Executive summary

Tuberculosis (TB) strains with drug resistance are more difficult to treat than drug-susceptible ones, and present a major challenge for patients, health care workers and health care services. In addition, the increase of drug-resistant TB threatens global progress towards the targets set by the End TB Strategy⁷ of the World Health Organization (WHO). Thus, there is a critical need for the continual development of evidence-based policy recommendations on the treatment and care of patients with drug-resistant TB, based on the most recent and comprehensive evidence available.

In the past decade, WHO has developed and issued evidence-based policy recommendations for the treatment and care of patients with drug-resistant TB, published in a range of documents (see Box 1). More recently, WHO has started to consolidate guidelines, in response to requests from Member States to facilitate policy transfer at the country level. The first integrated recommendations for the management and care of multidrug- or rifampicin-resistant TB (MDR/RR-TB) were released in 2019 as the WHO consolidated guidelines on drug-resistant tuberculosis treatment.⁸ The consolidation of WHO recommendations on TB and drug-resistant TB has now been expanded to better outline the path that a patient will take following exposure to resistant strains of Mycobacterium tuberculosis, once infection has progressed to TB disease, and the patient has been identified by the health system and referred for drug-resistant TB treatment.

The guidance provided in this module outlines specific WHO recommendations on the overall treatment management, care and monitoring of patients with MDR/RR-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 formulate policy recommendations and accompanying remarks. However, it also incorporates new recommendations that were made in November 2019, based on new evidence that was available to WHO on the following: shorter regimens for MDR/RR-TB; the use of the bedaquiline, pretomanid and linezolid (BPaL) regimen for patients with MDR/RR-TB and additional fluoroquinolone resistance; the use of bedaquiline beyond 6 months; the use of bedaquiline in pregnancy; and the use of bedaquiline and delamanid together. In particular, this module focuses on public health recommendations on the use of effective treatment regimens for drug-resistant TB; specifically, regimens for isoniazid-resistant TB, all-oral shorter regimens for MDR/RR-TB, longer regimens for MDR/RR-TB, monitoring patient response to MDR/RR-TB treatment, starting antiretroviral therapy (ART) in patients on second-line anti-TB regimens, surgery for patients on MDR-TB treatment, and care and support measures for patients with MDR/RR-TB. Additionally, in an effort to inform the global community of the major gaps and research areas to be addressed to help inform the development of evidence-based recommendations, this document outlines the research priorities that will help us generate knowledge on evidence-based and attainable standards of health.

WHO treatment recommendations incorporated

The objective of the present update is to provide evidence-based information on critical areas that will help to inform the use of novel all-oral regimens and potential label expansion for new TB medicines – for example, concomitant bedaquiline and delamanid use, extended bedaquiline use, and assessment of bedaquiline use in special populations – and that will supersede earlier guidance. In this updated document, stakeholders will be able to distinguish between previous recommendations that remain valid, those that have been updated, and those that have been newly developed based on additional studies, considering the range of known benefits and potential harms, modelling exercises and other data to inform the decision-making process.

The recommendations included herein are a component of the WHO consolidated guidelines on tuberculosis, and are primarily intended for use by national TB control programmes (NTPs), public health agencies, and other key constituencies involved in the planning, implementation and monitoring of activities for the programmatic management of drug-resistant TB.

The methods used to develop and formulate the recommendations complied with WHO standards for guideline development, and were based on up-to-date evidence reviews, complemented with additional information on values and preferences, feasibility and acceptability, and cost. The GRADE approach was used to rate the certainty in the estimate of effect (i.e. quality of evidence) as high, moderate, low or very low; it was also used to determine the strength of the recommendations, rating them as strong or conditional.

Current WHO recommendations on treatment and care for drug-resistant TB

The present recommendations for the treatment and care of drug-resistant TB have been derived from earlier WHO guideline documents (Box 1), and a recent WHO guideline development exercise conducted at the end of 2019. The current recommendations supersede the WHO consolidated guidelines on drug-resistant tuberculosis treatment that were published in 2019.⁹

This module contains policy recommendations on treatment regimens for rifampicin-susceptible, isoniazid-resistant TB (Hr-TB) and MDR/RR-TB, including all-oral shorter and longer regimens for MDR/RR-TB, monitoring of patients on treatment, the timing of ART in MDR/RR-TB patients infected with HIV, the use of surgery for patients receiving MDR-TB treatment, and models of patient support and care. The recommendations are presented below.

