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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

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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


Drug resistant tuberculosis dr tb an update

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


Drug resistant tuberculosis dr tb an update

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 2006

Trends in Global Drug Resistance in New Cases (AZIZ, Lancet 2006)


Trends in global drug resistance in new cases aziz lancet 20061

Trends in Global Drug Resistance in New Cases(AZIZ, Lancet 2006)


How does drug resistance develop

How does drug resistance develop?

(aka Pathogenesis)


Treatment with streptomycin alone or pas alone patients with resistance days after tx started

Treatment with Streptomycin alone, or PAS alone% 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 number of bacilli – byclinicalextent of disease

  • LesionQuantityAFB

  • Granuloma 103 Latent

  • Infiltrates 106- - 107Negative

  • Cavity 108 - 109+ , ++

  • Manycavities, 1010 - 1012+++

  • Death 1013 too late!


Probability of developing resistance during therapy by number of drugs

Number of 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

  • 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

  • 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)


Failure rate with standardized retreatment in 103 countries by prevalence of initial mdr

Failure rate with standardized Retreatment in 103 countries – by prevalence of Initial MDR


Diagnosis of drug resistance

Diagnosis of drug resistance

(very briefly)


Diagnosis of dr tb

Diagnosis of DR-TB

  • 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)

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

  • 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(from Ling et al, Thorax, 2010)Sensitivity Specificity

35


Cepheid genexpert mtb rif boehme et al 2010 nejm

Cepheid GeneXpert MTB/RIFBoehme 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

INH Mono-resistance

Other forms of non-MDR resistance

MDR-TB


How good is the published evidence

How good is the published evidence?


One last thing how good is the published evidence

One last thing ….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)

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


Drug resistant tuberculosis dr tb an update

Treatment Failure in New casesIf Initial Drug ResistanceSystematic review of 57 studies with 20,000 patients.


Drug resistant tuberculosis dr tb an update

Initial Drug Resistance and Treatment outcomes(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 Mono-resistance to INH Standardized WHO Re-treatment(2HRZES/1HRZE/5HRE)


Intermittent therapy and treatment outcomes inh resistance from multivariate meta regression

Intermittent therapy and Treatment outcomes - INH resistance (from multivariate meta-regression)


Drug resistant tuberculosis dr tb an update

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

  • 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

  • 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

  • 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

IsoniazidRifampin

Ethambutol Pyrazinamide

Group 1

StreptomycinKanamycin

AmikacinCapreomycin

Group 2

OfloxacinLevofloxacin

MoxifloxacinGatifloxacin

Group 3

Group 4

Ethionamide Prothionamide

CycloserineTerizidone

Thioacetazone P-aminosalicylic acid

Group 5

Clofazimine ImipenemAmoxacillin/Clavulanate

MacrolidesLinezolid


Drug resistant tuberculosis dr tb an update

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

Dick Menzies, on behalf of:

The IPD in MDR Group


Drug resistant tuberculosis dr tb an update

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

  • “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

  • 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

    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)


    Drug resistant tuberculosis dr tb an update

    Figure 1. Study Selection

    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 OutcomesN = 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

    • 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

    • 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!Merci!Gracias!!


    References

    References

    • 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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