Isoniazid-resistant tuberculosis: A problem we can no longer ignore

Abstract

For decades, people working in tuberculosis (TB) knew that monoresistance to isoniazid (INH) was common. INH has been in clinical use since the 1950s, and drug resistance was expected because its use became widespread. But this knowledge did not necessarily lead to testing for INH-resistant, rifampicin-susceptible TB (Hr-TB) or to the use of special drug regimens for this form of TB. Indeed, for decades, no drug-susceptibility testing (DST) for any drug was done unless patients failed first-line therapy or had risk factors for drug-resistant TB (DR-TB). Simply put, we chose to ignore the problem. When the TB world woke up to the need for universal DST and included it as a key goal in the End TB Strategy released in 2015, the focus became rapid testing for rifampicin resistance (RR) as a means of achieving universal DST. Novel technologies such as Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) were rolled out in 2010, but the technology did not include INH-resistance testing [1]. Even today, access to any DST remains low, and when performed, DST is often limited to RR [2]. In 2020, we can no longer hide from this worrisome problem because Hr-TB is much more common than RR and could seriously jeopardize progress in the fight against TB. This is confirmed by an analysis of aggregated drug resistance data from 2003 to 2017 across 156 countries presented in the accompanying research study by Anna Dean and colleagues in PLOS Medicine, showing that-on average-7.4% (95% CI 6.5-8.4) of new cases and 11.4% (9.4-13.4) of previously treated patients have Hr-TB [3]. The overall prevalence of INH resistance (with or without concomitant RR) ranged between 10.7% (9.6-11.9) and 27.2% (24.6-29.9) depending on the treatment history and reached even more alarming levels in certain countries, particularly in the European and Western Pacific regions. The analysis by Dean and colleagues highlights major flaws in national surveillance systems, which go hand in hand with limited laboratory capacity. The small sample sizes available from some countries make national prevalence estimates imprecise. Furthermore, the diversity of detection methods employed across settings along with the widespread lack of quality control underscores the need for improved surveillance by countries. From a clinical standpoint, if INH resistance is not detected, new patients are managed as if they had pansusceptible TB, with a substantially increased risk of treatment failure or relapse and a greater propensity to acquire further resistance [4]. Yet, most research and policy efforts so far have been focused solely on RR as a proxy for multidrug-resistant (MDR)-TB. This means that hundreds of thousands of patients with Hr-TB are staying in the shadows, not receiving appropriate care, and all too often ending up developing MDR-TB.

Isoniazid-monoresistant tuberculosis in France: Risk factors, treatment outcomes and adverse events

“…Patients with a smear-positive test have a higher bacillary load, are more contagious and at higher risk of acquiring multidrug-resistant strains. Line-probe assays (FluoroType 1 MTBDR, GenoType MTBDRplus, BD MAX TM MDR-TB) are the only rapid molecular tests available to identify HR-TB at an early stage; however, they are currently not implemented as a routine diagnostic tool and often remain limited to reference laboratories where they are mainly performed on strains (Sulis and Pai, 2020). Without easy-to-use tools for early HR detection, many HR-TB cases will be overlooked and receive the standard DS-TB treatment regimen.…”

Molecular Detection of Drug-Resistant Mycobacterium tuberculosis in Sputum Specimens from the New and Previously Treated Tuberculosis Cases at the National Reference Chest Diseases Laboratory in Lusaka, Zambia

“…INHr is more common than RR and is a growing public health problem globally because research and policy directions are only focused on RR as a marker for MDR-TB. However, this growing problem of INHr is being ignored globally [61].…”

Drug Resistance to Anti-Tuberculosis Drugs: A Cross-Sectional Study From Makkah, Saudi Arabia

“…Moreover, our data were consistent with a comparable pattern previously chronicled by two national registries in Saudi Arabia [ 10 , 11 ]. Indeed, isoniazid is the most commonly effective yet most frequently resistant anti-TB agent worldwide [ 22 ].…”