Development of a multiplex fully automated assay for rapid quantification of CD4+ T cells from whole blood.

The development of cost-effective and rapid assays for the accurate counting of CD4 cells has remained prime focus for disease management. The lack of such assays has severely affected people living in resource-limited disease prevalent areas. CD4 count information plays a vital role in the effective management of HIV disease. There is an unmet need to develop rapid, cost-effective, portable and user-friendly point-of-care (POC) disease diagnostic platform technology for CD4+ T cell counting. Here, we have developed a flow-free magnetic actuation platform that uses antibody-coated magnetic beads to efficiently capture CD4+ T cells from a 30 µL drop of whole blood. On-chip cell lysate electrical impedance spectroscopy has been utilized to quantify the isolated CD4 cells. The developed assay has a limit of detection of 25 cells per µL and provides accurate CD4 counts in the range of 25-800 cells per µL. The whole immunoassay along with the enumeration process is very rapid and provides CD4 quantification results within 5 min time frame. The assay does not require off-chip sample preparation steps and minimizes human involvement to a greater extent. The developed impedance-based immunoassay has potential to significantly improve the CD4 enumeration process especially for POC settings.

Field Performance and Diagnostic Accuracy of a Low-Cost Instrument-Free Point-of-Care CD4 Test (Visitect CD4) Performed by Different Health Worker Cadres among Pregnant Women.

Measuring CD4 counts remains an important component of HIV care. The Visitect CD4 is the first instrument-free low-cost point-of-care CD4 test with results interpreted visually after 40 min, providing a result of ≥350 CD4 cells/mm3 The field performance and diagnostic accuracy of the test was assessed among HIV-infected pregnant women in South Africa. A nurse performed testing at the point-of-care using both venous and finger-prick blood, and a counselor and laboratory staff tested venous blood in the clinic laboratory (four Visitect CD4 tests/participant). Performance was compared to the mean CD4 count from duplicate flow cytometry tests on venous blood (FACSCalibur Trucount). In 2017, 156 patients were enrolled, providing a total of 624 Visitect CD4 tests (468 venous and 156 finger-prick samples). Of 624 tests, 28 (4.5%) were inconclusive. Generalized linear mixed modeling showed better performance of the test on venous blood (sensitivity = 81.7%; 95% confidence interval [CI] = 72.3 to 91.1]; specificity = 82.6%, 95% CI = 77.1 to 88.1) than on finger-prick specimens (sensitivity = 60.7%; 95% CI = 45.0 to 76.3; specificity = 89.5%, 95% CI = 83.2 to 95.8; P = 0.001). No difference in performance was detected by cadre of health worker (P = 0.113) or between point-of-care versus laboratory-based testing (P = 0.108). Adequate performance of Visitect CD4 with different operators and at the point of care, with no need of electricity or instrument, shows the potential utility of this device, especially for facilitating decentralization of CD4 testing services in rural areas.

Enhancing value and lowering costs of care: a qualitative exploration of a randomized linkage to care intervention in South Africa.

While interventions to improve HIV linkage and retention in care exist, none have demonstrated results sufficient to reach UNAIDS 90-90-90 goals. We explored values and costs of seeking clinical care through testing three strategies to improve linkage to care: Point of care CD4 testing alone (POC-CD4), POC-CD4 combined with transportation support and combined with care facilitation. We conducted in-depth interviews with participants and transcribed audio-recordings of care facilitation sessions. Participants described values and costs enhanced or addressed by the three interventions. Psychosocial support provided through the care facilitation intervention appeared salient. Participants named other values and costs of seeking care unrelated to the intervention, such as encouragement from healthcare workers and aversion to lifelong treatment. Combined with the quantitative results of this trial, these findings may point to why the care facilitation arm was successful but not the POC-CD4 only or transportation arms. It also provides guidance for future interventions.

Performance evaluation of an automated image-based fluorescence CD4+ cell analyzer.