1. Regimen for rifampicin-susceptible and isoniazid-resistant tuberculosis

1.1 In patients with confirmed rifampicin-susceptible, isoniazid-resistant tuberculosis (Hr-TB), treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration of 6 months.

(Conditional recommendation, very low certainty in the estimates of effect)

1.2 In patients with confirmed rifampicin-susceptible, isoniazid-resistant tuberculosis, it is not recommended to add streptomycin or other injectable agents to the treatment regimen.

(Conditional recommendation, very low certainty in the estimates of effect)

2. Shorter all-oral bedaquiline-containing regimen for multidrug- or rifampicin-resistant tuberculosis

2.1 A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended in eligible patients with confirmed multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) who have not been exposed to treatment with second-line TB medicines used in this regimen for more than 1 month, and in whom resistance to fluoroquinolones has been excluded.

(Conditional recommendation, very low certainty in the evidence)

3. Longer regimens for multidrug- or rifampicin-resistant tuberculosis

3.1 In multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) patients on longer regimens, all three Group A agents and at least one Group B agent should be included to ensure that treatment starts with at least four TB agents likely to be effective, and that at least three agents are included for the rest of treatment if bedaquiline is stopped. If only one or two Group A agents are used, both Group B agents are to be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it.

(Conditional recommendation, very low certainty in the estimates of effect)

3.2 Kanamycin and capreomycin are not to be included in the treatment of MDR/RR-TB patients on longer regimens.

(Conditional recommendation, very low certainty in the estimates of effect)

3.3 Levofloxacin or moxifloxacin should be included in the treatment of MDR/RR-TB patients on longer regimens.

(Strong recommendation, moderate certainty in the estimates of effect)

3.4 Bedaquiline should be included in longer multidrug-resistant TB (MDR-TB) regimens for patients aged 18 years or more.

(Strong recommendation, moderate certainty in the estimates of effect)

Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6–17 years.
(Conditional recommendation, very low certainty in the estimates of effect)

3.5 Linezolid should be included in the treatment of MDR/RR-TB patients on longer regimens.

(Strong recommendation, moderate certainty in the estimates of effect)

3.6 Clofazimine and cycloserine or terizidone may be included in the treatment of MDR/ RR-TB patients on longer regimens.

(Conditional recommendation, very low certainty in the estimates of effect)

3.7 Ethambutol may be included in the treatment of MDR/RR-TB patients on longer regimens.

(Conditional recommendation, very low certainty in the estimates of effect)

3.8 Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens.

(Conditional recommendation, moderate certainty in the estimates of effect)

3.9 Pyrazinamide may be included in the treatment of MDR/RR-TB patients on longer regimens.

(Conditional recommendation, very low certainty in the estimates of effect)

3.10 Imipenem–cilastatin or meropenem may be included in the treatment of MDR/ RR-TB patients on longer regimens.

(Conditional recommendation, very low certainty in the estimates of effect)¹⁰

3.11 Amikacin may be included in the treatment of MDR/RR-TB patients aged 18 years or more on longer regimens when susceptibility has been demonstrated and adequate measures to monitor for adverse reactions can be ensured. If amikacin is not available, streptomycin may replace amikacin under the same conditions.

(Conditional recommendation, very low certainty in the estimates of effect)

3.12 Ethionamide or prothionamide may be included in the treatment of MDR/RR-TB patients on longer regimens only if bedaquiline, linezolid, clofazimine or delamanid are not used, or if better options to compose a regimen are not possible.

(Conditional recommendation against use, very low certainty in the estimates of effect)

3.13 P-aminosalicylic acid may be included in the treatment of MDR/RR-TB patients on longer regimens only if bedaquiline, linezolid, clofazimine or delamanid are not used, or if better options to compose a regimen are not possible.

