1. Development of extensive drug resistance in Multi-Drug resistant tuberculosis patients MSF anti-TB programmes in Abkhazia and Uzbekistan Authors: Cathy Hewison, Vinciane Sizaire, Helen Cox, Stobdan Kalon, Stefan Nieman and Jonathan Polonsky

2. Some definitions Multi-Drug Resistant (MDR) TB: Tuberculosis resistant to at least Isoniazid and Rifampicin Multi-Drug Resistant (MDR) TB: Tuberculosis resistant to at least Isoniazid and Rifampicin Extensive Drug Resistant (XDR) TB: MDR TB resistant as well to a fluoroquinolone (Oflo- or moxifloxacin) and a 2 nd line injectable (Kanamycin or Capreomycin) Extensive Drug Resistant (XDR) TB: MDR TB resistant as well to a fluoroquinolone (Oflo- or moxifloxacin) and a 2 nd line injectable (Kanamycin or Capreomycin)

3. Settings Abkhazia: Abkhazia:  TB treatment as per WHO recommendation since 1998  DST survey (Sept 2000 – March 2002):  MDR TB rate in new cases = 4%  MDR TB rate in re-treatment cases = 18.7%  Nov 2004: Green Light Committee approval  Aug 2001: 1 st patient enrolled on MDR treatment  March 2003 – Sept 2005: Genotyping for the Long drug study

4. Settings Nukus (Uzbekistan) Nukus (Uzbekistan)  TB treatment as per WHO recommendation since 1998 with total coverage of Karakalpakstan achieved end of 2002  DST survey in 2001:  MDR TB rate in new cases = 13%  MDR TB rate in re-treatment cases = 40%  Early 2003: Green Light Committee approval  Sept 2003: 1 st patient enrolled on MDR treatment  Since May 2007: Genotyping study

5. Objectives Primary objectives Primary objectives  To evaluate the XDR rate among MDR TB patients at diagnosis  To evaluate the rate of MDR TB cases who become XDR while on an adapted treatment Secondary objectives Secondary objectives  Amongst patients who become XDR during MDR treatment:  Identify the potential risk factors for developing XDR  Evaluate treatment outcomes  Define needs in further research from the current findings and eventual operational implications

6. Method Retrospective cohort analysis of: Retrospective cohort analysis of:  All MDR TB patients diagnosed at the 1 st DST from the beginning of the project till end of December 2006, in order to evaluate the baseline XDR rate  All MDR TB patients enrolled on MDR treatment from the beginning of the project till end of December 2006, excluding those XDR at diagnosis, in order to evaluate the rate of MDR patients who become XDR while on treatment.

7. MDR TB diagnosis and follow-up Diagnosis: Diagnosis:  DST to all 1 st line TB drugs, except Z, performed systematically in all M+, by MGIT in Abkhazia and by L-J in Nukus (MGIT will be available in June 2007)  DST to 2 nd Line by L-J in all MDR patients identified Follow-up: Follow-up:  Abkhazia: Culture/DST 1x/month during the IP and 1x/2 months during the CP  Nukus:Culture from M2, 1x/month till culture conversion then 1x/2 months. DST 1x/3 months

8. MDR TB patients management Individual Treatment regimen: Individual Treatment regimen:  IP: Minimum of 4 in Abkhazia, 5 in Nukus, 2 nd Line TB drugs to which patient is susceptible, including an injectable for 4 to 6 months after culture conversion  CP: Same regimen but the injectable for 18 months DOT DOT Comprehensive management of side-effects Comprehensive management of side-effects Infection control measures in the hospital: Infection control measures in the hospital:  UV lights  Ventilation (difficult in the winter time)  High filtration masks for staff and visitors  Separation of the patients

9. MDR treatment outcomes Treatment outcomes are reported according to WHO and international definitions: Treatment outcomes are reported according to WHO and international definitions:  Cure  Treatment completed  Death  Failure  Default  Still on treatment

10. Results: Baseline XDR rate among MDR TB patients Abkahzia: Abkahzia:  Sept 2000 – Dec 2006:147 MDR patients diagnosed  6 (4.1%) were XDR at the time of diagnosis Nukus: Nukus:  Sept 2003 – Dec 2006: 428 MDR patients diagnosed  7 (1.6%) were XDR at diagnosis

11. Results: Development of XDR TB during MDR treatment and outcomes AbkhaziaNukus # MDR patients enrolled on treatment 102334 # patients who developed XDR TB 13(12.7%)27(8.1%) Outcomes amongst XDR 0 success 6 failures 3 defaulters 3 died 1 still on TT 5 success 11 failures 0 defaulter 5 died 6 still on TT

12. Results: Potential factors contributing to the development of XDR VariableLevelAbkhaziaNukus ORpORp Sex M vs F 2.30.441.250.58 Age group Linear variable 0.990.610.990.70 TB TT history New vs previously treated Prev treated w/ 2 nd L vs rest 0.211.480.140.520.421.260.410.58 Baseline resistance to 2 nd L Prior resistance to any 2 nd L vs none 1.800.324.82 < 0.001

13. Results: Discussion 4.1% in Abkhazia and 1.6% in Nukus of MDR patients are XDR at the time of diagnosis 4.1% in Abkhazia and 1.6% in Nukus of MDR patients are XDR at the time of diagnosis 13% in Abkhazia and 8% in Nukus of the MDR patients become XDR, while on a comprehensive MDR treatment 13% in Abkhazia and 8% in Nukus of the MDR patients become XDR, while on a comprehensive MDR treatment The only RF strongly associated with XDR development is the baseline resistance to 2 nd Line drugs, confirmed by the multivariate analysis in Nukus (OR=6.02, p < 0.001) The only RF strongly associated with XDR development is the baseline resistance to 2 nd Line drugs, confirmed by the multivariate analysis in Nukus (OR=6.02, p < 0.001) We need also to look at the level of adherence to treatment as a RF We need also to look at the level of adherence to treatment as a RF

14. Conclusions The apparition of XDR TB from a best practice MDR TB management is concerning The apparition of XDR TB from a best practice MDR TB management is concerning What are the mechanisms behind the XDR apparition? What are the mechanisms behind the XDR apparition?  True amplification  Re-infection  Multiple infections  Laboratory contamination

15. Conclusions MDR strains genotyping through the treatment and molecular epidemiology are needed to: MDR strains genotyping through the treatment and molecular epidemiology are needed to:  Estimate the relative contribution of double infection, super-infection or true resistance amplification  Better define the RF that contribute to the development of XDR  Identify clusters, within families or within the hospital

16. Operational implications If super-infection between patients during the stay in the hospital: If super-infection between patients during the stay in the hospital:  Urgent needs to improve infection control within the hospital  Consider ambulatory treatment from the beginning? If family clusters If family clusters  Aggressive active screening in all family members? If true amplification If true amplification  Use more aggressive treatment regimen, including 3 rd Line TB drugs  Call for research on new drugs