An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa

EBioMedicine. 2020 Nov;61:103053. doi: 10.1016/j.ebiom.2020.103053. Epub 2020 Oct 7.


Background: Mycobacterium tuberculosis (Mtb) infection is inferred from positive results of T-cell immune conversion assays measuring Mtb-specific interferon gamma production or tuberculin skin test (TST) reactivity. Certain exposed individuals do not display T-cell immune conversion in these assays and do not develop TB. Here we report a hitherto unknown form of this phenotype: HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN).

Methods: A community-based case-control design was used to systematically screen and identify adults living with HIV (HIV+), aged 35-60 years, who met stringent study criteria, and then longitudinally followed up for repeat IGRA and TST testing. Participants had no history of TB despite living in TB hyper-endemic environments in Cape Town, South Africa with a provincial incidence of 681/100,000. Mtb-specific antibodies were measured using ELISA and Luminex.

Findings: We identified 48/286 (17%) individuals who tested persistently negative for Mtb-specific T-cell immunoreactivity (three negative Quantiferon results and one TST = 0mm) over 206±154 days on average. Of these, 97·2% had documented CD4 counts<200 prior to antiretroviral therapy (ART). They had received ART for 7·0±3·0 years with a latest CD4 count of 505·8±191·4 cells/mm3. All HITTIN sent for further antibody testing (n=38) displayed Mtb-specific antibody titres.

Interpretation: Immune reconstituted HIV+ persons can be persistently non-immunoreactive to TST and interferon-γ T-cell responses to Mtb, yet develop species-specific antibody responses. Exposure is evidenced by Mtb-specific antibody titres. Our identification of HIV+ individuals displaying a persisting lack of response to TST and IGRA T-cell immune conversion paves the way for future studies to investigate this phenotype in the context of HIV-infection that so far have received only scant attention.

Keywords: Antibodies; Early clearance; Interferon gamma release assay; Resister; Tuberculin skin test.

MeSH terms

  • Adult
  • Antibodies, Bacterial / immunology*
  • Coinfection / epidemiology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • HIV Infections / epidemiology*
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma Release Tests
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis / immunology*
  • Public Health Surveillance
  • South Africa / epidemiology
  • Tuberculin Test / methods
  • Tuberculosis / diagnosis
  • Tuberculosis / epidemiology*
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology


  • Antibodies, Bacterial
  • Immunoglobulin G
  • Interferon-gamma