Tuberculosis in the United States, 2004

1. Tuberculosis in the United States, 2004 Thomas R. Navin, MD CDC March 2005

2. TB Presentation Overview • How we count TB cases in the U.S. • Descriptive epi • Analytic epi • New items on the horizon • Genotyping • New diagnostic tests • New drugs

5. TB Case Reports, Missouri, 1994-2004

6. TB Case Rates*, Missouri and United States, 1994-2004 * Rate per 100,000

7. TB Case Rates*, Log Scale * Rate per 100,000

9. Percent Foreign-born TB Cases, United States, 2004* D.C. 57% – 66% ≤ 25% 26% - 40% ≥ 67% *Percent foreign-born cases over total cases 41% - 56%(%foreign-born for U.S.= 53.7%)

10. Asian/Pacific Islander American Indian/Alaska Native Black White Hispanic TB Case Rates* by Race/Ethnicity** United States, 1993-2003 Cases per 100,000 *Cases per 100,000.**All races are non-Hispanic. In 2003, Asian/Pacific Islander category includes persons who reported race as Asian only and/or Native Hawaiian or Other Pacific Islander only.

11. No. of Cases Percentage 00 01 02 03 Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin. Primary MDR TBUnited States, 1993-2003

12. Primary MDR TB inU.S.-born vs. Foreign-born Persons, United States, 1993-2003 % Resistant Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

13. Estimated HIV Coinfection in Persons Reported with TB, United States,1993-2002 % Coinfection Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group.

14. Characteristics of TB Cases, 2004

15. Program Indicators: Completion of therapy, 2002

16. Program Indicators: DOT*, 2002 * DOT or DOT+SA

17. Preventable TB Case Analysis • Nearly half of Missouri’s TB cases are preventable. • The majority of preventable cases (85%) involved a missed opportunity to screen patients with risk factors for TB.

18. Recommendations Physicians in Missouri must remain aware of risk factors for TB and test at-risk asymptomatic persons: - contacts of infectious TB patients - persons with medical risk-factors for TB

19. Universal Genotyping of M. tuberculosis In 2004 CDC established the capacity to conduct universal TB genotyping. One isolate from every patient with TB can now be genotyped in real time.

20. Value of Genotyping Identify and prevent recent transmission • Enhance contact investigations • Identify nontraditional settings of transmission • Facilitate identification of outbreaks Improve clinical management • More readily identify false-positive cultures • Help distinguish between relapse and reinfection

21. CDC Genotyping Program Laboratory Algorithm Two tiered testing to maximize discriminatory power PCR • MIRU Variable number tandem repeats of mycobacterial interspersed repetitive units • Spoligotyping Spacer oligonucleotide IS6110-based RFLP • Done only for isolates that match by both PCR tests • When TB programs request it

22. Spoligotyping • PCR probes at 43 different sites 1 2 3 4 5 6 7 8 9 10 . . . . . . . . . . . . . 20 . . . . . . . . . . . . 30 . . . . . . . . . . . .40 . . . .43

23. Spoligotyping • Does the probe recombine (hybridize) with genetic material at that site? • Assign 1 or 0 to each of the 43 probes Yes = 1 No = 0

24. Spoligotyping = 111-111-111-111-111-111-100-111-111-111-110-000-111-111-1

25. Spoligotyping Each triplet gets assigned an octal code • Spoligotype then reported as 15 digits • 777777477760771 1 2 3 4 5 6 7 8 9 10 . . . . . . . . . . . . . 20 . . . . . . . . . . . . 30 . . . . . . . . . . . .40 . . . .43 111= 7 100 4 110 6 000 0 7 7 7 7 7 7 7 7 7 7 Always 1 or 0 for last probe

26. MIRUMycobacterial Interspersed Repetitive Units • Also uses PCR technologybut on a different part of the DNA • Looks at 12 different loci and counts Variable Number Tandem Repeats (VNTR)

27. MIRU Sample Printout Locus 6 3 repeats Locus 4 3 repeats CEQ 8000 Automated Sequencer Locus 7 1 repeat

28. MIRU • Looks at 12 different loci and counts VNTR • MIRU-VNTR pattern is then reported as a 12-digit number • Example: 123323153323 means there are 3 repeats at Locus 6

29. Reading Lab Report • Look at spoligotype and MIRU pattern (i.e., the PCR tests) is the first step • If don’t match any other isolate, then not part of a cluster, no further testing needed • If match another isolate’s PCR results, may indicate recent transmission

