Effect of isoniazid on antigen-specific interferon-γ secretion in latent tuberculosis

Martha Torres, Lourdes García-García, Pablo Cruz-Hervert, Heinner Guio, Claudia Carranza, Leticia Ferreyra-Reyes, Sergio Canizales, Susana Molina, Elizabeth Ferreira-Guerrero, Norma Téllez, Rogelio Montero-Campos, Guadalupe Delgado-Sánchez, Norma Mongua-Rodriguez, Jose Sifuentes-Osornio, Alfredo Ponce-de Leon, Eduardo Sada, Douglas B Young, Robert J Wilkinson, Martha Torres, Lourdes García-García, Pablo Cruz-Hervert, Heinner Guio, Claudia Carranza, Leticia Ferreyra-Reyes, Sergio Canizales, Susana Molina, Elizabeth Ferreira-Guerrero, Norma Téllez, Rogelio Montero-Campos, Guadalupe Delgado-Sánchez, Norma Mongua-Rodriguez, Jose Sifuentes-Osornio, Alfredo Ponce-de Leon, Eduardo Sada, Douglas B Young, Robert J Wilkinson

Abstract

Treatment of persons with latent tuberculosis (TB) infection at greatest risk of reactivation is an important component of TB control and elimination strategies. Biomarkers evaluating the effectiveness of treatment of latent TB infection have not yet been identified. This information would enhance control efforts and assist the evaluation of new treatment regimes. We designed a two-group, two-arm, randomised clinical study of tuberculin skin test-positive participants: 26 with documented contact with TB patients and 34 with non-documented contact. Participants in each group were randomly assigned to the immediate- or deferred-isoniazid treatment arms. Assays of in vitro interferon (IFN)-γ secretion in response to recombinant Rv1737 and overlapping synthetic peptide pools from various groups of immunodominant proteins were performed. During isoniazid therapy, a significant increase from baseline in the proportion of IFN-γ responders to the 10-kDa culture filtrate protein, Rv2031, Rv0849, Rv1986, Rv2659c, Rv2693c and the recombinant Rv1737 protein was observed (p⩽0.05). The peptide pool of Rv0849 and Rv1737 recombinant proteins induced the highest percentage of IFN-γ responders after isoniazid therapy. The in vitro IFN-γ responses to these proteins might represent useful markers to evaluate changes associated with treatment of latent TB infection.

Trial registration: ClinicalTrials.gov NCT00293228.

Conflict of interest statement

Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com

Copyright ©ERS 2015.

Figures

FIGURE 1
FIGURE 1
Flow diagram of study population. a) Documented contacts. b) Non-documented contacts.
FIGURE 2
FIGURE 2
a) Interferon (IFN)-γ response to the pooled peptides assessed, comparing subjects with and without household contact with a patient with active tuberculosis (TB). b) Percentage of IFN-γ responders (>100 pg·mL−1) comparing subjects with and without household contact with a patient with active TB. c) IFN-γ response to tested antigens among contacts who were assigned to deferred treatment, comparing the response 3 months before initiating treatment with that on treatment initiation. d) Percentage of IFN-γ responders to the assessed antigens among subjects who were assigned to deferred treatment, comparing the response 3 months before initiating treatment with that on treatment initiation. No significant differences in the amount of IFN-γ production or the proportion of individuals responding to peptide pools was observed between documented and non-documented contacts. Among individuals whose isoniazid treatment was deferred, with the exception of CFP-10-2, there was no difference in IFN-γ secretion or the proportion of participants responding to peptide pools at the two different time-points. Tx: treatment; ESAT-6: 6-kDa early secretory antigenic target; CFP-10: 10-kDa culture filtrate protein; PPD: purified protein derivative.
FIGURE 3
FIGURE 3
Percentage of interferon-γ responders during and after isoniazid treatment. a) Percentage of responders to ESAT-6-1, ESAT-6-2, ESAT-6-1 or ESAT-6-2 (labelled as ESAT-6), CFP-10-1, CFP-10-2, CFP10-1 or CFP10-2 (labelled as CFP-10), and combined ESAT-6 or CFP-10 remained similar during and after treatment. b) Responses to Rv0081, Rv0569 and Rv2031 were lower than responses to antigens shown in panel a. The percentage of responders remained stable or slightly increased during or after treatment. c) Responses to Rv0288c and Rv3019c decreased during or after treatment. d) Responses to antigens Rv0826, Rv0849, Rv1986-1, Rv1986-2, Rv2659c and Rv2693c tended to increase during and after treatment. e) Response to Rv1737, purified protein derivative (PPD) and phytohaemagglutinin (PHA). ESAT-6: 6-kDa early secretory antigenic target; CFP-10: 10-kDa culture filtrate protein.

