• 1.

    WHO, 2011. The Global Plan to STOP TB 2011–2015.Geneva:World Health Organization, (WHO/HTM/STB/2010.2).

  • 2.

    Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, Tahirli R, Gler MT, Blakemore R, Worodria W, Gray C, Huang L, Caceres T, Mehdiyev R, Raymond L, Whitelaw A, Sagadevan K, Alexander H, Albert H, Cobelens F, Cox H, Alland D, Perkins MD, 2011. Feasibility, diagnostic accuracy, and effectiveness of decentralized use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 377: 14951505.

    • Search Google Scholar
    • Export Citation
  • 3.

    Chang K, Lu W, Wang J, Zhang K, Jia S, Li F, Deng S, Chen M, 2012.Rapid and effective diagnosis of tuberculosis and rifampicin resistance with Xpert MTB/RIF assay: a meta-analysis. J Infect 64: 580588.

    • Search Google Scholar
    • Export Citation
  • 4.

    Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD, 2010. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 363: 10051015.

    • Search Google Scholar
    • Export Citation
  • 5.

    Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, Bekker LG, Wood R, 2011. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med 8: e1001067.

    • Search Google Scholar
    • Export Citation
  • 6.

    Nicol MP, Workman L, Isaacs W, Munro J, Black F, Eley B, Boehme CC, Zemanay W, Zar HJ, 2011. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infect Dis 11: 819824.

    • Search Google Scholar
    • Export Citation
  • 7.

    Rachow A, Clowes P, Saathoff E, Mtafya B, Michael E, Ntinginya EN, Kowour D, Rojas-Ponce G, Kroidl A, Maboko L, Heinrich N, Reither K, Hoelscher M, 2012. Increased and expedited case detection by Xpert MTB/RIF assay in childhood tuberculosis: a prospective cohort study. Clin Infect Dis 54: 13881396.

    • Search Google Scholar
    • Export Citation
  • 8.

    Hillemann D, Rusch-Gerdes S, Boehme C, Richter E, 2011. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol 49: 12021205.

    • Search Google Scholar
    • Export Citation
  • 9.

    Ligthelm LJ, Nicol MP, Hoek KG, Jacobson R, van Helden PD, Marais BJ, Warren RM, Wright CA, 2011. Xpert MTB/RIF for rapid diagnosis of tuberculous lymphadenitis from fine-needle-aspiration biopsy specimens. J Clin Microbiol 49: 39673970.

    • Search Google Scholar
    • Export Citation
  • 10.

    Tortoli E, Russo C, Piersimoni C, Mazzola E, Dal MP, Pascarella M, Borroni E, Mondo A, Piana F, Scarparo C, Coltella L, Lombardi G, Cirillo DM, 2012. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 2012 Jan 12 [Epub ahead of print].

    • Search Google Scholar
    • Export Citation
  • 11.

    Vadwai V, Boehme C, Nabeta P, Shetty A, Alland D, Rodrigues C, 2011. Xpert MTB/RIF, a new pillar in the diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 49: 25402545.

    • Search Google Scholar
    • Export Citation
  • 12.

    Vassall A, van Kampen S, Sohn H, Michael JS, John KR, den Boon S, Davis JL, Whitelaw A, Nicol MP, Gler MT, Khaliqov A, Zamudio C, Perkins MD, Boehme CC, Cobelens F, 2011. Rapid diagnosis of tuberculosis with the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness analysis. PLoS Med 8: e1001120.

    • Search Google Scholar
    • Export Citation
  • 13.

    Abimbola TO, Marston BJ, Date AA, Blandford JM, Sangrujee N, Wiktor SZ, 1999. Cost-effectiveness of tuberculosis diagnostic strategies to reduce early mortality among persons with advanced HIV infection initiating antiretroviral therapy. J Acquir Immune Defic Syndr 2012: 11.

    • Search Google Scholar
    • Export Citation
  • 14.

    Andrews JR, Lawn SD, Rusu C, Wood R, Noubary F, Bender MA, Horsburgh CR, Losina E, Freedberg KA, Walensky RP, 2012. The cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy in South Africa: a model-based analysis. AIDS 26: 987995.

    • Search Google Scholar
    • Export Citation
  • 15.

    Floyd K, Pantoja A, Glasziou P, 2010. Xpert MTB/RIF in the Global Plan 2011–2015. What Will It Cost? Geneva: World Health Organization Global Consultation on Xpert implementation.

    • Search Google Scholar
    • Export Citation
  • 16.

    WHO, 2011. Policy Statement: Automated Real-Time Nucleic Acid Amplification Technology for Rapid and Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB/RIF System. Geneva: World Health Organization, (WHO/HTM/TB/2011.4).

    • Search Google Scholar
    • Export Citation
  • 17.

