Development of extensive drug resistance in Multi-Drug resistant

tuberculosis patients

MSF anti-TB programmes in MSF anti-TB programmes in Abkhazia and UzbekistanAbkhazia and Uzbekistan

Authors: Cathy Hewison, Vinciane Sizaire, Helen Cox, Authors: Cathy Hewison, Vinciane Sizaire, Helen Cox, Stobdan Kalon, Stefan Nieman and Jonathan PolonskyStobdan Kalon, Stefan Nieman and Jonathan Polonsky

Some definitions

Multi-Drug Resistant (MDR) TBMulti-Drug Resistant (MDR) TB: : Tuberculosis resistant to at least Isoniazid Tuberculosis resistant to at least Isoniazid and Rifampicinand Rifampicin

Extensive Drug Resistant (XDR) TB:Extensive Drug Resistant (XDR) TB: MDR TB resistant as well to a MDR TB resistant as well to a fluoroquinolone (Oflo- or moxifloxacin) fluoroquinolone (Oflo- or moxifloxacin) and a 2and a 2ndnd line injectable (Kanamycin or line injectable (Kanamycin or Capreomycin)Capreomycin)

Settings

Abkhazia:Abkhazia: TB treatment as per WHO recommendation since 1998TB treatment as per WHO recommendation since 1998 DST survey (Sept 2000 – March 2002):DST survey (Sept 2000 – March 2002):

MDR TB rate in new cases = 4%MDR TB rate in new cases = 4% MDR TB rate in re-treatment cases = 18.7%MDR TB rate in re-treatment cases = 18.7%

Nov 2004: Green Light Committee approvalNov 2004: Green Light Committee approval Aug 2001: 1Aug 2001: 1stst patient enrolled on MDR treatment patient enrolled on MDR treatment March 2003 – Sept 2005: Genotyping for the Long March 2003 – Sept 2005: Genotyping for the Long

drug studydrug study

Settings

Nukus (Uzbekistan)Nukus (Uzbekistan) TB treatment as per WHO recommendation since 1998 TB treatment as per WHO recommendation since 1998

with total coverage of Karakalpakstan achieved end of with total coverage of Karakalpakstan achieved end of 20022002

DST survey in 2001:DST survey in 2001: MDR TB rate in new cases = 13%MDR TB rate in new cases = 13% MDR TB rate in re-treatment cases = 40%MDR TB rate in re-treatment cases = 40%

Early 2003: Green Light Committee approvalEarly 2003: Green Light Committee approval Sept 2003: 1Sept 2003: 1stst patient enrolled on MDR treatment patient enrolled on MDR treatment Since May 2007: Genotyping studySince May 2007: Genotyping study

Objectives

Primary objectivesPrimary objectives To evaluate the XDR rate among MDR TB patients at To evaluate the XDR rate among MDR TB patients at

diagnosisdiagnosis To evaluate the rate of MDR TB cases who become XDR To evaluate the rate of MDR TB cases who become XDR

while on an adapted treatmentwhile on an adapted treatment Secondary objectivesSecondary objectives

Amongst patients who become XDR during MDR Amongst patients who become XDR during MDR treatment:treatment:

Identify the potential risk factors for developing XDRIdentify the potential risk factors for developing XDR Evaluate treatment outcomesEvaluate treatment outcomes Define needs in further research from the current findings and Define needs in further research from the current findings and

eventual operational implicationseventual operational implications

Method

Retrospective cohort analysis of:Retrospective cohort analysis of: All MDR TB patients diagnosed at the 1All MDR TB patients diagnosed at the 1stst DST DST

from the beginning of the project till end of from the beginning of the project till end of December 2006, in order to evaluate the December 2006, in order to evaluate the baseline XDR ratebaseline XDR rate

All MDR TB patients enrolled on MDR All MDR TB patients enrolled on MDR treatment from the beginning of the project till treatment from the beginning of the project till end of December 2006, excluding those XDR at end of December 2006, excluding those XDR at diagnosis, in order to evaluate the rate of MDR diagnosis, in order to evaluate the rate of MDR patients who become XDR while on treatment.patients who become XDR while on treatment.

MDR TB diagnosis and follow-up

Diagnosis:Diagnosis: DST to all 1DST to all 1stst line TB drugs, except Z, performed line TB drugs, except Z, performed

systematically in all M+, by MGIT in Abkhazia and by systematically in all M+, by MGIT in Abkhazia and by L-J in Nukus (MGIT will be available in June 2007)L-J in Nukus (MGIT will be available in June 2007)

DST to 2DST to 2ndnd Line by L-J in all MDR patients identified Line by L-J in all MDR patients identified Follow-up:Follow-up:

Abkhazia: Culture/DST 1x/month during the IP and Abkhazia: Culture/DST 1x/month during the IP and 1x/2 months during the CP1x/2 months during the CP

Nukus:Culture from M2, 1x/month till culture Nukus:Culture from M2, 1x/month till culture conversion then 1x/2 months. DST 1x/3 monthsconversion then 1x/2 months. DST 1x/3 months

MDR TB patients management Individual Treatment regimen:Individual Treatment regimen:

IP: Minimum of 4 in Abkhazia, 5 in Nukus, 2IP: Minimum of 4 in Abkhazia, 5 in Nukus, 2ndnd Line TB drugs to Line TB drugs to which patient is susceptible, including an injectable for 4 to 6 which patient is susceptible, including an injectable for 4 to 6 months after culture conversionmonths after culture conversion

