1. HIV and TB Jeffrey D. Klausner, MD, MPH Professor of Medicine and Public Health Program in Global Health, Division of Infectious Diseases David Geffen School of Medicine Fielding School of Public Health Special thanks to: Caitlin Reed MD, MPH Medical Director, Inpatient TB Unit, Olive View – UCLA Medical Center Los Angeles County Department of Health Services September 2014 African-American HIV University

2. Disclosures Dr. Klausner is a faculty member of the University of California Los Angeles Dr. Klausner is a guest researcher with the US CDC Mycotics Diseases Branch Dr. Klausner is a member of the WHO STD Guidelines group Dr. Klausner is a board member of YTH, Inc, non-profit Dr. Klausner is medical advisor for Healthvana.com In the past 12 months, Dr. Klausner has received: –Travel support for meeting coordination and speaking from Standard Diagnostics, Inc. –Research funding or donated supplies from the NIH, CDC, Hologic, Inc., Alere, Inc., Chembio, Inc. Cepheid, Standard Diagnostics, Inc., and MedMira, Inc. JDKlausner@mednet.ucla.edu

3. Objectives: TB Update 1)Review of TB epidemiology & pathogenesis 2)New tests and treatment for latent TB 3)Diagnosis of active TB 4)TB puzzles

4. TB Frequency

5. Reported TB Cases, U.S. 1982-2012 CDC MMWR 2010

6. Where is TB? Global Tuberculosis Control 2011; WHO

7. TB is Not Gone 1/3 of the world’s population is infected with TB (Latent TB infection) Globally 9 million new cases of active TB / year 1.3 million TB deaths / year

8. Tuberculosis Cases in Foreign-born and U.S.-born Persons by Race/Ethnicity: California, 2010 Credit: CDPH TB Control Program

9. Natural History of TB Exposure Close Aerosol Contact With an Infectious Case Infection Latent Infection Asymptomatic Not Infectious Active TB disease 10% lifetime risk 5% first 2 years after infection 90% 10% Treat latent TB to prevent active TB X

10. Relative Risk for Developing Active TB by Risk Factors Risk FactorApproximate Risk HIV/AIDS170 * Lung Disease due to Silica30 Immunosuppression10-15 Cancer10-15 Hemophilia5-10 Kidney failure10-15 Malnutrition2-4 Diabetes2-4 Smoking2 Targeted Tuberculin Testing and Treatment of Latent TB Infection CDC, MMWR June 2000

12. Why do HIV-infected patients get TB? * 1) Immune suppression leads to activation of old TB 2) Re-exposure in clinics and hospitals leads to new infection

13. Latent TB Infection

14. Targeted TB screening 1) People at increased risk of recent infection Close contacts of active TB case Recent immigrants from countries with TB Work exposure –Nursing home, hospital, jail/prison 2) Risk factors for active TB Pts with HIV infection Other immunosuppressed persons

15. TB Screening Tests Tuberculin skin test (TST) Interferon-gamma release assays (IGRAs) –Quantiferon-Gold In-Tube (Cellestis) –T. Spot TB (Oxford Immunotect ) Quantiferon is the most commonly use TB screening test in patients with HIV-infection *

16. TB Skin Test 48-72 hrs Interpretation depends on risk factors Reader error No immune response in some pts Reactivity

17. Quantiferon TB Testing Measures immune response to TB antigens Similar principle to TST –Uses TB-specific antigens –Not affected by BCG vaccination (specific)

18. TST and Quantiferon Antigen presenting cell Memory T-cell Presentation of mycobacterial antigens IFN-  IL-8, etc. TNF-  Andersen P, et al. Lancet 2000;356:1099 Tuberculin skin test IGRA

19. Case 1 32 year old health care worker with positive Quantiferon Test Denies cough, fever, weight loss, night sweats Chest x-ray negative Treat for latent TB infection –9 months isoniazid daily or –4 months rifampin daily or –3 months of isoniazid/ rifapentine weekly

20. Treatment of latent TB in patients with HIV infection 6 months of isoniazid Some recommend 36 months ? Perhaps until CD4 > 500

21. Active TB Exposure Latent TB Infection Active TB Infection Symptomatic Death Treatment

22. TB Diagnostic Tests Smear microscopy (sputum, tissue) Mycobacterial Culture (sputum, blood, tissue) Nucleic Acid Amplification Tests (sputum, tissue)

23. Sputum Smear Microscopy Easy, rapid, cheap –Sensitivity*: In field conditions : 40-60% HIV- infected patients: 20-60% –Specificity: Not specific for M. tuberculosis Arrow: Acid Fast Bacilli * WHO Stop TB Diagnostics Working Group Strategic Plan 2006-20 15

24. Mycobacterial Culture Reference Standard for diagnosis of TB Can send from any body site Solid or liquid culture medium Limitation: –Slow (mean: 24 days for positives) –Resource intensive, costly

25. Drug Susceptibility Culture Testing Diagnosis of drug-resistant TB Conventional Methods: –Grow TB in culture –Assess for growth (resistant) or absence of growth (susceptible) at 4 weeks

26. Nucleic Acid Amplification Tests –Amplify nucleic acid segments specific for M. tuberculosis –Rapid: Results in 24-48 hours –Commercially Available: Mycobacterium Tuberculosis Direct (MTD) Amplicor M.Tb Test (Amplicor) Cepheid GeneXpert MTB Rif Cepheid GeneXpert MTB Rif

27. Case 2 66 yo homeless man with abnormal chest xray, weight loss, chronic cough Smear positive for AFB HIV-infected Treatment? –4 drug regimen: Rifampin, INH, PZA, Ethambutol –May stop PZA after 2 months –May stop Ethambutol if no resistance –For 6 to 9 months total duration

28. TB and HIV infection Difficult to diagnosis (low amount of TB) Drug-drug interactions Immune reconstitution inflammatory syndrome (IRIS) –Delay antiretroviral therapy until on TB treatment If CD4 < 50 delay 2 weeks If CD4 > 50 and stable, delay 8 weeks –Monitor for worsening –Consider addition of steroids

29. New developments in TB Ongoing search for point of care test –Urine LAM: antigen detection; potentially useful, in HIV-infected patients with CD4 <50 Reports of ‘Totally Drug Resistant’ TB Finally, new drugs for drug-resistant TB –Bedaquiline (Sirturo)– FDA approved Dec 2012 for MDR-TB –Delaminid – phase III trial

30. Olive View Inpatient TB Unit TB Unit 15 beds (10 staffed currently) Patients must be stable with lab- confirmed TB Categories of patients Infectious, need prolonged isolation Drug resistant TB requiring special management TB drug adverse reactions Public health detention

31. Group questions & dilemmas

32. Group 1 The patient has HIV infection but his TB skin test is negative What are 3 possible explanations?

33. Group 2 A patient has been started on TB medicines. He initially gets better and then gets worse. What are 3 possible explanations?

34. Group 3 Name 3 groups that are high risk for TB Describe 3 ways the risk for TB might be decreased in those groups?

35. Group 4 TB is a public health condition that gets reported to the health department. Name 3 other “reportable” conditions Describe what the health department does with that information

36. Thank you