Incidence of tuberculosis and the need of prophylactic treatment in persons living with HIV in Stockholm during the era of anti-retroviral therapy 1996-2013.

BACKGROUND: The aim of this observational cohort study was to determine the incidence and risk factors of active tuberculosis (TB) in persons living with HIV in a low endemic setting over a 17-year time period when combination antiretroviral therapy (ART) has been available. We thereby aimed to understand the usefulness of TB chemoprophylaxis among HIV patients with latent TB. METHODS: All 2127 adult patients diagnosed with HIV January 1996-December 2013 at the Karolinska University Hospital in Stockholm County were eligible. After exclusion of 259 patients transferred to other clinics, 1868 were followed until TB diagnosis, death or end of study period (December 2013). The median follow-up time was 7.9 years (interquartile range, 3.9-11.5). RESULTS: Active TB was diagnosed in 92 patients, corresponding to an incidence rate of 6.2 cases (95% CI 5.1-7.6) per 1000 person-years with a significant decline over time. The majority (52%) of TB cases were diagnosed within 1 month from HIV diagnosis. Being a migrant from a TB-endemic region, was the only patient characteristic associated with significantly higher risk of active TB (Hazard Ration, HR: 8.54, 95% confidence interval, CI: 3.09-23.61 in a multivariate regression analysis controlling for route of HIV transmission, year of HIV diagnosis and CD4-cell count and viral load at HIV diagnosis. The number needed to treat to prevent one case of TB among patients in this high-risk group was 22 (95% CI 26-47). CONCLUSION: The incidence of active TB in persons living with HIV in Stockholm County declined significantly after the introduction of ART but was still 80 times higher than in the general population at the end of the study period. The therapeutic gain of chemoprophylaxis in low endemic settings should be weighed against costs and side effects.

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.

BACKGROUND: Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. METHODS: BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150µg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. RESULTS: H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50µg of H4 in combination with the 500nmol IC31 adjuvant dose. CONCLUSIONS: The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50µg of H4 and 500nmol of IC31. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02066428 and NCT02074956.

Tuberculosis among HIV-infected patients in Stockholm, Sweden, 1987-2010: treatment outcomes and adverse reactions.

BACKGROUND: The treatment of patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB) is challenging. The aim of this study was to compare socio-demographic and clinical characteristics among HIV-infected patients before and after the introduction of combined antiretroviral therapy (cART) in a Swedish cohort, and to identify factors associated with anti-TB treatment success as well as adverse reactions. METHODS: This was a retrospective observational study of HIV/TB co-infected patients in Stockholm County from 1987 to 2010. The study population was stratified into an early and a late cohort (before and after the introduction of cART in 1996). Data were analyzed using descriptive statistics and multiple logistic regression analysis. RESULTS: The study population comprised 127 patients; the majority were foreign-born (87%). The proportion of female patients more than doubled from the early to the late cohort, and anti-TB treatment success increased from 65% to 91%. The median duration of successful treatment was 8 months in both cohorts. Predictors of treatment success in the late cohort were cART (odds ratio (OR) 13.3, 95% confidence interval (CI) 1.5-114.8) and a CD4 cell count at TB diagnosis > 200 cells/µl (OR 17.2, 95% CI 1.2-236.6). Severe adverse reactions in the late cohort occurred in 23% and were associated with the initiation of cART after TB diagnosis (OR 13.3, 95% CI 1.6-112.4). CONCLUSION: The introduction of cART was favourable for the treatment outcome of HIV-infected patients with concomitant TB. However, adverse reactions increased in patients who initiated cART during anti-TB treatment and these patients require careful attention.

Detection of proliferative responses to ESAT-6 and CFP-10 by FASCIA assay for diagnosis of Mycobacterium tuberculosis infection.

There is a large and growing worldwide need for reliable tests to diagnose active and latent tuberculosis (TB). Improved methodology for identifying individuals with true latent TB (LTBI), particularly those with a recent infection, would pave the way for targeted prophylactic treatment. The traditionally used tuberculin skin test (TST) is unspecific and impractical. Interferon gamma release assays (IGRA) are more specific than the TST but, like that test, cannot discriminate either between recent and remote TB infection, or between these and a mere immunological memory of previous TB infection. The Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) combines long-term antigen stimulation of whole blood and flow-cytometric analysis with quantification of the expanded T-lymphoblasts and can also be employed for measurement of cytokine responses.