(Conditional recommendation against use, very low certainty in the estimates of effect)

3.14 Clavulanic acid should not be included in the treatment of MDR/RR-TB patients on longer regimens.

(Strong recommendation against use, low certainty in the estimates of effect)

3.15 In MDR/RR-TB patients on longer regimens, a total treatment duration of 18–20 months is suggested for most patients; the duration may be modified according to the patient’s response to therapy.

(Conditional recommendation, very low certainty in the estimates of effect)

3.16 In MDR/RR-TB patients on longer regimens, a treatment duration of 15–17 months after culture conversion is suggested for most patients; the duration may be modified according to the patient’s response to therapy.

(Conditional recommendation, very low certainty in the estimates of effect)

3.17 In MDR/RR-TB patients on longer regimens containing amikacin or streptomycin, an intensive phase of 6–7 months is suggested for most patients; the duration may be modified according to the patient’s response to therapy.

(Conditional recommendation, very low certainty in the estimates of effect)

4. The bedaquiline, pretomanid and linezolid (BPaL) regimen for multidrug-resistant tuberculosis with additional fluoroquinolone resistance

4.1 A treatment regimen lasting 6–9 months, composed of bedaquiline, pretomanid and linezolid (BPaL), may be used under operational research conditions in multidrug-resistant tuberculosis (MDR-TB) patients with TB that is resistant to fluoroquinolones, who have either had no previous exposure to bedaquiline and linezolid or have been exposed for no more than 2 weeks.

(Conditional recommendation, very low certainty in the estimates of effect)

5. Monitoring patient response to MDR-TB treatment using culture

5.1 In multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) patients on longer regimens, the performance of sputum culture in addition to sputum smear microscopy is recommended to monitor treatment response(strong recommendation, moderate certainty in the estimates of test accuracy).It is desirable for sputum culture to be repeated at monthly intervals.

6. Starting antiretroviral therapy in patients on second-line anti-TB regimens

6.1 Antiretroviral therapy is recommended for all patients with HIV and drug-resistant tuberculosis requiring second-line antituberculosis drugs, irrespective of CD4 cell count, as early as possible (within the first 8 weeks) following initiation of antituberculosis treatment.

(Strong recommendation, very low quality evidence).

7. Surgery for patients on multidrug-resistant TB treatment.

7.1 In patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB), elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen.

(Conditional recommendation, very low certainty in the evidence)

8. Care and support for patients with multidrug- or rifampicin-resistant tuberculosis

8.1 Health education and counselling on the disease and treatment adherence should be provided to patients on tuberculosis (TB) treatment.

(Strong recommendation, moderate certainty in the evidence)

8.2 A package of treatment adherence interventions¹¹ may be offered to patients on TB treatment in conjunction with the selection of a suitable treatment administration option.¹²

(Conditional recommendation, low certainty in the evidence)

8.3 One or more of the following treatment adherence interventions (complementary and not mutually exclusive) may be offered to patients on TB treatment or to health care providers:

a) tracers¹³ and/or digital medication monitor¹⁴ (Conditional recommendation, very low certainty in the evidence);

b) material support¹⁵ to the patient (Conditional recommendation, moderate certainty in the evidence);

c) psychological support¹⁶ to the patient (Conditional recommendation, low certainty in the evidence);

d) staff education¹⁷ (Conditional recommendation, low certainty in the evidence).

8.4 The following treatment administration options may be offered to patients on TB treatment:

a) Community- or home-based directly observed treatment (DOT) is recommended over health facility-based DOT or unsupervised treatment (Conditional recommendation, moderate certainty in the evidence).

b) DOT administered by trained lay providers or health care workers is recommended over DOT administered by family members or unsupervised treatment (Conditional recommendation, very low certainty in the evidence).

c) Video-observed treatment (VOT) may replace DOT when the video communication technology is available, and it can be appropriately organized and operated by health care providers and patients. (Conditional recommendation, very low certainty in the evidence)

8.5 Patients with multidrug-resistant TB (MDR-TB) should be treated using mainly ambulatory care rather than models of care based principally on hospitalization.

