Yukari C Manabe1, Bruno B Andrade2,3,4, Nikhil Gupte1,5, Samantha Leong6, Manisha Kintali6, Mitch Matoga7, Cynthia Riviere8, Wadzanai Samaneka9, Javier R Lama10, Kogieleum Naidoo11,12, Yue Zhao13, W Evan Johnson13, Jerrold J Ellner6, Mina C Hosseinipour7,14, Gregory P Bisson15, Padmini Salgame6, Amita Gupta1. 1. Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 2. Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil. 3. Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER), José Silveira Foundation, Salvador, Bahia, Brazil. 4. Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. 5. Byramjee-Jeejeebhoy Government Medical College Johns Hopkins University Clinical Research Site, Pune, India. 6. Department of Medicine, Center for Emerging Pathogens, Rutgers, New Jersey Medical School, Newark, New Jersey, USA. 7. University of North Carolina Project Malawi, Lilongwe, Malawi. 8. Les Centres GHESKIO Clinical Research Site, Port au Prince, Haiti. 9. University of Zimbabwe College of Health Sciences, Clinical Trials Research Centre, Harare, Zimbabwe. 10. Asociacion Civil Impacta Salud y Educacion, Lima, Peru. 11. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. 12. CAPRISA-MRC Human Immunodeficiency Virus - Tuberculosis Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa. 13. Department of Medicine, Boston Medical Center, Boston, Massachusetts, USA. 14. Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. 15. Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract
BACKGROUND: People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death. METHODS: The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma. RESULTS: In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1β, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1β, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-β) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87-.94) and a specificity of 0.71(95% CI: .68-.75) with an area under the curve (AUC) of 0.81 (95% CI: .78-.83) for incident TB. CONCLUSION: Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions. CLINICAL TRIALS REGISTRATION: NCT01380080.
BACKGROUND:People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death. METHODS: The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma. RESULTS: In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1β, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1β, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-β) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87-.94) and a specificity of 0.71(95% CI: .68-.75) with an area under the curve (AUC) of 0.81 (95% CI: .78-.83) for incident TB. CONCLUSION: Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions. CLINICAL TRIALS REGISTRATION: NCT01380080.
Authors: Deivide Oliveira-de-Souza; Caian L Vinhaes; María B Arriaga; Nathella Pavan Kumar; Artur T L Queiroz; Kiyoshi F Fukutani; Subash Babu; Bruno B Andrade Journal: Sci Rep Date: 2020-07-09 Impact factor: 4.379
Authors: Caian L Vinhaes; Mariana Araujo-Pereira; Rafael Tibúrcio; Juan M Cubillos-Angulo; Fernanda O Demitto; Kevan M Akrami; Bruno B Andrade Journal: Life (Basel) Date: 2021-01-18