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Tuberculosis February 21, 2007

Tuberculosis February 21, 2007. Timothy R. Sterling, M.D. Vanderbilt University Medical Center Director of TB Research, Nashville-Davidson Metro Health Department. Overview. TB Epidemiology TB/HIV Drug Resistance Diagnosis of TB TB Treatment Treatment Regimens TB/HIV

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Tuberculosis February 21, 2007

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  1. Tuberculosis February 21, 2007 Timothy R. Sterling, M.D. Vanderbilt University Medical Center Director of TB Research, Nashville-Davidson Metro Health Department

  2. Overview • TB Epidemiology • TB/HIV • Drug Resistance • Diagnosis of TB • TB Treatment • Treatment Regimens • TB/HIV • Diagnosis and Treatment of Latent Infection • Infection control

  3. Global TB Epidemiology2004 • Estimated # new TB cases: 8.9 million • Estimated # prevalent cases: 14.6 million • Estimated # deaths: 1.7 million • Estimated # infections: 2 billion • 33% of population WHO Report 2006. Global tuberculosis control. WHO/HTM/TB/2006.362

  4. Impact of HIV on TB Epidemiology • HIV responsible for the global TB resurgence • sub-Saharan Africa

  5. Global Incidence of MDR-TBResistance to INH + rifampin • TB cases in 2004 • Resistance surveys for: • New cases (90 countries) • Previously treated cases (77 countries) • Logistic regression estimated rate among all 184 countries in the world • Global estimates: • 424,203 cases in 2004 • 4.3% of all new and previously treated TB cases • China, India, Russian Federation accounted for 62% of estimated global burden of MDR-TB WHO—Zignol M et al. J Infect Dis 2006;194:479-85.

  6. Multidrug-Resistant Tuberculosis • Global “hotspots”: Russia, Latvia, India, Dominican Republic • Risk factors: • prior TB treatment • noncompliance • adding one drug to failing regimen • HIV?; outbreaks among AIDS patients • Treatment: 18-24 months • complex regimens

  7. XDR TB Extensively Drug Resistant Revised WHO Case Definition (Oct 11, 2006): Resistance to at least isoniazid and rifampin (MDR) plus resistance to: • Fluoroquinolones + • 1 of the second-line injectable drugs • amikacin, kanamycin, or capreomycin

  8. Diagnosis of Tuberculosis • Clinical signs/symptoms • Chest radiograph • Microscopy • Culture • DNA probe after growth in culture • Nucleic acid amplification

  9. Sputum • Sputum expectoration • 3 samples • Every 8 hours, with 1 specimen in early AM • For hospitalized patients; more convenient though few data • Sputum induction • In persons from whom expectorated sputum cannot be obtained or is smear-negative • Repeated sputum induction (3-4) increases yield • Cost-effective, even in resource-poor countries • Bronchoscopy • Unclear whether yield is greater than with repeated sputum induction • Consider when sputum induction negative but CXR suggests TB

  10. Microscopy • Techniques: • Acid-Fast (Ziehl-Neelsen; Kinyoun) • Fluorochrome (auramine-rhodamine) • Faster, easier to interpret • Sputum • + smear requires 5,000-10,000 bacilli/ml • 50% (34-80%) sensitive; nonspecific • Extrapulmonary specimens • Lower sensitivity

  11. Diagnosis of TBCulture • 80% sensitive; 98% specific • Solid media: • 7H-11, Lowenstein-Jensen • 21-42 days required for growth • Liquid media: • 7H-12 Bactec (radiometric); MGIT (fluorescent) • 5-10 days for growth • DNA probe once growth in culture: • M. tuberculosis complex, MAI, M. kansasii, M. gordonae

  12. Diagnosis of TBNucleic Acid Amplification • FDA-approved for respiratory specimens from untreated patients • SensitivitySpecificity • AFB smear + 95% 98% • AFB smear neg 48% 95% • Greater sensitivity if TB suspected clinically

  13. Diagnosis of TBNucleic Acid Amplification • Does not replace need to obtain AFB smear and culture • If high index of suspicion but NAA negative, TB has not been ruled out • Expensive • Extrapulmonary specimens: limited data, but less sensitive

  14. Treatment of TB • Goal of therapy: • kill M. tuberculosis, prevent resistance + relapse • Induction phase: • Isoniazid kills 95% of organisms (growing rapidly) during first 2 days of treatment • RIF, PZA then supplant INH in cidal role during the 2-month induction phase (slowly metabolizing bacilli) • Continuation phase • Rifampin primarily effective against persistent bacilli, though INH also cidal Mitchison DA. IJTLD 2000;4:796-806

