TABLE 5.
Summary of changes to the World Health Organization (WHO) multidrug-resistant (MDR)/rifampicin-resistant (RR) tuberculosis (TB) treatment recommendations between 2019 and current updates
| Recommendations in the 2019 update | Recommendations in the current update |
| Section 1: Regimens for isoniazid-resistant TB | Section 1: Regimen for rifampicin-susceptible and isoniazid-resistant TB |
| In patients with confirmed rifampicin-susceptible and isoniazid-resistant 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) | 1.1 In patients with confirmed rifampicin-susceptible, isoniazid-resistant TB (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) (No change) |
| In patients with confirmed rifampicin-susceptible and isoniazid-resistant TB, 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) | 1.2 In patients with confirmed rifampicin-susceptible, isoniazid-resistant TB, 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) (No change) |
| Section 2: The composition of longer MDR-TB regimens | Section 3: Longer regimens for MDR/RR-TB |
| In 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 the treatment after 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) | 3.1 In MDR- or RR-TB (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) (Editing of the word “after” to “if” with reference to stopping bedaquiline) |
| 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) | 3.2 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) (No change) |
| 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) | 3.3 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) (No change) |
| Bedaquiline should be included in longer MDR-TB regimens for patients aged ≥18 years (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) | 3.4 Bedaquiline should be included in longer MDR-TB regimens for patients aged ≥18 years (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) (No change) |
| Linezolid should be included in the treatment of MDR/RR-TB patients on longer regimens (Strong recommendation, moderate certainty in the estimates of effect) | 3.5 Linezolid should be included in the treatment of MDR/RR-TB patients on longer regimens (Strong recommendation, moderate certainty in the estimates of effect) (No change) |
| 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) | 3.6 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) (No change) |
| 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) | 3.7 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) (No change) |
| Delamanid may be included in the treatment of MDR/RR-TB patients aged ≥3 years on longer regimens (Conditional recommendation, moderate certainty in the estimates of effect) | 3.8 Delamanid may be included in the treatment of MDR/RR-TB patients aged ≥3 years on longer regimens (Conditional recommendation, moderate certainty in the estimates of effect) (No change) |
| 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) | 3.9 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) (No change) |
| 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) | 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)ƒƒ (No change) |
| Amikacin may be included in the treatment of MDR/RR-TB patients aged ≥18 years 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) | 3.11 Amikacin may be included in the treatment of MDR/RR-TB patients aged ≥18 years 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) (No change) |
| 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) | 3.12 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) (No change) |
| 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) | 3.13 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) (No change) |
| 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)¶ | 3.14 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)ƒƒ (No change) |
| Section 3: The duration of longer MDR-TB regimens | Section 3: Longer regimens for MDR/RR-TB |
| 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) | 3.15 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) (No change to wording, but combined with section above: Section 3: Recommendations on the use of longer regimens for MDR/RR-TB) |
| 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) | 3.16 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) (No change to wording, but combined with section above: Section 3: Recommendations on the use of longer regimens for MDR/RR-TB) |
| In MDR/RR-TB patients on longer regimens that contain 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) | 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) (No change to wording, but combined with section above: Section 2.2: Recommendations on the use of longer regimens for MDR/RR-TB) |
| Section 4: Use of the standardised shorter MDR-TB regimen | Section 2: Shorter, all-oral, bedaquiline-containing regimen for MDR/RR-TB |
