Journal of Infectious Diseases Advance Access published January 26, 2015 1 Effect of immune status on serial QuantiFERON-TB Gold In-Tube LTBI screening in persons with HIV in a low TB incidence country Monica Sañé Schepisi 1, Mario Pasquale Parracino 1, Alessia Mammone 1, Rita Bellagamba 2, Carmela Pinnetti 2, Stefania Cicalini 2, Alessandro Sampaolesi 2, Adriana Ammassari 2, Delia Goletti 1 and Enrico Girardi 1 1 Department of Epidemiology and Preclinical Research 2 Clinical Department, National Institute for Infectious Diseases (INMI) L. Spallanzani, IRCCS, Rome, Italy Corresponding author contact information: Enrico Girardi, MD, Director, Clinical Epidemiology Unit - Department of Epidemiology and Preclinical Research Istituto Nazionale Malattie Infettive "L. Spallanzani" IRCCS Via Portuense 292, 00149 Roma Italy. tel (+39) 0655170901 - Fax (+39) 065582825 - Email: enrico.girardi@inmi.it The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
2 To the Editor: We read the article by Aichelburg et al. [1] with great interest. This 3 year prospective study reported the incidence of Interferon-Gamma Release Assays (IGRA) conversions and reversions within a cohort of HIV-infected individuals in a low tuberculosis (TB) incidence country. Concordant baseline and follow-up results of QuantiFERON-TB Gold In-Tube (QFT-GIT) were found in 86% of 794 HIV-infected individuals, while 9% of those initially converted to a positive result and 33% of those initially positive reverted to. Screening for latent TB infection (LTBI) and preventive treatment of those testing positive is widely recommended for persons living with HIV/AIDS (PLWHA). Current Center for Disease Control and Prevention and National Institute of Health Guidelines, recommend testing all HIV-infected persons with the tuberculin skin test (TST) or an IGRA [2]. For individuals with diagnostic tests for LTBI who have advanced HIV infection, screening should be repeated after initiation of antiretroviral (ART) treatment and CD4 cell increase [3]. This latter recommendation is supported by the results of studies conducted in low TB burden countries [4 6], showing TST conversion rates up to 11.8% among HIV-positive patients following ART induced immune system recovery. Similar evidence, however, is not available for IGRAs. We conducted a cohort study at the National Institute for Infectious Diseases (INMI) L. Spallanzani, in Rome, Italy, in order to assess the potential utility of repeating QFT-GIT testing in a cohort of >18 year old HIV-infected patients. Participants were included in the study if they were HIVinfected and underwent screening for LTBI by QFT-GIT form June 2006 to June 2012. Suspicion of active TB at the time of first testing and diagnosis of TB within 1 month of QFT-GIT testing were exclusion criteria. Study participants were offered a second QFT-GIT between January 2013 and June 2014. Main outcome measures in the analysis were frequency of conversion or reversion of QFT-GIT. In contrast to Aichelburg et al., who considered CD4 cell count at nadir and enrollment, we focused our analysis on CD4 cell count variation as a potential determinant of QFT-GIT conversion and reversion over the follow-up period.
3 In the analysis, 193 HIV-infected patients were included. At baseline, their average CD4 cell count was 325/μl (IQR 88-496). A total of 115 subjects (59.6%) were antiretroviral naive or were on ART <1 month. Plasma HIV RNA <50 copies/ml was found in 41/167 subjects (24.6%). QFT-GIT was positive in 15 cases (7.8%) and indeterminate in 13 cases (6.7%). A positive test result was associated with being born in countries with higher TB incidence) and with higher CD4 cell count. In subjects born in countries with <20/100,000 TB incidence (n=163) there were 9 QFT- GIT positives (5.5%), whereas among those born in countries with TB incidence >20/100,000 (n=30) 6 had positive test results (20.0%) (OR 3.8, 95%CI 1.2 12.61; p<0.05). Percentages of positive QFT paralleled increasing CD4 cell ranges: 1.9% (1/54), 4.5% (1/22) and 11.1% (13/117) among subjects with CD4 cell count between 0-99/μl, 100-199/μl and >200 cells/μl, respectively (p<0.05 for linear trend). After a median follow-up of 2.6 years (IQR, 1.7-4.0), all patients were on ART and average CD4 cell counts increased to 523 cells/μl (IQR, 305-712), with 78.5% of subjects having HIV RNA <50 copies/ml. At test repetition, 3 among 165 initially QFT-GIT (1.8%) converted to positive, 4 among 15 initially positive (26.6%) reverted to, and all those who had indeterminate results tested [Figure 1]. Overall, concordant baseline and follow-up results were observed in 172/193 (89.1%) subjects. At follow-up, average CD4 cell count increased by 206/ul in the conversion group and by 200/ul (from 337 to 537) in the concordant patients. In contrast, an average decline of 17 CD4 cells/ul was found in the reversion group [Figure 1]. The findings of our prospective study confirm the percentages of QFT-GIT concordance and reversion found by Aichelburg et al., while conversion was reported less frequently among our patients. Although our findings should be regarded as preliminary due the limited size of the study population, they may support the hypothesis that differences in QFT-GIT results over time might be determined by the variation in immunological condition, and that conversions may reflect immune reconstitution in individuals with unrevealed LTBI who were falsely at enrolment. A large cohort study would be needed to confirm this hypothesis and to evaluate the utility of repeated IGRA testing in order to identify candidates for LTBI treatment among persons with HIV infection.
