine Exit of manufacturers from the market (e.g. kanamycin)

Some products not assessed by a stringent regulatory authority

Treatment models
Over-reliance on hospitalization Need to move towards decentralisation and a patient centred approach Individualisation of treatment presents challenges for programmatic scale up.

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

R&D Investment

TAG. 2012 TB R&D Report.

Where to now?
Whats the way forward?

MSF Access Campaign

Overarching Goal
Advocate for a package of care that includes diagnosis, treatment and models of care that leads to improved health and survival for those living with MDRTB and control 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

Better Diagnostics
Scaling up
Xpert use and other new diagnostic tools late in pipeline. Survey of current guidelines and implementation 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

The TB diagnostics pipeline

Feasibility and proof of principle Seek TB Reference level Colorimetric TLA (DST) NAA based assays Alere Q
Twist Dx; IonianTechn; Biohelix Techn; Enigma; Wave 80; NorthWestern Univ.; Daktari

Development optimization (design lock) Abbott NAAT BD Max NAAT

Evaluation studies TREK Sensititre NIPRO (LPA)

Demonstration studies

P O L I C Y

Qiagen (China)

Hain Genotype MTBDR sl

TB-LAMP (completed)

District, Subdistrict, microscopy

Epistem Genedrive Ustar Biotechnologies EasyNatTB TrueNAT MTB

Antibody detection (MBio) Peripheral level Beta-lactamase assay (GlobalBio Diagnostics) VOC based assays

Alere Determine LAM (completed)

Culture based test

NAA based test

FIND is a co-sponsor

Fast-Follower technologies for NAA-based test

+ + _ + ?
Adapted from :TB Diagnostic Technology Landscape. Semiannual Update. UNITAID. December 2012

NCEs for MDR-TB

Access including compassionate use (pre-registration), cost, access plan, IP and 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

Repurposed Drugs
Current Barriers
Lack of approved indication for TB Need for clear guidance on data required for approval/dossier submission (WHO new drugs taskforce) Access (price or supply restrictions) Drug not registered in countries

Innovation Needed
Growing evidence for importance of repurposed drugs in constructing potent all-oral regimens with NCEs Identify gaps in information

necessary for TB indication

Drugs Advocacy Goals

Guidelines and implementation
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

Enabling Environment
DRTB Patient Manifesto and Public Events (Union conference) Ensure appropriate resources available for scale up
GFATM, PEPFAR Domestic resources

Guidelines and enabling environment

Streamline GLs as new data comes in (consolidate market WHO groups (New drugs task force) Dashboard of policies and implementation Use of GDF and utilization of quality assured meds (esp India)

TB Trial Principals: An Ideal Regimen

1. 2. 3. 4. 5. 6. 7. 8. 9. Contain at least one new class of drug Be broadly applicable for use against MDR and XDR strain Contain 3 to 5 effective drugs (not have more than 5 drugs) Not combining drugs of same class Be an oral regimen (will not utilize an injectable agent) Have a simple dosing schedule Have a good side effect profile with limited monitoring Be of a short duration of 6 months or less Have minimal interactions with anti-retrovirals

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)

Thank you!