| In MDR/RR-TB patients who have not been previously treated for >1 month with second-line medicines used in the shorter MDR-TB regimen or in whom resistance to fluoroquinolones and second-line injectable agents has been excluded, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (Conditional recommendation, low certainty in the estimates of effect) | 2.1 A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended in eligible patients with confirmed MDR/RR-TB who have not been exposed to treatment with second-line TB medicines used in this regimen for >1 month, and in whom resistance to fluoroquinolones has been excluded (Conditional recommendation, very low certainty in the evidence) (Updated recommendation) |
| Not included in 2019 guidelines | Section 4: The BPaL regimen for MDR-TB with additional fluoroquinolone resistance |
| Not included in 2019 guidelines | 4.1 A treatment regimen lasting 6–9 months, composed of bedaquiline, pretomanid and linezolid (BPaL), may be used under operational research conditions in 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 ≤2 weeks (Conditional recommendation, very low certainty in the estimates of effect) (New recommendation) |
| Section 5: Monitoring patient response to MDR-TB treatment using culture | Section 5: Monitoring patient response to MDR-TB treatment using culture |
| In MDR/RR-TB patients on longer regimens, the performance of sputum culture in addition to sputum smear microscopy is recommended to monitor treatment response. It is desirable for sputum culture to be repeated at monthly intervals (Strong recommendation, moderate certainty in the estimates of test accuracy) | 5.1 In MDR/RR-TB patients on longer regimens, the performance of sputum culture in addition to sputum smear microscopy is recommended to monitor treatment response. It is desirable for sputum culture to be repeated at monthly intervals (Strong recommendation, moderate certainty in the estimates of test accuracy) (No change) |
| Section 6: Start of antiretroviral therapy in patients on second-line anti-TB regimens | Section 6: Start of antiretroviral therapy in patients on second-line anti-TB regimens |
| Antiretroviral therapy is recommended for all patients with HIV and drug-resistant TB requiring second-line anti-TB drugs, irrespective of CD4 cell count, as early as possible (within the first 8 weeks) following initiation of anti-TB treatment (Strong recommendation, very low-quality evidence) | 6.1 Antiretroviral therapy is recommended for all patients with HIV and drug-resistant TB requiring second-line anti-TB drugs, irrespective of CD4 cell count, as early as possible (within the first 8 weeks) following initiation of anti-TB treatment (Strong recommendation, very low quality evidence) (No change) |
| Section 7: Surgery for patients on MDR-TB treatment | Section 7: Surgery for patients on MDR-TB treatment |
| In patients with RR-TB or 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) | 7.1 In patients with RR-TB or 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) (No change) |
| Section 8: Care and support for patients with MDR/RR-TB | Section 8: Care and support for patients with MDR/RR-TB |
| Health education and counselling on the disease and treatment adherence should be provided to patients on TB treatment (Strong recommendation, moderate certainty in the evidence) | 8.1 Health education and counselling on the disease and treatment adherence should be provided to patients on TB treatment (Strong recommendation, moderate certainty in the evidence) (No change) |
| A package of treatment adherence interventions+ may be offered to patients on TB treatment in conjunction with the selection of a suitable treatment administration option (Conditional recommendation, low certainty in the evidence)§ | 8.2 A package of treatment adherence interventions+ may be offered to patients on TB treatment in conjunction with the selection of a suitable treatment administration option§ (No change) |
| One or more of the following treatment adherence interventions (complementary and not mutually exclusive) may be offered to patients on TB treatment or to healthcare providers: | 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 healthcare providers: |
| 1) tracersƒ and/or digital medication monitor## (conditional recommendation, very low certainty in the evidence) | a) tracersƒ and/or digital medication monitor## (conditional recommendation, very low certainty in the evidence) |
| 2) material support¶¶ to the patient (conditional recommendation, moderate certainty in the evidence) | b) material support¶¶ to the patient (conditional recommendation, moderate certainty in the evidence) |
| 3) psychological support++ to the patient (conditional recommendation, low certainty in the evidence) | c) psychological support++ to the patient (conditional recommendation, low certainty in the evidence) |
| 4) staff education§§ (conditional recommendation, low certainty in the evidence) | d) staff education§§ (conditional recommendation, low certainty in the evidence) (No change) |
| The following treatment administration options may be offered to patients on TB treatment: | 8.4 The following treatment administration options may be offered to patients on TB treatment: |