    WHO, 2011. Rapid Implementation of the Xpert MTB/RIF Diagnostic Test: Technical and Operational “How-to”; Practical Considerations. Geneva: World Health Organization, (WHO/HTM/TB/2011.2).

    • Search Google Scholar
    • Export Citation
  • 18.

    WHO, 2011. Checklist of Prerequisites to Country Implementation of Xpert MTB/RIF and Key Action Points at Country Level. Geneva: World Health Organization, (WHO/HTM/TB/2011.12).

    • Search Google Scholar
    • Export Citation
 
 
 
 

 

 
 

 

 

 

 

 

 

Transforming TB Diagnosis: Can Patients and Control Programs Afford to Wait?

View More View Less
  • Dartmouth College, Hanover, New Hampshire; GHESKIO, Port-au-Prince, Haiti; Weill Cornell Medical College, New York, New York; Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland

For every new public health intervention tool, whether it be antiretroviral drugs for human immunodeficiency virus, bed nets for malaria, or vaccines for rotavirus, there is, and should be, a public debate about whether the benefits of the tool are worth the cost and disruption that will accompany its implementation. The World Health Organization (WHO), as the United Nations agency with primary responsibility for international health policy, norms, and standards, is often criticized for moving too slowly or, rarely, too quickly in providing recommendations about new tools. With regard to Xpert MTB/RIF, the new, rapid, molecular test for tuberculosis and rifampin resistance, we think WHO has got it just about right, moving quickly with an evidence-based policy decision allowing the test's rapid uptake.

The Context

Sputum smear microscopy, still the only tuberculosis (TB) diagnostic that is widely available, has notoriously poor sensitivity that leaves at least half of TB cases undetected, gives no information about drug resistance, and is difficult to implement and sustain with controlled quality. The limitations of microscopy are particularly significant when it comes to patients who are human immunodeficiency virus (HIV)-infected or who have multidrug-resistant TB (MDR-TB)—two groups that present unique challenges for TB control and have fuelled a resurgence of the epidemic.

In 2007, following guidance from WHO, which included specific measures to address the needs for proper care for HIV-associated and MDR-TB, the World Health Assembly called for universal access to culture and drug susceptibility testing (DST), marking a seismic shift in diagnostic strategy for disease-endemic countries. The updated Global Plan to Stop TB (2011–2015) responded with a call for significant investment in laboratory services and a dramatic increase in testing of smear-negative and potentially drug-resistant cases with molecular- and culture-based methods.1 However, the cost of meeting these targets using existing culture and DST tools, which necessitate the construction and maintenance of sophisticated laboratories with containment facilities and practices, could easily overwhelm TB control budgets. Moreover, the actual clinical impact of such testing is limited because systems for the rapid transportation of specimens to these centralized laboratories and the rapid report of testing results are largely unavailable in disease-endemic areas. Reporting delays associated with culture and DST, even using rapid liquid media, has been shown to result in significant diagnostic dropout, decreasing the effectiveness of culture by 20–30% because culture-positive patients do not get their results.2

How A New Tool Fits In

Into this vacuum stepped a new molecular test, Xpert MTB/RIF. The Xpert MTB/RIF assay, developed through a partnership between the Foundation for Innovative New Diagnostics (FIND), the University of Medicine and Dentistry in New Jersey and Cepheid, Inc., CA, addressed many of the technical hurdles blocking effective case management through culture and DST. By using a bactericidal reagent to liquefy sputum in the first and only manual step in the assay, it eliminated the need for complex biosafety equipment. By using a real-time molecular amplification platform targeting the rpoB gene, it delivered case detection and MDR screening in 100 minutes, making it possible to inform patients before they are lost to follow-up. Finally, by automating specimen processing, amplification and detection in a cartridge pre-loaded with all necessary reagents, it essentially eliminated the need for containment infrastructure and molecular training. The cartridge employs a filter for bacterial concentration, which both enhances sensitivity and makes the assay immune to amplicon contamination events that frequently undermine molecular testing. Published evaluations of Xpert MTB/RIF have shown consistent excellent performance, with case detection sensitivity similar to conventional culture,3 but with significant increases in the number of patients started on therapy because of the much faster time to result.2,4,5 Accuracy data for the detection of TB in children6,7 and for the detection of extrapulmonary TB811 also show great promise.

The technology has its limitations. It is a sophisticated device that requires annual calibration, maintenance, and stable electricity, and is therefore not suitable for many peripheral diagnostic settings in disease-endemic countries. This is also why research and development efforts must continue to focus on developing tests more suitable for such settings. The technological advantages of Xpert MTB/RIF also come at a cost—Xpert MTB/RIF testing is currently similar to the operational cost of culture, which it is intended to replace or augment, but is more expensive than microscopy. National governments and donors supporting TB control efforts need to know if broad implementation of Xpert testing is cost-effective and if it is affordable.

