High Prevalence and Mortality from Extensively DrugResistant XDR TB in TBHIV Coinfected Patients in

1
High Prevalence and Mortality from Extensively
Drug-Resistant (XDR) TB in TB/HIV Coinfected
Patients in Rural South Africa

• NR Gandhi, A Moll, R Pawinski, U Lalloo, AW
  Sturm,
• K Zeller, J Andrews, G Friedland
• Yale University School of Medicine, New Haven CT
  USA
• Nelson R. Mandela School of Medicine, Durban,
  South Africa
• Philanjalo, Tugela Ferry, KwaZulu Natal, South
  Africa

2
Background

• HIV and Tuberculosis (TB) epidemics in South
  Africa closely intertwined
• Roughly 80 of new TB cases in KwaZulu Natal
  coinfected with HIV
• Annual mortality rate among coinfected patients
  40 before antiretroviral (ARV) medications
• Reduced to 12 in TB/ARV integration study1
• 10 of 14 (71) deaths from multidrug-resistant TB

1Gandhi, Moll, Pawinski et al. IAS Toronto 2006
abstract MOPE0181
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Multidrug-Resistant (MDR) TB

• MDR TB resistance to isoniazid and rifampicin
• MDR TB rate in KwaZulu Natal in 2002
• 1.7 of new TB cases
• 10 of 110 (9.1) with MDR TB in TB/ARV
  integration study
• 6 of 10 MDR TB patients resistant to all first
  and second line TB drugs
• Isoniazid, rifampicin, ethambutol, streptomycin,
  kanamycin, ciprofloxacin

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Extensively Drug-Resistant (XDR) TB

• Recent CDC WHO report2 described TB resistant
  to second line TB medications
• Extensively Drug-Resistant (XDR) TB
• Found in 347 isolates worldwide
• Few data regarding presence in Africa and in high
  HIV prevalence settings

2Emergence of Mycobacterium Tuberculosis with
Extensive Resistance to Second Line
DrugsWorldwide 2000-2004. MMWR.200655301-305
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Objectives

• To assess the extent of MDR TB and XDR TB among
  patients presenting to a rural district hospital
  in KwaZulu Natal, South Africa
• To describe patient and treatment characteristics
  of patients with XDR TB

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Methods

• Cross-sectional study of patients suspected
• with active TB at a rural district hospital
• Isolates collected for mycobacterial culture
  (MGIT) from January 2005 to March 2006

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Methods

• Cross-sectional study of patients suspected
• with active TB at a rural district hospital
• Isolates collected for mycobacterial culture
  (MGIT) from January 2005 to March 2006
• Standard of Care patients with treatment failure
  or retreatment cases

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Methods

• Cross-sectional study of patients suspected
• with active TB at a rural district hospital
• Isolates collected for mycobacterial culture
  (MGIT) from January 2005 to March 2006
• Standard of Care patients with treatment failure
  or retreatment cases
• Inpatient Survey all patients in TB wards

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Methods

• Cross-sectional study of patients suspected
• with active TB at a rural district hospital
• Isolates collected for mycobacterial culture
  (MGIT) from January 2005 to March 2006
• Standard of Care patients with treatment failure
  or retreatment cases
• Inpatient Survey all patients in TB wards
• All TB suspects patients presenting to district
  hospital with TB symptoms
• (e.g., cough, fever, weight loss, etc)

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Methods

• Drug susceptibility testing performed on all
  cultures positive for M. tuberculosis
• Isoniazid, rifampicin, ethambutol, streptomycin,
  ciprofloxacin, kanamycin
• Chart review performed for patients with strains
  resistant to all tested drugs (XDR TB cases)
• Demographics, prior TB treatment, prior hospital
  admissions, HIV status, survival
• Molecular fingerprinting by spoligotyping on all
  XDR TB isolates

