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Changes in Total Lymphocyte Count as a Surrogate for Changes in CD4 Count Following Initiation of HAART: Implications for Monitoring in Resource-Limited Settings

Mahajan, Anish P. MD, MPH*; Hogan, Joseph W. ScD; Snyder, Brad MS; Kumarasamy, N. MD; Mehta, Kalindi MD*; Solomon, Suniti MD; Carpenter, Charles C. J. MD*; Mayer, Kenneth H. MD*; Flanigan, Timothy P. MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2004 - Volume 36 - Issue 1 - p 567-575
Clinical Science

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 (≥50 over 6 months, ≥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 ≥100 cells/mm3 at 1 year of HAART was +766 cells/mm3 while that of patients with a CD4 count rise of <100 cells/m3 was +100 cells/mm3. 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 ≥+100 vs. those with change <+100. From a regression analysis, we found that mean change in TLC per 1 cell/mm3 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.

From *School of Medicine, Brown University, Providence, RI, †Center for Statistical Sciences and Department of Community Health, Brown University, Providence, RI, and ‡Y.R.G. Centre for AIDS Research and Education, Chennai, India.

Received for publication May 2, 2003; accepted February 17, 2004.

A. P. Mahajan is currently at the University of California, Los Angeles, Medical Center.

Supported by the Lifespan-Tufts-Brown Center for AIDS Research (CFAR grant #P30-AI 42853), NIH grant R01-AI-50505, NIH grant R01 5U01AI046381 and AIDS International Research and Training Program of the Fogarty International Center of the National Institutes of Health, USA (grant #TW00237).

Reprints: Timothy Flanigan, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906 (e-mail:

© 2004 Lippincott Williams & Wilkins, Inc.