National Survey of Drug-Resistant Tuberculosis in China Dr. Yanlin Zhao

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1 National Survey of Drug-Resistant Tuberculosis in China Dr. Yanlin Zhao National Centre for Tuberculosis Control and Prevention of China CDC National TB Reference Laboratory, China CDC

2 BACKGROUND China lists as 2 nd among the 22 TB high-burden countries. In 1979, 1984/1985, 1990, 2000, nationwide epidemiological prevalence survey. Prevalence survey in 2000 shows 18.6% of initial resistance and 46.5% acquired resistance. During 1996~2008, 13 province have taken part in drugresistance surveillance organized by WHO/IUATLD. Initial: 14.8%~42.1%; Acquired: 33.7%~66% Estimation of MDR-TB in China: 5.0%, 26%

3 Objectives 1. To interpret the epidemiological status of drug resistant tuberculosis in China 2. To analyze the risk factor for drug resistance occurrence among tuberculosis patients 3. To explore the predominant mycobacterium bacillus biological characteristics in China 4. To understand the micro-evolution of the prevalent strains in China.

4 Selection of the 70 sites 70 clusters (sites) were selected according to new smear-positive cases reported by each province relative to the total number of cases nationwide in 2004 and All provinces should have at least one cluster.

5 Method 1.70 clusters(counties) from all 31 provinces 2.51 smear positive new cases and 17 smear positive retreatment cases with newly diagnosed 3. DST(proportion method) against 6 anti-tb drugs 1/29/2013 5

6 Design and preparation 2 Pilots

7 Design and Preparation Experience and lessons

8 Design and preparation Training objectives: all persons(about 700 persons) involved in this survey Training contents: Interaction method, role play and practice

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10 Resource of reagents and disposables for the laboratory

11 Anti-TB baseline survey lauching meeting ( 1 st Apr. 2007) Record files and register book

12 Logistics Monthly report Newsletter special address special fixed telephone fixed people 24h response established reporting and recording feedback machanism

13 Quality assurrance Leader group Experts panel Executive office Standardization of definition Standardization of methods Standardization of the parameters of the equipment, reagents and disposals Standardization of the implementation period of the time

14 Supervision Supervision for all clusters, Special supports to priority sites( 2 people from central level work in Tibet 3 weeks)

15 Strain files management

16 Strain logistic box special vehicle

17 Consent informs Questionaires

18 Panel testing for all persons who are responsible for DST Panel testing from Hongkong Supernational Reference Laboratory

19 Database of investigation Data input double blinded input the data by Peking University and 100% recheck by NRL

20 DST work in NRL Lowenstein-Jensen (L-J) media and proportion method was used for DST. 6 anti-tb drugs were included: sonazied(inh), Rifampine(RFP), Streptomycin(SM), Ethembutol(EMB), ofloxacin (Ofx); Kanamycin(Km) Proficiency test for DST was done to NRL by Hong Kong Super-National reference laboratory. 10% of the isolates were randomly chosen to repeat DST, the outcome was eligible according to WHO s guideline. Species identification work in NRL Selective L-J media method was used.

21 Case Enrollment & Culture Result Category Anticipated # Actual Completeness Estimated Culture + New Patient % 3010 TB 3037 NTM 103 Treated Patient % 1010 TB 892 NTM 37 Total # : considering 15% loss of samples due to failure to recover the culture or to growth of NTM. New patiens: 3010/ ; Treated patients: 1010/ : calculated under the estimation that drug resistance rate in new cases is 6% and 16% in previously treated cases, with a precision of ±1.2% / ±3.2% for CI 95% and a design effect of 2.

22 Results TB tested from 4069 cases Percentage of MDR-TB New case 5.71% Retreated case 25.64% Total 8.32% Percentage of XDR-TB New case 0.47% Retreated case 2.06% Total 0.68% thousand annually and 9 thousand cases among them are XDR patients. 1/29/

23 National prevalence of drug-resistant TB: China (2007) New cases (N = 3037) Previously treated cases (N =892) n (%) 95% CI n (%) 95% CI Susceptible to all 4 first line drugs 2009 (65.8) (45.5) Resistance to INH or RMP (not both) 338 (11.2) (16.1) Multidrug resistance (MDR) 175 (5.7) (25.6) Any resistance to OFX or KM 131 (4.2) (11.4) OFX resistance 88 (2.7) (8.7) KM resistance 59 (2.0) (4.8) MDR + resistance to OFX or KM 58 (1.8) (8.5) Extensively drug resistance 15 (0.47) (2.1) Zhao et al, NEJM, 2012

24 Previously treated MDRTB cases: last treatment completion and the location of last treatment Zhao et al, NEJM, 2012 January 29, Bill & Melinda Gates Foundation 24

25 Risk factors for drug-resistant TB among previously treated cases Drug-resistant TB (non-mdr)* Multidrug- resistant TB Women 1.7 ( ) 2.2 ( ) Age >60 years 0.79 ( ) 0.42 ( ) Lived in area with DOTS implementation after ( ) 1.7 ( ) No. of prior TB treatment episodes and medical facility providing last TB treatment One prior treatment and other medical facilities 1.0 (Ref) 1.0 (Ref) One prior treatment and TB hospital 1.6 ( ) 1.5 ( ) 2 prior treatments and other medical facilities 1.5 ( ) 3.3 ( ) 2 prior treatments and TB hospital 4.0 (1.2-14) 13 (3.9-46) Zhao et al, NEJM, 2012 January 29, Bill & Melinda Gates Foundation 25

26 Preventing MDRTB: new tools + system change Reduce sub-optimal treatment in CDC and hospital system by using treatment regimens based on resistance testing Make sure patients starting treatment in hospitals are followed up after discharge till they complete treatment; build linkage between hospital system and CDC system Improve treatment provided by TB hospitals: appropriate drug regimens, improved infection control, better follow-up after discharge Improve community case-management of patients on treatment (perhaps using adherence technology) January 29, Bill & Melinda Gates Foundation 26

27 Building hospital-cdc collaboration to prevent and treat M/XDR TB CDC system Patients evaluated for TB Specialized hospital Patients evaluated for TB No MDR MDR No MDR M/XDR Routine treatment (1 st -line drugs) M/XDR treatment (2 nd -line drugs) Effective case management in community

28 DOTS Program (in CDC) Diagnosis Smear microscopy Empiric treatment Standardized regimen using 1 st -line drugs Community casemanagement Self or family members Hospital-CDC collaboration Financing model for MDRTB Quality-assured drugs Incentive model for HCW s Innovative Program (CDC & hospital) Molecular diagnosis Rapid dx of TB Rapid dx of MDR-TB Treatment based on testing for resistance 2 nd -line drugs for MDR 1 st -line FDC drugs for non-mdr Technology-supported case-management Use of mobile phone & med monitor

29 Risk factors for drug-resistant TB among new cases Drug-resistant TB (non-mdr)* Multidrug- resistant TB Women 0.90 ( ) 1.5 ( ) Age >60 years 0.88 ( ) Occupation as non-farmer 1.2 ( ) 1.4 ( ) Lived in area with DOTS implementation after ( ) History of treatment with TB drugs and prior TB diagnosis No treatment (with or without a prior TB diagnosis) 1.0 (Ref) 1.0 (Ref) Treatment of <1 month and a prior TB diagnosis 1.6 ( ) 1.2 ( ) Treatment of any duration and no prior TB diagnosis 1.2 ( ) 2.4 ( ) Zhao et al, NEJM, 2012 January 29, Bill & Melinda Gates Foundation 29

