title: Changes in total lymphocyte count as a surrogate for changes in CD4 count following initiation of HAART: implications for monitoring in resource-limited settings.
abstract: BACKGROUND
  A major obstacle to the administration of highly active antiretroviral therapy (HAART) in resource-limited settings is the high cost of CD4 count testing. The total lymphocyte count (TLC) has been proposed as a surrogate marker to monitor immune response to therapy.
  
  
  OBJECTIVE
  To assess, in a developed country setting, the capability and clinical utility of TLC change as a surrogate marker for CD4 count change in monitoring patients on HAART.
  
  
  METHODS
  Longitudinal co-variation between changes in TLC and concomitant changes in CD4 count following the initiation of HAART was examined using a retrospective cohort study of 126 HIV-positive patients attending The Miriam Hospital, Brown University, Providence, RI. Analyses included evaluation of the direction of TLC change as a marker for direction of CD4 change, using sensitivity and specificity; evaluation of absolute change in TLC as a marker for benchmark changes in CD4 (> or =50 over 6 months, > or =100 over 12 months), using receiver-operator characteristic (ROC) curves; and a regression model of change in TLC as a function of change in CD4, to understand within-individual variation of longitudinal TLC measures.
  
  
  RESULTS
  In the first 24 months of HAART, the sensitivity of a TLC increase as a marker for CD4 count increase over the same time period ranged from 86-94%, and the specificity ranged from 80-85%. The median change in TLC among patients with a CD4 count rise of > or =100 cells/mm at 1 year of HAART was +766 cells/mm while that of patients with a CD4 count rise of <100 cells/m was +100 cells/mm. The area under the corresponding ROC curve was 0.89, suggesting that change in TLC discriminates well between those with 1-year CD4 change of > or =100 vs. those with change <+100. From a regression analysis, we found that mean change in TLC per 1 cell/mm change in CD4 count was 7.3 (SE 1.2, P < 0.001). The degree of this association varied from individual to individual but was positive for all individuals.
  
  
  CONCLUSIONS
  Within the first 2 years of HAART, the direction of change in TLC appears to be a strong marker for direction of concomitant change in CD4 count (sensitivity 86-94% and specificity 80-85%, depending on length of interval). Positive and negative predictive values depend on the proportion of CD4 changes that are positive. In this cohort, that proportion is 87.9%, which yields high positive predictive value (96-98%) but lower negative predictive value (43-63%). Findings from the regression model suggest that taking multiple measurements of TLC at more frequent intervals may reduce variability and potentially improve predictive accuracy.
authors.affiliation: School of Medicine, Brown University, Providence, RI, 02906, USA.
authors.forename: Anish P
authors.initials: AP
authors.lastname: Mahajan
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Hogan
authors.forename: Brad
authors.initials: B
authors.lastname: Snyder
authors.forename: N
authors.initials: N
authors.lastname: Kumarasamy
authors.forename: Kalindi
authors.initials: K
authors.lastname: Mehta
authors.forename: Suniti
authors.initials: S
authors.lastname: Solomon
authors.forename: Charles C J
authors.initials: CC
authors.lastname: Carpenter
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Mayer
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Flanigan
mesh_terms: D000293:Adolescent; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers; D018791:CD4 Lymphocyte Count; D016903:Drug Monitoring; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D006295:Health Resources / Q000600:supply & distribution; D006801:Humans; D018655:Lymphocyte Count; D008954:Models, Biological; D012189:Retrospective Studies; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers