16.3 Latent tuberculosis infection treatment regimens


There are 3 recommended LTBI treatment regimens and 2 alternative treatment regimens1. 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 weekly2 :
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. This treatment has proven to be effective in preventing active TB in both HIV-infected and non-HIV-infected patients3,4.
WHO recommends this treatment in all patients regardless of their HIV status, including children of any age and pregnant women.
The main disadvantage of isoniazid monotherapy is the length of treatment. Patients 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.
All patients 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 HIV-infected patients, the treatment may be difficult due to additive adverse effects of antiretrovirals and isoniazid, the extending of the duration of treatment to 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)
This treatment has proven to be effective in preventing active TB in both HIV-infected and non-HIV- infected patients. WHO recommends this treatment in children 2 years and over, adolescents and adults, regardless of their HIV status.
It is short, requires few doses, has a high completion rate and the risk of hepatoxicity is low5,6.
The disadvantages of this regimen are the lack of FDC and the development of hypersensitivity reaction in almost 4% of patients4 (Section 16.8.3).

Combination isoniazid-rifapentine once daily for 1 month (1HP)
This treatment has proven to be effective in preventing active TB in HIV-infected patients. WHO recommends this treatment as an alternative regimen in patients 13 years and over, regardless of their weight and HIV status.
The treatment is short, has a high completion rate and the risk of hepatoxicity is low7. However, cutaneous reactions (rash, itching) are common. 

Rifapentine containing regimens are not currently recommended for pregnant women. Despite some reassuring data8, safety is not definitively established.

16.3.3 Rifampicin-containing regimens

Combination isoniazid-rifampicin once daily for 3 months (3HR)
This treatment has proven to be effective in preventing active TB in both HIV-infected and non-HIV- infected patients. WHO recommends this treatment in all patients regardless of their HIV status, including children of any age and pregnant women.
It is short, safe, has a good completion rate3 and FDC are available for children and adults. Hypersensitivity reaction may occur in approximately 2% of patients9.

Rifampicin monotherapy once daily for 4 months (4R)
This treatment has proven to be effective in preventing active TB in non-HIV-infected patients of all ages. WHO recommends this regimen as an alternative regimen in all patients regardless of their HIV status, including children of any age and pregnant women.
The advantages of this regimen (better safety profile and completion rate compared to 6H)10 should be weighed against the risk associated with use of rifampicin in monotherapy (development of resistance to rifampicin in patients with undiagnosed active TB).

Notes on rifamycin-containing regimens:

  • Rifapentine and rifampicin have interactions with many drugs, particularly antiretrovirals (Appendix 19) and contraceptives (Chapter 9, Section 9.2.1).
  • For pregnant women taking rifampicin, administer phytomenadione (vitamin K) in the last few weeks of pregnancy (Chapter 9, Section 9.2.1).
  • Rifapentine and rifampicin are not interchangeable.
  • Rifabutin can replace rifampicin if rifampicin cannot be used due to drug interactions2.



References

  1. WHO consolidated guidelines on tuberculosis: module 1: prevention: tuberculosis preventive treatment, World Health Organization, 2020.
    https://www.who.int/publications/i/item/who-consolidated-guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment

  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

  3. 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://www.acpjournals.org/doi/10.7326/M17-0609?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

  4. 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://www.thelancet.com/journals/langlo/article/PIIS2214-109X(17)30372-8/fulltext

  5. 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://www.nejm.org/doi/10.1056/NEJMoa1104875?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

  6. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624831/

  7. BRIEF TB/A5279 Study Team. One month of Rifapentine plus Isoniazid to prevent HIV-related Tuberculosis. n engl j med 2019; 380: 1001.
    https://www.nejm.org/doi/full/10.1056/NEJMoa1806808

  8. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624829

  9. 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

  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://www.nejm.org/doi/full/10.1056/NEJMoa1714283