A prospective multicentre diagnostic accuracy study for the Truenat tuberculosis assays

Adam Penn-Nicholson, Sivaramakrishnan N Gomathi, Cesar Ugarte-Gil, Abyot Meaza, Evelyn Lavu, Pranav Patel, Bandana Choudhury, Camilla Rodrigues, Sarabjit Chadha, Mubin Kazi, Aurélien Macé, Pamela Nabeta, Catharina Boehme, Raman R Gangakhedkar, Sanjay Sarin, Ephrem Tesfaye, Eduardo Gotuzzo, Philipp du Cros, Srikanth Tripathy, Morten Ruhwald, Manjula Singh, Claudia M Denkinger, Samuel G Schumacher, Truenat Trial Consortium, Members of the Truenat Trial Consortium:, Kelemework A Asmare, Sergio Carmona, Stefano Ongarello, Emmanuel Moreau, L Prabakaran, Aradhana Chauhan, Sunita Singh, Beemakonda Hari, Egambaram Sangeetha, Marikani Sangliraman, Munusamy Balasubramanian, Premkumar Michel, Rajesh K Mondal, Rajendran Priya, Somasundaram Kalaivani, Venkatraman Nagalakshmi, Victor Sharanya, Kori Arti, Patel G K Dharti, Patel C Ghanshyam, Rathod Y Harshdeepsinhji, Ahmed Arifuddin, Das Jyotirmoy, Kurmi Prosanta, Nayan J Das, Tatiana Cáceres, Silvia G Perez, Lesly F Suarez, Luz Villa-Castillo, Katherine Alania, Carlos Mogollon, Nora Mego Correo, Luz Aguirre Yanac, Manuel Quezada Nizama, Jose Velarde Albitez, Cintia Pezo Hernandez, Kirubel Eshetu, Habteyes Hailu Tola, Abebaw Kebede, Zemedu Mohammed, Paul Aia, Jennifer Banamu, Karen Johnson, Rendi Moke, Kari Seki, William Pomat, Tamarah Koleala, Rosemary Simbil, Deborah Williamson, Maria Globan, Nomin-Dora Tenakanai, Dorish Walsh, Chris Sohenalo'e, Stephanie Main Jane Greig, Nova Wilks, Tope Adepoyibi, G Khai Lin Huang, Adam Penn-Nicholson, Sivaramakrishnan N Gomathi, Cesar Ugarte-Gil, Abyot Meaza, Evelyn Lavu, Pranav Patel, Bandana Choudhury, Camilla Rodrigues, Sarabjit Chadha, Mubin Kazi, Aurélien Macé, Pamela Nabeta, Catharina Boehme, Raman R Gangakhedkar, Sanjay Sarin, Ephrem Tesfaye, Eduardo Gotuzzo, Philipp du Cros, Srikanth Tripathy, Morten Ruhwald, Manjula Singh, Claudia M Denkinger, Samuel G Schumacher, Truenat Trial Consortium, Members of the Truenat Trial Consortium:, Kelemework A Asmare, Sergio Carmona, Stefano Ongarello, Emmanuel Moreau, L Prabakaran, Aradhana Chauhan, Sunita Singh, Beemakonda Hari, Egambaram Sangeetha, Marikani Sangliraman, Munusamy Balasubramanian, Premkumar Michel, Rajesh K Mondal, Rajendran Priya, Somasundaram Kalaivani, Venkatraman Nagalakshmi, Victor Sharanya, Kori Arti, Patel G K Dharti, Patel C Ghanshyam, Rathod Y Harshdeepsinhji, Ahmed Arifuddin, Das Jyotirmoy, Kurmi Prosanta, Nayan J Das, Tatiana Cáceres, Silvia G Perez, Lesly F Suarez, Luz Villa-Castillo, Katherine Alania, Carlos Mogollon, Nora Mego Correo, Luz Aguirre Yanac, Manuel Quezada Nizama, Jose Velarde Albitez, Cintia Pezo Hernandez, Kirubel Eshetu, Habteyes Hailu Tola, Abebaw Kebede, Zemedu Mohammed, Paul Aia, Jennifer Banamu, Karen Johnson, Rendi Moke, Kari Seki, William Pomat, Tamarah Koleala, Rosemary Simbil, Deborah Williamson, Maria Globan, Nomin-Dora Tenakanai, Dorish Walsh, Chris Sohenalo'e, Stephanie Main Jane Greig, Nova Wilks, Tope Adepoyibi, G Khai Lin Huang

Abstract

Background: Bringing reliable and accurate tuberculosis (TB) diagnosis closer to patients is a key priority for global TB control. Molbio Diagnostics have developed the Truenat point-of-care molecular assays for detection of TB and rifampicin (RIF) resistance.

Methods: We conducted a prospective multicentre diagnostic accuracy study at 19 primary healthcare centres and seven reference laboratories in Peru, India, Ethiopia and Papua New Guinea to estimate the diagnostic accuracy of the point-of-care Truenat MTB, MTB Plus and MTB-RIF Dx assays for pulmonary TB using culture and phenotypic drug susceptibility testing as the reference standard, compared with Xpert MTB/RIF or Ultra.

