Elsevier

The Lancet

Volume 375, Issue 9728, 22–28 May 2010, Pages 1830-1843
The Lancet

Series
Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis

https://doi.org/10.1016/S0140-6736(10)60410-2Get rights and content

Summary

Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of the estimated 440 000 cases of MDR tuberculosis that occurred in 2008, only 7% were identified and reported to WHO. Of these cases, only a fifth were treated according to WHO standards. Although treatment of MDR and XDR tuberculosis is possible with currently available diagnostic techniques and drugs, the treatment course is substantially more costly and laborious than for drug-susceptible tuberculosis, with higher rates of treatment failure and mortality. Nonetheless, a few countries provide examples of how existing technologies can be used to reverse the epidemic of MDR tuberculosis within a decade. Major improvements in laboratory capacity, infection control, performance of tuberculosis control programmes, and treatment regimens for both drug-susceptible and drug-resistant disease will be needed, together with a massive scale-up in diagnosis and treatment of MDR and XDR tuberculosis to prevent drug-resistant strains from becoming the dominant form of tuberculosis. New diagnostic tests and drugs are likely to become available during the next few years and should accelerate control of MDR and XDR tuberculosis. Equally important, especially in the highest-burden countries of India, China, and Russia, will be a commitment to tuberculosis control including improvements in national policies and health systems that remove financial barriers to treatment, encourage rational drug use, and create the infrastructure necessary to manage MDR tuberculosis on a national scale.

Introduction

“Responding to drug-resistant tuberculosis is possibly one of the most profound challenges facing global health.”1

The past 20 years have seen the worldwide appearance of multidrug-resistant (MDR) tuberculosis,2, 3, 4, 5 followed by extensively drug-resistant (XDR) tuberculosis,6, 7, 8, 9 and, most recently, strains that are resistant to all antituberculosis drugs.10, 11, 12 MDR tuberculosis is caused by Mycobacterium tuberculosis that is resistant at least to isoniazid and rifampicin, and XDR tuberculosis by mycobacteria resistant to rifampicin and isoniazid, any fluoroquinolone, and one of the three injectable drugs, capreomycin, kanamycin, and amikacin. Drug resistance severely threatens tuberculosis control, since it raises the possibility of a return to an era in which drugs are no longer effective.13

Progress is being made in global control of drug-susceptible tuberculosis, as presented by Lonnröth and colleagues14 in the first report in this Series. In 2008, 5·7 million (61%) of the estimated 9·4 million new and relapsed tuberculosis cases were identified and treated on the basis of the WHO Stop TB Strategy.15 Partly as a result of these efforts, worldwide incidence of tuberculosis has been slowly falling since 2004.15 Data are insufficient to indicate whether incidence of MDR tuberculosis is rising or falling globally. However, the fact that only 7% of the estimated 440 000 (95% CI 390 000–510 000) cases of MDR disease worldwide were reported to WHO in 2008, and of these, only a fifth (1·2% of the total) were treated according to WHO recommended standards, is of major concern.15 These data show the depth of the challenge referred to by Upshur and colleagues1—that countries are confronted by huge political, structural, and economic constraints that have to be overcome to tackle the epidemic of drug-resistant tuberculosis. As a result, although the Millennium Development Goal of a reversal in the incidence of tuberculosis seems to have been achieved in 2004,15 progress in the management of MDR tuberculosis has been poor, and milestones in the Stop TB Partnership's Global Plan to Stop TB 2006–2015, are being missed.16 Unless countries can greatly intensify detection and treatment of drug-resistant cases, the possibility remains that MDR strains could become the dominant form of tuberculosis disease.17, 18

Key messages

  • An estimated 440 000 cases of multidrug-resistant (MDR) tuberculosis occurred worldwide in 2008 (3·6% of the estimated cases of tuberculosis in that year); most of these cases develop as a result of primary transmission (ie, in people never previously exposed to antituberculosis drugs).

  • Drug-resistant tuberculosis poses a major threat to existing control programmes since treatment is less effective, more complex, and far more costly than is that for drug-susceptible disease.

  • Tuberculosis control efforts are complicated by weak programmes with poor access to laboratory diagnosis and effective treatment. Investment in laboratory capacity and staff and the introduction of new rapid diagnostic tests are crucial.

  • Driving forces behind the epidemic of drug-resistant tuberculosis include poor political commitment and weak health policies, regulation, and enforcement—especially uncontrolled drug availability in the private sector.

