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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e318256b651
Clinical Science

The Reliability of Point-of-Care CD4 Testing in Identifying HIV-Infected Pregnant Women Eligible for Antiretroviral Therapy

Mnyani, Coceka N. MBChB, FCOG (SA)*; McIntyre, James A. MBChB, FRCOG*,†; Myer, Landon MBChB, PhD

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Author Information

*Anova Health Institute, Johannesburg, South Africa

Centre for Infectious Diseases Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.

Correspondence to: Coceka N. Mnyani, MBChB, FCOG (SA), Anova Health Institute, 12 Sherborne Road, Parktown, 2193, Johannesburg, South Africa (e-mail: mnyani@anovahealth.co.za).

The Anova Health Institute's Soweto PMTCT programme is supported by the US President's Emergency Plan for AIDS Relief (PEPFAR) via the US Agency for International Development, under Cooperative Agreement No. 674-A-00-08-00009-00. L. Myer was supported by an International Leadership Award from the Elizabeth Glaser Pediatric AIDS Foundation.

The authors have no conflicts of interest to disclose.

The views expressed in this report do not necessarily reflect those of PEPFAR or USAID.

Received December 15, 2011

Accepted March 19, 2012

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Abstract

Objective: Point-of-care (POC) CD4 testing may play an important role in identifying individuals who require antiretroviral therapy (ART), particularly during pregnancy. However, there have been no evaluations of POC CD4 testing in pregnant women. We compared the performance of the PIMA POC analyzer with laboratory-based testing in identifying pregnant women eligible for ART.

Design and Methods: Participants were 296 consecutive HIV-infected pregnant women in a prevention of mother-to-child transmission of HIV service in Johannesburg, South Africa. Parallel CD4+ cell count testing was done using capillary specimens for the PIMA analyzer and venous samples for flow cytometry.

Results: The median age was 28 years, and the median gestation was 19 weeks (interquartile range, IQR, 16–24). The median PIMA and laboratory CD4+ cell counts were 352 cells (IQR, 251–491) cells per cubic millimeter and 367 (IQR, 251–524) cells per cubic millimeter, respectively. The mean difference between the PIMA and the laboratory CD4 results was 20.5 (95% confidence interval: 11.7 to 29.3) cells per cubic millimeter with limits of agreement from −133.9 to 175.0. The PIMA correctly identified 93% of women who were ART eligible based on a laboratory CD4+ ≤350 cells per cubic millimeter. There was no evidence of variability in the agreement of PIMA and laboratory-based CD4 testing by participant age or gestation.

Conclusions: These data show good agreement between the PIMA analyzer and laboratory-based CD4 enumeration, comparable to levels in nonpregnant HIV-infected adults. The reliability of the PIMA did not vary with gestation despite the hemodilution of pregnancy. POC CD4 technologies may be used to identify ART-eligible women in prevention of mother-to-child transmission of HIV settings to help promote the rapid initiation of ART.

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INTRODUCTION

The use of antiretroviral therapy (ART) in eligible HIV-infected pregnant women significantly decreases the risk of mother-to-child transmission (MTCT) of HIV and reduces maternal morbidity and mortality.1,2 Given that the majority of vertical transmission takes place in women who are ART eligible, identifying these women during antenatal care and initiating ART during pregnancy is an important function of the programs to prevent MTCT.3 CD4+ cell count testing is critical to determine ART eligibility in pregnant women because a large proportion of HIV-infected pregnant women have asymptomatic HIV disease but a high prevalence of immunosuppression.4 A recent review found that clinical staging detected only 23% of ART-eligible pregnant women, whereas immunologic assessment identified 94%.5

Although CD4 testing is critical for identifying ART eligibility, the availability of testing is often a barrier to accessing ART.5 In low- and middle-income countries reporting data in 2010, only 30% of HIV-infected pregnant women were assessed for ART eligibility using CD4+ cell count testing.6 In many resource-limited settings, there is limited access to CD4+ cell count testing technology; where CD4 testing is available, laboratory-based testing requires specimen transport and the return of results, introducing delays in ART initiation.7 ART-eligible patients often have to visit health care facilities several times before they receive their CD4+ cell count results and for those who qualify to be initiated on ART.7 The need for repeat clinic visits before ART initiation is one of the key factors contributing to large numbers of patients being lost to initiation, both in pregnancy and routine care. These delays are a particular concern during pregnancy where the timing of ART initiation can be critical in MTCT.8

