16.8 Follow-up for patients treated for latent tuberculosis infection

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    For the modality of administration of LTBI treatments, see Chapter 13.

    16.8.1 Baseline assessment of liver function 

    Before initiating LTBI treatment, look for clinical signs of hepatic disease and specific risks of hepatotoxicity.

     

    For patients with hepatic disease, baseline liver function tests (LFTs), i.e. aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin should be performed.
    The benefit of LTBI treatment should be weighed against the potential risk of aggravation of existing hepatic disease. LTBI treatment is contra-indicated in patients with end-stage hepatic disease or LFTs > 5 times the upper limit of normal (ULN) and should be used with caution in patients with LFTs > 3 times ULN [1] Citation 1. World Health Organization. WHO operational handbook on tuberculosis. Module 1: prevention - tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://apps.who.int/iris/rest/bitstreams/1272664/retrieveWorld Health 
    .

     

    Depending on available resources, baseline LFTs can be performed in groups at risk for hepatotoxicity (e.g. patients with HIV infection, women during pregnancy and post-partum period, chronic alcohol consumption, age > 35 years, concomitant use of hepatotoxic drugs, history of hepatic disease).

    16.8.2 Follow-up

    All patients should be evaluated monthly for signs and symptoms of active TB, adherence (Appendix 22), and adverse effects.

     

    TST or IGRA should not be repeated.

     

    In patients with pre-existing hepatic disease:

    • Baseline LFTS are normal: monitor LFTs monthly.
    • Baseline LFTs are elevated or LFTs increase during LTBI treatment: monitor LFTs once a week [2] Citation 2. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52.
      https://doi.org/10.1164/rccm.200510-1666ST
      .

     

    Other patients should be tested if they develop symptoms of hepatotoxicity.

     

    Any problems with adherence should be addressed with the patient.

     

    If signs and symptoms of active TB develop, the patient should undergo full evaluation (Chapter 3 and Chapter 4).

    16.8.3 Management of adverse effects

    Hepatotoxicity

    Clinical features resemble that of viral hepatitis. Early symptoms include malaise, fatigue, loss of appetite, muscle and joint pain. Nausea, vomiting and abdominal pain are common in severe disease. Jaundice, scleral icterus, dark (tea-coloured) urine and discoloured stool are signs of clinical worsening.
    Clinical hepatitis can be fatal, so action should be taken immediately.

     

    • Patient with symptoms of hepatitis:

    Stop all TB drugs and perform LFTs:

    • AST or ALT or bilirubin ≥ 3 times ULN or severe symptoms: do not resume LTBI treatment.
    • AST, ALT, and bilirubin < 3 times ULN and mild symptoms (no jaundice): after discussion with the patient on benefits and risk, treatment may be resumed. Closely monitor the patient and perform LFTs once a week. Continue treatment as long as LFTs levels remain < 3 ULN and there are no signs of worsening hepatitis.
    • LFTs not available: do not resume LTBI treatment. 

     

    • Patient without symptoms of hepatitis, but elevated LFTs: 
      • AST or ALT ≥ 5 times ULN or bilirubin ≥ 3 ULN: stop and do not resume LTBI treatment.
      • AST and ALT < 5 times ULN and bilirubin < 3 ULN: stop LTBI treatment. Perform LFTs once a week. If LFTs return to normal, after discussion with the patient on benefits and risk, treatment may resumed. Closely monitor the patient and perform LFTs once a week.

     

    Note: 10 to 20% of patients taking isoniazid alone may have a mild, transient, asymptomatic elevation of LFTs (AST and/or ALT). In most cases, this does not require treatment interruption. 

    Hypersensitivity reaction

    Possible hypersensitivity reactions have been reported in approximately 2% of patients on 3HR regimen and 4% of patients on 3HP regimens, typically after the first 3 to 4 doses [3] Citation 3. Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME; Tuberculosis Trials Consortium. Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. Clin Infect Dis. 2015 Aug 15;61(4):527-35. 
    https://doi.org/10.1093/cid/civ323
    .

     

    Symptoms may include flu-like syndrome (fever, chills and malaise, headache), persistent nausea and vomiting and/or watery diarrhoea requiring rehydration in severe cases, cutaneous reactions (rash, with vesicles in severe cases), and more rarely, angioedema, shortness of breath, acute bronchospasm, and hypotension.

     

    In all cases, treatment should be stopped immediately. Symptoms usually resolve within 24 hours after TB drug withdrawal.

    In case of mild reaction, consider resuming the treatment. In this case, the patient should be observed at least 4 hours after each dose is administered to detect first signs of hypersensitivity reaction.

    In case of moderate to severe reactions, do not resume treatment and consider a regimen without a rifamycin (6H).

     

    Other adverse effects

    See Appendix 17.

     

    References
    • 1.World Health Organization. WHO operational handbook on tuberculosis. Module 1: prevention - tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
      https://apps.who.int/iris/rest/bitstreams/1272664/retrieveWorld Health 
    • 2.Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR; ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-52.
      https://doi.org/10.1164/rccm.200510-1666ST
    • 3.Sterling TR, Moro RN, Borisov AS, Phillips E, Shepherd G, Adkinson NF, Weis S, Ho C, Villarino ME; Tuberculosis Trials Consortium. Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. Clin Infect Dis. 2015 Aug 15;61(4):527-35. 
      https://doi.org/10.1093/cid/civ323