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Drug Resistant Tuberculosis (DR-TB): An Update. Dr. Dick Menzies Montreal Chest Institute. Definitions. Primary DR: Resistance in person treated <1 month or not at all Acquired DR: Resistance in person treated > 1 month Mono-drug resistance: Resistance to 1 drug

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Drug resistant tuberculosis dr tb an update

Drug Resistant Tuberculosis (DR-TB): An Update

Dr. Dick Menzies

Montreal Chest Institute


Definitions
Definitions

  • Primary DR: Resistance in person treated <1 month or not at all

  • Acquired DR: Resistance in person treated > 1 month

  • Mono-drug resistance: Resistance to 1 drug

  • Poly-drug resistance: Resistance to >1 drug, but not MDR.

  • MDR: resistant to isoniazid and rifampin

  • XDR: MDR & resistance to Quinolones & Injectable


Epidemiology of dr tb summary
Epidemiology of DR-TB - summary

  • Global total in new cases: 17%

    • 3% MDR and 0.5% XDR

    • 14% other forms (INH most common)

  • Highest in Former Soviet Union

    • And certain Latin American countries

    • Increasing in China, India, S Africa

  • Low in Canada – mostly seen in immigrants from these high risk regions


Global TB Estimates

Estimated number of cases

Estimated number of deaths

All forms of TB Greatest number of cases in Asia; greatest rates per capita in Africa

9.23 million

1.7 million

Multidrug-resistant

TB (MDR-TB)

489,000

(5.3%)

120,000

40,000

(0.5%)

20,000

Extensively drug-resistant TB (XDR-TB)

Adapted from a slide provided by Dr. Paul Nunn, WHO Geneva


Proportion with MDR-TB in new and previously treated cases, 1994-2007

MDR in

New patients

Previously treated patients



Trends in global drug resistance in new cases aziz lancet 20061
Trends in Global Drug Resistance in New Cases 1994-2007(AZIZ, Lancet 2006)


How does drug resistance develop

How does drug resistance develop? 1994-2007

(aka Pathogenesis)


Treatment with streptomycin alone or pas alone patients with resistance days after tx started
Treatment with Streptomycin alone, or PAS alone 1994-2007% Patients with resistance - Days after Tx started

Source: Rieder, Interventions for TB control, IUATLD.


Treating tb with one drug improvement then worsening the fall and rise phenomenon
Treating TB with one drug – Improvement then worsening – the fall and rise phenomenon

Source: Toman Case Finding and Chemotherapy


Rate of spontaneous mutations of m tuberculosis to anti tb drugs
Rate of spontaneous mutations of M Tuberculosis to anti-TB drugs

Streptomycin 10-6

Isoniazid 10-6 - 10-7

Rifampin 10-8 - 10-9

Ethambutol 10-7 - 10-8

INH&Rif 10-14


Total n umber of bacilli by clinical extent of disease
Total n drugsumber of bacilli – byclinicalextent of disease

  • LesionQuantity AFB

  • Granuloma 103 Latent

  • Infiltrates 106- - 107 Negative

  • Cavity 108 - 109 + , ++

  • Manycavities, 1010 - 1012 +++

  • Death 1013 too late!


Probability of developing resistance during therapy by number of drugs

Number of Drugs drugs

Total number of bacilli

104

106

108

1010

1012

One

1%

63%

100%

100%

100%

Two

0

0

.01%

1%

60%

Three

0

0

0

0

0

Probability of developing resistance during therapy – by number of drugs


Transient drug resistance during therapy with two or more drugs effect of default
Transient drug resistance during therapy with two or more drugs (effect of default)

From Toman, Case Finding and Chemotherapy


Association of mdr tb and regulation of tb drugs
Association of MDR-TB and regulation of TB drugs drugs (effect of default)

  • Ecologic survey of 100 countries

    • Mostly low-middle income countries

  • Significant correlation of poor regulations of TB drug sales and MDR in new cases

    • Sales in private pharmacies

    • Dispensing/prescription by private MDs rather than TB programme


Ecologic study mdr and tx outcomes
Ecologic study: MDR and Tx outcomes drugs (effect of default)

