1.1 Background

Globally, tuberculosis (TB) continues to be a significant public health problem, with an estimated 10 million people developing TB in 2019 and 7.1 million reported to have been diagnosed and notified (1). The gap between the numbers estimated and notified is large and has worsened during the coronavirus disease (COVID-19) pandemic (2). 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 bacteria (MTBC) with resistance to rifampicin (RIF) or isoniazid (INH), or both. The relative gap was even larger for MDR/RR-TB in 2019, with an estimated 0.5 million new cases of MDR/RR-TB, of which only 206 030 were detected and notified (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 largely undetected.

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 TB patients. Ideally, to guide the selection of an effective regimen, all TB patients should have DST for all anti-TB drugs that might be included in their treatment regimen before treatment is started. However, the initiation of treatment should not be delayed waiting for DST results; also, efforts to build laboratory capacity (especially DST) should not slow the detection and enrolment of DR-TB patients 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 (3) - calls for the early diagnosis of TB and universal access to DST. WHO defines universal access to DST as rapid DST for at least RIF among all patients with bacteriologically confirmed TB, and further DST for at least fluoroquinolones (FQs) and second-line injectable agents among all TB patients with RIF resistance (4). 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, all bacteriologically confirmed TB patients should receive DST for at least RIF (in 2018, only about 61% of such patients were tested for RIF resistance), and all patients with RR-TB should receive DST for at least FQs.¹ 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 should not delay the start of treatment (5).

Furthermore, as described in the Framework of indicators and targets for laboratory strengthening under the End TB Strategy (6), 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. Based on current treatment recommendations, countries embarking on interventions to detect and treat DR-TB should, in addition, establish laboratory capacity to perform phenotypic DST for drugs that are recommended for use in MDR-TB regimens (7) and for which there are reliable DST methods (e.g. bedaquiline [BDQ], linezolid [LZD], 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 patients being treated for DR-TB.

An increasing number of novel tools serve similar purposes; hence, WHO has introduced a class-based recommendation approach. 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 tools.

The classes are defined by the type of technology (e.g. automated or reverse hybridization nucleic acid amplification tests [NAATs]), the complexity of the test for implementation (e.g. low, moderate or high - considering the requirements of infrastructure, equipment and technical skills of laboratory staff) and the target conditions (e.g. diagnosis of TB, and detection of resistance to first-line or second-line drugs). The level of complexity is only one of the elements that should guide implementation. Other important elements include diagnostic accuracy, the epidemiological and geographical setting, operational aspects (e.g. turnaround times, throughput, existing infrastructure and specimen referral networks), economic aspects and qualitative aspects on acceptability, equity, and end-user values and preferences.

Linked to this change to class-based recommendations is the joint announcement by the Global TB Programme at WHO (WHO/GTB) and the WHO Prequalification (PQ) Unit on the pathways to a WHO endorsement for new in vitro diagnostics for TB (8). All products will continue to be reviewed by WHO/GTB initially, to determine whether the product warrants a new class:

  • if a new class is warranted, the product will be assessed as a "first in class" through a GDG process; and
  • if the product is deemed to fall under an existing class with the same recommendations, the dossier will be forwarded to the WHO PQ Unit for assessment, to ensure the quality of the product and manufacturing processes, and to ensure that the performance of the new test is similar to that of existing products in the class before listing.

¹ The original End TB Strategy called for the testing of all RR-TB patients 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, which makes rapid DST for amikacin unnecessary


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