Point-of-care (POC) CD4+ cell count testing has been suggested as a possible solution to the problems of limited access to and problematic delays in laboratory-based CD4+ cell count testing.8 POC CD4 testing allows for testing in the patient care setting, and results are available within minutes of sample collection. There are several POC CD4 technologies: results may be either qualitative around a particular threshold or quantitative and expressed as an absolute CD4+ cell count and/or a CD4+ percentage.9,10 Existing data from nonpregnant adults suggest that POC CD4 technologies that provide absolute CD4+ cell counts seem to have good agreement with laboratory-based flow cytometetry.11–15 Preliminary evidence suggests that POC testing can improve adult HIV care by increasing the number of adults initiated on ART and decreasing the time to ART initiation.16–18

Despite the potential impact of POC CD4+ testing, there has been little research on its role in ART initiation in pregnancy. To address these issues, we investigated the performance of a POC CD4 analyzer in an antenatal clinic setting in Johannesburg, South Africa.

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MATERIALS AND METHODS

Between January and September 2011, we enrolled consecutive HIV-infected pregnant women making their first visit to a large primary care antenatal clinic, Chiawelo Clinic. The clinic is a high volume high HIV prevalence clinic, and during the study period, 1862 pregnant women presented to the clinic as first visits; the HIV prevalence was 24%. This was a prospective study, and women were enrolled if they consented to having laboratory and PIMA CD4+ cell count tests done. After routine care in this setting, all pregnant women were offered an HIV test at the first visit, and for those who tested HIV positive, a venous specimen for a CD4+ cell count was collected and a 1-week return date was given for collection of results. HIV testing was done using Advanced Quality Rapid Anti-HIV (1&2) Test (In Tec Products, Inc, Xiamen, China) as the screening test and the First Response HIV Card Test 1-2.0 (PMC Medical) as the confirmatory test.

In the study, all participants had capillary blood specimens taken for the PIMA analyzer (Alere; Alere Healthcare, Waltham, MA) following the manufacturer's instructions and using the specified lancets. Capillary blood specimens were processed for each patient immediately after being drawn. The PIMA analyzer is a POC CD4 testing device that reports the absolute CD4+ cell count. The analyzer uses disposable cartridges that require 25 μL of capillary or venous whole blood, and the CD4 result is ready within 20 minutes of testing.19 One PIMA CD4 analyzer device was used for all participants, and daily quality control using standard beads was done before using the machine, per manufacturer's instructions. Antenatal clinic staffs were trained on correct fingerprick sampling method for capillary specimens and the use of the device. The majority of PIMA CD4 tests were done by one staff member and a professional midwife working in the antenatal clinic, and the rest of the tests were done by other trained nurses in the clinic.

Specimens for laboratory-based CD4+ cell count testing were collected by antenatal clinic staff in EDTA-filled blood tubes within an hour of PIMA CD4 testing, laboratory specimens were collected from the clinic twice a day, and testing was done by the South African National Health Laboratory Service within 24 hours of phlebotomy. Laboratory-based CD4+ cell count testing was done on a Beckman Coulter Flow Cytometer (Beckman Coulter, Miami, FL) using the standardized panleucogating/CD4 method.20 Daily quality control material was analyzed to assess instrument stability, reproducibility, and accuracy (FlowCheck beads; Immunotrol low and normal levels; Beckman Coulter). The referring laboratory participates in the South African National Health Laboratory Services External Quality Assurance (SA-NHLS-EQA) programme21 and the Beckman Coulter Interlaboratory Quality Assurance Programme (IQAP).22 With these controls in place, there is an acceptable bias within the laboratory-based CD4 enumeration of ±30 cells when the absolute count is 350 cells per cubic millimeter or less.

Information on the participants' age, ART use, and gestational age at the first antenatal visit was collected from the clinic records. Participant identifiers were removed from the database once data analysis was complete. The study was approved by the University of the Witwatersrand's Human Research Ethics Committee. Participants provided verbal informed consent for laboratory and PIMA CD4 testing; PIMA test results were not used to make treatment decisions.

Data were analyzed using Stata version 11.0 (Stata Corporation, College Station, TX). Distributions of CD4+ cell counts are described using medians (with interquartile ranges, IQR) and means (with standard deviations). The overall performance of the PIMA CD4 analyzer compared with laboratory CD4 testing was assessed using the method of Bland and Altman,23 comparing the difference between the 2 methods by their average. Pitman test was used to examine the equality of variances in the difference over the range of average CD4 cell counts.24 We calculated sensitivity and specificity of PIMA-based CD4 enumeration in detecting ART eligibility based on a laboratory CD4 value of <350 cells per cubic millimeter following World Health Organization guidelines, with corresponding positive and negative predictive values and 95% confidence intervals (CI). Analyses were stratified by categories of patients' age and gestational age. Linear regression models with standard model diagnostics were used to examine if age or gestational age (both examined in continuous or categorical forms) were associated with the intraindividual difference between PIMA and laboratory CD4 values. All statistical tests are 2 sided at alpha = 0.05.

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RESULTS

Of the 397 consecutive women diagnosed during the study period, a total of 305 participants were included in the study, of whom 287 (94%) were ART naive. Nine participants were excluded from the final analysis due to missing CD4+ cell count results: 8 missing laboratory results and 1 missing PIMA result due to machine error. Gestational ages were not available for 6 participants.

The characteristics of the participants are presented in Table 1. The majority of pregnant women presented for their first antenatal visit in the second trimester; the median gestational age at booking was 19 (IQR, 16–24) weeks; and the median age was 28 (IQR, 24–32) years. The median PIMA CD4 result was 352 (IQR, 251–491) cells per cubic millimeter, and the median laboratory CD4 result was 367 (IQR, 251–524) cells per cubic millimeter. There were 134 (45%) participants with CD4+ cell counts ≤350 cells per cubic millimeter according to the laboratory CD4 results and 146 (49%) according to the PIMA CD4.

Table 1
Table 1
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Figure 1 shows a scatter plot of laboratory-based versus PIMA CD4 cell counts (Pearson product–moment correlation coefficient, 0.939). The mean difference between the PIMA and the laboratory CD4 results was 20.5 cells per cubic millimeter (CI: 11.7 to 29.3) with limits of agreement from −133.9 to 175.0 (Pitman test, P < 0.001; Fig. 2). The median difference between the laboratory and the PIMA CD4 results was 9 cells per cubic millimeter (IQR, −60 to +20). When the analysis was restricted to subgroups of participant age and gestation (Table 2), there was no significant variability in the level of agreement related to age or gestational age categories. In a linear regression model, neither participant age nor gestational age (whether modeled as continuous or categorical variables) was associated with the difference between laboratory and PIMA CD4 results (not shown).

Figure 1
Figure 1
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Table 2
Table 2
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Figure 2
Figure 2
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Table 3 shows the performance characteristics of the PIMA analyzer in detecting ART eligibility based on a laboratory CD4+ cell count threshold of 350 cells per cubic millimeter. The overall percent agreement was 89. The PIMA CD4 analyzer was able to accurately identify 93% (124 of 134) of pregnant women as ART eligible (95% CI: 87% to 96%). Of the 10 participants misdiagnosed as ART ineligible, the median PIMA CD4+ cell count was 379 (range, 351–442) cells per cubic millimeter. The PIMA also misdiagnosed 7% (22 of 296) of the participants as ART eligible when their laboratory CD4+ cell counts were >350 cells per cubic millimeter; the median PIMA CD4+ cell count in this group was 315 (range, 171–350) per cubic millimeter. The positive predictive value of the PIMA in detecting ART eligibility based on laboratory CD4+ cell counts ≤350 cells per cubic millimeter was 85% and the negative predictive value was 93%. When this analysis was subdivided into strata of participant age and gestation age at CD4+ cell count testing, there was little change in the performance characteristics of the PIMA analyzer.