30. When To Ask For RFLP? • To decide if isolates with matching spoligo and MIRU are truly clustered—when you need additional evidence for or against match • Not necessarily needed • An ‘unusual’ PCR cluster is likely a true cluster • If it is obvious that the persons with matching isolates transmitted TB among each other

31. RFLP • Third method • Less automated, requires more lab resources • Experienced laboratorian must “eyeball” • Each genotyping lab will assign unique number to each distinct RFLP in its database • The PCR tests use standardized coding • But the RFLP label in itself has no meaning outside the lab which assigned it

32. RFLP • Lab assigns unique number or label to each RFLP in its database • RFLP designation arbitrary and does not correspond to genetic make-up Ex: 051 052 051

33. Presence of Any Epidemiologic Links Discovered during Contact/Cluster Investigations of 555 Cases in Intrasite Genotyping Clusters (NTGSN)

34. Interferon-gamma Assays • QuantiFERON Gold • T Spot TB assay

35. Interferon-gamma Assays • QuantiFERON Gold now FDA approved • Measures IFN release from T cells • Based on M. tuberculosis specific antigens • ESAT6 and CFP10 • Should not give false-positive result due to: • BCG vaccination • Nontuberculous mycobacteria • CDC working on publishing guidelines for use

36. Interferon-gamma Assays • T Spot TB assay • Enzyme-linked immunospot assay • Counts number of T cells producing IFN • Based on ESAT6 and CFP10 • Not yet FDA approved (available in Europe)

37. Treatment regimens for tuberculosis:New drug candidates Andrew Vernon, MD, MHS Chief, Clinical and Health Systems Research Branch Division of TB Elimination March 2005 …with thanks to Rick O’Brien

38. 2004 Distribution of TB Trials Consortium Clinical Sites Barcelona Kampala 28 clinical sites worldwide CDC Administrative, Statistical, and Data Management Center Rio de Janeiro Durban

39. New drugs • Moxifloxacin • Ethambutol congeners (SQ-109) • Diarylquinolines • Nitroimidazole (PA-824)

40. Fluoroquinolones • No cross-resistance with other TB drugs • Commonly used for MDR TB • Role in therapy of drug susceptible TB uncertain

41. Relative TB activity of Fluoroquinolones HIGHEST: Gatifloxacin, Moxifloxacin, Sparfloxacin NEXT: Levofloxacin LOWER: Ciprofloxacin , Ofloxacin

42. Features of Quinolones and TB Therapy Drug Serum Peak Half life TB MIC Ciprofloxacin 750 2.3 4 2.0 Ofloxacin 400 4.6 7 2.0 Levofloxacin 500 6.0 7 1.0 Sparfloxacin 400 1.3 20 0.5 Gatifloxacin 400 4.4 7 0.5 Moxifloxacin 400 4.5 12 0.5

43. Activity of Moxi in Combination Therapy 2/5 mice had 1 cfu each 2.5 logs 6/6 mice culture pos. 3/6 mice culture pos.

44. Clinical Trails of Moxifloxacin • Multiple studies substituting moxi for ethambutol • CDC plans phase II trial substituted moxi for INH (MRZE) vs. the standard control regimen (HRZE) • Will measure sputum-culture conversion • If successful, future plan to move clinical trials of Moxi in very short regimens (<6 months)

45. Congeners of Ethambutol • Targeting the enzymes involved in long chain fatty acid metabolism unique to mycobacteria • Based on computerized screening of possible compounds for predicted activity based on organic structure (Dr. Cliff Barry and colleagues [NIAID]) • Current lead compound SQ-109moving into animal and human trials soon (Sequella Inc.)

46. Diarylquinolines (DARQ)(lead compound = R207910)

47. Nitroimidazoles • Potent bactericidal antitubercular compound series • Narrow spectrum of activity (TB specific) • Promising efficacy: comparable to INH in animal models • Active on non-replicating (latent?) TB • Leading candidate: PA-824

48. PA-824 development • Acquired by Global Alliance for TB Drug Development • Currently being developed in partnership with Chiron • Animal efficacy studies promising • Animal and human toxicology studies to begin soon

49. What are the prospects for more new drugs soon? • Moxifloxacin – in multiple clinical trials • Ethambutol congeners (SQ-109) – moving to clinical phase • Diarylquinolines (DARQ) – moving to clinical phase • Nitroimidazole (PA-824) – in pre-clinical phase