Tuberculosis, Active

Timothy R. Sterling, M.D.

PATHOGENS

  • M. tuberculosis
  • M. bovis

CLINICAL

  • Hx: cough >2 wks, fever, night sweats, weight loss, hemoptysis, SOB, chest pain; can also present as acute pneumonia or systemic illness
  • CXR: upper lobe infiltrate classic (can be cavitary); lymphadenopathy
  • Clinical and radiographic manifestations may be atypical in HIV+ persons, especially with low CD4 count (< 200): lower-lobe infiltrates, adenopathy alone, and even normal CXR.
  • Extrapulmonary disease is more common in HIV+ pts, especially with low CD4 counts.
  • TB is often subclinical in HIV+ pts, particularly with low CD4. The disease can be "unmasked" on ART.
  • Immune reconstitution inflammatory syndrome (IRIS) may result in the 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 is probably more sensitive than QuantiFERON-TB Gold In-tube in HIV+.
    • Used for identifying latent TB infection.
    • 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 not elvitegravir), and methadone. Dose adjustments are necessary (see specific ART module for drug dosing recommendations).
  • Check drug susceptibilities; treat with at least two drugs to which the isolate is susceptible.
  • Rx duration is determined by the site of disease and 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.
  • Alternative regimen:
    • A 4-month regimen of INH, rifapentine (RPT; 1200 mg), PZA, and moxifloxacin (400 mg) for 8 weeks, then INH, RPT, and moxifloxacin for 9 weeks is an option for persons > 12 years old with drug-susceptible pulmonary TB.
  • Refer to Health Department so pt can receive directly-observed therapy (DOT)
  • Dosing less frequently than daily for the regimen of INH, RIF, PZA, and EMB is possible via DOT, though daily (7 or 5 days per week) is preferred.

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 you can monitor visual acuity (e.g.,>8 yrs) or drug resistance is strongly suspected.
  • Can use rifabutin in place of RIF in persons on HIV PIs, NNRTI, and integrase inhibitors. Dose adjustments necessary
  • Check drug susceptibilities; treat with at least two drugs to which the isolate is susceptible.
  • Rx duration determined by the site of disease, response to therapy
  • Alternative: for children > 12 years old.
    • A 4-month regimen of INH, rifapentine (RPT; 1200 mg), PZA, and moxifloxacin (400 mg) for 8 weeks, then INH, RPT, and moxifloxacin for 9 weeks is an option with drug-susceptible pulmonary TB.
  • Refer to the Health Department so pt can receive directly observed therapy (DOT).
  • Dosing less frequently than daily for the regimen of INH, RIF, PZA, EMB is possible via DOT, though daily (7 or 5 days per week) is preferred.

Isolation

  • Respiratory isolation for cough >2 wks + abnormal CXR while evaluating for TB.
  • Can discontinue isolation if TB evaluation is negative with three sputa (expectorated or induced) smear-negative, or two sputa are GeneXpert negative.
    • However, start treatment if there is a high suspicion of active TB.
  • 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 the local health department for treatment and contact investigation.
  • DOT preferred for both adults and children
  • MDR-TB (resistance to at least INH and RIF) should be managed with experts in resistant TB infections.
  • Caution regarding drug interactions, toxicity, and paradoxical worsening (IRIS). Consult expert.
  • If HIV+ and CD4 < 100, give daily TB treatment for the first 60 days, then no less frequent than 3x/wk.
  • When to start ART in relation to starting TB therapy (DHHS Guidelines):
    • If already on ART at the 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 are known.

Isoniazid

Pyridoxine limits peripheral neuropathy due to INH

Pyrazinamide

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

Rifabutin

Fewer drug interactions than rifampin

Rifampin

A crucial drug in first-line therapy

FOLLOW UP

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

OTHER INFORMATION

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

Basis for recommendation

  1. Carr W, Kurbatova E, Starks A, et al. Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis - United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(8):285-289.  [PMID:35202353]

    Comment: Recommendations that incorporate a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment

  2. Nahid P, Dorman SE, Alipanah N, et al. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):853-67.  [PMID:27621353]

    Comment: Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided.

  3. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.  [PMID:20577159]

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

  4. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a... September 28, 2022

    Comment: Updated reference on drug-drug interactions.

References

  1. Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021;384(18):1705-1718.  [PMID:33951360]
  2. Furin J, Cox H, Pai M. Tuberculosis. Lancet. 2019;393(10181):1642-1656.  [PMID:30904262]

    Comment: Recent review on diagnosis and treatment.

  3. Meintjes G, Brust JCM, Nuttall J, et al. Management of active tuberculosis in adults with HIV. Lancet HIV. 2019;6(7):e463-e474.  [PMID:31272663]

    Comment: Helpful article detailing some of the frequent issues that arise when treating people with HIV and TB.

  4. Mfinanga SG, Kirenga BJ, Chanda DM, 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. 2014;14(7):563-71.  [PMID:24810491]

    Comment: Trial finding that ART can be delayed in those with CD4 >200 for up to six months.

  5. 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(16):1471-81.  [PMID:22010913]

    Comment:
    Among persons with low CD4 (median 25), the 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.

  6. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482-91.  [PMID:22010914]

    Comment: The 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. The benefit of starting at 2 weeks is seen only among persons with CD4 < 50. IRIS risk is high.

  7. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010;363(11):1005-15.  [PMID:20825313]

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

  8. Sterling TR, Pham PA, Chaisson RE. HIV infection-related tuberculosis: clinical manifestations and treatment. Clin Infect Dis. 2010;50 Suppl 3:S223-30.  [PMID:20397952]

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

  9. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362(8):697-706.  [PMID:20181971]

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

  10. 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. 2009;58(1):7-10.  [PMID:19145221]

    Comment: Guidance that NAA should be used at least once in a patient with TB.

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Last updated: October 19, 2022