title: Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease.
abstract: BACKGROUND
  Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART.
  
  
  METHODS
  Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels.
  
  
  RESULTS
  Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95%CI 1.4-4.9) for D-dimer, and 3.8 (95% CI: 1.8-7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001).
  
  
  CONCLUSIONS
  Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.
  
  
  BACKGROUND
  Parent study: ClinicalTrials.gov NCT00342355.
authors.affiliation: Project Phidisa, Pretoria, South Africa. lledwaba@phidisa.org
authors.forename: Lotty
authors.initials: L
authors.lastname: Ledwaba
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Tavel
authors.forename: Paul
authors.initials: P
authors.lastname: Khabo
authors.forename: Patrick
authors.initials: P
authors.lastname: Maja
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.forename: Phumele
authors.initials: P
authors.lastname: Sangweni
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Dean
authors.initials: D
authors.lastname: Follmann
authors.forename: Julia A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Susan
authors.initials: S
authors.lastname: Orsega
authors.forename: Beth
authors.initials: B
authors.lastname: Baseler
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
authors.forename: H Clifford
authors.initials: HC
authors.lastname: Lane
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000097:blood*; D001777:Blood Coagulation / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D015658:HIV Infections / Q000150:complications / Q000401:mortality* / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D008297:Male; D011379:Prognosis; D013019:South Africa; D015996:Survival Rate; D019562:Viral Load
chemical_list: D015415:Biomarkers