1. Epidemiology of Tuberculosis in Northeastern United States, 1993-2005 Kenneth G. Castro, M.D. Assistant Surgeon General, USPHS Director, Division of Tuberculosis Elimination National Center for HIV, Hepatitis, STD, and TB Prevention* Coordinating Center for Infectious Diseases * Proposed Northeast TB Controllers Meeting Princeton, New Jersey October 24, 2006

2. Acknowledgements United States TB controllers, state and local health departments CDC, DTBE, SEOIB and FSEB –Lori Armstrong− Sandy Althomsons –Elvin Magee− Val Robison –Tom Navin− Dave Crowder –Dan Ruggiero− John Jereb –Mark Lobato− Margaret Oxtoby –Edwin Rodriguez− Tracy Agerton –Farah Parvez− Sonal Munsiff –Vernard Green− Tom Privett –Zach Taylor

3. TB Cases Analyzed National TB Surveillance System Reported 1993 to 2005 Northeastern States: Maine, New Hampshire, Vermont, Connecticut, Massachusetts, Rhode Island, New York, New Jersey Compared to all other states in the U.S.

4. TB Case Rates,* United States, 2005 < 3.5 (year 2000 target) 3.6–4.8 > 4.8 (national average) D.C. *Cases per 100,000. NE states

5. Reported TB Case Rates in U.S., NE vs. Other States, 1993-2005 Year Rate TB Cases/ 100,000

6. Reported TB Cases by Age Group, NE States vs. Others, 1993–2005 Percent of Case Count

7. Reported TB Cases by Race/Ethnicity,* NE States vs. Others, 1993–2005 Hispanic (25%) Black (36%) Asian (20%) White (18%) Amer Indian/Nat Alaskan (<1%) Nat Hawaiian/ Pacific (<1%) *All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases. Unknown not included. Hispanic (23%) Black (31%) Asian (19%) White (25%) NE States Other States Amer Indian/Nat Alaskan (1%) Nat Hawaiian/ Pacific (<1%)

8. Reported TB Cases by Birth Origin, NE States vs. Others, U.S., 1993–2005* Note: Unknown not included Birth Origin NE States n (%) Other States n (%) US-Born21,051 (49.2)116,601 (59.7) Foreign-born21,769 (50.8)78,741 (40.3)

9. TB Cases, by Previous Diagnosis, NE States vs. Others, U.S., 1993–2005* Note: Unknown and missing not included *Updated as of March 29, 2006. NE States n (%) Other states n (%) Previous diagnosis of TB 1,695 (4.0)10,785 (5.5) No previous diagnosis of TB 41,153 (96.0)183,777 (94.5)

10. HIV Test Results of TB Cases, NE States vs. Others, U.S., 1993–2005* HIV Status NE States n (%) Other states n (%) HIV Positive8,357 (19.4)18,025 (9.2) HIV Negative15,180 (35.3)64,023 (32.6) Missing or Unknown 19,456 (45.3)114,511 (58.2)

11. * Excludes unknown and missing. Directly observed therapy (DOT); Self-administered therapy (SA) Mode of Treatment Administration in Persons Reported with TB, NE States vs. Others, U.S., 1993–2003*

12. Percent Completion of TB Therapy,* NE States vs. Others, U.S., 1993-2005 *Healthy People 2010 target: 90% completed in 1 yr or less. Note: Excludes persons with initial isolate resistant to rifampin and children <15 years old with meningeal, bone or joint, or miliary disease excluded. Percent Year

13. Reason Therapy Stopped in TB Cases, NE States vs. Others, U.S., 1993–2005* Percent

14. MDR TB* in NE States vs. Others, U.S., 1993-2005 % MDR TB Year of Reporting %MDR TB cases = no. of TB cases with Mycobacterium tuberculosis isolates resistant to isoniazid and rifampin, among all cases tested to isoniazid and rifampin

15. MDR TB by Birth Origin, NE States vs. Others, U.S., 1993-2005 Birth OriginNE States n (%) Other US n (%) Foreign-born390 (34.5)1082 (64.2) U.S.-born735 (65.1)589 (35.0) Unknown origin4 (0.4)13 (0.8) Total1129 (100.0)1684 (100.0)

16. TB Epidemiology Summary in NE States* Heterogeneous states (high, medium, low incidence) Consistently higher rates Majority (58.6%) younger than 44 years Most (82%) racial/ethnic minorities Lower proportion (49.2%) U.S.-born Higher prevalence (19.2%) HIV infection Larger proportion on DOT+SA and SA only treatment COT improving (82%), room for improvement MDR decreased 1993-2000, recent stagnation * Compared with other states, U.S., 1993-2005

18. Second-Line Drug Classes for MDR TB Treatment Amikacin, Kanamycin Ciprofloxacin, Ofloxacin Ethionamide, Prothionamide Thioamides PAS Polypeptides Serine analogues Capreomycin WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006. Aminoglycosides Fluoroquinolones Cycloserine First line drugs +

