INT J TUBERC LUNG DIS 12(4):417–423 © 2008 The Union High level of discordant IGRA results in HIV-infected adults and children A. M. Mandalakas,* A. C. Hesseling, † N. N. Chegou, ‡ H. L. Kirchner, § X. Zhu,* B. J. Marais, † G. F. Black, ‡ N. Beyers, † G. Walzl ‡ * Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; † Desmond Tutu TB Centre, Department of Pediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, Tygerberg, ‡ Division of Molecular Biology and Human Genetics, Department of Science and Technology/National Research Foundation Centre of Excellence in Biomedical Tuberculosis Research and MRC Centre for Molecular and Cellular Biology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa; § Center for Health SUMMARY Research, Geisinger Health System, Danville, Pennsylvania, USA SETTING: Tygerberg district, Western Cape Province, South Africa. OBJECTIVE: To measure the agreement of two interferon- gamma release assays (IGRAs) and the tuberculin skin test (TST) for the detection of Mycobacterium tubercu- losis infection in human immunodeficiency virus (HIV) infected adults and children in a setting highly endemic for tuberculosis (TB). DESIGN: Cross-sectional study. RESULTS: In HIV-infected adults (n  20) and children (n  23), tests yielded discordant results, with 61% of individuals testing positive with T-SPOT.TB, 41% with TST and 28% with QuantiFERON ® TB Gold (QTF). In children, there was poor agreement between the TST and T-SPOT.TB (kappa []  0.02), but moderate agree- ment between the TST and QTF (  0.44). In adults, there was moderate agreement between the TST and T-SPOT.TB (  0.43), and the TST and QTF (  0.46). In children and adults, there was fair agreement between the T-SPOT.TB and QTF (  0.33). Twenty per cent of adults had 1 indeterminate IGRA results. CONCLUSIONS: There is poor to moderate agreement between the TST and IGRAs in HIV-infected adults and children. T-SPOT.TB may have improved sensitivity for detection of M. tuberculosis infection in HIV- infected individuals compared to the QTF and the TST. In HIV-infected individuals, IGRA test properties are af- fected by test cut-off point and nil control responses. KEY WORDS: interferon-gamma release assays; ESAT-6; CFP-10; M. tuberculosis; exposure age; HIV; CD4 NINE MILLION people contract tuberculosis (TB) and 2 million people die from TB annually. 1 Children represent 11–15% of this disease burden. 2 The risk of progression to active TB following Mycobacterium tuberculosis infection in human immunodeficiency virus (HIV) infected adults is 5–10% per year, 3 and persists despite antiretroviral treatment (ART). 4 The risk of pro- gression to disease following M. tuberculosis infection in HIV-infected children is at least 6–8 fold higher than in non-HIV-infected children, 5 with a TB incidence of 9.2% recently recorded in HIV-infected children who did not receive isoniazid preventive treatment (IPT). 6 The diagnosis of M. tuberculosis infection is com- plicated by the lack of a gold standard. The negative predictive value (NPV) of the tuberculin skin test (TST) is reduced in immunocompromised individuals, the very young and/or severely malnourished children and in the presence of severe TB. 7 TST sensitivity in detect- ing recent infection may be limited, as demonstrated by individuals who convert their TST 6–12 weeks after documented M. tuberculosis exposure. 8 The positive predictive value (PPV) of TST is reduced in popula- tions with exposure to non-tuberculous mycobacteria (NTM) and/or M. bovis bacille Calmette-Guérin (BCG) vaccination. 7 The potential benefits of an accurate diagnostic test of M. tuberculosis infection in HIV- infected individuals include timely institution of pre- ventive or curative treatment. T-cell-based interferon-gamma (IFN-) release as- says (IGRAs), utilising early secretory antigenic target 6 (ESAT-6), culture filtrate protein 10 kDa (CFP-10) and TB7.7, may offer enhanced sensitivity in the diag- nosis of M. tuberculosis infection in HIV-infected individuals compared to the TST. 9–11 However, few studies have directly compared IGRAs and the TST in HIV-infected adults and children in TB-endemic set- tings. Discordant results between TST and IGRAs have not been well studied in HIV-infected individuals. Correspondence to: A M Mandalakas, Division of Global Child Health, Department of Pediatrics, School of Medicine, Case Western Reserve University, 11100 Euclid Avenue—MS 7052, Cleveland, OH 44106, USA. Tel: (1) 216 844 3224. Fax: (1) 216 844 6265. e-mail: anna.mandalakas@case.edu Article submitted 17 July 2007. Final version accepted 13 December 2007.