16.3 Latent tuberculosis infection treatment regimens

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    There are 3 recommended LTBI treatment regimens and 2 alternative treatment regimens [1] Citation 1. World Health Organization. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment         . The decision to prescribe one regimen rather than the other should take into consideration: 

    • Drug-susceptibility of the strain of the presumed source patient, if known.
    • Co-morbidities (e.g. HIV infection, pre-existing hepatic disease or neuropathy).
    • Risk of drug interactions (especially with antiretrovirals), tolerability, length of treatment and likelihood of adherence.
    • Individual characteristics (e.g. age, pregnancy, living conditions, individual preference).
    • Epidemiological and programmatic aspects (e.g. HIV prevalence, available drugs, national recommendations).

     

    Table 16.1 – LTBI treatment regimens

     

    Recommended regimens

    Isoniazid daily for 6 months (6H)
    or 36 months (36H)

    isoniazid PO once daily:
    < 30 kg: 10 mg/kg (7 to 15 mg/kg)
    ≥ 30 kg: 5 mg/kg (4 to 6 mg/kg)
    (max. dose 300 mg daily)

    OR
    Isoniazid + rifapentine weekly
    for 3 months (3HP)

    isoniazid PO once weekly: 
    < 30 kg and ≥ 2 years: 20 to 30 mg/kg
    ≥ 30 kg: 900 mg
    +
    rifapentine PO once weekly [2] Citation 2. Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC. 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11.
    http://dx.doi.org/10.15585/mmwr.rr6901a1         :
    10 to 14 kg and ≥ 2 years: 300 mg
    14.1 to 25 kg and ≥ 2 years: 450 mg
    25.1 to 32 kg: 600 mg
    32.1 to 49.9 kg: 750 mg
    ≥ 50 kg: 900 mg max.

    OR
    Isoniazid + rifampicin daily
    for 3 months     (3HR)

    isoniazid PO once daily:
    < 30 kg: 10 mg/kg (7 to 15 mg/kg)
    ≥ 30 kg: 5 mg/kg (4 to 6 mg/kg)
    (max. dose 300 mg daily)
    +
    rifampicin PO once daily:
    < 30 kg: 15 mg/kg
    ≥ 30 kg: 10 mg/kg
    (max. dose 600 mg daily)
     
    Alternative regimens

    Isoniazid + rifapentine daily
    for 1 month     (1HP)

     isoniazid PO once daily:
    ≥ 13 years: 300 mg
    +
    rifapentine PO once daily:
    ≥ 13 years: 600 mg

    OR
    Rifampicin daily for 4 months (4R)

    rifampicin PO once daily:
    < 30 kg: 15 mg/kg
    ≥ 30 kg: 10 mg/kg
    (max. dose 600 mg daily)

     

    16.3.1 Isoniazid monotherapy

    Isoniazid monotherapy (or isoniazid preventive therapy, IPT) is the treatment currently most often used for LTBI. 

    WHO recommends this treatment in children, adolescents and adults (including pregnant women), regardless of their age and HIV status [1] Citation 1. World Health Organization. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment         .
    The main disadvantage of isoniazid monotherapy is the length of treatment. People are usually healthy and may not be motivated to complete a 6-month therapy.
    Adverse effects (e.g. peripheral neuropathy, hepatotoxicity) can also lead to treatment interruption.
    Persons at risk of peripheral neuropathy should receive pyridoxine (vitamin B6) for the entire duration of treatment to prevent this risk (for doses, see Appendix 17).
    In people with HIV infection, the treatment may be difficult due to additive adverse effects of antiretrovirals and isoniazid, the duration of treatment (36 months) in some adolescents and adults (Section 16.4.2) and the high number of tablets to be taken daily. The number of tablets can be reduced using a fixed-dose combination (FDC) of isoniazid/cotrimoxazole/pyridoxine.