19. Characteristics of KZN XDRTB Patients CharacteristicsNo. (%) No prior TB Treatment26 (51) Prior TB treatment –Cure or Completed treatment 14 (28) –Treatment Default or Failure 7 (14) HIV-infected (44 tested)44 (100) Dead (Includes 34% on ARV)52 (98) Identical M. tb spoligotype 26/30 * Moll A, Gandhi NR, Pawinski R, Lalloo U, Sturm AW, Zeller K, Andrews J, Friedland G. HIV associated Extensively Drug-Resistant TB (XDR-TB) in Rural KwaZulu-Natal (South Africa MRC Expert Consultation Sept 8, 2006)

20. Hospital Total Cases % HIV Infected % Deaths Median Wks Dx to Death A6593727 B511008916 C7095774 D2991834 E714434 F1682 4 I13100854 J2896934 Prison4298794 HIV-related MDR TB Outbreak Investigations by CDC & Health Departments, USA, 1988–92

21. U.S. Response to TB Resurgence National MDR-TB Action Plan & New Resources Improved Case Identification & Training Updated Diagnostic Labs, Real-time Drug Resistance, & Strain Fingerprinting Updated Infection Control and Rx Recommendations DOT & Improved Rx CompletionRebuilt Research Capacity AJRCCM 1994;149:1359-74

22. Global 7-point Action Plan to Combat XDR TB Emphasizes Essentials of Proper TB Control 1. Conduct rapid surveys of XDR-TB (determine burden) 2. Enhance laboratory capacity (emphasis on rapid DST) 3. Improve technical capacity of clinical and public health practitioners to effectively respond to XDR-TB outbreaks and manage patients 4. Implement infection control precautions (PLHA focus) 5. Increase research support for anti-TB drug development 6. Increase research support for rapid diagnostic test development 7. Promote universal access to ARVs under joint TB/HIV activities MRC Consultation, Johannesburg, South Africa. Sept 7, 2006

23. Revised WHO Case Definition for XDR TB (Oct 10, 2006) Goals Public health surveillance Reliable DST methodology Clinical relevance Relatively simple Resistance to at least isoniazid and rifampin (MDR) plus resistance to fluoroquinolones and one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin)

24. TB Treatment Outcomes, by Selected Drug Resistance Patterns, Latvia, 2000-2003* * Leimane V, et al. WHO XDR TB Task Force Meeting. Oct 9, 2006 (from N = 820 evaluated) Percent

25. XDR (WHO) TB Cases in U.S., Northeast vs. Other States, 1993-2005 No. XDR TB Cases Year of Report

26. XDR (WHO) TB Cases in U.S., Foreign-born vs. U.S.-born, 1993-2005 No. XDR TB Cases Year of Report

27. XDR (WHO) TB Cases in Northeast States, Foreign-born vs. U.S.-born,1993-2005 Year of Report No. XDR TB Cases

28. XDR (WHO) TB Cases in Other States, Foreign-born vs. U.S.-born,1993-2005 Year of Report No. XDR TB Cases

29. XDR (WHO) TB Cases in U.S.-born vs. Foreign-born Persons, 1993-2005 1993-19982000-2005 U.S.-born193 Foreign-born12

30. TB Clinical Development Pipeline CompoundDevelopment StageSponsor / Coordinator GatifloxacinPhase III EC / OFLOTUB Consortium; IRD*; WHO TDR  ; Lupin Ltd. MoxifloxacinPhase II / III Bayer; TB Alliance; CDC  ; University College of London; Johns Hopkins University Early Bactericidal ActivityJohnson & Johnson (Tibotec) Early Bactericidal ActivityOtsuka Pharmaceutical Co., Ltd. Phase ITB Alliance Phase ILupin Ltd. * Institut de Recherche pour le Developement  World Health Organization, Tropical Disease Research  Centers for Disease Control and Prevention Novel compounds, highlighted in blue boxes, are active against MDR/XDR TB Diarylquinoline TMC207 Nitroimidazo-oxazole OPC-67683 Nitroimidazole PA-824 Pyrrole LL-3858

31. Examples of Rapid Drug Resistance Methods Test GenoType ® MTBDRINNO-LiPA Rif.TB Company Hain LifescienceInnogenetics M. tuberculosis detectionYes Detection RMP resistanceYes Detection INH resistanceYesNo Strip AssayYes DNA basis: PCRYes Direct assayNoYes (modified version) RMP resistance:rpoB geneYes INH resistance:katG geneYesNo

32. Microscopic-Observation Drug Susceptibility Assay for the Diagnosis of TB* Moore DAJ, et al. N Engl J Med 2006;355:1539-50

33. Actual and BRDPI-Adjusted Federal Funds for TB*, CDC, 1990-2006 Actual $ BRDPI Adjusted * Adjusted to 1990 US$ by Biomedical Research & Development Price Index ** Includes TB/HIV and lab dollars