| a) community- or home-based DOT is recommended over health facility-based DOT or unsupervised treatment (conditional recommendation, moderate certainty in the evidence) | a) community- or home-based 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 healthcare workers is recommended over DOT administered by family members or unsupervised treatment (conditional recommendation, very low certainty in the evidence) | b) DOT administered by trained lay providers or healthcare workers is recommended over DOT administered by family members or unsupervised treatment (conditional recommendation, very low certainty in the evidence) |
| c) VOT may replace DOT when video communication technology is available, and it can be appropriately organised and operated by healthcare providers and patients (conditional recommendation, very low certainty in the evidence) | c) VOT may replace DOT when the video communication technology is available, and it can be appropriately organised and operated by healthcare providers and patients (conditional recommendation, very low certainty in the evidence) |
| (No change) | |
| Patients with MDR-TB should be treated using mainly ambulatory care rather than models of care based principally on hospitalisation (Conditional recommendation, very low-quality evidence) | 8.5 Patients with MDR-TB should be treated using mainly ambulatory care rather than models of care based principally on hospitalisation (Conditional recommendation, very low quality evidence) (No change) |
| A decentralised model of care is recommended over a centralised model for patients on MDR-TB treatment (Conditional recommendation, very low certainty in the evidence) | 8.6 A decentralised model of care is recommended over a centralised model for patients on MDR-TB treatment (Conditional recommendation, very low certainty in the evidence) (No change) |
The WHO Consolidated Guidelines on Tuberculosis, Module 4: Drug-Resistant Tuberculosis Treatment were a compilation of existing and new recommendations on the treatment and management of MDR/RR-TB and as such they included new recommendations published in 2019 and existing recommendations that had been previously published. In the current update (2020), there are two new recommendations (recommendations 2.1 and 4.1) and a minor change to the wording of a pre-existing recommendation (recommendation 3.1). Recommendation 2.1 is an update to a previous recommendation on shorter regimens for MDR/RR-TB while recommendation 4.1 was based on a new Population, Intervention, Comparator, Outcomes (PICO) question concerning the bedaquiline, pretomanid and linezolid (BPaL) regimen. Recommendations on the duration of longer regimens for MDR/RR-TB (recommendations 3.15, 3.16 and 3.17) were combined into the section on the composition of longer regimens for MDR/RR-TB (recommendations 3.1–3.14); however, the wording of the recommendations on duration remained unchanged. All other recommendations remain unchanged. DOT: directly observed treatment; VOT: video-observed treatment. #: group A = levofloxacin/moxifloxacin, bedaquiline, linezolid; group B = clofazimine, cycloserine/terizidone; group C = ethambutol, delamanid, pyrazinamide, imipenem–cilastatin, meropenem, amikacin (streptomycin), ethionamide/prothionamide, p-aminosalicylic acid (see also table 3). ¶: imipenem–cilastatin and meropenem are administered with clavulanic acid, which is available only in formulations combined with amoxicillin (amoxicillin–clavulanic acid). When included, clavulanic acid is not counted as an additional effective TB agent and should not be used without imipenem–cilastatin or meropenem. +: treatment adherence interventions include social support such as material support (e.g. food, financial incentives, transport fees), psychological support, tracers such as home visits or digital health communications (e.g. short message service (SMS), telephone calls), medication monitor and staff education. The interventions should be selected based on an assessment of the individual patient's needs, provider's resources and conditions for implementation. §: treatment administration options include DOT, non-daily DOT, VOT or unsupervised treatment. ƒ: tracers refer to communication with the patient, including home visits or via SMS, telephone (voice) call. ##: 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. ¶¶: material support can be food or financial support: meals, food baskets, food supplements, food vouchers, transport subsidies, living allowance, housing incentives or financial bonus. This support addresses the indirect costs incurred by patients or their attendants in order to access health services and, possibly, tries to mitigate the consequences of income loss related to the disease. ++: psychological support can be counselling sessions or peer-group support. §§: staff education can be adherence education, chart or visual reminders, educational tools and desktop aids for decision-making and reminders. ƒƒ: 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.