References

    1. Dye C, Glaziou P, Floyd K, et al. . Prospects for tuberculosis elimination. Ann Rev Pub Health 2013; 34: 271–286.
    1. Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 2009; 7: 845–855.
    1. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000; 49: 1–51.
    1. Munoz L, Santin M. Interferon-γ release assays versus tuberculin skin test for targeting people for tuberculosis preventive treatment: an evidence-based review. J Infect 2013; 66: 381–387.
    1. Brock I, Munk ME, Kok-Jensen A, et al. . Performance of whole blood IFN-γ test for tuberculosis diagnosis based on PPD or the specific antigens ESAT-6 and CFP-10. Int J Tuberc Lung Dis 2001; 5: 462–467.
    1. Adetifa IM, Ota MO, Jeffries DJ, et al. . Interferon-γ ELISPOT as a biomarker of treatment efficacy in latent tuberculosis infection: a clinical trial. Am J Respir Crit Care Med 2013; 187: 439–445.
    1. Johnson JL, Geldenhuys H, Thiel BA, et al. . Effect of isoniazid therapy for latent TB infection on QuantiFERON-TB gold in-tube responses in adults with positive tuberculin skin test results in a high TB incidence area: a controlled study. Chest 2014; 145: 612–617.
    1. Chee CB, KhinMar KW, Gan SH, et al. . Latent tuberculosis infection treatment and T-cell responses to Mycobacterium tuberculosis-specific antigens. Am J Respir Crit Care Med 2007; 175: 282–287.
    1. Wilkinson KA, Kon OM, Newton SM, et al. . Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens. J Infect Dis 2006; 193: 354–359.
    1. Pai M, Joshi R, Dogra S, et al. . Persistently elevated T cell interferon-γ responses after treatment for latent tuberculosis infection among health care workers in India: a preliminary report. J Occup Med Toxicol 2006; 1: 7.
    1. Ewer K, Millington KA, Deeks JJ, et al. . Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis. Am J Respir Crit Care Med 2006; 174: 831–839.
    1. Goletti D, Parracino MP, Butera O, et al. . Isoniazid prophylaxis differently modulates T-cell responses to RD1-epitopes in contacts recently exposed to Mycobacterium tuberculosis: a pilot study. Respir Res 2007; 8: 5.
    1. Kabeer BS, Raja A, Raman B, et al. . IP-10 response to RD1 antigens might be a useful biomarker for monitoring tuberculosis therapy. BMC infectious diseases 2011; 11: 135.
    1. Latorre I, Altet N, de Souza-Galvao M, et al. . Specific Mycobacterium tuberculosis T cell responses to RD1-selected peptides for the monitoring of anti-tuberculosis therapy. Scand J Infect Dis 2012; 44: 161–167.
    1. Rustad TR, Harrell MI, Liao R, et al. . The enduring hypoxic response of Mycobacterium tuberculosis. PLoS One 2008; 3: e1502.
    1. Sherman DR, Voskuil M, Schnappinger D, et al. . Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin. Proc Natl Acad Sci USA 2001; 98: 7534–7539.
    1. Goletti D, Butera O, Vanini V, et al. . Response to Rv2628 latency antigen associates with cured tuberculosis and remote infection. Eur Respir J 2010; 36: 135–142.
    1. Chiacchio T, Petruccioli E, Vanini V, et al. . Higher frequency of T-cell response to M. tuberculosis latency antigen Rv2628 at the site of active tuberculosis disease than in peripheral blood. PLoS One 2011; 6: e27539.
    1. Gideon HP, Wilkinson KA, Rustad TR, et al. . Bioinformatic and empirical analysis of novel hypoxia-inducible targets of the human antituberculosis T cell response. J Immunol 2012; 189: 5867–5876.
    1. Bøyum A. Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol 1976; 5: Suppl. 9–15.
    1. Herrera MT, Torres M, Nevels D, et al. . Compartmentalised bronchoalveolar IFN-γ and IL-12 response in human pulmonary tuberculosis. Tuberculosis (Edinb) 2009; 89: 38–47.
    1. Higuchi K, Harada N, Mori T. Interferon-γ responses after isoniazid chemotherapy for latent tuberculosis. Respirology 2008; 13: 468–472.
    1. Bastos ML, Menzies D, Belo MT, et al. . Changes in QuantiFERON®-TB Gold In-Tube results during treatment for tuberculous infection. Int J Tuberc Lung Dis 2013; 17: 909–916.
    1. Pollock NR, Kashino SS, Napolitano DR, et al. . Evaluation of the effect of treatment of latent tuberculosis infection on QuantiFERON-TB gold assay results. Infect Control Hosp Epidemiol 2009; 30: 392–395.
    1. Lee SH, Lew WJ, Kim HJ, et al. . Serial interferon-gamma release assays after rifampicin prophylaxis in a tuberculosis outbreak. Respir Med 2010; 104: 448–453.
    1. Lalvani A, Nagvenkar P, Udwadia Z, et al. . Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians. J Infect Dis 2001; 183: 469–477.
    1. Gideon HP, Wilkinson KA, Rustad TR, et al. . Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines. PLoS pathogens 2010; 6: e1001237.
    1. Black GF, Thiel BA, Ota MO, et al. . Immunogenicity of novel DosR regulon-encoded candidate antigens of Mycobacterium tuberculosis in three high-burden populations in Africa. Clin Vaccine Immunol 2009; 16: 1203–1212.
    1. Honaker RW, Stewart A, Schittone S, et al. . Mycobacterium bovis BCG vaccine strains lack narK2 and narX induction and exhibit altered phenotypes during dormancy. Infect Immun 2008; 76: 2587–2593.
    1. Rangaka MX, Wilkinson KA, Glynn JR, et al. . Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 45–55.
    1. Menzies R, Vissandjee B. Effect of bacille Calmette-Guérin vaccination on tuberculin reactivity. Am Rev Respir Dis 1992; 145: 621–625.
    1. O’Shea MK, Fletcher TE, Beeching NJ, et al. . Tuberculin skin testing and treatment modulates interferon-gamma release assay results for latent tuberculosis in migrants. PLoS One 2014; 9: e97366.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit