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

Background

2 regions:Karakalpakstan (Uzbekistan) & Dashoguz (Turkmenistan).

Combined population of 2.8 million.DOTS implemented from 1998-2003Case notification in 2002 (462/100,000

& 213/100,000 in Karak. and Dash. respectively)

(Background)DOTS outcomes for all SS (+) cases Karakalpakstan, 1998-

2003

Cure rate42%

Death rate11%

Default rate11%

Treatment completed

20%

Failure rate16%

Success Rate 62%

(Background) DST survey : July 2001-Jan

2002Karakalpakstan

Type of Resistance

New cases (%) (N=106)

Re-treatment cases (%)

(N=107)

TOTAL(N= 213)

Mono-resist. 14.1 17.7 15.9

PDR 18.8 22.4 21.6

MDR 13.2 40.2 26.8Any resistance

48.1 80.4 64.3Dashoguz: MDR rates 4% in new and 18% in re-treatment cases

(Background)Drug resistance and treatment

outcome in 6 former Soviet Union countriesTOT

nSuccess

%Failure

%MDR

%

Abkhasia 112 65 7.1% 18.7%

Karabagh 30 77 17% 16%

Kemerovo prison 304 52 31.6% 40%

Kazakhstan 115 56 19% 37%

Karakalpakstan 645 55.3 15% 40%

Doshoguz 505 69 12.4% 18%

*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.

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

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.

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

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

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.

(Results)Amplification of drug

resistanceFirst-line drug resistance profile

Diagnosis,

number of

strains

Repeat testing, number of identical strains (%)

Amplification detected among identical strains(%, 95% confidence interval)

Pan-susceptible

177 12 (7%) 2 (1.1%, 0.1-4.0)

Mono-resistant

72 10 (14%)

1 (1.4%, 0.0-7.5)

Poly-resistant

65 16 (25%)

11 (17%, 9-28)

MDR 68 24 (35%)

5 (7%, 2-16)

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

Patient Drug R at diagnosis

Resistance at end of intensive phase

Resistance 2 months into the continuation phase

Treatment outcome

Amplified drug resistance during treatment.

1 SUSC S S Failure S

2 HS   HRS Failure R

3 HS   HRS Failure R

4 HS HRS HRS Failure R

5 HS HRS   Default R

6 HES HRES HRS Failure R

7 HSZ HESZ   Comp E

8 HRS HRESZ   Failure EZ

9 HRS HRSZ   Died Z

10 HRES HRESZ   Cured Z

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

Patient Drug R at diagnosis

Resistance at end of intensive phase

Resistance 2 months into the continuation phase

Treatment outcome

Amplified drug resistance during treatment.

11 SUSC SUSC HRS Failure HRS

12 S HS   Failure H

13 HS HRES   Failure RE

14 HSZ HRESZ   Died RE

15 HES HRES HRES Failure R

16 HES HRESZ   Failure RZ

17 HESZ HESZ HRSZ Failure R

18 HR   HRES Failure ES

19 HRES HRESZ HRZS Died Z

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

Discussion

• 19 out of 62 patients with identical strains developed additional drug resistance.

• 17% patients with PDR-TBamplified resistance further MDR

• 7% MDR-TB developed further 1st line resistance.

• Overall 11/314 (3.5%) not initially infected with MDRdeveloped MDR after SCC.

• Majority with amplificationpoor outcome.

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.

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.

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

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

Acknowledgements

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