Effect of isoniazid preventive therapy on immune responses to mycobacterium tuberculosis: an open label randomised, controlled, exploratory study.
BACKGROUND
With the renewed emphasis to implement isoniazid preventive therapy (IPT) in Sub-Saharan Africa, we investigated the effect of IPT on immunological profiles among household contacts with latent tuberculosis.


METHODS
Household contacts of confirmed tuberculosis patients were tested for latent tuberculosis using the QuantiFERON®-TB Gold In-Tube (QFN) assay and tuberculin skin test (TST). HIV negative contacts aged above 5 years, positive to both QFN and TST, were randomly assigned to IPT and monthly visits or monthly visits only. QFN culture supernatants from enrolment and six months' follow-up were analysed for M.tb-specific Th1, Th2, Th17, and regulatory cytokines by Luminex assay, and for M.tb-specific IgG antibody concentrations by ELISA. Effects of IPT were assessed as the net cytokine and antibody production at the end of six months.


RESULTS
Sixteen percent of contacts investigated (47/291) were randomised to IPT (n = 24) or no IPT (n = 23). After adjusting for baseline cytokine or antibody responses, and for presence of a BCG scar, IPT (compared to no IPT) resulted in a relative decline in M.tb-specific production of IFN gamma (adjusted mean difference at the end of six months (bootstrap 95% confidence interval (CI), p-value) -1488.6 pg/ml ((-2682.5, -294.8), p = 0.01), and IL- 2 (-213.1 pg/ml (-419.2, -7.0), p = 0.04). A similar decline was found in anti-CFP-10 antibody levels (adjusted geometric mean ratio (bootstrap 95% CI), p-value) 0.58 ((0.35, 0.98), p = 0.04). We found no effect on M.tb-specific Th2 or regulatory or Th17 cytokine responses, or on antibody concentrations to PPD and ESAT-6.


CONCLUSIONS
IPT led to a decrease in Th1 cytokine production, and also in the anti CFP-10 antibody concentration. This could be secondary to a reduction in mycobacterial burden or as a possible direct effect of isoniazid induced T cell apoptosis, and may have implications for protective immunity following IPT in tuberculosis-endemic countries.


BACKGROUND
ISRCTN registry, ISRCTN15705625. Registered on 30(th) September 2015.
Department of Internal Medicine, College of Health Sciences, Makerere University, P.O Box 7072, Kampala, Uganda. andiaodanga@yahoo.com.
Irene Andia
IA
Biraro
Department of Internal Medicine, College of Health Sciences, Makerere University, P.O Box 7072, Kampala, Uganda. m.c.egesa@gmail.com.
Moses
M
Egesa
Department of Internal Medicine, College of Health Sciences, Makerere University, P.O Box 7072, Kampala, Uganda. calebgwapa@gmail.com.
Simon
S
Kimuda
Department of Immunology and Infection, London School of Hygiene &Tropical Medicine, London, UK. steven.smith@Ishtm.ac.uk.
Steven G
SG
Smith
Department of Immunology and Infection, London School of Hygiene &Tropical Medicine, London, UK. Frederic.toulza@Ishtm.ac.uk.
Frederic
F
Toulza
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda. jonathan.levin@mrcuganda.org.|School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. jonathan.levin@mrcuganda.org.
Jonathan
J
Levin
Department of Internal Medicine, College of Health Sciences, Makerere University, P.O Box 7072, Kampala, Uganda. mlj10@case.edu.
Moses
M
Joloba
Department of Internal Medicine, College of Health Sciences, Makerere University, P.O Box 7072, Kampala, Uganda. akatamba@yahoo.com.
Achilles
A
Katamba
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda. Stephen.cose@mrcuganda.org.|Department of Clinical Research, London School of Hygiene &Tropical Medicine, London, UK. Stephen.cose@mrcuganda.org.
Stephen
S
Cose
Department of Immunology and Infection, London School of Hygiene &Tropical Medicine, London, UK. hazel.dockrell@Ishtm.ac.uk.
Hazel M
HM
Dockrell
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, Entebbe, Uganda. Alison.elliott@mrcuganda.org.|Department of Clinical Research, London School of Hygiene &Tropical Medicine, London, UK. Alison.elliott@mrcuganda.org.
Alison M
AM
Elliott
D000293:Adolescent; D000328:Adult; D000917:Antibody Formation; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007538:Isoniazid / Q000627:therapeutic use*; D055985:Latent Tuberculosis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
D000995:Antitubercular Agents; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; D016207:Cytokines; D007371:Interferon-gamma; D007538:Isoniazid