C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV-infected adults: A phase 3 trial

Henrik Aggerbeck, Morten Ruhwald, Søren T Hoff, Bettine Borregaard, Elizabeth Hellstrom, Mookho Malahleha, Mirna Siebert, Mashra Gani, Vincent Seopela, Andreas Diacon, Madeleine Lourens, Peter Andersen, Keertan Dheda, Henrik Aggerbeck, Morten Ruhwald, Søren T Hoff, Bettine Borregaard, Elizabeth Hellstrom, Mookho Malahleha, Mirna Siebert, Mashra Gani, Vincent Seopela, Andreas Diacon, Madeleine Lourens, Peter Andersen, Keertan Dheda

Abstract

Background: C-Tb, an ESAT-6/CFP-10-based skin test, has similar sensitivity for active TB compared to tuberculin skin test (TST) and QuantiFERON-TB-Gold-In-Tube (QFT). However, data are limited in children and HIV-infected persons.

Methods: Asymptomatic South African contacts <5 years (n = 87; HIV-uninfected), or symptomatic individuals of all ages presenting to clinics with suspected TB (n = 1003; 30% HIV-infected) were recruited from eight South African centres. C-Tb and TST were allocated to either forearm double blinded. Samples for QFT were collected in parallel, and test-positivity rates were compared.

Results: In participants with microbiologically confirmed TB (n = 75; 45% HIV-infected) sensitivity of C-Tb, TST and QFT were similar (72% versus 75% versus 73%; p>0.5). All 3 tests had similar positivity rates in HIV-infected participants with active TB, however, positivity rates were reduced when CD4 counts were <100 cells/μL. In participants where active TB was excluded (n = 920), C-Tb (41%), TST (43%), and QFT (44%) also had similar test-positivity rates. Among asymptomatic contacts aged below five, 32% (28/87) tested positive with C-Tb and 32% (28/87) with TST (concordance 89%). Overall, C-Tb and TST showed a similar safety profile.

Conclusion: C-Tb was safe and showed similar test-positivity rates, compared to TST and QFT, in children and HIV-infected persons with active or latent M. tuberculosis infection. These data inform the utility of C-Tb in clinical practice.

Trial registration: ClinicalTrials.gov NCT01642888. EudraCT 2011-005078-40.

Conflict of interest statement

HA, MR, BBJ and PA are employed at SSI, a governmental non-profit research organization, who holds pending intellectual property rights over C-Tb. All intellectual property rights have been transferred to SSI. The other authors have declared no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Overview of the trial participants.
Fig 1. Overview of the trial participants.
*These were clinic attendees that on follow-up segregated into those with microbiologically confirmed active TB and non-TB participants. Efficacy data are presented as number of test positives/n (%).
Fig 2. Test positivity rate according to…
Fig 2. Test positivity rate according to HIV status and CD4 count.
The data shown excludes participants with unknown HIV status and healthy control group. Error bars indicate 95% CI. Cut-point for TST was 5 mm in HIV-infected and 15 mm in others. C-Tb: N = 921 (625 HIV-uninfected, 296 HIV-infected). TST: N = 923 (627 HIV-uninfected, 296 HIV-infected). QFT: N = 818 (126 indeterminate, 538 HIV-uninfected, 280 HIV-infected). Data specific to the active and non-TB groups are shown in S2–S4 Tables. *HIV-uninfected versus HIV-infected p†CD4 counts ≥100 cells/μL versus counts <100 cells/μL in HIV-infected; p<0.05.
Fig 3. Test positivity rates in different…
Fig 3. Test positivity rates in different subgroups of children comparing TST and C-Tb along an exposure gradient.
Healthy control group (5–11 years, n = 100), asymptomatic PTB contacts

