Two research studies in this week's PLoS Medicine suggest that a new automated DNA test for tuberculosis (Xpert MTB/RIF), which can detect TB within 2 hours and has been endorsed by the World Health Organization, can significantly increase TB detection rate compared to other tests, particularly in HIV positive patients who have a high risk of being infected with TB, including multidrug resistant TB. An accompanying Essay and Perspective highlight the economic challenges and implications of such diagnostic tests.
In the first study, led by Stephen Lawn from the Desmond Tutu HIV Centre at the University of Cape Town in South Africa, the authors collected sputum from HIV-infected adults with no current TB diagnosis who were enrolling at an HIV treatment clinic in a South African township. The authors then compared the diagnostic accuracy of Xpert MTB/RIF with several other tests, including liquid culture (the reference test).
Nearly a fifth of the patients had culture-positive TB and Xpert MTB/RIF identified three-quarters of these patients. Furthermore, the new test had a low false-positive rate and was able to detect all cases of smear-positive, culture-positive TB but only 43.4% of smear-negative, culture-positive cases from a single sputum sample. The new test also correctly identified rifampicin resistance, a marker for multidrug resistant TB, in all four patients who had this form of TB, but incorrectly identified resistance in three patients with drug-sensitive TB.
The authors say: "In this population of individuals at high risk of TB, intensive screening using the Xpert MTB/RIF assay increased case detection by 45% compared with smear microscopy, strongly supporting replacement of microscopy for this indication. " They continue: "However, despite the ability of the assay to rapidly detect rifampicin-resistant disease, the specificity for drug resistant TB was sub-optimal."
In a smaller study led by Lesley Scott from the University of the Witwatersrand in Johannesburg, South Africa, the authors compared the performance of Xpert MTB/RIF on a single sputum sample with that of smear microscopy, liquid culture and two other nucleic acid amplification tests (MTBDRplus and LightCycler MTB) in 311 adults suspected to have TB in Johannesburg, South Africa, a region where many adults are HIV-positive. Although these findings are likely to be affected by the study's small size, the results suggest that Xpert MTB/RIF may provide a more accurate rapid diagnosis of TB than smear microscopy and other currently available tests in regions where HIV and TB are endemic.
The authors conclude: "The Xpert MTB/RIF test has superior performance for rapid diagnosis of Mycobacterium tuberculosis over existing … smear microscopy and other molecular methodologies in an HIV- and TB-endemic region. Its place in the clinical diagnostic algorithm in national health programs needs exploration."
In an Essay in the same issue, David Dowdy from the University of California in San Francisco, and colleagues discuss the challenges of economic analysis of diagnostic tests for tuberculosis, and argue that standard cost-effectiveness analyses may give misleading results when blindly applied to the scale-up of TB diagnostics.
To be useful to both policy-makers and decision-makers, the authors suggest that such analyses should establish society's valuation of false-positive tests relative to false-negative tests; evaluate the consequences of false-negative and false-positive diagnoses when new diagnostics are implemented in field settings; and set local cost-effectiveness thresholds for disease-specific interventions.
Furthermore, a Perspective by Carlton Evans from the Universidad Peruana Cayetano Heredia in Lima, Peru (not involved in any of the research studies here) stresses that although the new MTB/RIF-test has the capacity to be a "game-changer" in TB diagnosis, the new research in this week's PLoS Medicine raises important points of concern as the field progresses to implementation of this innovative technology. He emphasizes the shameful context that almost 2 million people die each year from TB, and very few of them would have been saved by any diagnostic test.
Evans says; "Specifically, these deaths occur in mainly HIV-negative people, almost all of whom die from drug-susceptible TB, principally because of the inadequacy of basic, inexpensive health care provision for this curable infectious disease."
Article by Lawn and colleagues
Funding: SDL, KK, and MN were funded by the Wellcome Trust, London, UK and MN also received funding from EDCTP. RW was funded in part by the US National Institutes of Health (NIH) through a CIPRA grant 1U19AI53217-01 and RO1 grant (A1058736-01A1). The authors are grateful to the Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland for providing access to the Xpert MTB/RIF assay cartridges with preferential pricing. The funding sources played no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing Interests: The Academic Editor, Madhukar Pai, declares that he consults for the Bill & Melinda Gates Foundation (BMGF). The BMGF supported the Foundation for Innovative New Diagnostics (FIND), which was involved in the development of the Xpert MTB/RIF assay. He also co-chairs the Stop TB Partnership's New Diagnostics Working Group that was involved in the WHO endorsement of the Xpert assay. The authors declare that the University of Cape Town (Mark Nicol as Principal Investigator) has received research funding from FIND to conduct research around the evaluation and impact of GeneXpert MTB/RIF technology. All other authors have declared that no competing interests exist.
