PATHOGENS

  • M. tuberculosis 
  • M. bovis 

CLINICAL

  • Hx: cough >2 wks, fever, night sweats, weight loss, hemoptysis, SOB, chest pain
  • CXR: upper lobe infiltrate classic (may be cavitary); atypical presentations in children or HIV+ adults; lymphadenopathy
  • Clinical and radiographic manifestations may be atypical in HIV+ persons, especially with low CD4 count: lower-lobe infiltrates, adenopathy alone, and even normal CXR.
  • Extrapulmonary disease more common in HIV+ pts, especially with low CD4 counts.
  • TB often subclinical in HIV+ pts, particularly with low CD4. Disease can be "unmasked" on ART
  • Immune reconstitution inflammatory syndrome (IRIS) may result in worsening of TB symptoms on TB and HIV treatment

DIAGNOSIS

  • Characteristic Sx (see "Clinical")
  • Sputum AFB smear: 50% sensitive. Lower sensitivity in HIV+ pts.
  • AFB Cx: 80% sensitive
  • Nucleic acid amplification (NAA) tests: sensitive, specific for sputum AFB smear +; less sensitive for smear-negative sputum (negative NAA does not exclude TB if sputum AFB smear-negative); expensive; also low sensitivity for non-respiratory specimens
  • QuantiFERON-TB Gold In-tube and T.SPOT.TB (interferon-gamma release assays [IGRA]) FDA-approved. Limited data in HIV+; T.SPOT.TB probably more sensitive than QuantiFERON-TB Gold In-tube in HIV+. Does not distinguish between latent infection and active disease.
  • GeneXpert MTB/RIF test (FDA-approved) can detect M. tb and rifampin resistance directly in clinical specimens in approximately 2 hours
  • New tests not yet FDA-approved but endorsed by WHO:
    • Line-probe assays (e.g., MTBDRplus and MTBDRsl by Hain Lifescience) can detect M. tb in culture or directly in clinical specimens; can also detect genotypic mutations associated with resistance: INH, rifampin, injectable agents, fluoroquinolones

TREATMENT

Adults

  • Isoniazid (INH) 5mg/kg (300 mg max) + rifampin (RIF) 10 mg/kg (600 mg max) + pyrazinamide (PZA) 15-30 mg/kg (2 g max) + ethambutol (EMB) 15-25 mg/kg (1.6g max) + pyridoxine (vitamin B6) 50 mg (all PO once-daily x 8 wks), then INH + RIF (same doses PO once-daily); see below for duration
  • Can use rifabutin in place of RIF in persons on PIs, NNRTIs, integrase inhibitors (but notelvitegravir), methadone. Dose adjustments necessary (see specific ART module for drug dosing recommendations)
  • Check drug susceptibilities; treat with at least 2 drugs to which isolate is susceptible
  • Rx duration determined by site of disease, response to therapy. Pulmonary and most extrapulmonary: 6 mos (except if at high risk for relapse--see "Other Information"); CNS: 12 mos; bone/joint: 9-12 mos
  • Refer to health department so pt can receive directly-observed therapy (DOT)
  • Dosing less frequent than daily is possible if via DOT.
  • RIF 10 mg/kg (600 mg max) can be given with EFV (standard 600 mg dose; may need to increase to 800 mg, especially if patient weighs >60 kg)

Children

  • INH 10-15 mg/kg (300 mg max) + RIF 10-20 mg/kg (600 mg max) + PZA 15-30 mg/kg (2 g max) + EMB 15-20 mg/kg (1 g max), all PO once daily.
  • Use EMB only if can monitor visual acuity (e.g. >8 yrs) or drug resistance strongly suspected
  • Can use rifabutin in place of RIF in persons on HIV PIs, NNRTI, integrase inhibitors. Dose adjustments necessary
  • Check drug susceptibilities; treat with at least 2 drugs to which isolate is susceptible
  • Rx duration determined by site of disease, response to therapy
  • Refer to health department so pt can receive directly observed therapy (DOT)
  • Dosing less frequent than daily is possible if via DOT.

Isolation

  • Respiratory isolation for cough >2 wks + abnormal CXR
  • Can discontinue if 3 sputa (expectorated or induced) are smear-negative. However, if high suspicion of active TB, start treatment
  • If smear + or on Rx, can discontinue isolation after 2 wks of Rx plus clinical improvement, plus AFB smear-negative (3 specimens).