CP: Same regimen but the injectable for 18 monthsCP: Same regimen but the injectable for 18 months DOTDOT Comprehensive management of side-effectsComprehensive management of side-effects Infection control measures in the hospital:Infection control measures in the hospital:

UV lightsUV lights Ventilation (difficult in the winter time)Ventilation (difficult in the winter time) High filtration masks for staff and visitorsHigh filtration masks for staff and visitors Separation of the patientsSeparation of the patients

MDR treatment outcomes

Treatment outcomes are reported according Treatment outcomes are reported according to WHO and international definitions:to WHO and international definitions: CureCure Treatment completedTreatment completed DeathDeath FailureFailure DefaultDefault Still on treatmentStill on treatment

Results: Baseline XDR rate among MDR TB patients

Abkahzia:Abkahzia: Sept 2000 – Dec 2006:147 MDR patients Sept 2000 – Dec 2006:147 MDR patients

diagnoseddiagnosed 6 (4.1%) were XDR at the time of diagnosis6 (4.1%) were XDR at the time of diagnosis

Nukus:Nukus: Sept 2003 – Dec 2006: 428 MDR patients Sept 2003 – Dec 2006: 428 MDR patients

diagnoseddiagnosed 7 (1.6%) were XDR at diagnosis7 (1.6%) were XDR at diagnosis

Results: Development of XDR TB during MDR treatment and outcomes

AbkhaziaAbkhazia NukusNukus

# MDR patients enrolled # MDR patients enrolled on treatmenton treatment

102102 334334

# patients who developed # patients who developed XDR TBXDR TB

13 13

(12.7%)(12.7%)

27 27

(8.1%)(8.1%)

Outcomes amongst XDROutcomes amongst XDR 0 success0 success

6 failures6 failures

3 defaulters3 defaulters

3 died3 died

1 still on TT1 still on TT

5 success5 success

11 failures11 failures

0 defaulter0 defaulter

5 died5 died

6 still on TT6 still on TT

Results: Potential factors contributing to the development of XDR

VariableVariable LevelLevel AbkhaziaAbkhazia NukusNukus

OROR pp OROR pp

SexSex M vs FM vs F 2.32.3 0.440.44 1.251.25 0.580.58

Age groupAge group Linear variableLinear variable 0.990.99 0.610.61 0.990.99 0.700.70

TB TT TB TT historyhistory

New vs previously treatedNew vs previously treated

Prev treated w/ 2Prev treated w/ 2ndnd L vs rest L vs rest

0.210.21

1.481.48

0.140.14

0.520.52

0.420.42

1.261.26

0.410.41

0.580.58

Baseline Baseline resistance resistance to 2to 2ndnd L L

Prior resistance to any 2Prior resistance to any 2ndnd L L vs nonevs none

1.801.80 0.320.32 4.824.82 < 0.001< 0.001

Results: Discussion

4.1% in Abkhazia and 1.6% in Nukus of MDR patients 4.1% in Abkhazia and 1.6% in Nukus of MDR patients are XDR at the time of diagnosis are XDR at the time of diagnosis

13% in Abkhazia and 8% in Nukus of the MDR 13% in Abkhazia and 8% in Nukus of the MDR patients become XDR, while on a comprehensive patients become XDR, while on a comprehensive MDR treatmentMDR treatment

The only RF strongly associated with XDR The only RF strongly associated with XDR development is the baseline resistance to 2development is the baseline resistance to 2ndnd Line Line drugs, confirmed by the multivariate analysis in Nukus drugs, confirmed by the multivariate analysis in Nukus (OR=6.02, p < 0.001)(OR=6.02, p < 0.001)

We need also to look at the level of adherence to We need also to look at the level of adherence to treatment as a RFtreatment as a RF

Conclusions

The apparition of XDR TB from a best practice The apparition of XDR TB from a best practice MDR TB management is concerningMDR TB management is concerning

What are the mechanisms behind the XDR What are the mechanisms behind the XDR apparition?apparition? True amplificationTrue amplification Re-infectionRe-infection Multiple infectionsMultiple infections Laboratory contaminationLaboratory contamination

Conclusions

MDR strains genotyping through the treatment MDR strains genotyping through the treatment and molecular epidemiology are needed to:and molecular epidemiology are needed to: Estimate the relative contribution of double infection, Estimate the relative contribution of double infection,

super-infection or true resistance amplificationsuper-infection or true resistance amplification Better define the RF that contribute to the development Better define the RF that contribute to the development

of XDRof XDR Identify clusters, within families or within the hospitalIdentify clusters, within families or within the hospital

Operational implications

If super-infection between patients during the stay in If super-infection between patients during the stay in the hospital:the hospital: Urgent needs to improve infection control within the Urgent needs to improve infection control within the

hospitalhospital Consider ambulatory treatment from the beginning?Consider ambulatory treatment from the beginning?

If family clustersIf family clusters Aggressive active screening in all family members?Aggressive active screening in all family members?

If true amplificationIf true amplification Use more aggressive treatment regimen, including 3Use more aggressive treatment regimen, including 3rdrd Line Line

TB drugsTB drugs Call for research on new drugsCall for research on new drugs