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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

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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

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% WHO standards actually treated to  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.

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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 drug susceptible 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 INH Monotherapy: INH-resistant bacteria proliferate -Never add a single drug to a failing regimen -FQ usage in the community

Devasia RA, AJRCCM, 2009

INH mono-resist. mutants killed with addition of RIF, but RIF-resist. mutants proliferate

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MDR-TB INH RIF Compliance (many factors) Drug quality and supply Improperly trained HCW Poorly functioning system INH resistant bacteria multiply to >10 8 and spontaneous mutations Infection control Delay in diagnosis 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 virulence, airway colonization, transmissibility, and lung function decline. Oliver A, Clin Microbiol Infect, 2010 : adaptive mutations have effects on

• 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

XDR-TB n = 26

Confirmed by DST

n = 61

HIV negative

DS-TB n = 15

Culture/smear + ≤1 month TB treatment

LTBI n = 20

Asymptomatic TST+ QFN +

Converters

n = 12 2 consecutive neg cultures

Non converters

n=14 > 9 months anti XDR treatment

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 .

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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)

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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)

Rif

R

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

Gene Xpert (WHO endorsed)

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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 cost effectiveness of smear-microscopy, chest radiography, IGRAs suspected TB combined with a single Xpert-MTB/RIF assay in 480 patients with 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 C T values in 496 patients with suspected TB Xpert C T values have poor rule-in [cut-point ≤20.2; sensitivity 32.3%; specificity 97.1%] Moderately good rule-out value 20% of individuals with C smear-negatives. T for smear positivity [cut-point ≤31.8; NPV 80.0%]. Thus, values >31.8 were smear-positive patients erroneously ruled out as 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)% 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

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

N= 199 XDR-TB

A 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 Hilleman D, J Clin Micro, 2009

Smear positive Smear negative -N= 140 sputum samples -sensitivity for 2 nd line agents is sub optimal 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  174)  Overall and 12-month mortality rates were 42%, 36% (n= Contrast (11/48) Mitnick et al, NEJM, 2008 ; median time to conversion was 90 days, and mortality in 48 XDR-TB patients was only 23%

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

          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 Discovery South African National Research Foundation EDCTP NIH Fogerty South African MRC