  • 161 – reported treatment outcomes to WHO in 2003 and 2004

  • 121 – Had > 250 cases annually

  • 118 - Initial MDR prevalence - (WHO)

  • 103 – Used standard Tx schemes (GDF)

    • 78 WHO Initial regimen (6 months RIF)

    • 27 Union Initial regimen (2 months RIF)



Diagnosis of drug resistance

Diagnosis of drug resistance – by prevalence of Initial MDR

(very briefly)


Diagnosis of dr tb
Diagnosis of DR-TB – by prevalence of Initial MDR

  • Old methods – proportional on solid media

    • Slow – 4-8 weeks for culture

      • Another 4-8 weeks for sub-cultures for DST

    • Relatively inexpensive – so used in low-income

  • Current methods – Indirect in liquid media

    • Faster but more expensive

    • Still 2-4 weeks for culture

    • Then another 2-4 weeks for DST


Microscopically observed drug susceptibility mods
Microscopically Observed Drug Susceptibility (MODS) – by prevalence of Initial MDR

Direct inoculation of specimens – for detection & DST

Microscopic colony detection

Average time to results: 9 to 11 days

Excellent sensitivity and specificity

Low costs - materials & equipment

Labour intensive

www.modsperu.org


Newest and fastest molecular tests line probe assays
Newest and fastest: Molecular tests – Line probe assays – by prevalence of Initial MDR

  • Detection of MTB & INH & RIF-resistance

  • Requires extraction, amplification

  • Colorimetric development using immobilized probes

  • Excellent sensitivity and specificity

    • Lower for INH (more mutations)

    • But limited field studies

    • Still potential for contamination

  • Expensive ($50-60 per test)


Accuracy of line probe assays from ling et al thorax 2010 sensitivity specificity
Accuracy of Line Probe assays – by prevalence of Initial MDR (from Ling et al, Thorax, 2010)Sensitivity Specificity

35


Cepheid genexpert mtb rif boehme et al 2010 nejm
Cepheid GeneXpert MTB/RIF – by prevalence of Initial MDR Boehme et al. 2010 NEJM

  • Automated RT-PCR

  • Simple 1-step specimen preparation

  • Minimal biohazard risks

  • Results in 2 HOURS!!

  • Demonstration studies (6673 patients, 6 sites):

  • Sensitivity for diagnosis

    99% in smear +

    80% in smear - / culture +

  • Rifampicin resistance

    95% sensitive

    98% specific


Treatment of dr tb

Treatment of DR-TB – by prevalence of Initial MDR

INH Mono-resistance

Other forms of non-MDR resistance

MDR-TB


How good is the published evidence
How good is the published evidence? – by prevalence of Initial MDR


One last thing how good is the published evidence
One last thing …. – by prevalence of Initial MDR How good is the published evidence?

  • Trials of retreatment

    • N = 4, all published before 1980

  • Trials of INH resistant patients

    • N = 5, also older studies

  • Trials of current standardized retreatment

    • NONE

  • Phase 3 Trials of MDR treatment

    • NONE


Isoniazid resistance excluding mdr
Isoniazid resistance (excluding MDR) – by prevalence of Initial MDR

Global weighted mean, 1994-2007*

  • 7.4% in new cases

  • 12.4% in previously treated

    Treatment

  • Dogma: “INH-R is of little importance”. Treat with standard therapy

  • Evidence – two systematic reviews

    • New cases – some of whom had INH-R

    • Studies of INH-R or retreatment

  • Risk of failure & acquiring MDR-TB


Treatment Failure in New cases – by prevalence of Initial MDR If Initial Drug ResistanceSystematic review of 57 studies with 20,000 patients.


Initial Drug Resistance and Treatment outcomes – by prevalence of Initial MDR (from Meta-regression) Systematic review of 57 studies with 20,000 patients.