General Treatment Issues

  • Refer all cases to local health department for treatment and contact investigation.
  • DOT preferred for both adults and children
  • Caution regarding drug interactions, toxicity, paradoxical worsening (IRIS). Consult expert.
  • If HIV+ and CD4 < 100, give daily TB treatment for first 60 days, then no less frequent than 3x/wk
  • When to start ART in relation to starting TB therapy (2015 DHHS Guidelines):
    • If already on ART at time of TB diagnosis, continue ART and start TB Rx
    • If not on ART, timing depends on CD4 count:
      • CD4 < 50: start ART within 2 wks of TB Rx
      • CD4 >50: start ART within 8-12 wks of TB Rx

Selected Drug Comments

Drug

Recommendation

Ethambutol

least potent of first-line agents but must be in regimen until sensitivities known

Isoniazid

pyridoxine limits peripheral neuropathy due to INH

Pyrazinamide

Allows for 6-month (short-course) therapy. Hepatotoxicity, hyperuricemia possible.

Rifabutin

fewer drug interactions than rifampin

Rifampin

crucial drug in first-line therapy

FOLLOW UP

  • Pts should be followed by health department while on therapy. Seen monthly for signs/Sx of toxicity, and sputum Cx to document negative Cx. Generally not followed after completion of therapy, but should return if signs/Sx of TB recur

OTHER INFORMATION

  • Based on ATS/CDC/IDSA Guidelines. See ref below. Includes recommendation to extend treatment to 9 mos if cavitary disease plus Cx + after 2 mos of tx

References

  1. Dheda K, Barry CE, Maartens G: Tuberculosis. Lancet Sep 13  [PMID:26377143]
  2. Horsburgh CR, Barry CE, Lange C: Treatment of Tuberculosis. N Engl J Med 373:2149, 2015  [PMID:26605929]
  3. Mfinanga SG et al: Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. Lancet Infect Dis 14:563, 2014  [PMID:24810491]
  4. Boehme CC et al: Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 363:1005, 2010  [PMID:20825313]

    Comment: Performing test once was 98% sensitive for smear-positive pulmonary TB and 73% sensitive for smear-negative TB; performing 3 tests increased sensitivity to 90% for smear-negative disease. Detection of rifampin resistance was 98% sensitive and specific.

  5. Sterling TR, Pham PA, Chaisson RE: HIV infection-related tuberculosis: clinical manifestations and treatment. Clin Infect Dis 50 Suppl 3:S223, 2010  [PMID:20397952]

    Comment: Update on clinical manifestations, treatment issues, and drug interactions.

  6. Mazurek GH et al: Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep 59:1, 2010  [PMID:20577159]

    Comment: Updated CDC guidelines for use of QuantiFERON-TB Gold, QuantiFERON-TB Gold In-tube, and T.SPOT.TB

  7. Abdool Karim SS et al: Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 362:697, 2010  [PMID:20181971]

    Comment: Initiating ART during TB treatment decreased risk of death by 56% compared to waiting until after completion of anti-TB Rx. Benefit of starting within 4 weeks (vs. 8-12 weeks) of TB Rx start seen only among pts with CD4 < 50

  8. Centers for Disease Control and Prevention (CDC): Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep 58:7, 2009  [PMID:19145221]
  9. Pai M, Zwerling A, Menzies D: Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 149:177, 2008  [PMID:18593687]

    Comment: Review of interferon gamma release assays

  10. Nahid P, Pai M, Hopewell PC: Advances in the diagnosis and treatment of tuberculosis. Proc Am Thorac Soc 3:103, 2006  [PMID:16493157]

    Comment: Update on TB Dx and treatment

  11. Blumberg HM et al: American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 167:603, 2003  [PMID:12588714]

    Comment: Excellent review. New recommendation: INH + rifapentine (RPT) once/wk may be given in continuation phase if noncavitary disease, sputum smear-negative after 2 mos, and pt HIV-neg. INH + RPT contraindicated in HIV+ pts.

  12. CDC; Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis; http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm Updated June 2013;

    Comment: Recommendations re: drug-drug interactions and dose adjustments. Web site is updated regularly

  13. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. http://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0Updated November 4, 2015

    Comment: Updated reference on drug-drug interactions.

  14. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0Updated April 8, 2015

    Comment: Updated reference on drug-drug interactions.

  15. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011; 365:1482.

    Comment: Primary endpoint was death or new AIDS-defining event among persons starting ART within 2 weeks vs. 8-12 weeks after starting anti-TB Rx. Benefit of starting at 2 weeks seen only among persons with CD4 < 50. IRIS risk high.

  16. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011; 365:1471.

    Comment: Among persons with low CD4 (median 25), risk of death was 34% lower in persons starting HAART within 2 weeks of anti-TB therapy compared to persons starting HAART 8 weeks after anti-TB therapy.

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Last updated: January 6, 2016

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TY - ELEC T1 - Tuberculosis, Active ID - 545213 A1 - Sterling,Timothy,M.D. Y1 - 2016/01/06/ PB - Johns Hopkins HIV Guide UR - https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_HIV_Guide/545213/all/Tuberculosis__Active ER -