Considering the public health need for standardized practices on LTBI management and the recommendations in the recent WHO guidelines (1), the Expert Committee recommended the addition of rifapentine to the core list of the EML and EMLc for the treatment of latent tuberculosis infection, with this restricted indication to be noted in the List. The Committee recommended that eligibility for treatment with rifapentine should be as stated in the WHO guidelines.
An application was submitted by Dr Alberto Matteelli of the WHO TB/HIV and Community Engagement unit for inclusion of rifapentine (RPT) as an individual medicine, to be used in combination with isoniazid (INH), for the treatment of latent tuberculosis infection (LTBI).
Expert reviews of the application were prepared by two members of the Expert Committee. The Global TB Community Advisory Board, Treatment Action Group, and TB Proof supported the application, as did the Community Research Advisory Group (CRAG).
It is estimated that about one third of the world’s population is infected with M. tuberculosis (2). Most infected individuals demonstrate no signs or symptoms of active disease, nor are they infectious; they are, however, at risk of developing active disease and becoming infectious in the future. In general, people infected with M. tuberculosis have a 10% lifetime risk of falling ill with tuberculosis. The risk is much higher, however, for immunocompromised individuals (e.g. people living with HIV, malnutrition or diabetes) or people who use tobacco (3).
Public health relevance
In May 2014 the World Health Assembly passed a resolution approving the post-2015 Global TB Strategy (subsequently renamed as the END-TB Strategy) with its ambitious vision of a world free of tuberculosis and targets for 2035 that include a 90% reduction in tuberculosis incidence (compared with 2015) (4). The application to include rifapentine on the EML and EMLc was made as a means of contributing to achievement of the targets of the End TB Strategy.
The application presented a systematic review and meta-analysis, assessing which treatment is effective in preventing development of active tuberculosis disease in individuals identified with LTBI and at high risk of progression to active disease (5). Fifty-three randomized controlled trials evaluated LTBI treatment and recorded at least one of the two pre-specified end‑points (prevention of active tuberculosis, and/or hepatotoxicity of grade III or above). The results of clinical trials demonstrated the effectiveness of the
12-week regimen of rifapentine and isoniazid (3RPT/INH), administered once weekly for the treatment of LTBI in adults, compared with the 6- or 9-month INH regimen (6INH, 9INH), considered as standard for this indication.
Randomized controlled trials explored the effectiveness of RPT/INH in children aged 2 years or more (6), HIV-infected (7) and non-HIV-infected (6) patients. Non-inferiority in terms of efficacy, and significantly better treatment adherence and completion of the 3RPT/INH regimen compared with INH were observed, although higher treatment completion rates could have been biased in favour of 3RPT/INH.
Table 2 [See full text TRS] compares the RPT/INH regimen with the current standard of care: 9 months of INH treatment. Data on efficacy, safety and completion rates are derived from the TBTC-S26 study: an open-label, randomized, non-inferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis (6).
Universal treatment of all individuals with LTBI is not recommended because of uncertainties concerning the balance between benefit and harm. A positive benefit/harm trade-off is certainly present in those individuals with LTBI who are at risk for progression from LTBI to active tuberculosis disease: people living with HIV; adult and child contacts of pulmonary tuberculosis cases; patients starting treatment with an anti-tumour necrosis factor; patients receiving dialysis; patients preparing for organ or haematological transplantation; and patients with silicosis (8, 9).
The results of a recent network meta-analysis of published data (5) and the TBTC-S26 study (6) show that 3RPT/INH is well tolerated when used for the treatment of LTBI, including by children (2–17 years old) and by HIV-infected and HIV-non-infected adults. The 3RPT/INH regimen is associated with less hepatotoxicity and more possible hypersensitivity reactions than the standard 6INH or 9INH therapy. A total of five toxicity-attributable deaths were reported, mostly from a single trial. All were due to severe hepatitis in INH treatment groups, and at least four occurred in patients who were on INH for 12 months or longer (5).
In the TBTC-S26 main study, the overall incidence of serious adverse events (SAEs) was low; SAEs were reported in 2.7% of patients in the INH arm and 1.5% of patients in the RPT/INH arm (6). In the paediatric sub-study of TBTC-S26, SAEs were reported in six children (1.2%), all of whom were in the INH arm. In the HIV sub-study of TBTC-S26, SAEs were reported in 10.8% of INH patients and 3.9% of RPT/INH patients.
Cost / cost effectiveness
Based on market prices in the USA, a full course of preventive therapy with RPT for an adult will cost US$ 273. Sanofi has proposed a reduced pricing strategy, such that a full course of RPT treatment would cost US$ 72. Costs outside USA are difficult to predict. A recent study based on assumptions of the translation of trial results to current practice yielded favourable cost–effectiveness and cost-savings results for RPT (10).
In 2014, WHO published Guidelines on the management of latent tuberculosis infection, which recommends systematic testing and treatment of LTBI in several at-risk populations. Five regimens are recommended by WHO for the treatment of LTBI: 6-month isoniazid; 9-month isoniazid; 3 months of weekly rifapentine plus isoniazid; 3–4 months of isoniazid plus rifampicin; and 3–4 months of rifampicin alone (strong recommendation, moderate to high quality of evidence) (8).
Drug-specific adverse reactions can occur with both RPT and INH. WHO does not have specific recommendations on standards of clinical monitoring during LTBI treatment because of the lack of evidence on the optimal monitoring strategy. However, the Organization suggests regular routine clinical monitoring of individuals receiving treatment for LBTI through a monthly visit to healthcare providers (1).
1. Guidelines on the management of latent tuberculosis infection. Geneva: World Health Organization; 2015. Available from: http://apps.who.int/iris/bitstream/10665/136471/1/9789241548908_eng.pdf?ua=1&ua=1.
2. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA. 1999;282(7):677-86.
3. Tuberculosis Fact Sheet No. 104, reviewed March 2015. Geneva: World Health Organization. Available from: http://www.who.int/mediacentre/factsheets/fs104/en/.
4. Resolution WHA67.1. Global strategy and targets for tuberculosis prevention, care and control after 2015. In: Sixty-seventh World Health Assembly, Geneva, 19–24 May 2014. Resolutions and decisions, annexes Geneva: World Health Organization; 2014. Available from: http://apps.who.int/gb/ebwha/pdf_files/WHA67-REC1/A67_2014_REC1-en.pdf.
5. Stagg HR, Zenner D, Harris RJ, Munoz L, Lipman MC, Abubakar I. Treatment of latent tuberculosis infection: a network meta-analysis. Ann Intern Med. 2014;161(6):419-28.
6. 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. N Engl J Med. 2011;365(23):2155-66.
7. Martinson NA, Barnes GL, Moulton LH, Msandiwa R, Hausler H, Ram M, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med. 2011;365(1):11-20.
8. Guidelines on the management of latent tuberculosis infection. Geneva: World Health Organization; 2015. Available from: http://apps.who.int/iris/bitstream/10665/136471/1/9789241548908_eng.pdf?ua=1&ua=1.
9. Linas BP, Wong AY, Freedberg KA, Horsburgh CR, Jr. Priorities for screening and treatment of latent tuberculosis infection in the United States. Am J Respir Crit Care Med. 2011;184(5):590-601.
10. Shepardson D, MacKenzie WR. Update on cost-effectiveness of a 12-dose regimen for latent tuberculous infection at new rifapentine prices. Int J Tuberc Lung Dis. 2014;18(6):751.