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Results
1539 Patients with Isolates sent
995 (65) Culture-Negative
544 (35) Culture-Positive for M.tb
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Results
1539 Patients with Isolates sent
995 (65) Culture-Negative
544 (35) Culture-Positive for M.tb
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544 patients Culture-Positive for M.tb
323 (59) Not Resistant to both Isoniazid
Rifampicin
221 (41) Resistant to Isoniazid Rifampicin
(MDR TB)
14
544 patients Culture-Positive for M.tb
323 (59) Not Resistant to both Isoniazid
Rifampicin
221 (41) Resistant to Isoniazid Rifampicin
(MDR TB)
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544 patients Culture-Positive for M.tb
323 (59) Not Resistant to both Isoniazid
Rifampicin
221 (41) Resistant to Isoniazid Rifampicin
(MDR TB)
128 cases of MDR TB In US in 2004
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544 patients Culture-Positive for M.tb
323 (59) Not Resistant to both Isoniazid
Rifampicin
221 (41) Resistant to Isoniazid Rifampicin
(MDR TB)
53 (24 of MDR, 10 Culture-Positive) Resistant
to all tested drugs (XDR TB)
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544 patients Culture-Positive for M.tb
323 (59) Not Resistant to both Isoniazid
Rifampicin
221 (41) Resistant to Isoniazid Rifampicin
(MDR TB)
347 cases of XDR TB Worldwide
53 (24 of MDR, 10 Culture-Positive) Resistant
to all tested drugs (XDR TB)
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Demographics of XDR TB Patients
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Prior TB Treatment
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New Infection with XDR TB

• Majority never previously treated or had previous
  cure or treatment completion
• Suggests newly infected with drug-resistant TB
  strains
• Not development of drug resistance on therapy

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Transmission of XDR TB

• 64 of patients hospitalized for any cause before
  onset of XDR TB
• 2 healthcare workers died with confirmed XDR TB
• 4 other workers died with suspected XDR TB
• Nosocomial transmission in hospitals probable
• Transmission in community also possible since 36
  XDR TB patients with no prior hospitalizations

22
HIV Characteristics
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Molecular Fingerprinting

• 26 of 30 (87) XDR TB isolates found to be
  genetically similar
• Suggestive of recent infection with
  drug-resistant strain

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Mortality

• 52 of 53 (98) XDR TB patients have died
• Median survival from sputum collection 16 days
  (range 2-210 days)
• No significant difference by demographics, data
  collection group, previous TB or
  hospitalizations,
• HIV status, or use of ARVs

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Survival from Sputum Collection
26
Survival from Sputum Collection
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Summary

• Multidrug-resistant TB substantially more common
  in a rural district of KwaZulu Natal compared
  with previously published rates
• An extensively drug-resistant strain of TB
  accounts for nearly one-quarter of all MDR TB
  cases found
• Recent transmission in both hospital and
  community
• All patients HIV tested were HIV-infected
• Rapidly fatal

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Implications

• MDR XDR TB have emerged as significant causes
  of death among TB/HIV coinfected patients
• Routine sputum culture and drug susceptibility
  testing allowed identification of MDR XDR TB
• Success of ARV and TB DOTS programs threatened by
  MDR XDR TB
• Transmission of MDR and XDR TB must be addressed
  to further improve survival for HIV coinfected
  patients

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Recommendations

• Routine culture of TB suspects in high HIV
  settings
• Scale up laboratory capacity for TB culture and
  drug susceptibility testing
• Improvements in Infection Control necessary
• Improved ventilation in wards
• Isolation facilities for suspected MDR TB cases
• Increased vigilance to identify undiagnosed TB
  cases
• Contact tracing of all TB, MDR XDR TB cases
• Resources to strengthen TB Control programs

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Acknowledgements

• Study Supported by the Doris Duke Charitable
  Foundation, Irene Diamond Fund the Presidents
  Fund of Yale University
• Tugela Ferry Dr Francois Eksteen, Dr Theo van de
  Merwe, Eugene Meyer, TB DOTS Staff, TB Contact
  Tracing Team, Home Based Care Program
• Nelson Mandela School of Medicine Nicola
  Deghaye, Prinesh Gounden, Dr Nesri Padayatchy
• Lynn Roux Inkosi Albert Luthuli Hospital
  Microbiology Lab
• KZN Department of Health Bruce Margo, Dr Thilo
  Govender
• King George V Hospital Dr Ramjee
• Johnson Johnson International Scholar Dr
  Deborah Goldstein
• Patients and families who are participating in
  the study