Tuberculosis (TB) affects an estimated 10 million people per year (range 8.9-11.0 million) and is one of the world's leading infectious disease killers. TB is responsible for an estimated 1.2 million TB deaths among HIV-negative people (range, 1.1-1.3 million), and an additional 208 000 deaths among HIV-positive persons (range, 177 000-242 000). Of the estimated 10 million, approximately 70% are diagnosed and treated and also reported to the World Health Organization (WHO), resulting in 7.1 million TB notifications by National TB Programmes. Of the 7.1 million persons notified in 2019, 5.9 million (84%) had pulmonary TB .
For several decades WHO has developed and issued recommendations on the treatment of TB. The most recent WHO recommendations for treating people suffering from drug-susceptible TB have been defined in WHO's Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2010 and 2017 updates (see Annex). A focus of these guidelines was a 6-month treatment regimen composed of four first-line TB medicines, namely isoniazid, rifampicin, ethambutol and pyrazinamide, recommended for treatment of drug-susceptible TB. This regimen is well known and has been widely adopted worldwide for decades; while using it, approximately 85% of patients will have a successful treatment outcome. This regimen is based on seminal TB treatment studies conducted by the British Medical Research Council in the second half of 20th century. In addition to the recommendation on the treatment regimen, the 2010 and 2017 updates of the guideline included a number of recommendations on the modalities and formulations used for treatment, frequency of treatment administration, special situations and patient care during treatment. The consolidated and updated guidelines in the current Module 4: Treatment - Drug-susceptible tuberculosis treatment brings together, without modifications, all valid and evidence-based recommendations from the 2010 and 2017 guideline updates and adds a new section stemming from the most recent round of guidelines development in 2021 - the recommendations for the 4-month regimens to treat drug-susceptible TB (DS-TB).
This module of the consolidated guidelines includes only recommendations related to treatment since all recommendations on patient care and support, for both the drug-susceptible and drug-resistant TB (DR-TB) have been merged in a dedicated guideline module on "Tuberculosis care and support¹.
The update of the guidelines for treatment of DS-TB is important in the context of the End TB Strategy , which recommends treatment and patient support for all people with TB. This update by WHO aims to use the best available evidence on the treatment of DS-TB in order to inform policy decisions made by national TB control programme managers, national policy-makers and medical practitioners in a variety of geographical, economic and social settings.
The objectives of the updated Guidelines are:
1) to provide updated recommendations based on newly emerged evidence on the treatment of drug-susceptible TB; and
2) to provide a summary of changes in the new guidelines together with all the existing and valid WHO recommendations on the treatment of DS-TB.
The guidance provided in this module outlines specific WHO recommendations on the overall treatment management, care and monitoring of patients with DS-TB. It brings forward recommendations developed by various WHO-convened guideline development groups (GDGs), using the Grading of
Recommendations Assessment, Development and Evaluation (GRADE) approach to summarize the evidence, and to formulate policy recommendations and accompanying remarks. The recommendations and remarks in the current module on the treatment of DS-TB are the result of collaborative efforts of professionals from a range of specialties who have extensive expertise and experience in public health policy, TB programme management, the care and management of patients with TB, members of affected communities and TB survivors.
The recommendations included herein are part of WHO's consolidated guidelines on TB and are primarily intended for use by national TB control programmes, public health agencies, and other key constituencies involved in the planning, implementation and monitoring of activities for the programmatic management of DS-TB.
These recommendations have been developed through several meetings of the GDGs and have then been consolidated in the present module. The recommendation on the use of the 4-month regimens stem from the GDG meetings that took place in 2021. The remainder of the recommendations have been consolidated from the GDGs that took place in 2009 and 2016, as expressed in the 2010 and 2017 guidelines update.
Summary of WHO recommendations on drug-susceptible TB treatment
Treatment of drug-susceptible TB using 6-month regimen
1. New patients with pulmonary TB should receive a regimen containing 6 months of rifampicin: 2HRZE/4HR (strong recommendation, high certainty of evidence).
2. Wherever feasible, the optimal dosing frequency for new patients with pulmonary TB is daily throughout the course of therapy (strong recommendation, high certainty of evidence).
3. In all patients with drug-susceptible pulmonary TB, the use of thrice-weekly dosing is not recommended in both the intensive and continuation phases of therapy, and daily dosing remains the recommended dosing frequency (conditional recommendation, very low certainty of evidence).
4. The use of fixed-dose combination (FDC) tablets is recommended over separate drug formulations in treatment of patients with drug-susceptible TB (conditional recommendation, low certainty of evidence).
5. In new pulmonary TB patients treated with the regimen containing rifampicin throughout treatment, if a positive sputum smear is found at completion of the intensive phase, the extension of the intensive phase is not recommended (strong recommendation, high certainty of evidence).
Treatment of drug-susceptible TB using 4-month regimens
6. People aged 12 years or older with drug-susceptible pulmonary TB may receive a 4-month regimen of isoniazid, rifapentine, moxifloxacin and pyrazinamide (2HPMZ/2HPM) (conditional recommendation, moderate certainty of evidence) - new recommendation.
7. In children and adolescents between 3 months and 16 years of age with non-severe TB (without suspicion or evidence of MDR/RR-TB), a 4-month treatment regimen (2HRZ(E)/2HR) should be used (strong recommendation, moderate certainty of evidence) - new recommendation.
Drug-susceptible TB treatment and antiretroviral therapy (ART) in people living with HIV
8. It is recommended that TB patients who are living with HIV should receive at least the same duration of TB treatment as HIV-negative TB patients (strong recommendation, high certainty of evidence).
9. ART should be started as soon as possible within two weeks of initiating TB treatment, regardless of CD4 cell count, among people living with HIV. Adults and adolescents (strong recommendation, low to moderate certainty of evidence); Children and infants (strong recommendation, very low certainty of evidence).
The use of adjuvant steroids in the treatment of TB meningitis and pericarditis
10. In patients with tuberculous meningitis, an initial adjuvant corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks should be used (strong recommendation, moderate certainty of evidence).
11. In patients with tuberculous pericarditis, an initial adjuvant corticosteroid therapy may be used (conditional recommendation, very low certainty of evidence).