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Risk of acquired drug resistance during DOTS tuberculosis treatment in a setting of high drug resistance. Helen S. Cox 1,3 , Stefan Niemann 2 , Gabit Ismailov 3 , Daribay Doshetov 4 , Juan Daniel Orozco 3 , Lucie Blok 5,6 , Sabine Rüsch-Gerdes 2 , Yared Kebede 5

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  1. Risk of acquired drug resistance during DOTS tuberculosis treatment in a setting of high drug resistance Helen S. Cox1,3, Stefan Niemann2, Gabit Ismailov3, Daribay Doshetov4, Juan Daniel Orozco3, Lucie Blok5,6, Sabine Rüsch-Gerdes2, Yared Kebede5 1Australian International Health Institute, Melbourne, Australia, 2Forchungszentrum Borstel, National Reference Center for Mycobacterium, Borstel, Germany, 3Médecins Sans Frontières, Karakalpakstan, Uzbekistan, 4Ministry of Health, Nukus, Karakalpakstan, Uzbekistan, 5Médecins Sans Frontières, Amsterdam, Holland. 6Royal Tropical Institute, Holland (current

  2. Background • 2 regions:Karakalpakstan (Uzbekistan) & Dashoguz (Turkmenistan). • Combined population of 2.8 million. • DOTS implemented from 1998-2003 • Case notification in 2002 (462/100,000 & 213/100,000 in Karak. and Dash. respectively)

  3. (Background)DOTS outcomes for all SS (+) cases Karakalpakstan, 1998-2003 Success Rate 62%

  4. (Background) DST survey : July 2001-Jan 2002Karakalpakstan Dashoguz: MDR rates 4% in new and 18% in re-treatment cases

  5. (Background) Drug resistance and treatment outcome in 6 former Soviet Union countries *M. Bonnet, V. Sizaire, Y. Kebede et al; Does one size fit all? Drug resistance and standard treatments: results of six tuberculosis programs in former Soviet countries. Int J Tuberc Lung Dis 2005 9(10):1147-1154.

  6. Study Objective Quantify the extent of acquired drug resistance during standardized chemotherapy among a cross-sectional sample of patients enrolled in a DOTS TB program in a high resistance setting in Uzbekistan and Turkmenistan

  7. Study Design • Samples taken from four districts in each region between July 2001 and March 2002. • Sputum smear +ve patients were enrolled. • Repeat samples for smear positives at end of intensive phase and 2 months into cont. phase obtained • Written informed consent was obtained. • Patients were started on Cat I (intermittent cont.) & Cat II regimen. • Hospitalized during intensive phase • DOT by health worker in cont. phase.

  8. Laboratory testing and statistical analysis • Sputum samples sent to SRL, Borstel, Germany for analysis. • DST for H,R,E,S,Z by LJ proportion method and BACTEC 460TB • Fingerprinting done using IS6110 • All isolates were analyzed by spoligotyping technique. • Molecular typing data analyzed with bio-numeric software • Epi-info used for data entry and analysis

  9. Results • Both DNA fingerprinting and DST results were available from 382 patients. • Repeat samples obtained from 82 patients. • 20 excluded (10 different strain, 5 double infection, 5 lab contamination) • 62 infected with same strain as at diagnosis

  10. Results • Of the 382 patients at diagnosis > 50% of were infected with strains with some resistance • A third were infected with strains resistant to 2 or more first line drugs. • Overall, 19 of the 62 identical strains (31%) developed new drug resistance during treatment.

  11. (Results)Amplification of drug resistance

  12. Amplification of drug resistance during treatment and treatment outcomes for 19 patients in which amplification was detected.New cases : Category I DOTS treatment 2HREZ(S)/ 4H3R3

  13. Amplification of drug resistance during treatment and treatment outcomes for 19 patients in which amplification was detected.Previously treated: Category II DOTS treatment 2HRZES/ 1HREZ/ 5H3R3E3

  14. Reversion of drug resistance • Some strains became susceptible to drugs that were initially resistant. • 5 strains lost resistance to E • 3 strains lost resistance to S

  15. Discussion • 19 out of 62 patients with identical strains developed additional drug resistance. • 17% patients with PDR-TBamplified resistance further MDR • 7% MDR-TB developed further 1st line resistance. • Overall 11/314 (3.5%) not initially infected with MDRdeveloped MDR after SCC. • Majority with amplificationpoor outcome.

  16. Discussion • Limited study on drug amplification in SCC • Large scale study done in Tomsk (Russia)* • 42% not initially infected with MDR-TB and have failed treatment, acquired MDR-TB. • H or R resistance highest rate of resistance amplification (71% developed MDR-TB) • Tomsk study didn’t include molecular typing (DNA finger printing) *Seung KJ et al. The effect of Initial Drug resistance on treatment Response and Acquired Drug Resistance during Standardized Short-Course Chemotherapy for Tuberculosis. CID 2004;39:1321-1328.

  17. Discussion • Present study included mol. Genotyping • Highest rate of resistance amplification among H and S resistant isolates. • Beijing genotype* highly prevalent in FSU regions more susceptible to amplify resistance *Cox HS, Kubica T, Male R, Doshetov D, Kebede Y, Rüsch-Gerdes S, Niemann S. The Beijing genotype and drug resistant tuberculosis in the Aral Sea region of Central Asia. Resp Res 2005, 6:134.

  18. Discussion • Amplification level under estimated  only smear +ve cases were re-tested. • If all samples cultured  additional amplification might have been detected • Reversion of resistance to susceptible • Less accurate DST for E and S • DST for E is often problematic • Different resistance profile within same bacillary population

  19. Summary • Demonstrated high level of drug resistance amplification after DOTS SCC in settings with underlying resistance to first line drugs. • Need for projects to weigh additional cost for DST against management of newly created MDR-TB systematic DST vital. • Standard regimen using 2nd line drugs for patients at risk of MDR amplification required. • Further determine, what level of drug resistance prevalence would require routine DST to avoid creation of unnecessary and costly drug resistance. • Strategy to reduce risk of amplification through integration of DR-TB management

  20. Acknowledgements We would like to thank MSF national and expatriate staff, MOH staff of Karakalpakstan and Doshoguz; and the SRL in Borstel, Germany.

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