A parsimonious host inflammatory biomarker signature predicts incident TB and mortality in advanced HIV

Post Date: 
2019-11-25
Publication: 
Clinical Infectious Diseases
Summary: 

BACKGROUND:
People with advanced HIV (CD4<50) remain at high risk of TB or death despite the initiation of antiretroviral therapy. 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:
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 (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, TNF-α, and TNF-β) achieved a sensitivity of 0.90 (95% CI: 0.87-0.94) and a specificity of 0.71(95% CI: 0.68-0.75) with an area under the curve (AUC) of 0.81 (95% CI: 0.78-0.83) 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.

Citation: 
Yukari C Manabe, MD; Bruno B Andrade; Nikhil Gupte; Samantha Leong; Manisha Kintali; Mitch Matoga; Cynthia Riviere; Wadzanai Sameneka; Javier R Lama; Kogieleum Naidoo; Yue Zhao; William Evan Johnson; Jerrold Ellner, MD; Mina C Hosseinipour; Gregory P Bisson; Padmini Salgame, PhD; Amita Gupta, MD. A parsimonious host inflammatory biomarker signature predicts incident TB and mortality in advanced HIV. Clin Infect Dis. 2019 Nov 25. pii: ciz1147. doi: 10.1093/cid/ciz1147. [Epub ahead of print]. PMID: 31761933.
Collaborators: 

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil
Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER), José Silveira Foundation, Salvador, Bahia, Brazil.
Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Byramjee-Jeejeebhoy Government Medical College- Johns Hopkins University Clinical Research Site, Pune, India.
Department of Medicine, Center for Emerging Pathogens, Rutgers, New 24 Jersey Medical School, Newark, NJ, USA.
UNC Project Malawi, Lilongwe Malawi.
Les Centres GHESKIO Clinical Research Site, Port au prince, Haiti.
University of Zimbabwe College of Health Sciences-Clinical Trials Research Centre, Harare, Zimbabwe.
Asociacion Civil Impacta Salud y Educacion, Lima, Peru.
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
CAPRISA-MRC HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
Department of Medicine, Boston Medical Center, Boston, MA, USA.
Department of Medicine, Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.