The Lancet Respiratory Medicine CommissionThe epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis
Introduction
With the notable exception of sub-Saharan Africa, the incidence of tuberculosis has declined over the past two decades in most regions of the world.1, 2 However, gains in tuberculosis control are threatened by the emergence of resistance to antituberculosis drugs. Approximately 20% of tuberculosis isolates globally are estimated to be resistant to at least one major drug (first-line or group A or B second-line), with approximately 10% resistant to isoniazid. WHO has defined multidrug-resistant (MDR) tuberculosis as resistance to at least isoniazid and rifampicin, when first-line therapy is unlikely to cure the disease and a switch to a second-line drug regimen is recommended. Similarly, extensively drug-resistant (XDR) tuberculosis is MDR tuberculosis that is also resistant to the fluoroquinolones and second-line injectable drugs, indicating the probable failure of the standardised second-line treatment regimen. Two modes exist by which patients contract drug-resistant tuberculosis. Primary resistance results from infection with a drug-resistant strain, whereas resistance that develops during therapy is referred to as secondary or acquired resistance. Amplification of resistance might occur when resistance to additional drugs emerges during the treatment course, often in association with inadequate therapy. Globally, approximately 5% of patients with tuberculosis are estimated to have either MDR or XDR types, but the distribution of cases is not uniform; it is substantially higher in some regions, and increasing incidence has been reported in several countries.1 The high mortality due to most patients remaining untreated is a key reason for this apparently stable estimated global rate of drug-resistant tuberculosis. Approximately 30% of MDR tuberculosis isolates are either fluoroquinolone-resistant or aminoglycoside-resistant, and approximately 10% of MDR tuberculosis isolates can be classed as XDR tuberculosis, or as having resistance to additional drugs beyond XDR tuberculosis (ie, totally drug resistant). This expansion of resistance has ushered in an era of programmatically incurable tuberculosis, in which insufficient effective drugs remain to construct a curative regimen. The availability of newer drugs, such as bedaquiline and delamanid,3, 4, 5 has not averted this problem and resistance to both bedaquiline and delamanid in the same patient has already been reported.6 The effect on patients is profound, because drug resistant tuberculosis is associated with a higher morbidity than drug-sensitive tuberculosis7 and is responsible for approximately 20% of the global tuberculosis mortality, with mortality rates estimated at around 40% for patients with MDR tuberculosis and 60% for those with XDR tuberculosis.1
Provision of effective first-line treatment was hoped to prevent the emergence of drug-resistant tuberculosis as a public health problem. However, data suggest that primary transmission of MDR and XDR tuberculosis is now driving the spread of resistance, including in high-burden countries such as China, India, and South Africa. The inability to cure infectious patients raises ethical and medicolegal questions regarding the freedom of affected individuals to work and travel and how to prevent onward transmission. Drug-resistant tuberculosis causes a strain on health systems because of the chronic nature of the disease, and because of the risk of transmission to health-care workers.7 Drug-resistant tuberculosis also jeopardises tuberculosis control through its economic effect, because the high cost of managing drug-resistant tuberculosis is not sustainable in some settings and an anticipated shortfall in global resources has been reported by the STOP TB partnership.1 In the USA, average inpatient costs have been estimated to be US$81 000 for patients with MDR tuberculosis and $285 000 for those with XDR tuberculosis.8 In South Africa, management of MDR and XDR tuberculosis, despite only accounting for less than 5% of all tuberculosis cases, is estimated to consume over a third of the total tuberculosis programme resources.9 Of the US$6·3 billion available in 2014 to respond to the global tuberculosis epidemic, $3·8 billion was used for diagnosis and treatment of drug-susceptible tuberculosis, and $1·8 billion (47%) for MDR tuberculosis.10 Tuberculosis and drug-resistant tuberculosis are no longer the concern of individual countries, because international travel and migration support transmission across international boundaries and around the world.
Addressing drug-resistant tuberculosis requires an urgent and concerted effort to manage the disease and prevent onward transmission with sustained research to develop and assess new tools. In this Commission, we report on the global status of drug-resistant tuberculosis and how it emerges, followed by state-of-the-art detection and patient management options; we discuss transmission and intervention to reduce transmission; and research needs are assessed and prioritised. We therefore present for consideration a contemporary situational analysis and roadmap for combating and eradicating drug-resistant tuberculosis as a global public health problem. An array of views is presented on drug-resistant tuberculosis with the aim to highlight challenges and to provide practicable solutions and a roadmap for progress. A patient-orientated perspective is also presented, including audio and video interviews with patients with drug-resistant tuberculosis (panel 1).