  15. Treatment of TB • Culture-positive pulmonary tuberculosis caused by drug-susceptible organisms • American Thoracic Society • Centers for Disease Control & Prevention • Infectious Diseases Society of America Am J Respir Crit Care Med 2003;167:603-62

  16. Initial Treatment RegimensDrug Combinations and Dosing Intervals InitialContinuationRating 2 weeks18 weeksHIV-HIV+ HRZE daily HR 2x/week A (II) B (II) + H/RPT 1x/week* B (I) E (I) 6 weeks HRZE 2x/wk * no cavity on initial CXR, and smear-negative after 2 months.Extend Rx if cx+ at 2 mos H: isoniazid R: rifampin RPT: rifapentine Z: pyrazinamide E: ethambutol

  17. Additional Points • Ethambutol can be discontinued as soon as susceptibility to isoniazid + rifampin demonstrated • Obtain monthly sputum cultures until 2 consecutive negative cultures • Culture after 2 months of treatment VERY important • HIV testing recommended in all patients

  18. Optimal Duration of TB TreatmentRegardless of HIV status Site of DiseaseDuration Pulmonary 6 months* Bone/joint 6-9 months CNS/meningeal 9-12 months Other extrpulmonary 6 months *Extend to 9 months if cavitary and culture + at 2 months American Thoracic Society, Centers for Disease Control, IDSA. Treatment of Tuberculosis. AJRCCM 2003;167:603-62

  19. Renal Failure • Drugs excreted by kidneys: • ethambutol • pyrazinamide (metabolites) • Maintain dose, but increase interval: • Thrice-weekly dosing • Administer drugs after hemodialysis (DOT) • Pyrazinamide, cycloserine dialyzed out

  20. Hepatic DiseaseTreatment whenunderlying liver disease • Treat with standard therapy • Other options: • RZE x 6 months • HRE x 9 months • RE (+/- FQ) x 12 months (no data) • Check baseline transaminases, bili, alk  • Follow closely, along with symptoms H: isoniazid R: rifampin FQ:fluoroquinolone Z: pyrazinamide E: ethambutol

  21. Hepatic DiseaseTreatment when hepatitis develops on therapy • Stop treatment: • isoniazid, rifampin, pyrazinamide • Check hepatitis A, B, C serology • Assess for other hepatotoxins • alcohol • acetominophen • Could continue treatment with ethambutol, aminoglycoside, fluoroquinolone • Sequential drug rechallenge of 1st-line agents when AST < 2x upper limit of normal

  22. Pregnancy • No aminoglycosides • Congenital deafness • Pyrazinamide: • U.S.: probably OK • WHO, IUATLD: OK • Breastfeeding fine with 1st-line agents

  23. Children • Treatment same as in adult, except: • No ethambutol if visual acuity cannot be monitored, unless: • High risk of drug resistance (INH) • Upper lobe infiltrate/cavity (higher organism burden) • Cultures often difficult to obtain • Rely on susceptibilities of presumed source case

  24. Recommendations for Treatment of TB in HIV-Infected Patients • TB/HIV patients with CD4 < 100 should not receive once- or twice- weekly therapy • Daily therapy during induction • Daily or thrice-weekly therapy during continuation MMWR 2002;51:214-5

  25. Treatment of TB/HIVDrug Interactions • Possible combinations: • rifampin + efavirenz • rifabutin + ritonavir-boosted protease inhibitors • Avoid these combinations: • rifampin + : saquinavir, indinavir, nelfinavir, amprenavir (fos), atazanavir, or delavridine • rifabutin +: delavridine, saquinavir • Nucleoside/tide reverse transcriptase inhibitors and enfuvirtide not affected rifamycins, so can be given

  26. Immune Reconstitution Inflammatory Syndrome • Clinical Manifestations • Constitutional: fever, weight loss, • Pulmonary: cough, increased infiltrates • Extrapulmonary: • Lymphatic: increased cervical, intra-thoracic, intra-abdominal adenopathy • Serositis: pleural, pericardial effusions • CNS: expanding tuberculomas • Other: soft tissue, bone abscesses, skin, +PPD

  27. Risk Factors for IRISIn (roughly) decreasing order of importance • HAART initiation within 2 months of starting anti-tuberculosis treatment • Disseminated/extrapulmonary TB • Low baseline CD4 (< 100/mm3)--trend, but consistent • Increase in CD4% on HAART • HIV-1 RNA decline on HAART • Antiretroviral therapy-naïve Narita 1998, Wendel 2001, Navas 2002, Breen 2004, Breton 2004, Burman 2004, Shelburne 2005

