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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: [email protected]
Conflict of interest: none
Overview
1. The burden of XDR-TB and why is it important in the
global context?
2. Pathogenesis- some local work
3. Diagnosis (GeneXpert, Hain SL)
4. Prognosis of XDR-TB and treatment of TB in the prechemotherapeutic era
5. Current status in hospitals in Africa: what do we do
with the accumulating pool of untreatable cases?
6. Impact on health care workers and other ethical
dilemmas
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
Proportions of MDR-TB among previously treated TB cases.
M/XDR-TB Surveillance and Control: 2010 Global Update
What is the size of the problem globally?
 Worldwide 440 000 cases of MDR-TB in 2008
(3·6% 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
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
1.
2.
3.
Anti-Tuberculosis Drug Resistance in the World Report 2008:Fourth
Global Report, WHO, 2008
South African National Department of Health Report, 2008
WHO. Global TB Control. A short update to the 2009 report.
Why is XDR-TB a threat?
 Mortality rates are substantially higher (annual mortality
in patients with XDR TB approaches 40%)
Dheda K, Lancet, 2010
O’Donnell M, IJTLD, 2010
Gandhi N, Lancet, 2006
 Drastically increases the costs of running a TB program
(despite annually treating 500 000 cases of drugsusceptible TB and < 10 000 MDR/XDR-TB, the latter
eats up > 50% of the annual TB drug budget).
Cost of treating TB with different DST patterns:
MDR-TB= 110 to 180 fold more expensive
XDR-TB= ~400x more expensive
Can destabilize well or modestly functioning National
TB Programs (NTPs).
Pathogenesis of drug resistant TB
Drug-resistant mutants in
large bacterial population
Monotherapy: INH-resistant
bacteria proliferate
INH
INH
RIF
INH mono-resist. mutants
killed with addition of RIF,
but RIF-resist. mutants
proliferate  MDR-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
INH resistant bacteria Infection control
Delay in diagnosis
multiply to >108 and
spontaneous mutations
develop to RIF
Gandhi N and Dheda K et al, Lancet, 2010
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)
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
• 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
Immunology studies: SUBJECT
GROUPS
n = 61
HIV negative
XDR-TB
n = 26
Confirmed by
DST
Converters
n = 12
2 consecutive neg
cultures
DS-TB
n = 15
Culture/smear +
≤1 month TB
treatment
Non converters
n=14
> 9 months antiXDR treatment
LTBI
n = 20
Asymptomatic
TST+ QFN +
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
IFNγ.
INCREASE LEVELS OF CD4+CD25+FOXP3+ CELLS
•
XDR-TB converters and XDR-TB non converters VS DS-TB and LTBI
•
XDR-TB non converters VS XDR-TB converters
MYCOBACTERIAL SURVIVAL ASSAY:
SUMMATION
The ability of effector cells to kill monocyte derived
macrophages (MDM) is attenuated with the addition of
Tregs
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
Gandhi and Dheda, Lancet, 2010
Schaaf and Dheda, Clin Chest Med, 2009
Dheda and Warren, Inf Dis Clin N Am, 2010
C Boehme, FIND Diagnostics
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%.
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
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.
How should Xpert be integrated with
existing diagnostic algorithms?
 Assessed the diagnostic accuracy and/or costeffectiveness of smear-microscopy, chestradiography, IGRAs combined with a single
Xpert-MTB/RIF assay in 480 patients with
suspected TB
Grant Theron and Anil Pooran (submitted)
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)
Bacterial burden and
infectiousness
Theron, Peter and Dheda, AJRCCM, 2011
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 >31.8 were
smear-positive patients erroneously ruled out as
smear-negatives.
Theron, Peter and Dheda, Clin Infect Dis, 2011 (in press)
Xpert MTB/RIF research gaps
Beyond diagnostic accuracy to patient
outcomes
Early proof
of concept
studies
Large scale
evaluation
studies: What
is the
diagnostic
accuracy?
Phased
demonstration
and
implementatio
n studies:
What is the
technical
feasibility?
What are the
short-term
patient
outcomes?
Diagnostic
RCTs
addressing
long-term
patient
outcomes
(morbidity,
morality etc.)
DST: Line probe assay
 Hain Lifescience GenoType®
MTBDRplus (CE marked)
 Clinical samples (sens, spec):
Rif (99; 99%) INH (85; 99)%
 Hain sl (FQ, capeomycin or
AGs, ethambutol)
Morgan M, BMC Infect Dis, 2005;
Ling D, Eur Resp J, 2008
Barnard M, AJRCCM, 2008
 63 isolates: FQ (91%),
AG/capreo (85%), and
ethambutol (69%)
Hillemann D, J Clin Micro, 2009
 Main drawback is that Hain MDR+ and Hain sl
works poorly in smear negative TB
Barnard M, AJRCCM, 2008
N= 199 XDR-TB
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
A
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
Hilleman D, J Clin Micro, 2009
-N= 140 sputum
samples
Smear positive
Smear negative
-sensitivity for 2nd
line agents is suboptimal and differs
by smear status.
- 42% of XDR-TB
samples were
indeterminate.
 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
O’Donnell M, IJTLD, 2009
Kaplan-Meier probabilities of XDR-TB culture-conversion (n= 174)
 The overall culture-conversion rate was
19% (33/174)
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)
Sondalo (1938)- 3500 beds
St Helliere
 Surgical techniques promoting partial or complete lung
collapse were also used.
 With the advent of effective anti-TB therapy, the need for
sanatoria dwindled.
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?
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.
Is discharging such patients into impoverished communities
(often living in single roomed dwellings) justified?
 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.
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
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
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……...
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!
Acknowledgements
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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. O’Donnell
University of Florida- Kevin Fennelley
University of Calgary- Julie Jarand
Funding Agencies:
EUFP7
South African
National Research
Foundation
Discovery
EDCTP
NIH Fogerty
South African
MRC