Isoniazid (INH) resistance is not always known at the beginning of the tuberculosis (TB) diagnostic pathway. INH status (susceptible or resistant) is only known once samples have been cultured and tested for drug susceptibility, which can take several weeks. This is different from rifampicin (RIF) status (susceptible or resistant), which can be ascertained right from the beginning with rapid molecular assays. The main challenges to knowing the full diagnostic profile for patients suspected of having TB include INH monoresistance, assigning the right patient to the right diagnostic pathway, diagnostic testing setting, cost containment and reimbursement, and implementing next-generation sequencing.

INH monoresistance

The TB epidemic is a major threat to global health. Mycobacterium tuberculosis complex (MTBc) is the leading cause of death from a single infectious agent. RIF and INH are the two most effective drugs against TB and part of the TB first-line treatment regimen. However, not all patients respond to these treatments, because they can be infected by rifampicin-resistant (RR) TB or multidrug-resistant (MDR) TB.

If patients are only tested for RIF resistance, INH monoresistance can go undetected at this stage of the diagnostic pathway. TB strains with undetected INH monoresistance could also acquire resistance to other drugs while subjected to inappropriate treatment, leading to MDRTB or extensively drug-resistant (XDR) TB – for example, MDR-TB plus resistance to any fluoroquinolone antibiotic and at least one of three injectable second-line drugs.

A recent systematic review and metaanalysis carried out by Gegia showed that the standard World Health Organisation (WHO) regimen may be suboptimal when treating INH-resistant TB and may lead to treatment failure, relapse and acquired MDR-TB. Molecular tests including both RIF and INH allow for a more rapid and efficient way to determine the most appropriate treatment.

Assign the right patient to the right diagnostic pathway

There seems to be a lack of consensus among clinicians across Europe on which patient profile should undergo molecular testing for drug-resistant TB. Diagnostic strategies vary between European countries and medical institutions, and it is not clear which diagnostic pathway should be used.

There may be a gap between WHO recommendations and what is feasible or practiced by healthcare providers. Good communication between microbiologists and clinicians is also important.

The right expertise is needed by laboratory personnel to interpret the results and help clinicians make informed decisions on diagnosis and treatment regimens.

Where molecular testing should be carried out

The setting depends on how the laboratory system is organised, which varies from country to country. In some countries, the clinical laboratory system is centralised – as it is in the UK – and in others, it is regional. In France and Italy, molecular testing is carried out in public hospitals and results are then sent to TB reference laboratories.

Looking at cost containment and reimbursement

It has been shown that MDR-TB results in a higher financial cost to healthcare systems. Healthcare facilities are under increasing pressure from governments to control costs. Isolating patients in hospitals is costly and it is important to have suspected TB confirmed as soon as possible. The earlier the clinician receives the preliminary report, the easier it is to optimise healthcare costs.

Implement next-gen sequencing

Over the next 5-10 years, next-generation sequencing (NGS) has the potential to change TB diagnostic testing by delivering more targeted results for individualised treatment regimens. It is already being used in Germany and Italy on MDR-TB cases that have been detected using molecular and culture testing. NGS has the ability to detect INH resistance mutations outside of the commonly targeted regions of the inhA and katG genes. As costs decrease and genotyping and phenotyping data become linked, this testing method is gaining momentum for TB diagnostics and surveillance.

In spite of these major challenges, rapid molecular TB testing can provide the following benefits to laboratories and clinicians: greater predictive value, shorter time to results to detect INH monoresistance, RIF monoresistance or MDR-TB, rapid communication to the clinician, faster clinical decisions, improved cost-effectiveness and improved laboratory efficiency.