CD4 Enumeration Technologies: A Systematic Review of Test Performance for Determining Eligibility for Antiretroviral Therapy

Abstract

BackgroundMeasurement of CD4+ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration.Methods and FindingsStudies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained.ConclusionsA wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.

Performance evaluation of the touchscreen-based Muse™ Auto CD4/CD4% single-platform system for CD4 T cell numeration in absolute number and in percentage using blood samples from children and adult patients living in the Central African Republic

“…The procedure was fast and needed only 30 min to be completed. The technique was found to be very easy to carry out and highly precise in terms of repeatability and reproducibility, with intra- and inter- run variabilities less than 15%, considered as acceptable for clinical use [10, 18]. The interperson variation, which could introduce further assay variation, was however not assessed in the present study.…”

“…The Muse™ Auto CD4/CD4% system for CD4 T cell counting allows minimizing the sources of variations, is less expensive, is small, is simple to use and yet reproducible. Similarly, previous studies have yet reported that point-of-care non-flow cytometry-based CD4 T cell counting device, such as the PIMA™ CD4 from Alere (Alere, Jena, Germany) [38] or Partec CyFlow miniPOC from Partec (Partec GmbH, Munster, Germany) [39] may be interchangeable with the existing conventional CD4 T cell enumeration platforms [10]. All these more affordable CD4 dedicated flow cytometers introduced into the market are thought to ensure decentralization of the HIV-monitoring services [9, 10].…”

“…Similarly, previous studies have yet reported that point-of-care non-flow cytometry-based CD4 T cell counting device, such as the PIMA™ CD4 from Alere (Alere, Jena, Germany) [38] or Partec CyFlow miniPOC from Partec (Partec GmbH, Munster, Germany) [39] may be interchangeable with the existing conventional CD4 T cell enumeration platforms [10]. All these more affordable CD4 dedicated flow cytometers introduced into the market are thought to ensure decentralization of the HIV-monitoring services [9, 10]. Indeed, point-of-care CD4 T cell counting technologies reduce the time and increase patient retention along the testing and treatment cascade compared to conventional laboratory-based testing [40], which are therefore considered to be useful tools to perform CD4 T cell counting for expedite result delivery.…”

“…A number of technologies are available for CD4 T cell enumeration, with considerable variation in cost, complexity and operating requirements [8–10]. The traditional approach to measure absolute CD4 T lymphocyte counts is to use the total leukocyte count (or lymphocyte count) obtained from the hematology analyzer and then use the percentage of CD4 T lymphocytes from the flow cytometric analysis to calculate the absolute values—the so-called “dual platform” (DP) approach, which is however often associated with inter-laboratory variation as high as 40% [9, 10].…”

“…The traditional approach to measure absolute CD4 T lymphocyte counts is to use the total leukocyte count (or lymphocyte count) obtained from the hematology analyzer and then use the percentage of CD4 T lymphocytes from the flow cytometric analysis to calculate the absolute values—the so-called “dual platform” (DP) approach, which is however often associated with inter-laboratory variation as high as 40% [9, 10]. Thus, the need to derive accurate and precise absolute CD4 T lymphocyte counts has led to the development of instruments that can produce both percentage and absolute values, termed “single-platform” approach.…”