  • Outbreaks of MDR and extensively drug-resistant (XDR) tuberculosis have emphasised the need for effective infection-control measures, which are absent in most high-burden settings.

  • Nonetheless, some countries have reversed rising epidemics of MDR tuberculosis with wise use of existing technologies, and set an example for others.

  • That new drugs, presently in the pipeline, are not exposed to the same health-system and programme weaknesses that created MDR and XDR tuberculosis is imperative.

In this Series report on drug-resistant tuberculosis, we will explore the size and causes of the MDR and XDR tuberculosis epidemic, and discuss the possible responses that are needed by policy makers globally and nationally if the challenge of drug-resistant tuberculosis is to be adequately faced.

Section snippets

What is the size of the problem?

WHO estimates that 440 000 cases of MDR tuberculosis occurred in 2008 (3·6% of the estimated total incident tuberculosis episodes).19 Of these, 360 000 were new and relapse (recurrence after successful previous treatment) cases (ie, likely transmission of an MDR strain), and 94 000 were in individuals previously treated for the disease (ie, likely acquired resistance during previous treatment).

India and China together carry nearly 50% of the global burden, followed by Russia (9%). MDR

How did we reach the present situation?

Resistance to antituberculosis drugs arises as a result of spontaneous mutations in the genome of M tuberculosis and not as a result of horizontal gene transfer.37, 38 These resistance-conferring mutations occur at predictable rates for each antituberculosis drug (eg, isoniazid 10−6, rifampicin 10−8).37 Thus, in patients with active tuberculosis disease, subpopulations of resistant mycobacteria spontaneously arise,39 and can emerge as the dominant strain in the presence of drug-selection

Effect of HIV/AIDS

The association between HIV/AIDS and drug-resistant tuberculosis is complex and multifaceted.83 HIV co-infection is not believed to increase the rate at which spontaneous resistance-conferring mutations occur, although it might increase the number of mutants that arise overall by enlarging the pool of individuals with active tuberculosis disease.84 Additionally, HIV co-infection might increase selection for spontaneous mutations in several ways. Without proper management, individuals with

How can we use existing technologies to improve outcomes?

Overall, although restricted in their effectiveness, existing technologies seem sufficient to begin turning the tide against drug-resistant tuberculosis, if properly used.17, 27, 94 These results have been achieved with political commitment, drug-susceptibility testing of every case of tuberculosis, and specialist management of MDR tuberculosis in centres of excellence, with currently available technologies. The countries that have achieved these results are small and centralised (Estonia and

What new knowledge or technologies do we need?

The epidemic of MDR and XDR tuberculosis worldwide has exposed defects in our attempts to control tuberculosis. Although much can be done to fight MDR and XDR tuberculosis with existing technologies, we would be unwise to rely on these techniques alone. The prospects for development of new diagnostic tests, drugs, and vaccines are the subject of past work139 and reports in this Series,140, 141, 142 and we will touch here only on some of the important implications for management of MDR

Conclusions

MDR and XDR tuberculosis are major challenges to tuberculosis control, but are not yet being sufficiently addressed. National governments have yet to make available adequate resources for control efforts.15 Unless countries invest substantially in management of MDR tuberculosis, the possibility remains that MDR strains could become the dominant form of tuberculosis.17, 18 Moreover, the future possibility of strains that are totally resistant to all antituberculosis drugs becoming widespread is

Search strategy and selection criteria

We searched Medline using the search terms: “tuberculosis”, “multidrug-resistant tuberculosis”, “MDR-TB”, “extensively drug-resistant tuberculosis”, and “XDR-TB”. Reference lists of identified articles were then searched for further relevant reports. Publications in English were reviewed. Reports published in the previous 10 years were selected mainly, but when relevant, we reviewed primary historical sources for frequently cited information or knowledge.

References (149)

  • D Shingadia et al.

    Diagnosis and treatment of tuberculosis in children

    Lancet Infect Dis

    (2003)
  • M Perkins et al.

    Progress towards improved tuberculosis diagnostics for developing countries

    Lancet

    (2006)
  • HS Schaaf et al.

    Multidrug- and extensively drug-resistant tuberculosis in Africa and South America: epidemiology, diagnosis and management in adults and children

    Clin Chest Med

    (2009)
  • R Upshur et al.

    Apocalypse or redemption: responding to extensively drug-resistant tuberculosis

    Bull World Health Organ

    (2009)
  • Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons—Florida and New York, 1988–1991

    JAMA

    (1991)
  • T Frieden et al.

