Challenges in the

management of MDR-TB
Ignacio Monedero MD, MPH, PhD

What is not a challenge in MDR-TB control?

Where to start
Discovered by Robert Koch
24th of March 1882

TB can be cured in more than

95% with
RHZE in 6 months
70s decade

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

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

Do you think that diagnose and

cure rates have changed since the
publication of the model?

NO

WHO Global TB Report 2013

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 60s
No new diagnose tools: DST from the 60s

In the 60s, good solutions to control TB in

strong Health systems
Research was stopped
Resistance was a limited problem

Outline of challenges
1. Co-morbidities and challenges in
Diagnose
2. 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

Challenges in diagnose of TB
and comorbidities (HIV/TB)
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

Correlation Between Extent of HIV-Induced ImmunoSuppression and Clinical Manifestation of Tuberculosis

Median CD4 cell count / mm3

500

400

300

200

Pulmonary tuberculosis

Lymphatic, serous tuberculosis

Tuberculous meningitis
Disseminated tuberculosis

100

Duration of HIV infection

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

< 50 CD4

> 500 CD4

CULTURE

SMEAR

CHEST X
RAY

CXR and direct smear not sensitive enough to exclude

pulmonary TB in patient with advanced
immunosuppression

Several postmortem studies in sub-Saharan Africa

have demonstrated that 50% PLH who died from
unknown causes died actually from TB

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 dont 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

GeneXpert
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

similar to liquid
medium culture
OK for sputum, even smear -ve
Product
anddifferentiation
system design
MOTTs
test cartridges for GeneXpert System
Technical
several GeneXpert
modules can beno
combined
simplicity,
need for
in 1 workstation
laboratory
swap replacement of detection unit

GeneXpert
System
module

Performance
Sensitivity

specific for MTB

sensitivity better than smear, similar to culture
detection of R resistance via rpoB gene

~1 day technician training for non-mycobacteriologists

MTB

cartridge

TB/HIV, more difficult to diagnose, worst

prognosis more difficult to cure and also

Prone to outbreaks
need for Infection control
Not enough work in TB prevention

HIV-associated multidrug-resistant
tuberculosis (MDR-TB) outbreaks in
industrialized countries, 19881995

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

Tugela Ferry, South Africa

Ambulatory Waiting room
Source: Sarita Shah, Tugela Ferry Care and Research Collaboration

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-

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 dont 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

The strangest side effect ever

Toxicity

Resistance

Pill
burden

lengthy

TB/HIV

Poverty /
employment /
addictions

All contributing to a
reduced cure rate

Late
diagnose or
not even
access

Outline of challenges
1. Co-morbidities and challenges in
Diagnose
2. 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 challenges
1. 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 challenges
3. 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

We need to break this shameful trend

Do your part!!!
We need a lobby among

journalist and patients

Many thanks

Ignacio Monedero MD,

MPH, PhD