4 Footnotes The authors have no conflicts of interest to declare. This study was supported in part through funds provided by the 2009 AIDS Programme-Italian Ministry of Health. This work was presented in part as an oral presentation at the 2013 Annual Congress of the European Respiratory Society in Barcelona, Spain. Corresponding author contact information: Enrico Girardi, MD Director, Clinical Epidemiology Unit - Department of Epidemiology and Preclinical Research Istituto Nazionale Malattie Infettive "L. Spallanzani" IRCCS Via Portuense 292, 00149 Roma Italy. tel (+39) 0655170901 - Fax (+39) 065582825 - Email: enrico.girardi@inmi.it Figure Legend Figure 1. QuantiFERON-TB Gold In-Tube results and CD4+ average CD4+ cell count variation over time in 193 HIV-1 infected persons.
5 References [1] Aichelburg MC, Reiberger T, Breitenecker F, Mandorfer M, Makristathis A, Rieger A.J. Reversion and conversion of interferon-γ release assay results in HIV-1-infected individuals. Infect Dis. 2014 Mar 1;209(5):729-33. [2] Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castros K. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection United States, 2010. Morbidity and Mortality Weekly Report. 2010;59(RR05):1 25. [3] Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf accessed October 2014 [4] Schluger N W, Perez D, Liu Y M. Reconstitution of immune responses to tuberculosis in patients with HIV infection who receive antiretroviral therapy. Chest 2002; 122: 597 602. [5] Girardi E, Palmieri F, Zaccarelli M, et al. High incidence of tuberculin skin test conversion among HIV-infected individuals who have a favourable immunological response to highly active antiretroviral therapy. AIDS 2002; 16: 1976 1979. [6] Fisk T L, Hon H M, Lennox J L, Fordham von Reyn C, Hors- burgh C R Jr. Detection of latent tuberculosis among HIV- infected patients after initiation of highly active antiretroviral therapy. AIDS 2003; 17: 1102 1104. [7] Pai M1, Joshi R, Dogra S, Zwerling AA, Gajalakshmi D, Goswami K, Reddy MV, Kalantri A, Hill PC, Menzies D, Hopewell PC.T-cell assay conversions and reversions among household contacts of tuberculosis patients in rural India. Int J Tuberc Lung Dis. 2009 Jan;13(1):84-92.
6 Figure 1. QuantiFERON-TB Gold In-Tube results and CD4+ average CD4+ cell count variation over time in 193 HIV-1 infected persons. Baseline Follow up 161 (97.0%) +196 CD4+ cells/ l (from 328 to 524) 165 (85.5%) 329 CD4+ cells/ l 3 (1.2%) positive +206 CD4+ cells/ l (from 421 to 627) 1 (0.6%) indeterminate 142 CD4+ cells/ l (from 204 to 62) 193 HIV infected 325 CD4+ cells/ l 13 (6.7%) indeterminate 140 CD4+ cells/ l 13 (100%) +267 CD4+ cells/ l (from 140 to 407) 4 (26.7%) 17 CD4+ cells/ l (from 367 to 350) 15 (7.8%) positive 444 CD4+ cells/ l 11 (73.3%) positive +257 CD4+ cells/ l (from 472 to 729)