References

    1. Dheda K, Barry CE III, Maartens G. Tuberculosis. Lancet 2015. September 13;387(10024):1211–26. 10.1016/S0140-6736(15)00151-8
    1. Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, et al. LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 2009. May;33(5):956–73. 10.1183/09031936.00120908
    1. World Health Organization. Guidelines on the management of latent tuberculosis infection. 2015. Report No.: WHO/HTM/TB/2015.01.
    1. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974. February;99(2):131–8.
    1. Lawn SD, Bekker LG, Middelkoop K, Myer L, Wood R. Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions. Clin Infect Dis 2006. April 1;42(7):1040–7. 10.1086/501018
    1. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993;17(6):968–75.
    1. Mancuso JD, Mody RM, Olsen CH, Harrison LH, Santosham M, Aronson NE. The Long-term Effect of Bacille Calmette-Guerin Vaccination on Tuberculin Skin Testing: A 55-Year Follow-Up Study. Chest 2017. August;152(2):282–94.
    1. Seddon JA, Paton J, Nademi Z, Keane D, Williams B, Williams A, et al. The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection. Thorax 2016. October;71(10):932–9. 10.1136/thoraxjnl-2015-207687
    1. Denkinger CM, Dheda K, Pai M. Guidelines on interferon-gamma release assays for tuberculosis infection: concordance, discordance or confusion? Clin Microbiol Infect 2011. June;17(6):806–14. 10.1111/j.1469-0691.2011.03555.x
    1. Turkova A, Welch SB, Paton JY, Riordan A, Williams B, Patel SV, et al. Management of paediatric tuberculosis in leading UK centres: unveiling consensus and discrepancies. Int J Tuberc Lung Dis 2014. September;18(9):1047–56. 10.5588/ijtld.14.0094
    1. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 2014. January;27(1):3–20. 10.1128/CMR.00034-13
    1. Aggerbeck H, Giemza R, Joshi P, Tingskov PN, Hoff ST, Boyle J, et al. Randomised Clinical Trial Investigating the Specificity of a Novel Skin Test (C-Tb) for Diagnosis of M. tuberculosis Infection. PLoS ONE 2013;8(5):e64215 10.1371/journal.pone.0064215
    1. Hoff ST, Peter JG, Theron G, Pascoe M, Tingskov PN, Aggerbeck H, et al. Sensitivity of C-Tb: a novel RD-1-specific skin test for the diagnosis of tuberculosis infection. Eur Respir J 2015. December 17;47(3):919–28. 10.1183/13993003.01464-2015
    1. Ruhwald M, Aggerbeck H, Gallardo RV, Hoff ST, Villate JI, Borregaard B, et al. Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon gamma release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med 2017. January 31;5(4):259–68. 10.1016/S2213-2600(16)30436-2
    1. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children - 2nd ed. 2014. Report No.: WHO/HTM/TB/2014.03.
    1. World Health Organization. Recommendation on 36 months isoniazid preventive therapy to adults and adolescents living with HIV in resource-constrained and high TB- and HIV-prevalence settings. 2015 update. 2015. Report No.: WHO/HTM/TB/2015.15.
    1. Mori T, Sakatani M, Yamagishi F, Takashima T, Kawabe Y, Nagao K, et al. Specific detection of tuberculosis infection: an interferon-gamma-based assay using new antigens. Am J Respir Crit Care Med 2004. July 1;170(1):59–64. 10.1164/rccm.200402-179OC
    1. Piccini P, Chiappini E, Tortoli E, de MM, Galli L. Clinical peculiarities of tuberculosis. BMC Infect Dis 2014;14 Suppl 1:S4.
    1. World Health Organization. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva; 2018.
    1. Market assessment of tuberculosis diagnostics in South Africa, 2012–2013. Int J Tuberc Lung Dis 2015. February;19(2):216–22. 10.5588/ijtld.14.0565
    1. Cobelens FG, Egwaga SM, van GT, Muwinge H, Matee MI, Borgdorff MW. Tuberculin skin testing in patients with HIV infection: limited benefit of reduced cutoff values. Clin Infect Dis 2006. September 1;43(5):634–9. 10.1086/506432
    1. Sollai S, Galli L, de MM, Chiappini E. Systematic review and meta-analysis on the utility of Interferon-gamma release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a 2013 update. BMC Infect Dis 2014;14 Suppl 1:S6.
    1. Starke JR. Interferon-gamma release assays for diagnosis of tuberculosis infection and disease in children. Pediatrics 2014. December;134(6):e1763–e1773. 10.1542/peds.2014-2983
    1. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries. Policy Statement. 2011.
    1. Bergstedt W, Tingskov PN, Thierry-Carstensen B, Hoff ST, Aggerbeck H, Thomsen VO, et al. First-in-man open clinical trial of a combined rdESAT-6 and rCFP-10 tuberculosis specific skin test reagent. PLoS ONE 2010;5(6):e11277 10.1371/journal.pone.0011277
    1. Sandgren A, Hollo V, Quinten C, Manissero D. Childhood tuberculosis in the European Union/European Economic Area, 2000 to 2009. Euro Surveill 2011;16(12):pii: 19825
    1. Santin M, Munoz L, Rigau D. Interferon-gamma release assays for the diagnosis of tuberculosis and tuberculosis infection in HIV-infected adults: a systematic review and meta-analysis. PLoS ONE 2012;7(3):e32482 10.1371/journal.pone.0032482
    1. Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev 2011. April;24(2):351–76. 10.1128/CMR.00042-10
    1. Chiappini E, Bonsignori F, Mazzantini R, Sollai S, Venturini E, Mangone G, et al. Interferon-gamma release assay sensitivity in children younger than 5 years is insufficient to replace the use of tuberculin skin test in western countries. Pediatr Infect Dis J 2014. December;33(12):1291–3. 10.1097/INF.0000000000000432
    1. Sali M, Buonsenso D, Goletti D, D'Alfonso P, Zumbo A, Fadda G, et al. Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children. PLoS ONE 2015;10(10):e0138952 10.1371/journal.pone.0138952
    1. Walter SD, Irwig LM. Estimation of test error rates, disease prevalence and relative risk from misclassified data: a review. J Clin Epidemiol 1988;41(9):923–37.
    1. Albert PS, Dodd LE. A cautionary note on the robustness of latent class models for estimating diagnostic error without a gold standard. Biometrics 2004. June;60(2):427–35. 10.1111/j.0006-341X.2004.00187.x
    1. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006. November;10(11):1192–204.
    1. Mancuso JD, Mazurek GH, Tribble D, Olsen C, Aronson NE, Geiter L, et al. Discordance among commercially available diagnostics for latent tuberculosis infection. Am J Respir Crit Care Med 2012. February 15;185(4):427–34. 10.1164/rccm.201107-1244OC

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