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XDR TB in South Africa From clinical management
to public health action Time to bring back
sanitoria now overdue!

• Keertan Dheda, FCP(SA), FCCP, PhD (Lond), FRCP
  (Lond)
• Associate Professor and Head
• Lung Infection and Immunity Unit
• Division of Pulmonology, Department of Medicine,
• University of Cape Town
• email keertan.dheda_at_uct.ac.za
• Conflict of interest none

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Overview

• The burden of XDR-TB and why is it important in
  the global context?
• Pathogenesis- some local work
• Diagnosis (GeneXpert, Hain SL)
• Prognosis of XDR-TB and treatment of TB in the
  pre-chemotherapeutic era
• Current status in hospitals in Africa what do we
  do with the accumulating pool of untreatable
  cases?
• Impact on health care workers and other ethical
  dilemmas

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Definitions

• MDR-TB
• XDR-TB (H and R plus any FQ and at least one of
  the three injectables i.e amikacin, kanamycin,
  capreomycin)
• Global XDR-TB Task Force- 2006 (MMWR, Nov
  2006)
• (i) Significantly poorer treatment outcomes
• (ii) DST to these drugs more reliable and
  reproducible
• and more accessible in resource-limited settings
• TDR-TB, XXDR-TB, super XDR-TB (resistance to all
  known classes)- prognostic significance unclear
• Velayati AA, Chest, 2009
• Shah S, Emerging Infect Dis, 2011

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Proportions of MDR-TB among previously treated TB
cases.
M/XDR-TB Surveillance and Control 2010 Global
Update
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What is the size of the problem globally?

• Worldwide 440 000 cases of MDR-TB in 2008 (36
  of the total incident TB episodes)
• (360 000 new cases)
• Only 7 reported and 1-2 actually treated to WHO
  standards
• XDR-TB globally 25000 XDR-TB cases annually

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Size of the problem in SA

• 2004 3278 MDR cases
• 2005 4305 MDR cases
• 2006 6716 MDR cases
• 2007 7369 MDR cases
• (16000 to 18000 estimated cases for 2007/8)
• About 5 to 10 thought to be XDR-TB
• Anti-Tuberculosis Drug Resistance in the World
  Report 2008Fourth Global Report, WHO, 2008
• South African National Department of Health
  Report, 2008
• WHO. Global TB Control. A short update to the
  2009 report.

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Why is XDR-TB a threat?

• Mortality rates are substantially higher (annual
  mortality in patients with XDR TB approaches 40)
• Dheda K, Lancet, 2010
• ODonnell M, IJTLD, 2010
• Gandhi N, Lancet, 2006
• Drastically increases the costs of running a TB
  program (despite annually treating 500 000 cases
  of drug-susceptible TB and lt 10 000 MDR/XDR-TB,
  the latter eats up gt 50 of the annual TB drug
  budget).  
• Gandhi NR, Lancet. 2006.

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Cost of treating TB with different DST
patternsMDR-TB 110 to 180 fold more
expensiveXDR-TB 400x more expensive
Can destabilize well or modestly functioning
National TB Programs (NTPs).
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Pathogenesis of drug resistant TB

-Never add a single drug to a failing regimen -FQ
usage in the community Devasia RA, AJRCCM, 2009
Compliance (many factors) Drug quality and
supply Improperly trained HCW Poorly functioning
system Infection control Delay in diagnosis
Gandhi N and Dheda K et al, Lancet, 2010
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Pathogenesis of drug resistant TB

• Unclear why despite good compliance DR develops
• (i) Evidence that Beijing strains have a greater
  propensity to propagate after acquiring DR
  mutations
• S. Borrell, S. Gagneux, IJTLD, 2009
• (iii) May be better pre-adapted to survive
• (ii) May exhibit an increased mutation rate
  (mutator phenotype)- no evidence
• Dos Vultos T, PLOS One, 2008
• (iv) Other mechanisms- efflux pumps, cell wall
  permeability
• (iv) Immunopathology (Kaplan, Inf Imm, 2003)

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Pathogenesis of drug resistant TB

• DR mutations are associated with compensatory
  mutations evolutionary adaptation
• S. Borrell, S. Gagneux, IJTLD, 2009
• Hypothesised that this impacts on biochemical and
  physiological pathways- altering proteome and
  hence structure

Pseudomonas and other infections adaptive
mutations have effects on virulence, airway
colonization, transmissibility, and lung function
decline. Oliver A, Clin Microbiol Infect, 2010
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• Proteins differentially expressed in different
  strains grey bars proteins more abundant in the
  hypo-virulent strain, and black bars in the
  hyper-virulent strain.
• Desouza GA. Mol Cell Proteomics. 2010

Structurally XDR-TB has thickened cell wall with
different type of cell division Velayati AA, ERJ,
2009 Farnia P, Int J Clin Exp Med 2010
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Immunology studies SUBJECT GROUPS
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Does an altered proteome modulate the host
immune response?

