Evolution of XDR-TB. A. Willem Sturm Interim Director K-RITH Nelson R Mandela School of Medicine University of KwaZulu-Natal

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1 Evolution of XDR-TB in KwaZulu-Natal A. Willem Sturm Interim Director K-RITH Nelson R Mandela School of Medicine University of KwaZulu-Natal

2 Drug resistance among culture positive TB cases by South African Province ( ) Any Drug Resistance (%) MDR (%) Province No History of Prior History of Prior TB No History of Prior History of Prior TB TB Treatment** Treatment** TB Treatment** Treatment** Eastern Cape Free State*** Gauteng KwaZulu-Natal Limpopo Mpumalanga North West Western Cape South Africa (Weyer et al, 2004)

3 53 cases of XDR-TB diagnosed in CoSH in Tugela Ferry (early 2005) Proportion Surviving Days since Sputum Collected (Gandhi et al, 2006)

4 Questions What happened between 2002 and 2005? Where did these 53 XDR cases come from? Was (is) this a hospital outbreak at CoSH or a more wide spread problem? Are the data an underrepresenting the MDR situation?

5 1396 cases suspected of PTB attending CoSH out-patient department 475 culture positive (2005)? infected in hospital 185 MDR 30 XDR 14 history of prior hospitalisation? infected in community 16 never hospitalised community transmission (Gandhi et al, 2006)

6 Questions What happened between 2002 and 2005? Where did these 53 XDR cases come from? Was (is) this a hospital outbreak at CoSH or a more wide spread problem? Are the data an underrepresenting the MDR situation?

7 Proportion of F15/LAM4/KZN strains amongst genotyped isolates Year Total no. genotyped No. (%) KZN strains Total no. (%) MDR No. (%) MDR KZN strains (2) 9 (3) 4 (44) (19) 27 (26) 12 (44) (15) 56 (40) 15 (27) (31) 24 (75) 8 (33) (9) 8 (35) 1 (13) (17) 15 (32) 4 (27) (31) 28 (62) 8 (29) (17) 64 (73) 13 (20) (8) 38 (23) 10 (26) Total (11) 269 (31) 75 (28) p < (Pillay and Sturm, 2007)

8 Fig 1. Resistance development in the KZN family of strains of Mycobacterium tuberculosis from 1994 till 2006 Resistance found for the first time in: Resistance to: none IE IS ISE IR IRE IRET IREEtT IRS IRSE IRSEEtT IRSETCa IRSEEtTK IRSEEtFq IRSEEtKFq IRSEKFq I isoniazid; S streptomycin; E ethambutol; Et ethionamide; R rifampicin; T thiacetazone Ca capreomycin; K kanamycin/amikacin; Fq fluoroquinolones (Pillay and Sturm, CID, Dec. 2007)

9 Situation in KZN in 2006/07 Culture and DST results of all patients in KZN on sputum specimens received between 1 Jan and 30 June 2007 Susceptibility testing done routinely for: isoniazide rifampicine ethambutol streptomycin kanamycine ofloxacin

10 KwaZulu-Natal Province Population size: 9,616, health districts divided in subdistricts

11 Differences in number of TB cases in districts of KZN District Population New TB cases MDR Cases XDR Cases Amajuba 477, ethekwini 3,152, ilembe 571, Sisonke 304, Ugu 718, Umgungundlovu 946, Umkhanyakude 584, Umzinyathi 465, Uthukela 670, Uthungulu 903, Zululand 820, Total 9,616,

12 Differences in incidence of TB cases in districts of KZN Incidence of new TB Incidence of MDR Incidence of XDR District (per /yr) (per /yr) (per /yr) Amajuba ethekwini ilembe Sisonke Ugu Umgungundlovu Umkhanyakude Umzinyathi Uthukela Uthungulu Zululand Total

13 Association between no. of new cases of TB diagnosed by culture and percentage MDR

14 Differences in rates of MDR and XDR cases in districts of KZN No. of MDR per No. of XDR per District 100 new TB cases 100 new TB cases Amajuba ethekwini ilembe Sisonke Ugu Umgungundlovu Umkhanyakude Umzinyathi Uthukela Uthungulu Zululand Total

15 From 2005, CoSH is the only health care facility with culture diagnostics performed on all possible TB cases Includes Msinga (CoSH)

