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

Abstract

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/mm 3 . 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.

Phenotype Definition for “Resisters” to Mycobacterium tuberculosis Infection in the Literature—A Review and Recommendations

“…included HCW who worked for more than 3 years in a TB hospital where mask wearing was not mandated ( 34 ). In comparison, the ResisTB, Sequella and the Worcester based studies recruited participants from known high TB incidence areas ( 28 , 29 , 58 ). In addition, the ResisTB study used age as a proxy for exposure frequency and duration with older age (ages 35–60 years) representing a group who would have prolonged exposure in a high TB incidence environment ( 29 ).…”

“…In comparison, the ResisTB, Sequella and the Worcester based studies recruited participants from known high TB incidence areas ( 28 , 29 , 58 ). In addition, the ResisTB study used age as a proxy for exposure frequency and duration with older age (ages 35–60 years) representing a group who would have prolonged exposure in a high TB incidence environment ( 29 ). The results obtained from these community based studies are specific to the community described and one should be wary of making generalized conclusions.…”

“…The ResisTB study is a community based case-control study conducted in Cape Town, South Africa ( 29 ). Participants were recruited from ART clubs at HIV clinics in Cape Town.…”

“…During this period, these individuals would have been extremely susceptible to infection and disease. By the time of enrollment all participants were immune reconstituted on ART for at least one year with the most recent CD4+ count > 200 cells/mm 3 ( 29 ).…”

“…In parallel, a subset of control participants with an initial positive IGRA test were re-contacted for a second IGRA after an average of 292 ± 70 days. Those participants who tested IGRA positive in two consecutive tests (IGRA double+) and displayed a TST > 5 mm are defined as HIV-1-infected IGRA positive tuberculin positive (HIT, n=35) ( 29 ).…”