    16.3.2 Rifapentine-containing regimens 

    Combination isoniazid-rifapentine once weekly for 3 months (3HP)

    WHO recommends this treatment in children 2 years and over, adolescents and adults, regardless of their HIV status [1] Citation 1. World Health Organization. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment         .
    It is short, requires few doses, has a high completion rate and the risk of hepatoxicity is low [3] Citation 3. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bliven-Sizemore E, et al. Three Months of Rifapentine and Isoniazid for Latent Tuberculosis Infection. New England Journal of Medicine. 2011;365(23):2155–66.
    https://doi.org/10.1056/NEJMoa1104875         [4] Citation 4. Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, et al. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr. 2015;169(3):247–55. 
    https://doi.org/10.1001/jamapediatrics.2014.3158         .
    The disadvantages of this regimen are the lack of FDC and the development of hypersensitivity reaction in almost 4% of patients [5] Citation 5. Badje et al. Effect of isoniazid preventive therapy on risk of death in west African, HIV-infected adults with high CD4 cell counts: long-term follow-up of the Temprano ANRS 12136 trial. Lancet Glob Health 2017; 5: e1080–89.
    https://doi.org/10.1016/S2214-109X(17)30372-8         (Section 16.8.3).

    Combination isoniazid-rifapentine once daily for 1 month (1HP)

    WHO recommends this treatment as an alternative regimen in adolescents 13 years and over and adults, regardless of their weight and HIV status [1] Citation 1. World Health Organization. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment         .
    The treatment is short, has a high completion rate and the risk of hepatoxicity is low [6] Citation 6. BRIEF TB/A5279 Study Team. One month of Rifapentine plus Isoniazid to prevent HIV-related Tuberculosis. n engl j med 2019; 380: 1001.
    https://doi.org/10.1056/NEJMoa1806808         . However, cutaneous reactions (rash, itching) are common. 

     

    Rifapentine containing regimens are not currently recommended for pregnant women. Despite some reassuring data [7] Citation 7. Moro RN, Scott NA, Vernon A, Tepper NK, Goldberg SV, Schwartzmann K, et al. Exposure to latent tuberculosis treatment during pregnancy. The Prevent TB and the iAdhere Trials. Annals ATS. 2018 May; 15 (5): 570.
    https://doi.org/10.1513/AnnalsATS.201704-326OC         , safety is not definitively established.

    16.3.3 Rifampicin-containing regimens

    Combination isoniazid-rifampicin once daily for 3 months (3HR)

    WHO recommends this treatment in children, adolescents and adults (including pregnant women), regardless of their age and HIV status [1] Citation 1. World Health Organization. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment         .
    It is short, safe, has a good completion rate [8] Citation 8. Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ. Treatment of latent tuberculosis infection: an updated network meta-analysis. Ann Intern Med. 2017 Aug 15; 167(4):248.
    https://doi.org/10.7326/M17-0609         and FDC are available for children and adults. Hypersensitivity reaction may occur in approximately 2% of patients [9] Citation 9. 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/retrieve         .

    Rifampicin monotherapy once daily for 4 months (4R)

    WHO recommends this treatment as an alternative in children, adolescents and adults (including pregnant women), regardless of their age and HIV status [1] Citation 1. World Health Organization. WHO consolidated guidelines on tuberculosis: Module 1: prevention: tuberculosis preventive treatment. Geneva: World Health Organization. 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment         .
    The advantages of this regimen (better safety profile and completion rate compared to 6H) [10] Citation 10. Menzies D, Adjobimey M, Ruslami R, Trajman A, Sow O, Kim H, et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. New Eng J Med. 2018 Aug 2;379(5):440. 
    https://doi.org/10.1056/NEJMoa1714283         should be weighed against the risk associated with use of rifampicin in monotherapy (development of resistance to rifampicin in persons with undiagnosed active TB).

     

    Notes:

    For rifamycin-containing regimens:

    • Rifapentine and rifampicin have interactions with many drugs, particularly antiretrovirals (Appendix 19) and contraceptives (Chapter 9).
    • For pregnant women taking rifampicin, administer phytomenadione (vitamin K) in the last few weeks of pregnancy (Chapter 9).
    • Rifapentine and rifampicin are not interchangeable.
    • Rifabutin can replace rifampicin if rifampicin cannot be used due to drug interactions [2] Citation 2. Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC. 2020. MMWR Recomm Rep 2020;69(No. RR-1):1–11.
      http://dx.doi.org/10.15585/mmwr.rr6901a1             .

     

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