Challenges in the management of MDR-TB

Ignacio Monedero MD, MPH, PhD

Where to start…• Discovered by Robert Koch

• 24th of March 1882 

• TB can be cured in more than 95% with

• RHZE in 6 months • 70’s decade

• MDR-TB Resistant to • RIF: best sterilizing drug ever• INH: best bactericidal drug ever

What is not a challenge in MDR-TB control?

Blower S, Blower S, et al. Lancet Infect Dis 2007; 7:443et al. Lancet Infect Dis 2007; 7:443..

MDR-TB case detection and treatment rates increase to the WHO target of 70%, without simultaneously increasing MDR-TB cure rates, XDR-TB could increase exponentially

We are treating poorly

MDR-TB

Do you think that diagnose and cure rates have changed since the

publication of the model?

NO

WHO Global TB Report 2013

We are treating poorly

MDR-TB

Why we are doing so poorly…• Because it is not easy… • Why is not easy?• Complete lack of research during more than 40

decades• No new drugs or regimens: TB drugs from 60´s • No new diagnose tools: DST from the 60’s

• In the 60’s, good solutions to control TB in strong Health systems

• Research was stopped• Resistance was a limited problem

Outline of challenges1. Co-morbidities and challenges in

Diagnose2. Challenges in treatment and regimens

• Need of new drugs and shorter regimens

3. Challenges in health systems• Access to care• Access to current drugs• Usually not considered as a social disease

4. Other threats

In general, performance of microbiological tests do not change whether patient is HIV-positive or

negative

Except for direct smear…

Smear-negative TB patient in PLH:

unmeasured source of deaths and

lost treatment opportunities

Challenges in diagnose of TBand comorbidities (HIV/TB)

Correlation Between Extent of HIV-Induced Immuno-Suppression and Clinical Manifestation of Tuberculosis

Duration of HIV infection

Med

ian

CD

4 ce

ll co

unt /

mm

3

0

100

200

300

400

500

De Cock KM, et al. J Am Med Assoc 1992;268:1581-7

Pulmonary tuberculosis

Lymphatic, serous tuberculosis

Tuberculous meningitis

Disseminated tuberculosis

< 50 CD4 > 500 CD4

CULTURE + +

SMEAR - +

CHEST X RAY

- +

Several postmortem studies in sub-Saharan Africa have demonstrated that 50% PLH who died from

unknown causes died actually from TB

CXR and direct smear not sensitive enough to exclude pulmonary TB in patient with advanced

immunosuppression

Something similar happens with TB/DM

State of relative reduced in immunity The higher the Hb 1Ac, the more

atypical presentation

Young physician working in Central Africa in 2005

From TB diagnose in HIV likelihood of TB-HIV

• Most severely ill TB-HIV patients who may die• Atypical symptoms and signs (or no signs)• CXR negative• Smear negative• Frequently, culture not available

• “Sorry, I think you have TB but… • all results are negative, you don’t have TB”

• The patient never returned • Died? TB highly prevalent in post-mortem studies of PLH• Asymptomatic active pulmonary TB• Screening: symptoms + induced sputum

Main diagnose tools are old fashion, reduced sensibility

Sputum smear fail to diagnose up to 30% of patients with normal

immune status

Classical phenotypic culture and drugs susceptibility test

• Need viability of the sample specimen• Culture can take 1-2 months• Technically difficult

• need a quality laboratory

• Delays in result report• Usual delay is 4-6 months in most high burden countries

• Drug susceptibility test • Reduced reliability • Most reliable for high action drugs: RIF, INH, FQ, Inyectables

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 R 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

Sensitivity similar to liquid medium culture OK for sputum, even smear -veMOTTs differentiationTechnical simplicity, no need for laboratory

GeneXpert®

Still too expensiv

e, not as acce

ssible as it

should

Not a point of care diagnose test

Prone to outbreaks… need for Infection control

Not enough work in TB prevention

TB/HIV, more difficult to diagnose, worst prognosis more difficult to cure and also

HIV-associated multidrug-resistant tuberculosis (MDR-TB) outbreaks in industrialized countries, 1988–1995

Wells CD, et al. JID 2007:196:s86-s107

Source: Sarita Shah, Tugela Ferry Care and Research Collaboration

Tugela Ferry, South Africa Ambulatory Waiting room

XDR-TB complicating the scenario

TB research, diagnose, prevention going at a different speed than other diseases…

2. Challenges in treatment and regimens

• Drugs and regimen works, but far than optimal

• After two years• After toxicity• After adherence dose by dose

• But health systems not• Not even in European countries

Current standards for MDR-TB 2008

• 6Km-Lvx-Eto-Cs-Z / 18 Lvx-Eto-Cs-Z • What do you think about 24 months treatment?• What do you think about toxicity of these regimens?

• Hearing loss, nausea, vomiting…• More than 15 pills per day + shot

• What about being poor and having to go daily to the health center?

• Often the patients enters too late in the treatment

4Km->Gtx-Pro-Clz-E-Z->INH /5 >Gtx-Pro-Clz-E-Z-

9 months, less to

xic, we are im

proving… but still many pills

We definitely need more and bette

r drugs

New drugs for the first time in 40 years

• Bedaquiline• Delamanid• Not enough to construct a new salvage

treatment• We need more new drugs• We need more sterilizing drugs

ATRIPLA® / VIRADAY®4Km->Gtx-Pro-Clz-E-Z->INH /

5 >Gtx-Pro-Clz-E-Z

MDR-TB drugs and doctors…• TB doctors maybe never using these drugs

• Not trained, learning by trial and error• Prone to errors• Patient not cured, not dead: increasing pattern of resistance

primary transmission

• Stock out of MDR-TB drugs• If no drugs: improvisation > resistance• Despite 210.000 people dying annually due to TB, the

pharma industry don’t see it as potential market • All countries I supervised had face drug shortages

MDR-TB not only an issue of drugs and doctors…

• Difficult population… reduced access to care

• Low education, low income capacities, addictions, social exclusion

• TB is a disease of the poor • MDR-TB is a disease of the poor among the poorest

• Not considering social determinants…• Doom to fail• Especial focus on big cities• Support on the adherence

Not easy been poor, nor holding a disease with

unpleasant drugs for 2 years

The strangest side effect ever

Toxicity Pill burden lengthy TB/HIV Poverty /

employment / addictions

Late diagnose or not even accessResistance

All contributing to a reduced cure rate

Outline of challenges1. Co-morbidities and challenges in

Diagnose2. Challenges in treatment and regimens

• Need of new drugs and shorter regimens

3. Challenges in health systems• Access to care• Access to current drugs• Usually not considered as a social disease

4. Other challenges

4. Other challenges1. Lack of funding

• For new diagnose test, tools, medicines, health systems, technical assistance…

• Shift and increase of MDR-TB should be a call to arms

2. Fund diversion• Risk in investing too much in MDR-TB by itself• Funding and attention going to other diseases or

projects

Nearly 5.000 Africans dying due to Ebola

Nearly 300.000 Africans dying due to TB, MDR and XDR-TB out of control

4. Other challenges3. Lack of lobby

• Most of HIV success due to strong lobby of patients and press

• Example: how in 30 years the panorama can be changed

Do your part!!!We need a lobby among

journalist and patients

We need to break this shameful trend

Many thanks

Ignacio Monedero MD, MPH, PhD