Recent controversies about MDR and XDR‐TB: Global implementation of the WHO shorter MDR‐TB regimen and bedaquiline for all with MDR‐TB?

Abstract

Tuberculosis (TB) is now the biggest infectious disease killer worldwide. Although the estimated incidence of TB has marginally declined over several years, it is out of control in some regions including in Africa. The advent of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) threatens to further destabilize control in several regions of the world. Drug-resistant TB constitutes a significant threat because it underpins almost 25% of global TB mortality, is associated with high morbidity, is a threat to healthcare workers and is unsustainably costly to treat. The advent of highly resistant TB with emerging bacillary resistance to newer drugs has raised further concern. Encouragingly, in addition to preventative strategies, several interventions have recently been introduced to curb the drug-resistant TB epidemic, including newer molecular diagnostic tools, new (bedaquiline and delamanid) and repurposed (linezolid and clofazimine) drugs and shorter and individualized treatment regimens. However, there are several controversies that surround the use of new drugs and regimens, including whether, how and to what extent they should be used, and who specifically should be treated so that outcomes are optimally improved without amplifying the burden of drug resistance, and other potential drawbacks, thus sustaining effectiveness of the new drugs. The equipoise surrounding these controversies is discussed and some recommendations are provided.

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

“…The improved treatment‐related outcomes among survivors in the phase 2(b) study and in observational studies 67,77 , the poor outcomes associated with the currently used toxic and prolonged MDR‐TB regimens, raises the ethical question whether we should wait for the results of these clinical trials, or whether bedaquiline should not be rolled out for all patients with MDR‐TB? The equipoise surrounding this issue, including potential mortality associated with bedaquiline and concerns about amplification of resistance, has been discussed in detail recently …”

“…The equipoise surrounding this issue, including potential mortality associated with bedaquiline and concerns about amplification of resistance, has been discussed in detail recently. 87 The optimal regimen and duration of treatment for XDR-TB remains unclear. The national TB programme in South Africa currently treats XDR-TB using a backbone of bedaquiline, linezolid and clofazimine.…”

New drugs and regimens for tuberculosis

“…9 While there is evidence supporting the effectiveness of the standardized shorter MDR-TB regimen under the above-mentioned conditions, 65 and feasibility of its use for MDR-TB with low-level fluoroquinolone resistance, 66,67 there are major concerns regarding its applicability and sustainability in endemic areas with a large number of previously treated MDR-TB patients and a substantial proportion of MDR-TB strains that are resistant to one or more of the drugs in the shorter regimen. 68 Preliminary findings of the STREAM Stage 1 (see Table 2) could not confirm noninferiority of the shorter MDR-TB regimen or the superiority of the WHO-recommended 18-to-24-month MDR-TB regimen. 69 The WHO recommendation regarding use of the shorter MDR-TB regimen remains unchanged.…”

“…The shorter MDR‐TB regimen has been conditionally recommended in specific situations where resistance to at least fluoroquinolones and second‐line injectable is considered unlikely by DST, or by reference to drug exposure history, use of second‐line medicines at country level or recent representative surveillance data . While there is evidence supporting the effectiveness of the standardized shorter MDR‐TB regimen under the above‐mentioned conditions, and feasibility of its use for MDR‐TB with low‐level fluoroquinolone resistance, there are major concerns regarding its applicability and sustainability in endemic areas with a large number of previously treated MDR‐TB patients and a substantial proportion of MDR‐TB strains that are resistant to one or more of the drugs in the shorter regimen . Preliminary findings of the STREAM Stage 1 (see Table ) could not confirm non‐inferiority of the shorter MDR‐TB regimen or the superiority of the WHO‐recommended 18‐ to‐24‐month MDR‐TB regimen .…”

Respiratory infections in the Asia‐Pacific region: Problems and cautious optimism

“…While it is generally well‐controlled since the 1960s in most Western countries, as Dheda et al . pointed out in their review, the explosion of drug‐resistant tuberculosis has undermined control efforts in large areas of Africa and the Asian sub‐continent and is now responsible for more than 25% of deaths . Spread of multidrug‐ and extensive drug‐resistant tuberculosis poses a global threat to health.…”