Published data already exist to help countries know whether Xpert is worth the cost of implementation. Vassal and colleagues12 modeled the cost-effectiveness of Xpert testing as a replacement for or as an addition to microscopy in India, South Africa, and Uganda. They report that, even when not factoring in the impact of early TB detection and treatment on disease transmission, Xpert MTB/RIF testing was cost-effective, with incremental cost-effectiveness ratios per disability-adjusted life-year averted below the WHO willingness-to-pay threshold. Other studies have found that Xpert MTB/RIF testing was cost-effective for reducing premature mortality in patients with advanced HIV infection, both at the time of presentation with TB symptoms,13 and before initiation of antiretroviral therapy.14 Regarding affordability, WHO has estimated that Xpert testing for all symptomatic individuals at risk for HIV-associated TB or MDR-TB would consume < 3% of current global TB control spending.15

Imperative To Test

The WHO policy guidance on Xpert MTB/RIF recognizes its transformational potential and has provided the information and support necessary to enable countries to make the most appropriate decisions on if, how, and where within their diagnostic algorithms they use Xpert MTB/RIF.1618 This guidance can and should be refined during the Xpert MTB/RIF implementation process; donor monies should fund ongoing research to delineate the most cost-effective approaches for its use. Current WHO guidance explicitly highlights the resource implications of rolling out the technology. These costs must also be balanced against the costs of inaction. For too long, the field of TB diagnostics had been stagnant. That stagnation had dire impact on patients who remain ill and infectious while waiting for a diagnosis, or who are mistreated through syndromic management. The Xpert MTB/RIF assay has a number of limitations, and will not meet the need for point-of-care diagnosis in many low-income countries, but offers an undeniable improvement over other available approaches. National TB control programs recognize this, and more than 47 developing countries have already implemented Xpert MTB/RIF testing in selected services. Early implementation can drive a virtuous cycle in the transformation of TB diagnosis and care: evidence of improved health outcomes in implementing countries will drive accelerated uptake of the test in other settings. This growing diagnostic market can, in turn, spur other groups to develop even better technologies. Furthermore, the process of adapting TB control programs and algorithms to include Xpert MTB/RIF will mean that emerging alternative technologies can be more effectively implemented because the ground will already have been prepared.

It is time to give full value to the promise of early and effective TB and MDR-TB diagnosis, and support countries to improve TB care and control through the implementation of innovations such as Xpert MTB/RIF. The WHO has put in place online mechanisms to rapidly and transparently share field experiences and operational research findings on Xpert MTB/RIF (https://extranet.who.int/xpertmtbrif). Other groups are also sharing information about the early implementation of Xpert MTB/RIF, including TB REACH (http://www.stoptb.org/global/awards/tbreach/interactive/pages/interventions10.html) and The Union/Treat TB's Xpert Research Mapping Project (http://xrmt.treattb.org/). To support the ongoing dissemination of information, we urge all those interested in the rational roll-out of Xpert MTB/RIF to contribute to these initiatives, growing this global knowledge base. Balanced against the cost of inaction, patients and countries cannot afford to wait.

  • 1.

    WHO, 2011. The Global Plan to STOP TB 2011–2015.Geneva:World Health Organization, (WHO/HTM/STB/2010.2).

  • 2.

    Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, Tahirli R, Gler MT, Blakemore R, Worodria W, Gray C, Huang L, Caceres T, Mehdiyev R, Raymond L, Whitelaw A, Sagadevan K, Alexander H, Albert H, Cobelens F, Cox H, Alland D, Perkins MD, 2011. Feasibility, diagnostic accuracy, and effectiveness of decentralized use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 377: 14951505.

    • Search Google Scholar
    • Export Citation
  • 3.

    Chang K, Lu W, Wang J, Zhang K, Jia S, Li F, Deng S, Chen M, 2012.Rapid and effective diagnosis of tuberculosis and rifampicin resistance with Xpert MTB/RIF assay: a meta-analysis. J Infect 64: 580588.

    • Search Google Scholar
    • Export Citation
  • 4.

    Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD, 2010. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 363: 10051015.

    • Search Google Scholar
    • Export Citation
  • 5.

    Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, Bekker LG, Wood R, 2011. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med 8: e1001067.

    • Search Google Scholar
    • Export Citation
  • 6.

    Nicol MP, Workman L, Isaacs W, Munro J, Black F, Eley B, Boehme CC, Zemanay W, Zar HJ, 2011. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infect Dis 11: 819824.

    • Search Google Scholar
    • Export Citation
  • 7.

    Rachow A, Clowes P, Saathoff E, Mtafya B, Michael E, Ntinginya EN, Kowour D, Rojas-Ponce G, Kroidl A, Maboko L, Heinrich N, Reither K, Hoelscher M, 2012. Increased and expedited case detection by Xpert MTB/RIF assay in childhood tuberculosis: a prospective cohort study. Clin Infect Dis 54: 13881396.