Results: Of 1807 enrolled participants with TB signs/symptoms, 24% were culture-positive for Mycobacterium tuberculosis, of which 15% were RIF-resistant. In microscopy centres, the pooled sensitivity of Truenat MTB and Truenat MTB Plus was 73% (95% CI 67-78%) and 80% (95% CI 75-84%), respectively. Among smear-negative specimens, sensitivities were 36% (95% CI 27-47%) and 47% (95% CI 37-58%), respectively. Sensitivity of Truenat MTB-RIF was 84% (95% CI 62-95%). Truenat assays showed high specificity. Head-to-head comparison in the central reference laboratories suggested that the Truenat assays have similar performance to Xpert MTB/RIF.

Conclusion: We found the performance of Molbio's Truenat MTB, MTB Plus and MTB-RIF Dx assays to be comparable to that of the Xpert MTB/RIF assay. Performing the Truenat tests in primary healthcare centres with very limited infrastructure was feasible. These data supported the development of a World Health Organization policy recommendation of the Molbio assays.

Trial registration: ClinicalTrials.gov NCT03712709.

Conflict of interest statement

Conflict of interest: A. Penn-Nicholson reports grants from Bill and Melinda Gates Foundation, during the conduct of the study; reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: S.N. Gomathi reports grants from Indian Council of Medical Research - India TB Research Consortium, during the conduct of the study. Conflict of interest: C. Ugarte-Gil has nothing to disclose. Conflict of interest: A. Meaza has nothing to disclose. Conflict of interest: E. Lavu has nothing to disclose. Conflict of interest: P. Patel reports grants from the Indian Council of Medical Research through the National Institute for Research in Tuberculosis Chennai, during the conduct of the study. Conflict of interest: B. Choudhury reports grants from Indian Council of Medical Research – India TB Research Consortium through the National Institute for Research in Tuberculosis Chennai, during the conduct of the study. Conflict of interest: C. Rodrigues has nothing to disclose. Conflict of interest: S. Chadha reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: M. Kazi has nothing to disclose. Conflict of interest: A. Macé reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: P. Nabeta reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: C. Boehme reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: R.R. Gangakhedkar has nothing to disclose. Conflict of interest: S. Sarin reports grants from Bill and Melinda Gates Foundation, during the conduct of the study; and reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: E. Tesfaye has nothing to disclose. Conflict of interest: E. Gotuzzo has nothing to disclose. Conflict of interest: P. du Cros reports grants from FIND and the Australian Dept of Foreign Affairs and Trade during the conduct of the study; other (consultancy) from TB Alliance, outside the submitted work; and is a member of the steering committee for the MSF Sponsored TB PRACTECAL Clinical Trial for novel regimens for MDR-TB treatment. Conflict of interest: S. Tripathy reports grants from ICMR-India TB Research Consortium (ICMR-ITRC), during the conduct of the study. Conflict of interest: M. Ruhwald reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Conflict of interest: M. Singh has nothing to disclose. Conflict of interest: C.M. Denkinger reports grants from the Bill and Melinda Gates Foundation, during the conduct of the study; and reports working for FIND until April 2019. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access. Since leaving FIND, C.M. Denkinger continues to hold a collaborative agreement with FIND. Conflict of interest: S.G. Schumacher reports working for FIND. FIND conducts multiple clinical research projects to evaluate multiple new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisation's external scientific advisory council. FIND does not attribute any financial value to such access.

Copyright ©The authors 2021.

Figures

FIGURE 1
FIGURE 1
Specimen flow at enrolment. NALC–NaOH: N-acetyl-l-cysteine–sodium hydroxide; MGIT: Mycobacterial Growth Indicator Tube; LJ: Löwenstein–Jensen; MTB: Mycobacterium tuberculosis; DST: drug susceptibility testing; RIF: rifampicin; NTM: nontuberculous mycobacteria. #: sputum 4 was not collected at PD Hinduja Hospital or in Papua New Guinea. All sites performed Xpert MTB/RIF except Peru, which performed Xpert MTB/RIF Ultra. As Truenat assays are not indicated for decontaminated sputum sediments and do not contribute to our study objective, test results are not presented within this article, but are available upon request.
FIGURE 2
FIGURE 2
STARD (Standards for Reporting of Diagnostic Accuracy Studies) diagram showing the number of participants enrolled, excluded and with data analysed. TB: tuberculosis. Truenat nondeterminate results are excluded from the accuracy analyses but are reported separately.
FIGURE 3
FIGURE 3
Performance of the Truenat, Xpert MTB/RIF and Ultra assays conducted at the reference laboratories. TB: tuberculosis; RIF: rifampicin. a) Performance of Truenat and Xpert MTB/RIF for TB detection (participants from Case Detection Group). b) Performance of Truenat and Xpert MTB/RIF for RIF resistance detection (all participants). c) Performance of Truenat and Ultra for TB detection (participants from Case Detection Group). d) Performance of Truenat and Ultra for RIF resistance detection (all participants).

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