HIV patients with latent tuberculosis living in a low-endemic country do not develop active disease during a 2 year follow-up; a Norwegian prospective multicenter study

Abstract

BackgroundInterferon-γ release assays (IGRA) serve as immunodiagnostics of tuberculosis (TB) infection to identify individuals with latent TB infection (LTBI) eligible for preventive anti-TB therapy. In this longitudinal study of HIV-infected LTBI patients we have observed for possible progression to active TB as well as evaluated repeated IGRA testing in a TB low-endemic setting.MethodsQuantiFERON TB-Gold In-tube® assay (QFT), TB-SPOT.TB® (TSPOT) and tuberculin skin test (TST) were performed on 298 HIV-patients recruited from seven out-patient clinics in Norway. Patients with active TB, LTBI and negative IGRA were followed with repeat QFTs and clinical evaluation over a period of 24 months.ResultsSeven HIV-patients (median CD4 count 270; IQR 50–340) were diagnosed with active TB at inclusion, all IGRA positive. Sixty-four (21%) HIV-patients (median CD4 count 471; IQR 342–638) were diagnosed with LTBI and of these 39 (61%) received TB preventive treatment. Neither treated nor untreated HIV-infected LTBI patients developed active TB during the 24 months. At baseline, the median interferon-γ (INF-γ) level measured by QFT was 3.48 IU/ml (IQR 0.94 – 8.91 IU/ml) for treated LTBI compared to 1.13 IU/ml (IQR 0.47 – 4.25 IU/ml) for untreated LTBI patients (p = 0.029). The QFT reversion rates were 75% for active TB, 23% for treated LTBI and 44% for untreated LTBI, whereas the conversion rate for the non-TB group was 7% despite no new TB exposure. There was no significant difference in the trend of INF-γ levels over time between treated and untreated LTBI patients.ConclusionThe prevalence of LTBI is high among HIV-patients, but the risk of developing active TB seems to be low in patients with high CD4 counts in this TB low-endemic setting. In several patients, especially with baseline IFN-γ levels close to cut-offs, the QFT tests reverted to negative independent of preventive anti-TB treatment indicating possibly false positive tests. This highlights the importance of defining reliable cut-offs for immunodiagnostic tests and deferring preventive therapy in selected patients. Randomized studies with longer follow-up time are needed to identify HIV-patients that would benefit from LTBI treatment in a TB low-endemic setting.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0667-0) contains supplementary material, which is available to authorized users.

QuantiFERON-TB Gold In-Tube Test for Tuberculosis Prevention in HIV-Infected Patients

“…None of the QFT-IT positive patients who completed at least 6 months of IPT developed active TB during the 3-year follow-up period. The effectiveness of QFT-IT-guided LTBI treatment in this study was consistent with the results of a previous Norwegian study (15); however, the risk of TB exposure during the follow-up period in our cohort might be greater because of the higher prevalence of TB in the Thai population. The use of both QFT-IT and TST at the initial screening enabled us to categorize patient groups with concordant and discordant test results and allow for the comparative evaluation of test performance.…”

“…Considering the unknown benefit of serial IGRA testing and associated costs (8,15), we utilized TST as the subsequent test in patients with initial negative QFT-IT and non-reactive TST results (i.e., group 4). Neither TST conversion nor active TB case was detected for patients in this group during the follow-up period.…”

“…Decreased T-cell responses after active TB and LTBI treatment have been demonstrated in non-HIVinfected individuals (9,11), however, to date, reports of changes in interferon-gamma (IFN-γ) levels after LTBI treatment remain controversial (12)(13)(14). Additionally, data regarding the long-term IFN-γ responses after IPT among HIV-infected patients from high-endemic TB settings are limited (15).…”

Understanding the Tuberculosis Disease Progression and Future Directions of Research in Tuberculosis: A Mini Review

“…(Pullar et al 2014). Other example is bacterial confirmation which is not always feasible in children.…”

“…In a prospective cohort study in lowendemic setting using QuantiFERON TB-Gold In-tube ® essay (QFT) to measure interferon-gamma (IFN-γ) level in LTBI/HIV co-infected patients on preventive treatment, it was found that the conversion of QFT to negative independent of the preventive anti-TB treatment indicating false positive results therefore QFT is unreliable in monitoring LTBI preventive treatment efficacy in TB low-endemic setting (Pullar et al 2014). Indeed, attempts were made to improve the reliability of diagnostic tool as well as to know the factors that contribute to false positive or false negative results.…”