    The emergence of drug-resistant tuberculosis in New York City

    N Engl J Med

    (1993)
  • V Ritacco et al.

    Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires

    J Infect Dis

    (1997)
  • J Rullán et al.

    Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain

    Emerg Infect Dis

    (1996)
  • NS Shah et al.

    Worldwide emergence of extensively drug-resistant tuberculosis

    Emerg Infect Dis

    (2007)
  • GB Migliori et al.

    Extensively drug-resistant tuberculosis, Italy and Germany

    Emerg Infect Dis

    (2007)
  • Countries that had reported at least one XDR-TB case by September 2009

  • GB Migliori et al.

    First tuberculosis cases in Italy resistant to all tested drugs

    Euro Surveill

    (2007)
  • Shah N, Richardson J, Moodley P, et al. Increasing second-line drug resistance among extensively drug-resistant...
  • MC Raviglione

    XDR-TB: entering the post-antibiotic era?

    Int J Tuberc Lung Dis

    (2006)
  • K Lönnroth et al.

    Tuberculosis control and elimination 2010–50: cure, care, and social development

    Lancet

    (2010)
  • Global tuberculosis control: short update to 2009 report

    (2009)
  • The global plan to stop TB, 2006–2015. Report No: WHO/HTM/STB.2006.35

    (2006)
  • C Dye et al.

    Slow elimination of multidrug-resistant tuberculosis

    Sci Transl Med

    (2009)
  • SM Blower et al.

    Modeling the emergence of the “hot zones”: tuberculosis and the amplification dynamics of drug resistance

    Nat Med

    (2004)
  • Multidrug and extensively drug-resistant tuberculosis: 2010 global report on surveillance and response

    (2010)
  • A Laszlo et al.

    Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994–1998

    Int J Tuberc Lung Dis

    (2002)
  • Anti-tuberculosis drug resistance in the world: the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Report No: WHO/HTM/TB/2008.394

    (2008)
  • I Dubrovina et al.

    Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics?

    Int J Tuberc Lung Dis

    (2008)
  • EA Nunes et al.

    Patterns of anti-tuberculosis drug resistance among HIV-infected patients in Maputo, Mozambique, 2002–2003

    Int J Tuberc Lung Dis

    (2005)
  • J Chirenda et al.

    The trend of resistance to anti-tuberculosis drugs in Botswana: results from the 4th national anti-tuberculosis drug resistance survey. 40th Union World Conference on Lung Health; Cancun, Mexico; Dec 3–7, 2009

    Int J Tuberc Lung Dis

    (2009)
  • C Dye

    Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis

    Nat Rev Microbiol

    (2009)
  • PA Selwyn et al.

    A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection

    N Engl J Med

    (1989)
  • Y Ben Amor et al.

    Underreported threat of multidrug-resistant tuberculosis in Africa

    Emerg Infect Dis

    (2008)
  • NR Gandhi et al.

    HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality

    Am J Respir Crit Care Med

    (2010)
  • C Wells et al.

    HIV infection and multidrug-resistant tuberculosis: the perfect storm

    J Infect Dis

    (2007)
  • Anti-tuberculosis drug resistance in the world: the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Report No: WHO/HTM/TB/2008.394

    (2008)
  • T Cohen et al.

    Challenges in estimating the total burden of drug-resistant tuberculosis

    Am J Respir Crit Care Med

    (2008)
  • Guidelines for surveillance of drug resistance in tuberculosis. Report No: WHO/HTM/TB/2009.422

    (2009)
  • Prevention and control of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis

    (2009)
  • HL David

    Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis

    Appl Microbiol

    (1970)
  • P Supply et al.

    Linkage disequilibrium between minisatellite loci supports clonal evolution of Mycobacterium tuberculosis in a high tuberculosis incidence area

    Mol Microbiol

    (2003)
  • G Kaplan et al.

    Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity

    Infect Immun

    (2003)
  • FA Post et al.

    Genetic polymorphism in Mycobacterium tuberculosis isolates from patients with chronic multidrug-resistant tuberculosis

    J Infect Dis

    (2004)
  • A van Rie et al.

    Reinfection and mixed infection cause changing Mycobacterium tuberculosis drug-resistance patterns

    Am J Respir Crit Care Med

    (2005)
  • TC Victor et al.

    Spread of an emerging Mycobacterium tuberculosis drug-resistant strain in the western Cape of South Africa

    Int J Tuberc Lung Dis

    (2007)
  • Cited by (870)

    View all citing articles on Scopus
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