Cohort studies with mono resistance to inh standardized who re treatment 2hrzes 1hrze 5hre
Cohort Studies with – by prevalence of Initial MDR Mono-resistance to INH Standardized WHO Re-treatment(2HRZES/1HRZE/5HRE)



Number of drugs in initial phase to which strains sensitive - INH resistance(from multivariate meta-regression)


My take therapy of inh r
My take – therapy of INH-R - INH resistance

  • Dogma wrong

  • Treat with fluoro-quinolone through-out

    • Two studies (CDC, and Russia) show that FQ equal to INH – can replace in regimen

  • Avoid intermittent therapy – at least initial 2 months

  • Give 4 effective drugs in first 2 months

  • Duration?: Longer=safer


Other forms of dr tb therapy
Other forms of DR-TB - therapy - INH resistance

  • If mono-RIF resistance:

    • INH/PZA/FQuin/EMB/Injectable – 2-6 mos

      • Then INH/EMB & FQuin – total 18 mos

  • If PZA resistance:

    • INH/RIF/EMB – 2 mos, INH/RIF – 7 mos

  • If EMB resistance:

    • Can ignore (its rare though)

  • If Strep resistance:

    • Can ignore (usually not tested)


Multi drug resistance therapy
Multi-Drug resistance - therapy - INH resistance

  • Long and difficult

  • Second line drugs – more toxic, and less effective

  • Optimal therapy controversial


Rational selection of mdr tb regimen
Rational selection of MDR-TB regimen - INH resistance

Isoniazid Rifampin

Ethambutol Pyrazinamide

Group 1

Streptomycin Kanamycin

Amikacin Capreomycin

Group 2

Ofloxacin Levofloxacin

Moxifloxacin Gatifloxacin

Group 3

Group 4

Ethionamide Prothionamide

Cycloserine Terizidone

Thioacetazone P-aminosalicylic acid

Group 5

Clofazimine Imipenem Amoxacillin/Clavulanate

Macrolides Linezolid


Individual Patient Data (IPD) - INH resistancemeta-analysis of patients with Multi-drug Resistant TuberculosisPreliminary results

Dick Menzies, on behalf of:

The IPD in MDR Group


The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB(members in alphabetic order)

D. Ashkin, S.Ahuja, M. Avendano, M. Bauer, M. Becerra, A. Benedetti, M. Burgos, R. Centis, E. Chan, C.Y. Chiang, F. Cobelens, H. Cox, E. Declercq, D. Enarson, D. Falzon, K. Flanagan, J. Flood, J. Furin, L. Garcia-Garcia, N. Gandhi, P. Hopewell, T. Holtz, S. Keshavjee, WJ.Koh, V. Leimane, C.C. Leung, J. Li, A.K. Maug, D. Menzies, G.B. Migliori, C.Mitnick, S.S. Munsiff, M. Narita, E. Nathanson, P. O’Riordan, M. Pai, D. Palmero, G. Pasvol, J. Pena, C. Perez, MID Quelapio, H.T. Quy, A. Ponce-de-Leon, V. Riekstina, J. Robert, S. Royce, M. Salim, H.S. Schaaf, K.J. Seung, L. Shah, K.P. Shean, T.S. Shim, S.S. Shin, Y. Shiraishi, Jose Sifuentes-Osornio, G. Sotgiu, M. Strand, P. Tabarsi, T.E. Tupasi, M. Vargas, M. Van der Walt, T.S. Van der Werf, A. Van Deun, P. Viiklepp, W.W. Yew, J.J. Yim


Research objectives
Research Objectives Patient Data in MDR-TB

  • “Which are the most (and least) effective drugs for MDR TB treatment?”

  • “What is the optimal number of drugs?”

    • Intensive phase

    • Continuation phase

  • “What is the optimal duration of treatment?”