• XDR-TB patients may have an altered
  immuno-phenotype when compared to DS-TB and LTBI,
  even when taking into account disease chronicity
  increased Tregs, decreased IFN?.

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INCREASE LEVELS OF CD4CD25FOXP3 CELLS

• XDR-TB converters and XDR-TB non converters
  VS DS-TB and LTBI
• XDR-TB non converters VS XDR-TB
  converters

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MYCOBACTERIAL SURVIVAL ASSAY SUMMATION
The ability of effector cells to kill monocyte
derived macrophages (MDM) is attenuated with the
addition of Tregs
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So, what exactly is Xpert MTB/RIF?

• Xpert is an automated real-time PCR platform for
  the diagnosis of TB and genotypic rifampicin
  resistance

• Recently gained approval as a frontline dx for
  individuals suspected of TB-HIV co-infection
• SA DoH plan to replace smear with Xpert for all
  TB suspects

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Gandhi and Dheda, Lancet, 2010 Schaaf and Dheda,
Clin Chest Med, 2009 Dheda and Warren, Inf Dis
Clin N Am, 2010
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• C Boehme, FIND Diagnostics

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Gene Xpert (WHO endorsed)

• Cost R1003 (Path Care)- 19 Jan 2010
• Indication Suspected active TB in HIV-infected
  and uninfected persons, including those suspected
  of DR-TB
• Sample and TT Sputum (within 2 hours)
• Where sited reference or district level
  laboratory (? clinic)
• How good is it Sensitivity 97 Specificity
  99 (smear negative TB 70). User-friendly and
  quick. Closed system.
• Low inconclusive rate 2.

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How does Xpert MTB/RIF perform?
TB
? slightly better than a single solid LJ culture
(3 weeks)
RifR

• Boehme et al, NEJM, 2010 (N 1730) Boehme et al,
  Lancet, 2011 (n 5000)

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Gene Xpert (WHO endorsed)

• Interpretation ve test treat for TB in the
  clinical context. Negative test rules out TB in
  uninfected but not HIV-infected persons.
• Theron and Dheda, AJRCCM, 2011
• Drawbacks PPV for DR-TB is only 75 so overcalls
  DR-TB but new cartridge being trialed. Expensive.
  

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How should Xpert be integrated with existing
diagnostic algorithms?

• Assessed the diagnostic accuracy and/or
  cost-effectiveness of smear-microscopy,
  chest-radiography, IGRAs combined with a single
  Xpert-MTB/RIF assay in 480 patients with
  suspected TB
• Grant Theron and Anil Pooran (submitted)

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How should Xpert be integrated with existing
diagnostic algorithms?

• Smear-microscopy combined with Xpert (if smear
  negative) is more cost-effective than either
  technique alone yet retains the advantage of same
  day diagnosis.
• Xpert negative- although CXR has poor rule-in
  value, it can reliably rule-out TB in
  approximately 1 in 4 of such cases.
• IGRAs had limited value
• Grant Theron and Anil Pooran (submitted)

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Bacterial burden and infectiousness

• Theron, Peter and Dheda, AJRCCM, 2011

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Bacterial burden and infectiousness

• Evaluated CT values in 496 patients with
  suspected TB
• Xpert CT values have poor rule-in cut-point
  20.2 sensitivity 32.3 specificity 97.1
• Moderately good rule-out value for smear
  positivity cut-point 31.8 NPV 80.0. Thus,
  20 of individuals with CT values gt31.8 were
  smear-positive patients erroneously ruled out as
  smear-negatives.
• Theron, Peter and Dheda, Clin Infect Dis, 2011
  (in press)

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Xpert MTB/RIF research gapsBeyond diagnostic
accuracy to patient outcomes
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DST Line probe assay

• Hain Lifescience GenoType MTBDRplus (CE marked)
• Clinical samples (sens, spec) Rif (99 99) INH
  (85 99)
• Morgan M, BMC Infect Dis, 2005
• Ling D, Eur Resp J, 2008
• Barnard M, AJRCCM, 2008

• Hain sl (FQ, capeomycin or AGs, ethambutol)
• 63 isolates FQ (91), AG/capreo (85), and
  ethambutol (69)
• Hillemann D, J Clin Micro, 2009

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• Main drawback is that Hain MDR and Hain sl works
  poorly in smear negative TB
• Barnard M, AJRCCM, 2008

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N 199 XDR-TB
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Hain MDR sl version- suggested to be used when
there R resistance is noted. Rapid evaluation of
drug-resistance for FQ, AG, capreomycin and
ethambutol
Only 1 small study (total 64 sputum samples ( 26
DR-TB)) FQ (89 8/9), AG/capreo (87 7/8), and
ethambutol (39 10/26) 100 specificity Hillema
n D, J Clin Micro, 2009
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• N 140 sputum samples
• sensitivity for 2nd line agents is sub-optimal
  and differs by smear status.
• - 42 of XDR-TB samples were indeterminate.