  28. Diagnosis of M. tuberculosis infectionTuberculin skin test (TST) • Tuberculin=broth culture filtrate of tubercle bacilli • Purified protein derivative (PPD), a standardized form of tuberculin, was introduced in 1934 • Contains ~ 200 antigens, including those shared by M. bovis BCG and non-tuberculous mycobacteria • T-cells sensitized by M. tuberculosis infection respond to M. tuberculosis antigens in PPD and release IFN- • Cutaneous induration due to delayed-type hypersenstivity to intradermal injection of PPD • Positive test determined by determining mm of induration • Inter- and intra-reader variability • Possible human error

  29. Tuberculin Skin Test • Sensitivity: • Presumably high in latently infected persons with normal immune response • Decreased in immunocompromised patients: • HIV (CD4 < 100), corticosteroids, other immunosuppressants, young children (< 1 year) • False negative until 8-12 weeks after infection • Specificity: • False positives due to environmental mycobacteria, BCG • Decreased specificity and positive predictive value in populations at low risk for TB infection • Improved specificity if greater mm induration for + test

  30. Interferon- Release Assays • Detection of IFN- or IFN--producing T-cells after stimulation of sensitized T-cells by M. tuberculosis antigens • Assesses cell-mediated immunity • Early-generation tests used PPD as the stimulus • As non-specific as the TST • More recent assays have used synthetic peptides of 2 proteins present in M. tuberculosis, but not BCG or most non-tuberculous mycobacteria (NTM): • Early secretory antigen target 6 (ESAT-6) • Culture filtrate protein-10 (CFP-10)

  31. CDC GuidelinesQuantiFERON-TB Gold • Can be used in all circumstances in which TST used: • Contact investigations, recent immigrants (BCG), serial testing (e.g., health-care workers) • TB risk among persons with + test unknown • Limited data: • Immunocompromised (e.g., HIV) • Close contacts • Persons at  risk of progressing to TB • Children (no data in persons < 17 years old) • Persons who undergo periodic screening (HCW) MMWR 2005;54(RR-15):49-55.

  32. Indications for Treatment of Latent Infection • Perform skin testing only on persons at high risk for progression to active TB • If persons in these high-risk groups are latently infected (i.e. PPD+), treat regardless of age Am J Resp Crit Care Med 2000;161:S221

  33. Treatment of Latent TB Infection2000 ATS/CDC • RegimenHIV- HIV+ • INH qD x 9 months AII AII • INH biw x 9 months BII BII • INH qD x 6 months BI CI • INH biw x 6 months BII CII • A: preferred I: Randomized Clinical Trial • B: acceptable alternative II: nonRCT • C: offer when cannot give A,B III: expert opinion

  34. Treatment of Latent TB Infection2000 ATS/CDC • RegimenHIV- HIV+ • RIF qD x 4 months BII BIII • A: preferred I: Randomized Clinical Trial • B: acceptable alternative II: nonRCT • C: offer when cannot give A,B III: expert opinion

  35. Initiating Respiratory Isolation • Policies vary at different hospitals • Cough > 2 weeks and abnormal CXR • Additional symptoms c/w TB • Epidemiology suggestive of TB: • Recent TB exposure • Incarceration • HIV (10% may have negative CXR)

  36. Discontinuing Respiratory IsolationTB suspects • CDC guidelines: • 3 negative AFB smears • Collected at least 8 (not 24) hours apart • At least one collection during early AM • Based on expert opinion, not evidence • To get patients out of isolation in < 48 hours • Another diagnosis assigned • Infectious TB unlikely MMWR 2005;54(RR-17): 1-121.

  37. When to Refer a TB Suspect to the Health Department • EARLY • As soon as they start anti-TB therapy • Allows for: • TB Clinic staff to visit patient in hospital • Establish rapport • Review medications, drug-drug interactions Nashville Metro Health Department TB clinic telephone #: 340-5650

  38. When Can a TB Suspect be Discharged? • On appropriate anti-TB treatment • Health department notified and follow-up, treatment plan in place • Stable residence at verifiable address

  39. When Can a TB Suspect be Discharged? • They can be discharged before they have 3 negative smears unless “home” includes: • Young children (< 5 y.o.) • Immunocompromised (e.g., HIV) • Prison • Nursing home • Homeless shelter

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