Detection and Prediction of Active Tuberculosis Disease by a Whole-Blood Interferon-γ Release Assay in HIV-1–Infected Individuals

Department of Dermatology, Division of Immunology, Allergy, and Infectious Diseases, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
Clinical Infectious Diseases (Impact Factor: 8.89). 03/2009; 48(7):954-62. DOI: 10.1086/597351
Source: PubMed
The sensitivity of whole-blood interferon-gamma release assays to detect or predict active tuberculosis in individuals infected with human immunodeficiency virus type 1 (HIV-1) has as yet not been determined. Methods. In this prospective, longitudinal, single-center study, 830 HIV-1-infected patients underwent testing with the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay. Clinical screening for active tuberculosis was performed at least every 3 months for a median follow-up time of 19 months.
At baseline, the QFT-GIT assay yielded positive or indeterminate results in 44 (5.3%) and 47 (5.7%) of the 830 patients, respectively. A positive QFT-GIT assay result occurred at significantly higher frequencies among black individuals than among white individuals (odds ratio, 4.84; 95% confidence interval, 2.25-9.97; P< .001), among patients from Africa than among patients from Austria (odds ratio, 6.57; 95% confidence interval, 2.99-14.25; P< .001), and among patients from high-prevalence countries than among patients from low-prevalence countries (odds ratio, 5.86; 95% confidence interval, 2.41-13.44; P< .001). In patients with indeterminate QFT-GIT assay results, both median actual and nadir CD4(+) T cell counts were significantly lower than in patients with interpretable QFT-GIT assay results (P< .001). At the time of baseline QFT-GIT screening, active tuberculosis was found in 7 (15.9%) of 44 individuals with a positive result and in 1 (0.1%) of 739 patients with a negative result. During the follow-up period, however, progression to active tuberculosis occurred exclusively in patients with a positive QFT-GIT assay result, at a rate of 8.1% (3 of 37 patients; P< .001). Collectively, the sensitivity of the QFT-GIT assay for active tuberculosis was 90.9% (95% confidence interval, 62.3%-98.4%).
Our results suggest that the QFT-GIT assay may be a sensitive tool for the detection and prediction of active tuberculosis in HIV-1-infected individuals.

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    • "The CMV QuantiFERON assay (CMV-QFT) is based on ELISA. Similar to the widely used diagnostic test for Mycobacterium tuberculosis [10] , the level of IFN-γ, which is mainly produced by specific CD8 + T cells, is quantified. In the immunosuppression/transplantation setting the CMV-QFT has been shown to be a useful predictor of spontaneous clearance of low-level viraemia [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Among HIV-1-infected individuals, cytomegalovirus (CMV) reactivation and disease occur in the setting of advanced immunosuppression. The value of a standardized assessment of CMV-specific T-cell mediated immunity by the CMV QuantiFERON assay (CMV-QFT) has not yet been thoroughly investigated in HIV-1-infected subjects. Methods: Prospective, longitudinal study in 153 HIV-1-infected subjects with a CD4+ T cell count < 350/μL who simultaneously underwent CMV-QFT, CMV serology testing and CMV-DNA quantification. Factors associated with CMV-QFT were evaluated. Clinical screening for CMV manifestations was then performed every 3 months. Results: Among the 141 CMV IgG-seropositive individuals the CMV-QFT assay yielded reactive results in 84% (118/141), negative results in 15% (21/141) and indeterminate (negative mitogen IFN-gamma response) results in 1% (2/141) of subjects. The mean actual CD4+ T cell count was significantly higher in CMV-QFT reactive subjects, when compared to CMV-QFT non-reactive individuals (183 ± 102 vs. 126 ± 104 cells/μL, P = 0.015). A significantly lower proportion of CMV-QFT reactive vs. non-reactive patients displayed CMV DNAemia > 100 copies/mL (23% (27/118) vs. 48% (11/23), P = 0.02). Furthermore, a statistically significant inverse association between mitogen IFN-gamma response and CMV-DNAemia > 1000 copies/mL was observed (P < 0.001). During the observational period, 5 CMV end-organ manifestations were observed. In three of the CMV cases the CMV-QFT yielded indeterminate results. Conclusions: While CMV-QFT reactivity indicates CMV-specific immunity, indeterminate results due to negative mitogen IFN-gamma response might reflect HIV-1-induced immunodeficiency. Thus, dependency upon CD4+ T cell count should be considered when interpreting CMV-QFT results.
