Changes in Total Lymphocyte Count as a Surrogate for Changes in
Changes in Total Lymphocyte Count as a Surrogate for Changes in
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/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 ≥+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.
The cost of highly active antiretroviral therapy (HAART) is dropping dramatically for low-income countries through various international initiatives. As availability of antiretroviral medications improves, it is important to develop feasible strategies for the clinical management of antiretroviral therapies in resource-limited settings. One of the major obstacles to the administration of HAART is the absence of sophisticated and expensive laboratory equipment and infrastructure required for monitoring the efficacy of therapy. In industrialized nations, changes in CD4 count and plasma viral load are used to determine the response of the virus to antiretroviral therapy. Standard methods of CD4 count and plasma viral load enumeration require highly trained personnel and tens of thousands of dollars of initial investment in laboratory instrumentation. In the few resource-limited countries where such laboratory facilities exist, they are often concentrated in major cities and the assays are too expensive for the majority of patients to use for routine monitoring of HAART.
With 40 million people living with HIV in low-income countries and an estimated 6 million people in these countries currently requiring life-sustaining HAART, the World Health Organization (WHO) and UNAIDS has issued the 3 by 5 Initiative, an effort to get 3 million people in resource-limited countries on antiretroviral therapy by the end of 2005. WHO offers technical recommendations to achieve this goal in their recently revised guidelines for scaling up antiretroviral therapy in resource-limited settings. Citing the urgency of providing therapy on a wide scale and the financial and technological constraints to drastically upgrading laboratory facilities, the Monitoring section of these guidelines stipulates that CD4 count testing is desirable but not essential for antiretroviral use in resource-limited settings. Where CD4 count testing is not available or too expensive for routine use, WHO recommends the use of total lymphocyte count (TLC) to monitor the immune response to HAART. TLC is an inexpensive and widely available laboratory parameter. TLC is easily obtained from the routine complete blood count (CBC) with differential by multiplying percentage lymphocytes by leukocyte count. In southern India, for example, the cost of a single TLC from a CBC is <$1 (US) whereas a single CD4 count by flow cytometry is approximately $30 (US). In India, where the average annual income is <$350 and annual per capita spending on health by the government is $133, the cumulative cost of monitoring HAART becomes a significant financial challenge. When computing cost on a annual basis, quarterly monitoring with TLC amounts to only $4 per year while that of CD4 count testing is $120 per year.
According to UNAIDS, even with the dramatic price reductions on HAART regimens to $300-$400 (US) per year, administration of antiretroviral therapy will remain unaffordable for many resource-limited countries. The extent of funding required for the wide range of activities that make up anti-retroviral therapy programs in addition to monitoring of therapy, including drug procurement, drug distribution, clinical management of complications, monitoring of therapy, assessment and support of drug adherence, necessitates cost-effective solutions where appropriate and achievable. In light of its low cost and widespread availability, TLC has already been a useful tool in low-income countries for predicting im-munosuppression and triggering opportunistic infection prophylaxis. Recent studies have also demonstrated that TLC alone and in combination with hemoglobin may be useful in determining when to initiate antiretroviral therapy. However, there are fewer studies examining the change of TLC in patients on antiretroviral therapy.
The purpose of this paper is to assess the capability and clinical utility of TLC change to serve as a surrogate marker for CD4 count change in monitoring patients on HAART, which has important implications for resource-limited settings. TLC and CD4 count changes-as opposed to cross-sectional values-are used because the standard quantification of immunologic response to therapy is change in CD4 count.
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/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 ≥+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.
The cost of highly active antiretroviral therapy (HAART) is dropping dramatically for low-income countries through various international initiatives. As availability of antiretroviral medications improves, it is important to develop feasible strategies for the clinical management of antiretroviral therapies in resource-limited settings. One of the major obstacles to the administration of HAART is the absence of sophisticated and expensive laboratory equipment and infrastructure required for monitoring the efficacy of therapy. In industrialized nations, changes in CD4 count and plasma viral load are used to determine the response of the virus to antiretroviral therapy. Standard methods of CD4 count and plasma viral load enumeration require highly trained personnel and tens of thousands of dollars of initial investment in laboratory instrumentation. In the few resource-limited countries where such laboratory facilities exist, they are often concentrated in major cities and the assays are too expensive for the majority of patients to use for routine monitoring of HAART.
With 40 million people living with HIV in low-income countries and an estimated 6 million people in these countries currently requiring life-sustaining HAART, the World Health Organization (WHO) and UNAIDS has issued the 3 by 5 Initiative, an effort to get 3 million people in resource-limited countries on antiretroviral therapy by the end of 2005. WHO offers technical recommendations to achieve this goal in their recently revised guidelines for scaling up antiretroviral therapy in resource-limited settings. Citing the urgency of providing therapy on a wide scale and the financial and technological constraints to drastically upgrading laboratory facilities, the Monitoring section of these guidelines stipulates that CD4 count testing is desirable but not essential for antiretroviral use in resource-limited settings. Where CD4 count testing is not available or too expensive for routine use, WHO recommends the use of total lymphocyte count (TLC) to monitor the immune response to HAART. TLC is an inexpensive and widely available laboratory parameter. TLC is easily obtained from the routine complete blood count (CBC) with differential by multiplying percentage lymphocytes by leukocyte count. In southern India, for example, the cost of a single TLC from a CBC is <$1 (US) whereas a single CD4 count by flow cytometry is approximately $30 (US). In India, where the average annual income is <$350 and annual per capita spending on health by the government is $133, the cumulative cost of monitoring HAART becomes a significant financial challenge. When computing cost on a annual basis, quarterly monitoring with TLC amounts to only $4 per year while that of CD4 count testing is $120 per year.
According to UNAIDS, even with the dramatic price reductions on HAART regimens to $300-$400 (US) per year, administration of antiretroviral therapy will remain unaffordable for many resource-limited countries. The extent of funding required for the wide range of activities that make up anti-retroviral therapy programs in addition to monitoring of therapy, including drug procurement, drug distribution, clinical management of complications, monitoring of therapy, assessment and support of drug adherence, necessitates cost-effective solutions where appropriate and achievable. In light of its low cost and widespread availability, TLC has already been a useful tool in low-income countries for predicting im-munosuppression and triggering opportunistic infection prophylaxis. Recent studies have also demonstrated that TLC alone and in combination with hemoglobin may be useful in determining when to initiate antiretroviral therapy. However, there are fewer studies examining the change of TLC in patients on antiretroviral therapy.
The purpose of this paper is to assess the capability and clinical utility of TLC change to serve as a surrogate marker for CD4 count change in monitoring patients on HAART, which has important implications for resource-limited settings. TLC and CD4 count changes-as opposed to cross-sectional values-are used because the standard quantification of immunologic response to therapy is change in CD4 count.