(Conditional recommendation, very low quality evidence)

8.6 A decentralized model of care is recommended over a centralized model for patients on MDR-TB treatment.

(Conditional recommendation, very low certainty in the evidence)

Main changes to the guidance in the current update

(see also Supplementary table)

  • One recommendation on shorter regimens to treat MDR/RR-TB has been updated. The shorter regimen conditionally recommended in this update comprises 6 Bdq with 4–6 Lfx/Mfx-Cfz-Z-E-Hh-Eto/ 5 Lfx/Mfx-Cfz-Z-E (in previous guidance, the shorter regimen comprised 4–6 Am-Mfx-Cfz-Eto-Z-E-Hh/ 5 Mfx-Cfz-Z-E). The new shorter regimen is recommended as a standardized package. New information has been included in these guidelines (Recommendations – Section 2) on the use of this shorter regimen, including implementation considerations for national TB programmes.
  • A new 6–9-month regimen composed of bedaquiline, pretomanid and linezolid (BPaL) has been conditionally recommended for use in patients with MDR/RR-TB and additional fluoroquinolone resistance, under operational research conditions only. A new section (Recommendations – Section 4) has been added to these guidelines to describe the evidence that was assessed in relation to this regimen, the eligible population and the conditions of use as part of operational research studies.
  • Additional guidance on the safety of extended bedaquiline use (beyond 6 months), the concurrent use of bedaquiline and delamanid, and the use of bedaquiline during pregnancy has been provided in the section on longer regimens for MDR/RR-TB (Recommendations – Section 3). The grouping of medicines into Groups A, B and C has not changed since the previous guidelines were issued by WHO in 2018.
  • The content of the guidelines has been updated, citing current references and the latest available evidence, including unpublished data on cost–effectiveness, safety and patient preferences for treatment.
  • The research gaps have been updated to reflect the latest evidence reviewed.

End TB Strategy. Global strategy and targets for tuberculosis prevention, care and control after 2015.Geneva: World Health Organization; 2014 (https://www.who.int/tb/strategy/en/, accessed 20 March 2020).

WHO consolidated guidelines on drug-resistant tuberculosis treatment (WHO/CDS/TB/2019.7).Geneva: World Health Organization; 2019 (https://www.who.int/tb/publications/2019/consolidated-guidelines-drug-resistant-TB-treatment/en/, accessed 6 March 2020).

WHO consolidated guidelines on drug-resistant tuberculosis treatment.Geneva,Switzerland: World Health Organization; 2019 (https://apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf?ua=1, accessed 20 March 2020).

¹⁰ Imipenem–cilastatin and meropenem are administered with clavulanic acid, which is available only in formulations combined with amoxicillin. Amoxicillin–clavulanic acid is not counted as an additional effective TB agent, and should not be used without imipenem–cilastatin or meropenem. 

¹¹ Treatment adherence interventions include social support such as material support (e.g. food, financial incentives or transport fees), psychological support, tracers such as home visits or digital health communications (e.g. SMS or telephone calls), medication monitor and staff education. The interventions should be selected based on the assessment of the individual patient’s needs, the provider’s resources and conditions for implementation.

¹² Treatment administration options include DOT, non-daily DOT, VOT or unsupervised treatment.

¹³ “Tracers” refer to the communication with the patient, including home visits or via SMS or telephone (voice) call.

¹⁴ A digital medication monitor is a device that can measure the time between openings of the pill box. The medication monitor can have audio reminders or send an SMS to remind the patient to take medications, along with recording when the pill box is opened.

¹⁵ Material support can be food or financial support: meals, food baskets, food supplements, food vouchers, transport subsidies, living allowance, housing incentives, or financial bonuses. This support addresses the indirect costs incurred by patients or their attendants in order to access health services, and may try to mitigate the consequences of income loss related to the disease.

¹⁶ Psychological support can be counselling sessions or peer-group support.

¹⁷ Staff education can be adherence education, chart or visual reminders, educational tools and desktop aids for decision-making and reminders.

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