Drug-resistant tuberculosis (TB) continues to be a public health problem, taking a heavy toll on patients, communities and health care systems. Recent global estimates indicate that there were about half a million new cases of multidrug- or rifampicin-resistant TB (MDR/RR-TB) in 2018, with less than 40% of the estimated burden being notified and 32% reported to have started second-line treatment (1). Current treatment regimens for MDR/RR-TB patients are far from satisfactory. Compared with treatments for drug-susceptible TB forms, these regimens require a longer course of treatment, a higher pill burden and the use of medicines with a higher toxicity profile; in addition, patients may develop significant adverse events and have poorer treatment outcomes. Globally, although treatment success rates have increased, almost 15% of MDR/RR-TB patients die from the disease, and 26% of those deaths are in patients with extensively drug-resistant TB (XDR-TB) (1).
The Global TB Programme of the World Health Organization (WHO) is now combining all current recommendations into one overall set of consolidated guidelines on TB. The guidelines will contain recommendations pertaining to all areas related to the programmatic management of TB (e.g. screening, preventive treatment, diagnostics, patient support, and the treatment of drugsusceptible and drug-resistant TB). The consolidated guidelines will contain modules specific to each programmatic area. This current module is on the treatment of drug-resistant TB; it presents WHO recommendations that have been newly developed and are published here for the first time, and existing recommendations that have been previously published in other WHO guidelines that applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Structure of the document
The Recommendations part of this document has eight main sections that cover aspects of the treatment of drug-resistant TB. The aspects covered are:
- the treatment of rifampicin-susceptible and isoniazid-resistant TB (Section 1);
- shorter all-oral bedaquiline-containing regimens for MDR/RR-TB (Section 2);
- the composition and duration of longer regimens for MDR/RR-TB (Section 3);
- the bedaquiline, pretomanid and linezolid (BPaL) regimen for MDR-TB with additional fluoroquinolone resistance (Section 4);
- monitoring of the patient response to MDR-TB treatment (Section 5);
- the use of antiretroviral therapy (ART) for people living with HIV infection (Section 6);
- the role of surgery for patients on MDR-TB treatment (Section 7); and
- the vital role of care and support for patients with MDR/RR-TB (Section 8).
Each section starts with the current WHO recommendations for that aspect, then gives information on the evidence used to inform that recommendation, a summary of the analyses that were carried out based on the evidence, considerations for specific subgroups, and considerations for monitoring and evaluation and implementation. Research gaps identified for each of the sections are presented at the end of this document, while online annexes provide more details on the methods, the Guideline Development Groups (GDGs), the analyses, unpublished data and statistical analysis plans. Each section reflects discussions held at GDG meetings over recent years. Additional information on the management of MDR/RR-TB is presented in the relevant chapter of the WHO operational handbook on tuberculosis, a separate document that is designed to aid implementation efforts. Eventually,the operational handbook will replace the Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis (2).
Effective treatment of TB, including its drug-resistant forms, relies on the use of several medicines administered in combination for an adequate duration. Significant progress has been made in recent years in identifying more efficacious, safer medicines and shorter treatment regimens. The development of new TB drugs and the use of repurposed drugs such as linezolid and clofazimine has set a positive course; however, regimens for drug-resistant TB continue to present safety concerns, require long duration and put a significant burden on health care systems. Since the 1990s, WHO has regularly evaluated evidence on the use of specific drug compositions and combinations of different regimen durations (3–12). Patients with drug-resistance patterns were often treated for 20 months or longer. In 2016, a standardized shorter treatment regimen (9–12 months) was recommended for patients with MDR/RR-TB strains not resistant to fluoroquinolones or second-line injectable agents, while longer regimens (18–20 months) continued to be an option for patients who were not eligible for the shorter option. Subsequent modifications to these treatment regimens led WHO to assess new evidence, which in turn resulted in revised recommendations, balancing effectiveness and harms on, for example:
- the use of all-oral longer treatment regimens; and
- the replacement of drugs associated with increased risk of treatment failure and relapse in the standardized shorter regimen.
Rationale for the update
The latest WHO evidence-based guidelines for the treatment of drug-resistant TB were released in December 2018 and incorporated into consolidated guidelines published in March 2019 (11). Subsequently, new evidence on treatment for MDR/RR-TB and XDR-TB became available to WHO through national programmes, researchers and technical partners, and from a public call for data from WHO in August 2019 (13). New data from patients on both longer (>18 months) and shorter (<12 months) MDR-TB regimens were validated and incorporated into the set of individual patient data (IPD) that had been established earlier to help inform development of WHO guidelines on drug-resistant TB (this dataset covers patients who have been treated for MDR/RR-TB, as of November 2019 it contains >13 000 patient records from 55 different studies or centres in 38 countries overall). International standards for meta-analysis were followed to assess the relative contributions of treatment regimens or combinations of medicines to patient treatment outcomes. WHO convened an independent GDG on 12–14 November 2019, to assess the results of these analyses using the GRADE system. The detailed recommendations presented here replace all previous and current WHO guidelines on the treatment of drug-resistant TB.
Scope of the 2020 update
This current module on drug-resistant TB management and care provides specific recommendations on the management and care of drug-resistant TB, including use of 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 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.
These updated recommendations resulted from the 2019 GDG meeting, convened by WHO to review and discuss results on the following:
- use of all-oral shorter regimens (9–12 months duration);
- use of BPaL in combination for patients with MDR/RR-TB with additional fluoroquinolone resistance;
- use of bedaquiline for longer than 6 months;
- concurrent use of bedaquiline and delamanid; and
- use of bedaquiline-containing regimens in pregnant women.
Access to these data was achieved through close collaboration and engagement with national TB control programmes (NTPs), researchers, and a not-for-profit product-development partnership (TB Alliance) investigating the effectiveness and safety of these interventions (see Annex 1).
The text clearly indicates where recommendations are new.
These guidelines are primarily targeted at policy-makers in ministries of health, or managers of NTPs who formulate country-specific TB treatment guidelines or who are involved in the planning of TB treatment programmes. It is expected that these updated recommendations will also be used by health professionals, including doctors, nurses and educators working in governmental and nongovernmental organizations, and by technical agencies involved in treating patients and organizing treatment services.