    • Initial intensive phase (duration of injectable)

    • Total duration


Study selection
Study Selection Patient Data in MDR-TB

  • 3 systematic reviews of MDR treatment:

    • Johnston et. al. (2009)

    • Orenstein et. al. (2009)

    • Akçakir et. al. (2010)

  • Inclusion criteria of these 3 reviews:

    • Original data, published since 1970

    • Bacteriological confirmation of INH- and RIF-resistant TB

    • Excluded if strictly XDR-TB patients

  • IPD eligibility

    • Investigators willing and able to share their data

    • At least 25 MDR cases

    • Treatment and treatment success known


  • Meta analysis methods
    Meta-analysis Methods Patient Data in MDR-TB

    at MDR TB diagnosis

    • Random effects logistic regression to obtain the odds ratio of treatment success for each drug

      • Models included a random intercept & random slope

      • Estimate OR for each study, then pool estimates

    • Multivariate approach controlled for:

      • gender

      • age

      • HIV

      • disease severity (AFB smear/CXR cavities)

      • past TB treatment (none, previous TB treatment, previous MDR TB treatment)


    Figure 1. Study Selection Patient Data in MDR-TB

    3 Systematic reviews identified – Orenstein, Johnston, Akcakir

    93 studies identified from 3 systematic reviews

    Excluded: 26 publications representing the same or overlapping cohorts

    67 individual cohorts

    Excluded - 35 cohorts

    13 – No author response

    8 – No longer have access to data

    5 – Inadequate outcome data

    2 – Refusals

    2 – No response following initial

    contact

    2 – No data on drug sensitivity testing

    2 – Data never sent

    1 – Cohort with less than 25 patients

    32 data sets included, with 9898 patients

    Excluded Patients

    410 - XDR TB

    127 - Extra-pulmonary TB

    208 - No treatment info

    9153 patients analyzed


    Treatment outcomes n 9 153 patients
    Treatment Outcomes Patient Data in MDR-TBN = 9,153 patients

    • Cure/complete (success) - 4932 (54%)

    • Failure/relapsed - 732 (8%)

    • Death - 1392 (15%)

    • Default - 2097 (23%)


    Draft who recommendations for new mdr treatment guidelines 1
    Draft WHO Recommendations for new MDR treatment guidelines(1)

    • Use rapid DST testing for resistance to INH and RIF or RIF alone at the time of diagnosis of TB over conventional testing or no testing

    • Use smear and culture over smear alone for monitoring

    • Use fluoroquinolones

    • Higher generation FQN > lower generation

    • Use ethionamide / prothionamide


    Draft who recommendations for new mdr treatment guidelines 2
    Draft WHO Recommendations for new MDR treatment guidelines(2)

    • Initial phase with 4 SLD TB drugs likely to be effective (including inj.) and Z

    • Regimen with FQ, Km, Eto/Pto, Cs or PAS, plus Z

    • Initial phase at least 8 months, total treatment of 21-24 months

    • ART in all HIV/MDR-TB patients

    • Use mainly ambulatory care rather than mainly hospital care


    Conclusions
    Conclusions guidelines(2)

    • DR-TB treatment is more complex, usually longer, and should be daily

    • DST essential to guide therapy

    • Evidence base for therapy of DR-TB is very weak – ‘expert’ opinion usually.

      • Hence strong differences in opinion

    • New drugs and RCT needed


    Acknowledgements
    Acknowledgements guidelines(2)

    • Systematic Reviews – Woojin Lew, Olivia Oxlade, Madhu Pai, Faiz Khan

    • Ecologic studies: Anita Paydar, Anton Mak

    • IPD meta-analysis: Melissa Bauer, Maria Holmes-Delgado, Sandra Ramoutar, Lena Shah,

    • Slides (with some edits) from:

      • Kitty Lambregts, Fuad Myrzayev, Matteo Zignol, Sarah Royce, Jessica Minion, Madhu Pai,


    Thank you merci gracias
    Thank you! guidelines(2)Merci!Gracias!!


    References
    References guidelines(2)

    • Akçakir Y. Correlates of treatment outcomes of Multidrug-Resistant Tuberculosis (MDR-TB): a systematic review and meta-analysis. Montreal: McGill University; 2010.

    • Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM. Treatment outcomes of multidrug-resistant tuberculosis: a systematic review and meta-analysis. PLOS One 2009;4(9).

    • Orenstein EW, Basu S, Shah NS et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 2009;9(3).

    • 2008 Emergency Update from WHO


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