    • Search Google Scholar
    • Export Citation
  • 8.

    Hillemann D, Rusch-Gerdes S, Boehme C, Richter E, 2011. Rapid molecular detection of extrapulmonary tuberculosis by the automated GeneXpert MTB/RIF system. J Clin Microbiol 49: 12021205.

    • Search Google Scholar
    • Export Citation
  • 9.

    Ligthelm LJ, Nicol MP, Hoek KG, Jacobson R, van Helden PD, Marais BJ, Warren RM, Wright CA, 2011. Xpert MTB/RIF for rapid diagnosis of tuberculous lymphadenitis from fine-needle-aspiration biopsy specimens. J Clin Microbiol 49: 39673970.

    • Search Google Scholar
    • Export Citation
  • 10.

    Tortoli E, Russo C, Piersimoni C, Mazzola E, Dal MP, Pascarella M, Borroni E, Mondo A, Piana F, Scarparo C, Coltella L, Lombardi G, Cirillo DM, 2012. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 2012 Jan 12 [Epub ahead of print].

    • Search Google Scholar
    • Export Citation
  • 11.

    Vadwai V, Boehme C, Nabeta P, Shetty A, Alland D, Rodrigues C, 2011. Xpert MTB/RIF, a new pillar in the diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 49: 25402545.

    • Search Google Scholar
    • Export Citation
  • 12.

    Vassall A, van Kampen S, Sohn H, Michael JS, John KR, den Boon S, Davis JL, Whitelaw A, Nicol MP, Gler MT, Khaliqov A, Zamudio C, Perkins MD, Boehme CC, Cobelens F, 2011. Rapid diagnosis of tuberculosis with the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness analysis. PLoS Med 8: e1001120.

    • Search Google Scholar
    • Export Citation
  • 13.

    Abimbola TO, Marston BJ, Date AA, Blandford JM, Sangrujee N, Wiktor SZ, 1999. Cost-effectiveness of tuberculosis diagnostic strategies to reduce early mortality among persons with advanced HIV infection initiating antiretroviral therapy. J Acquir Immune Defic Syndr 2012: 11.

    • Search Google Scholar
    • Export Citation
  • 14.

    Andrews JR, Lawn SD, Rusu C, Wood R, Noubary F, Bender MA, Horsburgh CR, Losina E, Freedberg KA, Walensky RP, 2012. The cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy in South Africa: a model-based analysis. AIDS 26: 987995.

    • Search Google Scholar
    • Export Citation
  • 15.

    Floyd K, Pantoja A, Glasziou P, 2010. Xpert MTB/RIF in the Global Plan 2011–2015. What Will It Cost? Geneva: World Health Organization Global Consultation on Xpert implementation.

    • Search Google Scholar
    • Export Citation
  • 16.

    WHO, 2011. Policy Statement: Automated Real-Time Nucleic Acid Amplification Technology for Rapid and Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB/RIF System. Geneva: World Health Organization, (WHO/HTM/TB/2011.4).

    • Search Google Scholar
    • Export Citation
  • 17.

    WHO, 2011. Rapid Implementation of the Xpert MTB/RIF Diagnostic Test: Technical and Operational “How-to”; Practical Considerations. Geneva: World Health Organization, (WHO/HTM/TB/2011.2).

    • Search Google Scholar
    • Export Citation
  • 18.

    WHO, 2011. Checklist of Prerequisites to Country Implementation of Xpert MTB/RIF and Key Action Points at Country Level. Geneva: World Health Organization, (WHO/HTM/TB/2011.12).

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Catharina C. Boehme, 16, Av de Budé, Geneva 1202. E-mail: Catharina.Boehme@finddiagnostics.org

Disclosure: Mark D. Perkins, Lakshmi Sundaram, and Catharina C. Boehme are employed by FIND, a non-profit that collaborates with industry partners, including Cepheid, Inc., the manufacturer of Xpert MTB/RIF, for the development, evaluation, and demonstration of new diagnostic tests for poverty-related diseases. This statement is made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

Authors' addresses: Elizabeth A. Talbot, Infectious Disease and International Health, Dartmouth College, Hanover, NH, E-mail: Elizabeth.Talbot@dartmouth.edu. Jean W. Pape, Center for Global Health, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, NY; and Les Centres GHESKIO, Port-au-Prince, Haiti, E-mail: JWPape@gheskio.org. Lakshmi Sundaram, Catharina C. Boehme, and Mark D. Perkins, Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland, E-mails: Lakshmi.Sundaram@finddiagnostics.org, Catharina.Boehme@finddiagnostics.org and Mark.Perkins@finddiagnostics.org.

Save