16 How resistant is our XDR TB?

17 Fig 1. Resistance development in the KZN family of strains of Mycobacterium tuberculosis from 1994 till 2006 Resistance found for the first time in: Resistance to: none IE IS ISE IR IRE IRET IREEtT IRS IRSE IRSEEtT IRSETCa IRSEEtTK IRSEEtFq IRSEEtKFq IRSEKFq I isoniazid; S streptomycin; E ethambutol; Et ethionamide; R rifampicin; T thiacetazone Ca capreomycin; K kanamycin/amikacin; Fq fluoroquinolones (Pillay and Sturm, CID, Dec. 2007)

18 Genotypic resistance in F15/LAM4/KZN XDR isolates (n=52) Mutations in rss gene: 100 % resistance to streptomycin, kanamycine, amikacin and capreomycin Mutations in pcn A gene: 69 % resistance to pyrazinamide

19 MICs of M. tuberculosis isolates Table 2b: MICs of 11 M. tuberculosis isolates in Middlebrook 7H9 broth Median (range) MIC (mg/l) Susc. MDR XDR PAS ( ) Capreomycin (4-16) Linezolid 2 (0.5-2) 0.5 ( ) 1 (0.5-4) Merepenem (8-32) Meropenem-clavulanic acid 1 1 (1-2) 1 (0.5-4)

20 How resistant is XDR M.tuberculosis in KZN? Most isolates are resistant to: 1. isoniazid 2. rifampicin 3. ethambutol 4. pyrazinamide 5. streptomycin 6. kanamycin 7. amikacin 8. capreomycin 9. ofloxacin 10.ethionamide

21 Tuberculosis in the Msinga sub-district compared with other parts of KwaZulu- Natal no. (%*) no. of MDR per no. of XDR per population new TB cases 100 new TB cases 100 new TB cases Msinga sub-district 160, (0.68) Umzinyathi without Msinga 305, (0.12) districts with academic centre** (n=3) 4,683, (0.32) 11 1 other districts ** (n=9) 4,466, (0.09) 28 2 * percentage of the population ** MDR and XDR: average of the districts How does Msinga (CoSH) differ from the rest of the province?

22 Differences between Msinga subdistrict and the rest of the province Msinga sub-district Culture and DST on all on first contact No delay in DST results Rest of province Culture and DST on indication Delay in DST results No delay in appropriate treatment Delay in appropriate treatment

23 53 cases of XDR-TB diagnosed in CoSH in Tugela Ferry Proportion Surviving Days since Sputum Collected (Gandhi et al, 2006)

24 Referral for treatment of MDR/XDR cases Total number of MDR/XDR diagnosed between 1 Jan 2006 and 30 June Total number referred for treatment to MDR/XDR referral hospital 1439 (40%) Waiting list for admission

25 Is Msinga (CoSH) different from the rest of the province? May be not! Many patients in the rest of the province die: before a specimen is taken or before the DST results become available

26 Clonal spread? If so, did it start in Msinga /Tugela Ferry/CoSH?

27 Whole genome sequencing F15/LAM4/KZN XDR isolates 8 sequences completed all same mutations in resistance genes

28 Geographical distribution of sequenced XDR isolates 8 isolates 7 locations 4 districts Tugela Ferry

29 Whole genome sequencing F15/LAM4/KZN XDR isolates 8 sequences completed All same mutations in resistance genes Isolates from 7 different geographical locations 4 districts Suggests clonal spread number needs to be extended

30 Clonal spread? If so, did it start in Msinga /Tugela Ferry/CoSH?

31 Tuberculosis in the Msinga sub-district compared with other parts of KwaZulu- Natal no. (%*) no. of MDR per no. of XDR per population new TB cases 100 new TB cases 100 new TB cases Msinga sub-district 160, (0.68) Umzinyathi without Msinga 305, (0.12) districts with academic centre** (n=3) 4,683, (0.32) 11 1 other districts ** (n=9) 4,466, (0.09) 28 2 * percentage of the population ** MDR and XDR: average of the districts

32 Origin of XDR isolates in 1 st half of 2005 (laboratory database) Tugela Ferry Other locations January - March 15 6 April - June Did it start in Tugela Ferry? We will never know!

33 Conclusions KwaZulu-Natal has an enormous TB burden MDR and XDR strains are present throughout the province F15/LAM4/KZN isolates from 2005 were already TDR Sequence data suggest clonal spread of the XDR phenotype of F15/LAM4/KZN Prevalence data and time-of-first appearance data suggest that it may have started in Msinga district/tugela Ferry/CoSH

34 The team Durban Prashini Moodley Manormoney Pillay Staff and students of the TB research laboratory in at NRMSM Tugela Ferry Tony Moll Staff at Church of Scotland Hospital Albert Einstein/Yale Sarita Shah Neel Gandhi Gerald Friedland Bill Jacobs and his team