30 Preventing drug-resistant TB among new cases Who are the patients with no prior diagnosis of TB but given TB drugs? Likely suspected to have TB and started on TB drugs Did not receive a diagnosis of TB because proper diagnosis not made Took TB drugs long enough, but improperly, such that MDRTB developed Mostly treated in hospital system Importance of performing proper diagnosis January 29, 2013 of TB 2011 Bill & Melinda Gates Foundation 30

31 Implications for new drug R&D Important to turn off the tap of DR-TB Current factors causing DR-TB will lead to rapid loss of any new drug to resistance Urgency in light of new TB drugs becoming available TMC-207, OPC67683, linozelid Need to improve system, adopt new diagnostics, and use new drugs in a rational manner in order to prevent DR-TB Level of quinolone resistance has 2011 Bill & Melinda Gates January 29, 2013 Foundation 31

32 Questions continues What s the population structure of the prevalent TB strains in China? What advantages do they have to become the prevalent strains? How do the prevalent strains interact with hosts and environment?

33 Drug resistance pattern 4000 TB Strains Drug resistant related mutations Spoligotyping 24 loci MIRU-VNTR plus IS6110 RFLP BJ/non-BJ strains Virulence & Pathogenicity Whole Genome Sequencing SNPs

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35 Distribution map of different spoligotypes

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38 Phenotypic drug resistance profiles and epidemiologic data of 11 Chinese M. tuberculosis isolates Isolates Virulence First-line drug resistance a Second-line drug resistance b Type Gender Age, years Genotype INH, RIF MDR Male 86 Beijing EMB Susceptible Male 17 Beijing INH, STR, EMB, RIF MDR Female 16 Beijing INH, STR, EMB, RIF MDR Female 16 Beijing INH, STR Susceptible Female 75 Beijing INH, STR Susceptible Male 34 Beijing STR OFX Susceptible Male 63 Beijing Susceptible Male 77 Beijing STR Susceptible Male 61 Non-beijing INH, RIF MDR Female 59 Non-beijing INH Susceptible Female 18 Non-beijing INH Susceptible Male 69 Non-beijing H37Rv 12 Susceptible Non-beijing

39 Table 2. Shared mutations in the high virulent strains Locus Id Nn-synonymous Mtation Fund Anotation a b c d e f Rv0336 Y376C Y376C Y376C 13E12 repeat family protein Rv0515 Y376C Y376C Y376C 13E12 repeat family protein Rv0775 R86Q R86Q R86Q R86Q hypothetical protein Rv0775 Rv1152 G105A G105A G105A G105A transcriptional regulatory protein Rv1295 G237S G237S G237S G237S threonine synthase Rv1588c A63T A63T A63T A63T REP13E12 repeat-containing protein Rv1934c N102S N102S N102S N102S acyl-coa dehydrogenase FADE17 Rv2124c Y1098D Y1098D Y1098D Y1098D 5-methyltetrahydrofolate-- homocystein methyltransferase Rv2769c A136V A136V A136V A136V PE family protein Rv3774 G124D G124D G124D G124D enoyl-coa hydratase Rv2543 A138V,A 139T A138V,A 139T A138V,A 139T A138V,A 139T A138V,A 139T A138V,A 139T lipoprotein LppA

40 Position of the 871 nonsynonymous SNPs by excluding common SNPs in Beijing genotype and non- Beijing genotype, respectively, Positions are Relative to the M. tuberculosis H37Rv Genome Sequence (From inner to outer: , , , , , , , , , , , green indicates susceptible strains, cyan indicates MDR strains)

41 Visible TB distribution model

42 大气监测数据可视化

43 4 dimension distribution by Genotypes

44 分枝杆菌迁徙可视化效果图

45 Acknowledgement people who made efforts and contribution to the survey Disease Prevention and Control Center of China (CDC) Beijing Tuberculosis and Thoracic Tumor Institute Peking Union Medical College of China Beijing University of China 31 provincial TB dispensary and 70 clusters

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47 Thank you for your attention!