1.1 Background

Globally, tuberculosis (TB) continues to be a significant public health problem, with an estimated 10.6 million people developing TB in 2022 and 7.5 million reported as being newly diagnosed (1). The gap between the numbers estimated and reported is large, and it worsened during the coronavirus disease (COVID-19) pandemic (2). However, there has been a major recovery after the 2 years of disruptions related to COVID-19. Drug-resistant TB (DR-TB) is another area of concern, particularly multidrug- or rifampicin-resistant TB (MDR/RR-TB), which is TB disease caused by Mycobacterium tuberculosis complex (MTBC) with resistance to rifampicin (RIF) and isoniazid (INH) or only to RIF. The relative gap was even larger for MDR/RR-TB in 2022, with an estimated 410,00 new cases of MDR/RR-TB, of which only about two in five were known to have been diagnosed and enrolled on treatment (1). In addition, an estimated 1.1 million people had TB disease caused by MTBC with resistance to INH and susceptibility to RIF (referred to as Hr-TB), which is difficult to detect and is therefore largely undetected (3).

The effective management of TB relies on the rapid diagnosis of TB, rapid detection of drug resistance and prompt initiation of an effective treatment regimen. Thus, there is a need for access to fast and accurate detection tests, and rapid and accurate drug susceptibility testing (DST) for all people with TB. In 2023, the first ever WHO standard on universal access to rapid TB diagnostics was issued; it emphasizes the need to undertake a comprehensive approach to diagnostics while following the care cascade and closing all gaps (4). Furthermore, it highlights the need for universal DST: all persons with TB should have initial rapid DST for the detection of resistance to RIF; rapid testing for INH and FQs as required; and follow-on testing for all other drugs that might be included in their treatment regimen ideally performed before treatment is started. However, the initiation of treatment should not be delayed while waiting for DST results; also, efforts to build laboratory capacity (especially DST) should not slow the detection and enrolment of people with DR-TB in care and treatment programmes.

The World Health Organization’s (WHO’s) global strategy for TB prevention, care and control for 2015–2035 – known as the End TB Strategy (5) – calls for the early diagnosis of TB and universal access to DST. To meet the End TB Strategy targets, molecular WHO-recommended rapid diagnostic tests (mWRDs) should be made available to all individuals with signs or symptoms of TB. Individuals with bacteriologically confirmed TB should receive testing for resistance to RIF, those with RR-TB should receive testing for resistance to FQs and those with pre-XDR-TB should receive testing for resistance to bedaquiline and linezolid (6).¹ In 2022, about 73% of people with bacteriologically confirmed TB were tested for RIF resistance and of these 50% were tested for FQ resistance. Recent WHO guidelines stress the importance of DST before treatment, especially for the medicines for which mWRDs are available (e.g. FQs, INH and RIF) but the start of treatment should not be delayed (7).

Furthermore, as described in the Framework of indicators and targets for laboratory strengthening under the End TB Strategy (8), all national TB programmes (NTPs) should prioritize the development of a network of TB laboratories that use modern methods of diagnosis (e.g. molecular methods and liquid culture), have efficient referral systems, use electronic data and diagnostics connectivity, use standard operating procedures (SOPs) and appropriate quality assurance (QA) processes, adhere to biosafety principles for all testing and have sufficient human resources. These priorities should be comprehensively addressed in national strategic plans and should be adequately funded.

Over recent decades, considerable effort has gone into building the laboratory, clinical and programmatic capacity to prevent, detect and treat TB and DR-TB. Many tools and guidance documents have been developed, including guidelines for the detection and treatment of MDR/RR-TB and Hr-TB; rapid tests to detect resistance to RIF, INH, FQs, ethionamide (ETO) and amikacin (AMK); model diagnostic testing algorithms; and guidance for scaling up laboratory capacities to combat DR-TB.

Recently, WHO approved the use of targeted next-generation sequencing (NGS) as a follow-on test for the detection of drug resistance (7). Targeted NGS tests couple the amplification of selected genes with NGS technology to detect resistance to many drugs with a single test. Because targeted NGS tests can interrogate entire genes to identify specific mutations associated with resistance, such tests may provide improved accuracy compared with other WHO-recommended molecular tests. The recommendations include the use of this technology for the rapid detection of resistance to three of the drugs used in the BPaLM regimen (i.e. bedaquiline [BDQ], linezolid [LZD] and moxifloxacin [MFX]); therefore, this updated handbook includes further implementation considerations and algorithms using this technology. The fourth BPaLM drug – pretomanid (Pa) – has recently had criteria established for DST, and these details are also included in this document. Based on current treatment recommendations, countries embarking on interventions to detect and treat DR-TB should, in addition, establish laboratory capacity to perform culture-based phenotypic DST for drugs that are recommended for use in MDR-TB regimens (9) and for which there are reliable phenotypic DST methods (e.g. BDQ, LZD, Pa, cycloserine [CS], clofazimine [CFZ] and delamanid [DLM]). The addition of a new molecular test for pyrazinamide [PZA] testing in the latest guidelines should facilitate testing for this drug. Also, countries should expand their capacity to monitor the culture conversion of people being treated for DR-TB.

An increasing number of novel tools serve similar purposes; hence, WHO has introduced recommendations that are class based, whereby, instead of evaluating and approving individual products, WHO will recommend a class that represents a group of products with similar characteristics and performances. This approach is expected to increase competitiveness in price, quality and services. The change was introduced in December 2020, with a guideline development group (GDG) recommending three new classes of nucleic acid amplification tests (NAATs).

Linked to this change to class-based recommendations was a joint announcement by the Global TB Programme at WHO (WHO/GTB) and the WHO Prequalification Unit (WHO PQ) on the pathways to a WHO endorsement for new in vitro diagnostics for TB (10). All products will continue to be reviewed by WHO/GTB initially, to determine whether a product warrants a new class or falls within an existing class. In the latter case, the product can proceed to WHO PQ, where both the product and the processes used to manufacture it will be assessed to ensure the test meets performance and quality standards. If a new class is warranted, the product will be assessed as a “first in class” through a GDG process before proceeding to WHO PQ.

1 The original End TB Strategy called for the testing of all persons with RR-TB for susceptibility to second-line injectable agents (kanamycin, capreomycin and amikacin). However, WHO currently recommends that injectable medicines be phased out as a priority in all treatment regimens and replaced by bedaquiline (BDQ), which makes rapid DST for amikacin unnecessary.

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