Smear positive
Smear negative
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• Initial optimism of encouraging outcomes in
  XDR-TB
• Mitnick C, NEJM, 2008 Keshavjee S, Lancet, 2008
  Sotgiu G, ERJ, 2009
• replaced disappointing data

• Review of 199 patients with XDR-TB
• Dheda K, Shean K, Warren R, Willcox P Lancet
  2010
• Become apparent that outcomes in high burden
  settings like South Africa are poorer than in
  intermediate to low burden settings
• Gandhi N, Lancet, 2006
• ODonnell M, IJTLD, 2009

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Kaplan-Meier probabilities of XDR-TB
culture-conversion (n 174)

• The overall culture-conversion rate was 19
  (33/174)

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Death in the whole cohort of patients from the
date of treatment-initiation

• Overall and 12-month mortality rates were 42,
  36 (n 174)
• Contrast Mitnick et al, NEJM, 2008 median time
  to conversion was 90 days, and mortality in 48
  XDR-TB patients was only 23 (11/48)

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Sondalo (1938)- 3500 beds
St Helliere
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• Surgical techniques promoting partial or complete
  lung collapse were also used.  
• With the advent of effective anti-TB therapy, the
  need for sanatoria dwindled.

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What is happening to these many culture
non-converters?

• Given the poor conversion rates, there are large
  numbers of treatment failures (defined as failure
  to culture-convert after twelve months of
  intensive in-patient XDR treatment with regimens
  including an injectable drug like capreomycin).
• While some patients die within weeks or months, a
  significant proportion of patients do survive for
  months or years.
• How should these living treatment failures be
  dealt with?

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Treatment failures

• Western Cape multi-disciplinary review committee
  that decides on XDR-TB treatment failures.
• Social assessment and a home visit culture
  positive patients are discharged back into the
  community.
• There are limited resources to track these
  patients and work is ongoing to determine their
  longevity and outcomes.

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Is discharging such patients into impoverished
communities (often living in single roomed
dwellings) justified?
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• XDR-TB treatment facilities in SA are filled to
  capacity. Thus, there are long waiting lists for
  beds facilitating disease transmission in the
  community.
• In some provinces like the Northern Cape,
  outpatient treatment of XDR-TB is already
  occurring.

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Further dilemmas

• There are no, or limited, palliative care
  facilities.
• Should treatment be withheld in recurrent
  defaulters when there is a risk of resistance
  amplification and no further therapeutic options?
  
• Forced detention is a contentious issue that has
  been debated but cannot currently be enforced in
  SA.
•  
• The same problems are occurring in low burden
  settings, where isolation facilities are limited
• Migliori GB. Eur Respir J, 2010
• Raviglione M. Int J Tuberc Lung Dis, 2006
•  

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KZN Health Care Workers
(23 XDR-TB and 208 MDR-TB HCWs in KZN)
O Donnell, Padayachi, Dheda Annals Intern Med
2010 Jarand J Dheda K, TMIH, 2010
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What are the priorities?

• Building a robust NTPs with improved laboratory
  and clinical capacity, and introduction newer
  rapid diagnostics
• Build community stay and palliative care
  facilities to prevent ongoing transmission by
  large numbers of untreatable or dying XDR-TB or
  failed MDR-TB patients.
• Thus, the time for rebuilding new sanatoria has
  now not only come but is overdue!
• The pool of untreatable cases is accumulating and
  will require swift action to avoid a human
  catastrophe...

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Summary

• Tuberculosis has now evolved into a
  therapeutically destitute disease, which is
  virtually untreatable
• The burden of XDR-TB is increasing worldwide
• Understanding the pathogenesis, virulence
  characteristics, and transmission patterns of
  XDR-TB are urgently required
• Improved rapid diagnostics for smear ve TB
• New drugs but must be protected and regulated
• TB is a good example of how a MDR pathogen can
  become a global threat
• Time to build sanitoria now overdue!

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Acknowledgements

• Division of Pulmonology and The Lung Infection
  and Immunity Unit Greg Symons, Caroline Whale,
  Elize Pietersen, Lititia Pool, Karen Shean,
  Samuel Murray, Lwazi Mhlanti, Vonnita Louw,
  Malika Davids, Motasim Badri, Paul Willcox
• Division of Cardiothoracic Surgery - Luven
  Moodley, Mark de Groot
• Brooklyn Chest Hospital (Cape Town) - Erma
  Mostert, Richard Burzelmann, Pieter Roussouw,
  Avril Burns
• Gordonia Hospital (Northern Cape) - Barbara
  Mastrapa
• UKZN Staff/Collaborators - Nesri Padayachee
• University of Stellenbosch - Robin Warren, Thomas
  Victor, Paul D. Van Helden
• WHO Collaborating Centre for Tuberculosis and
  Lung Diseases - Giovanni B. Migliori, Giovanni
  Sotgiu
• Albert Einstein College of Medicine - Max R.
  ODonnell
• University of Florida- Kevin Fennelley
• University of Calgary- Julie Jarand

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Funding Agencies

• EUFP7

• Discovery

• NIH Fogerty

South African National Research Foundation

• South African
• MRC

• EDCTP