Table 3
Table 3
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DISCUSSION

In this study, the performance of the PIMA CD4 analyzer in HIV-infected pregnant women appeared comparable to that of laboratory-based CD4 testing. There was a good agreement between the 2 measures: using a laboratory CD4+ cell count threshold of 350 cells per cubic millimeter, the PIMA CD4 analyzer was able to accurately identify 93% of pregnant women as ART eligible. Importantly, gestational age had no effect on the agreement between the 2 measures and also no effect on the performance of the PIMA analyzer in diagnosing ART eligibility.

The results on the reliability of the PIMA CD4 analyzer are consistent with findings from other evaluations in nonpregnant adults.11–15 However, to our knowledge, this is the first study to focus on the performance of the PIMA CD4 analyzer in HIV-infected pregnant women, and the results have important implications for ART initiation in pregnancy. Access to CD4+ cell count testing remains one of the most important barriers to HIV-infected pregnant women who may require ART during pregnancy for both maternal and child health. The availability of reliable POC CD4 testing in a prevention of mother-to-child transmission of HIV (PMTCT) setting has the potential to decrease time to initiation and increase the number of ART-eligible pregnant women who started on treatment. Among nonpregnant adults, observational studies assessing the impact of POC CD4 testing found a decrease in the proportion of patients lost to follow-up before ART initiation, a decrease in time to initiation, and an increase in the number initiated on ART.16–18 The potential impact of POC CD4 testing on ART initiation in eligible pregnant women requires urgent additional attention, as eliminating delays in ART initiation may result in improved outcomes for both HIV-infected mothers and their HIV-exposed infants.25 In many resource-limited settings, including South Africa, maternal and infant mortality rates have not decreased, largely due to HIV infection.26,27 Timely initiation of ART has an important role to play in reducing both maternal and infant morbidity and mortality.

Concerns have been raised about using the absolute CD4+ cell count to assess eligibility for ART in pregnant women. Pregnancy-associated hemodilution is associated with a decrease in absolute CD4+ cell count but not the CD4+ cell percentage.28,29 Despite calls to rather use the CD4+ cell percentage to assess for ART eligibility in pregnancy, the absolute CD4+ cell count continues to be used, even in the latest World Health Organization's guidelines.30 This evaluation focused on a technology that provides absolute CD4+ cell counts, and further research is required to evaluate POC CD4+ technologies that can provide CD4+ cell percentages.

Although the results from this study demonstrate the reliability of 1 type of POC CD4 testing in pregnant women, there is a need for more information on the operational aspects of POC CD4 technologies in an antenatal clinic setting. There is a limit to the number of CD4+ cell count tests that can be done per day using 1 machine, and this is an important consideration in high-volume clinics in settings where the antenatal HIV prevalence is high. The cost of buying several POC CD4 analyzers may be prohibitive in resource-constrained settings where the technology is most needed although there are data to suggest that the cost of the machines and consumables may offset high testing volumes.31

Data from this study should be interpreted in light of several important limitations. The study was conducted in a single antenatal clinic, and although this facility is broadly representative of antenatal care facilities in this setting, the results may not be generalizable to other countries. A single PIMA analyzer was used, and the majority of CD4 tests—88%—were done by 1 professional nurse; there may be heterogeneity in agreement between PIMA machines and operators, and this warrants further consideration. There was also no information on patient and provider acceptability of CD4 testing using the PIMA analyzer. However, there are also several notable strengths to our study: the large sample size, the sampling of consecutive HIV-infected pregnant women presenting to the antenatal clinic, and the wide range of CD4+ cell counts in the sample.

In summary, these data suggest good agreement between the PIMA CD4 analyzer and laboratory-based CD4 testing, similar to results obtained in other adult populations, with no variability by gestation. POC CD4 testing has a potentially important role in prevention of mother-to-child transmission of HIV settings, especially in resource-constrained settings, and further research is required on the operational aspects of POC CD4 testing PMTCT services.

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ACKNOWLEDGMENTS

The authors would like to acknowledge the patients and staff at Chiawelo Antenatal Clinic, Johannesburg, Soweto, and Alere Healthcare for providing the PIMA CD4 analyzer that was used in the study. The authors would also like to acknowledge Dr. Lindi Coetzee for providing information on quality assurance and control measures used for laboratory CD4 testing.

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Keywords:

HIV; pregnancy; CD4; point-of-care testing; antiretroviral therapy; South Africa

© 2012 Lippincott Williams & Wilkins, Inc.

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