Section snippets
Global epidemiology of MDR and XDR tuberculosis
Historically, knowledge of drug-resistant tuberculosis has been limited by the absence of reliable data from many of the countries with a high burden of tuberculosis. Drug susceptibility testing is technically challenging and requires specialist laboratory facilities that are not widely available in many tuberculosis-endemic countries. In 1994, WHO and International Union Against Tuberculosis and Lung Disease (IUATLD) launched a global surveillance programme to standardise methods and improve
Molecular epidemiology and transmission dynamics of drug-resistant tuberculosis in high-burden countries
Drug-resistant tuberculosis continues to be a threat to tuberculosis control.43 Molecular epidemiology has been important in advancing the knowledge of drug-resistant tuberculosis epidemics (figure 2). First, on a population basis, strain typing identifies strain relatedness, thus identifying chains of transmission (a cluster of isolates with identical genotypes according to IS6110 DNA fingerprinting,44 mycobacterial interspersed repetitive units–variable numbers of tandem repeat [MIRU–VNTR]
Historical notions on how drug resistance arises
In the past, the proximate cause of acquired drug resistance had been ascribed to poor adherence.154, 155 Thus, acquired drug resistance was dealt with using a programmatic approach, specifically the DOTS strategy, to improve adherence. The idea of DOTS arose from the move from sanatoria-based care to ambulatory care, on the basis of studies in India156 and Hong Kong157 in the late 1950s and the 1960s, the main outcomes of which were for ambulatory patients to achieve the same rates of
Diagnosis of MDR and XDR tuberculosis
Drug-resistant tuberculosis occurs when M tuberculosis bacilli undergo mutations that enable it to survive the effects of tuberculosis drug treatments. Unlike many other bacteria, no horizontal acquisition of resistance has been shown in M tuberculosis, and a drug-resistant strain can be defined as one that differs significantly from wild strains in its degree of susceptibility because of the increased proportion of resistant mutants.226 Testing the susceptibility of M tuberculosis to
Medical and surgical management of drug-resistant tuberculosis: general principles and treatment of children, patients with HIV, and in other specific clinical contexts
The management of drug-resistant tuberculosis is complex and several factors must be considered, including the prioritisation of effective treatment. Priorities should be decided upon while accounting for multiple clinical contexts, including HIV co-infection, diabetes, and vulnerable populations, such as pregnant women and children. More effective new and repurposed drugs are now routinely being used to treat drug-resistant tuberculosis, but resistance to these agents is already emerging. The
New drugs and strategies for treating drug-resistant tuberculosis
Developing new regimens for drug-resistant tuberculosis is challenging. Tuberculosis drugs work in combination, and an effective regimen should include at least one drug with potent bactericidal activity to rapidly reduce mycobacterial burden. This role is filled by isoniazid in drug-susceptible tuberculosis. Drugs with potent sterilising activity (eg, rifampicin and pyrazinamide in drug-susceptible tuberculosis), which effectively kill semidormant, persisting organisms that will cause relapse
Pharmacokinetic–pharmacodynamic factors in drug-resistant tuberculosis
A direct association exists between acquired drug resistance and drug pharmacokinetics181 and is best explained by use of antimicrobial pharmacokinetic–pharmacodynamic science. Similarly, drug exposures predict the clearing of viable M tuberculosis from the sputum.191, 395
Prevention and containment of transmission of highly drug-resistant (MDR and XDR) tuberculosis
Managing patients with highly drug-resistant tuberculosis is a rigorous process, so prevention of these infections is a far better option than treatment. Therefore, health-care delivery systems are crucial in ensuring that treatment of tuberculosis is effective, thereby preventing the emergence of drug resistance (panel 9). A full discussion of the effect of health-care delivery systems (private, public, inpatient, ambulatory, community-based, vertical, integrated) on the prevention of MDR
Patient-centred care for drug-resistant tuberculosis
The treatment of drug-resistant tuberculosis requires careful attention not only to the medical aspects of the disease but also to the psychosocial aspects. A patient-centred approach to tuberculosis is a central pillar in WHO's new End TB strategy, and there are multiple opportunities to enhance this type of care in the treatment of drug-resistant tuberculosis, including adherence support, treatment discontinuation, and palliative care. The fundamental underpinning of the patient-centred
Components of patient-centred and community-centred care for MDR and XDR tuberculosis: an advocacy perspective
The weak, vertical, unsupportive approach to treating MDR and XDR tuberculosis is failing. Of the estimated 480 000 new MDR tuberculosis cases in 2014, only 26% were diagnosed and only 23% were treated.1 People on treatment suffer from toxic side-effects of drugs, stigma, and economic loss. About 50% of patients who get treatment for MDR tuberculosis and 26% of those treated for XDR tuberculosis are cured. The failure of approaches to combat tuberculosis can be overcome; through not only
Conclusion
MDR tuberculosis, XDR tuberculosis, and resistance beyond XDR tuberculosis remains a major threat to global tuberculosis control because of the increasing burden it creates on health-care systems, economies, and societies, the threat to health-care workers in tuberculosis-endemic countries, the high mortality, and the unsustainably high costs of treating drug-resistant tuberculosis. Additionally, the development of totally drug-resistant or programmatically incurable tuberculosis has raised
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