Download - The Challenge of MDR-TB
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Challenges in the management of MDR-TB
Ignacio Monedero MD, MPH, PhD
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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?
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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
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Do you think that diagnose and cure rates have changed since the
publication of the model?
NO
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WHO Global TB Report 2013
We are treating poorly
MDR-TB
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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
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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
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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)
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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
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< 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
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Something similar happens with TB/DM
State of relative reduced in immunity The higher the Hb 1Ac, the more
atypical presentation
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Young physician working in Central Africa in 2005
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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
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Main diagnose tools are old fashion, reduced sensibility
Sputum smear fail to diagnose up to 30% of patients with normal
immune status
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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
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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 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
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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
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HIV-associated multidrug-resistant tuberculosis (MDR-TB) outbreaks in industrialized countries, 1988–1995
Wells CD, et al. JID 2007:196:s86-s107
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Source: Sarita Shah, Tugela Ferry Care and Research Collaboration
Tugela Ferry, South Africa Ambulatory Waiting room
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XDR-TB complicating the scenario
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TB research, diagnose, prevention going at a different speed than other diseases…
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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
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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
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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
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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
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ATRIPLA® / VIRADAY®4Km->Gtx-Pro-Clz-E-Z->INH /
5 >Gtx-Pro-Clz-E-Z
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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
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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
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The strangest side effect ever
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Toxicity Pill burden lengthy TB/HIV Poverty /
employment / addictions
Late diagnose or not even accessResistance
All contributing to a reduced cure rate
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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
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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
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Nearly 5.000 Africans dying due to Ebola
Nearly 300.000 Africans dying due to TB, MDR and XDR-TB out of control
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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
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Do your part!!!We need a lobby among
journalist and patients
We need to break this shameful trend
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Many thanks
Ignacio Monedero MD, MPH, PhD