Citation: Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, et al. (2011) Screening for HIV-Associated Tuberculosis and Rifampicin Resistance before Antiretroviral Therapy Using the Xpert MTB/RIF Assay: A Prospective Study. PLoS Med 8(7): e1001067. doi:10.1371/journal.pmed.1001067
CONTACT:
Stephen Lawn
Desmond Tutu HIV Centre
Institute of Infectious Disease and Molecular Medicine
Faculty of Health Sciences
Anzio Road
Observatory
Cape Town, Western Cape 7925
South Africa
+27 21 650 6970
stevelawn@yahoo.co.uk
Article by Scott and colleagues
Funding: This publication was made possible by the generous support of the American people through the US Agency for International Development. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the US government. The study was supported by the South Africa Tuberculosis and AIDS Training (SATBAT) program (National Institute of Health/Fogarty International Center) (1U2RTW007370/3) and ACTG, CTU (grant
number 5UM01 A1069463-05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The Academic Editor, Madhukar Pai, declares that he consults for the Bill & Melinda Gates Foundation (BMGF). The BMGF supported the Foundation for Innovative New Diagnostics (FIND), which was involved in the development of the Xpert MTB/RIF assay. He also co-chairs the Stop TB Partnership's New Diagnostics Working Group that was involved in the WHO endorsement of the Xpert assay. The authors have declared that no competing interests exist.
Citation: Scott LE, McCarthy K, Gous N, Nduna M, Van Rie A, et al. (2011) Comparison of Xpert MTB/RIF with Other Nucleic Acid Technologies for Diagnosing Pulmonary Tuberculosis in a High HIV Prevalence Setting: A Prospective Study. PLoS Med 8(7): e1001061. doi:10.1371/journal.pmed.1001061
CONTACT:
Lesley Scott
Senior Medical Scientist
Molecular Medicine and Haematology
University of the Witwatersrand
7 York Road Parktown
Johannesburg, Gauteng 2193
South Africa
lesley.scott@nhls.ac.za
Essay by Dowdy and colleagues
Funding: This work was developed without specific dedicated funding. AC is supported by the National Institutes of Health (K23 HL094141) and MP is supported by the Canadian Institutes of Health Research (CIHR). The funders had no role in the decision to publish or preparation of the manuscript.
Competing Interests: MP is co-chair of the Stop TB Partnership's New Diagnostics Working Group and a consultant for the Bill & Melinda Gates Foundation, which had no involvement in this manuscript. MP also serves as an editorial board member on PLoS Medicine. KRS serves as Coordinator for the Evidence Synthesis and Policy Subgroup of the Stop TB Partnership's New Diagnostics Working Group. All other authors have declared that no competing interests exist.
Citation: Dowdy DW, Cattamanchi A, Steingart KR, Pai M (2011) Is Scale-Up Worth It? Challenges in Economic Analysis of Diagnostic Tests for Tuberculosis. PLoS Med 8(7): e1001063. doi:10.1371/journal.pmed.1001063
CONTACT:
David Dowdy
Department of Medicine
University of California, San Francisco
505 Parnassus Ave., M-987
San Francisco
CA 94143
United States of America
+1 845-367-3164
ddowdy@jhsph.edu
Perspective by Carlton Evans
Funding: No specific funding was received to write this article.
Competing Interests: The author declares that he has no competing interests in relation to this article. He has worked as a consultant for WHO on TB social determinants and for Médecins Sans Frontières on TB infection control and diagnostics, and has received TB-related grants from the Sir Halley Stewart Trust (TB infection control and diagnostics), Imperial Healthcare charities/IFHAD (TB control), the Wellcome Trust (TB susceptibility, infection control, and diagnostics), and FIND (partial support for developing a field TB culture test). None of these funders played any role in the preparation of this article.
Citation: Evans CA (2011) GeneXpert—A Game-Changer for Tuberculosis Control? PLoS Med 8(7): e1001064. doi:10.1371/journal.pmed.1001064
CONTACT:
Carlton Evans
Universidad Peruana Cayetano Heredia
IFHAD: Innovation For Health And Development
Lab. de Investigación y Desarrollo #218
Av Honorio Delgado#430, Urb
Ingeniería San Martin de P
Lima,
Peru
carlton.evans@ifhad.org
Journal
PLOS Medicine