    Full-text · Article · Aug 2015 · PLoS ONE
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    • "The second study, conducted in Kenya, a high TB incidence country, which found that IGRA had a positive predictive value of 5.5% (6/110) among HIV-infected pregnant women during a mean follow up of 1.28 years, with a negative predictive value of 98.0% (145/148)[36]. The overall incidence of active TB in our study (2.2%, 0.44 per 100 person-years) was higher than that observed in Austria, a low TB transmission country (0.4%),[35] but much lower than the 2.7 per 100 person-years observed in Kenya, a high TB transmission country [36] . The incidence of active TB in those with a positive IGRA in the present study (1.30 per 100 personyears ) was 70% lower than that observed in Kenya (4.2 per 100 person-years)[36] . "
    [Show abstract] [Hide abstract] ABSTRACT: Background Predicting the risk of tuberculosis (TB) in people living with HIV (PLHIV) using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL), and interferon-gamma release assay (IGRA), to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART) is routinely provided. Materials and Methods A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count < = 350/μL). Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC) curve was calculated. Results Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/μL or pVL ≥ 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49–15.90, P = 0.009). A positive baseline IGRA predicted TB in patients with baseline CD4 ≥ 350/μL and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52–24.40, P = 0.01). Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6%) from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587–0.798) for the study cohort and 0.792 (95% CI: 0.776–0.808) and 0.766 in the 2 validation cohorts. Conclusions A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary exposure of low-risk patients to drug toxicity and simultaneously, reduce the burden of universal treatment on the healthcare system.
    Full-text · Article · Aug 2015 · PLoS ONE
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    • "The incidence rate and crude incidence of active TB in HIV-infected patients with positive IGRA results range from 0 to 4.621 cases per 100 person-years and from 0 to 20%, respectively (summarized inTable 3)1213141516, depending on the TB epidemiology of the country where the study was conducted, number of study subjects enrolled (range, 50 to 909 subjects), follow-up duration (range, 1.28 to 2.97 years), methods employed to detect and diagnose TB, receipt of IPT, CD4 counts (range, median, 305 to 447 cells/μL) and plasma HIV RNA loads (range, 1.85 to 4.8 log 10 copies/mL), and the proportion of study subjects on cART (range, 0 to 100%). The incidence rate or crude rate in our patients with positive IGRA results appears to be lower than those reported in studies conducted in countries of different levels of TB endemicity (Table 3)1213141516 18] . A recent study conducted in Brazil (TB incidence of 46 per 100,000 pop- ulation [19]) reported a TB incidence of 6.52 cases per 100 PYFU in HIV-infected patients with positive TST and without IPT [18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Interferon-gamma release assays (IGRAs) have been used to identify individuals at risk for developing active tuberculosis (TB). However, data regarding the risk of TB development in HIV-infected patients testing positive for IGRAs remain sparse in the era of combination antiretroviral therapy. Methods: Between 2011 and 2013, 608 HIV-infected patients without active TB undergoing T-Spot.TB testing were enrolled in this prospective observational study at a university hospital designated for HIV care in Taiwan with a declining TB incidence from 72 per 100,000 population in 2005 to 53 per 100,000 population in 2012. All of the subjects were followed until September 30, 2014. The national TB registry was accessed to identify any TB cases among those lost to follow-up. Results: T-Spot.TB tested negative in 534 patients (87.8%), positive in 64 patients (10.5%), and indeterminate in 10 patients (1.6%). In multivariate analysis, positive T-Spot.TB was significantly associated with older age (adjusted odds ratio [AOR], 1.172 per 10-year increase; 95% confidence interval [CI], 1.022-1.344, P=0.023), past history of TB (AOR, 13.412; 95% CI, 6.106-29.460, P<0.001), and higher CD4 counts at enrollment (AOR, per 50-cell/μl increase, 1.062; 95% CI, 1.017-1.109, P=0.007). Of the 64 patients testing positive for T-Spot.TB, none received isoniazid preventive therapy and all but 5 received combination antiretroviral therapy at the end of follow-up with the latest CD4 count and plasma HIV RNA load being 592.8 cells/μL and 1.85 log10 copies/mL, respectively. One patient (1.6%) developed active TB after 167 person-years of follow-up (PYFU), resulting in an incidence rate of 0.599 per 100 PFYU. None of the 534 patients testing negative for T-Spot.TB developed TB after 1380 PYFU, nor did the 24 patients with old TB and positive T-Spot.TB tests develop TB after 62.33 PYFU. Conclusions: The risk of developing active TB in HIV-infected patients with positive T-Spot.TB receiving combination antiretroviral therapy is low in Taiwan where the national TB program has led to a sustained decrease in TB incidence.
    Full-text · Article · May 2015 · PLoS ONE
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