title: C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings.
abstract: OBJECTIVE
  The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain.
  
  
  METHODS
  Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm).
  
  
  METHODS
  We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis.
  
  
  RESULTS
  Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB.
  
  
  CONCLUSIONS
  Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Tenforde
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Gupte
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Dowdy
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Asmuth
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Balagopal
authors.affiliation: University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
authors.affiliation: Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Patcharaphan
authors.initials: P
authors.lastname: Sugandhavesa
authors.affiliation: Asociación Civil Impacta Salud y Educación (IMPACTA) Peru Clinical Trials Unit, Lima, Peru.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Lama
authors.affiliation: Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Sandy
authors.initials: S
authors.lastname: Pillay
authors.affiliation: Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cardoso
authors.affiliation: National AIDS Research Institute, Pune, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Pawar
authors.affiliation: Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil.
authors.forename: Breno
authors.initials: B
authors.lastname: Santos
authors.affiliation: Les Centres Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunites (GHESKIO), Port-Au-Prince, Haiti.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Riviere
authors.affiliation: University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Noluthando
authors.initials: N
authors.lastname: Mwelase
authors.affiliation: University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kanyama
authors.affiliation: Malawi College of Medicine-Johns Hopkins University Research Project, Blantyre, Malawi.
authors.forename: Johnstone
authors.initials: J
authors.lastname: Kumwenda
authors.affiliation: University of Zimbabwe, Harare, Zimbabwe.
authors.forename: James G
authors.initials: JG
authors.lastname: Hakim
authors.affiliation: Y.R. Gaitonde Centre for AIDS Research and Education (YRG CARE), Chennai, India.
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Bollinger
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Semba
authors.affiliation: University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Campbell
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Amita
authors.initials: A
authors.lastname: Gupta
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000097:blood* / Q000453:epidemiology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000009:adverse effects*; D002097:C-Reactive Protein / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000097:blood*; D003906:Developing Countries; D005260:Female; D006801:Humans; D015994:Incidence; D008070:Lipopolysaccharides / Q000097:blood*; D008297:Male; D012306:Risk; D014376:Tuberculosis / Q000097:blood* / Q000453:epidemiology
chemical_list: D044966:Anti-Retroviral Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D008070:Lipopolysaccharides; D002097:C-Reactive Protein