BACKGROUND: Although AIDS-related mortality has declined since the introduction of antiretroviral therapy (ART), HIV/ AIDS patients are predominantly present in developing countries that lack high-cost diagnostic devices and human expertise. OBJECTIVE: New methods for counting CD4+ cells cost-effectively are needed to replace conventional flow cytometry-based diagnosis. METHODS: We developed a CD4+ cell analyzer, ADAMII, which is a benchtop fluorescence image-based CD3+/4+ cell counting analyzer. It bears a three-channel light source and performs CD3+/4+ counting assays. The automatic 3D stage captures a maximum of 136 images that are subsequently processed and analyzed using a software integrated into the system. RESULTS: Results obtained using ADAMII were compared with data obtained by conventional methods using a FACSCalibur flow cytometer and the point-of-care PIMA CD4 analyzer. Both comparisons between ADAMII vs. FACS and ADAMII vs. PIMA data yielded a strong correlation with an R2 value of 0.98, which ensures the feasibility of CD4 test by ADAMII. CONCLUSIONS: The proposed method using ADAMII can be easily employed in resource-limited areas to replace conventional flow cytometers, which are expensive and require highly trained staff.

Cost-Effectiveness Analysis of Early vs Late Diagnosis of HIV-Infected Patients in South Carolina.

OBJECTIVES: It is anticipated that early diagnosis, linkage to care, initiation of antiretroviral therapy (ART), and retention in care would lead to reduced opportunistic infections, reduction in human immunodeficiency virus-related morbidity and mortality and reduced rates of HIV transmission. This would be expected to lead to a reduction in the lifetime cost of care (LCC). This study analyzed existing data to determine to what extent early-versus-late HIV diagnosis affects LCC. METHODS: The South Carolina Department of Health and Environmental Control electronic HIV/acquired immunodeficiency syndrome reporting system data were used for this study. The first CD4 and viral load reported to the Enhanced HIV/AIDS Reporting System of the Centers for Disease Control and Prevention are considered the initial CD4 and viral load. Late HIV diagnosis was based on a CD4 count ≤200 at diagnosis. A previously validated simulation model developed by the John Snow Institute for the South Carolina Department of Health and Environmental Control was used to determine the discounted LCC. Comparisons were made between late and early HIV diagnosis. RESULTS: From 2013 through 2015, 2138 individuals were diagnosed as having HIV in South Carolina; 180 individuals were excluded from further analysis because an initial CD4 count was missing. Final analysis was based on 1958 individuals. Late HIV diagnosis occurred in 509 individuals (26%). When stratified based on CD4 count at diagnosis, the discounted LCC per person in those with an initial CD4 count ≤200 was $262,374 and in those with an initial CD4 count >500 was $416,766. Those with lower CD4 counts at diagnosis had more lost quality-adjusted life-years (QALYs; 7.95 QALYs lost per person with an initial CD4 count ≤200 compared with 4.45 QALYs lost per person with an initial CD4 count >500), more lifetime HIV transmissions (1.4 per person with an initial CD4 count ≤200 compared with 0.72 per person with an initial CD4 count >500), and lower additional life expectancy (30.73 additional years with an initial CD4 count ≤200 compared with 38.08 additional years with an initial CD4 count >500). CONCLUSIONS: Although individuals with lower CD4 counts at diagnosis had a lower discounted LCC, they had more lost QALYs, more lifetime HIV transmissions, and lower additional life expectancy.

The value of point-of-care CD4+ and laboratory viral load in tailoring antiretroviral therapy monitoring strategies to resource limitations.

OBJECTIVE: To examine the clinical and economic value of point-of-care CD4 (POC-CD4) or viral load monitoring compared with current practices in Mozambique, a country representative of the diverse resource limitations encountered by HIV treatment programs in sub-Saharan Africa. DESIGN/METHODS: We use the Cost-Effectiveness of Preventing AIDS Complications-International model to examine the clinical impact, cost (2014 US$), and incremental cost-effectiveness ratio [$/year of life saved (YLS)] of ART monitoring strategies in Mozambique. We compare: monitoring for clinical disease progression [clinical ART monitoring strategy (CLIN)] vs. annual POC-CD4 in rural settings without laboratory services and biannual laboratory CD4 (LAB-CD4), biannual POC-CD4, and annual viral load in urban settings with laboratory services. We examine the impact of a range of values in sensitivity analyses, using Mozambique's 2014 per capita gross domestic product ($620) as a benchmark cost-effectiveness threshold. RESULTS: In rural settings, annual POC-CD4 compared to CLIN improves life expectancy by 2.8 years, reduces time on failed ART by 0.6 years, and yields an incremental cost-effectiveness ratio of $480/YLS. In urban settings, biannual POC-CD4 is more expensive and less effective than viral load. Compared to biannual LAB-CD4, viral load improves life expectancy by 0.6 years, reduces time on failed ART by 1.0 year, and is cost-effective ($440/YLS). CONCLUSION: In rural settings, annual POC-CD4 improves clinical outcomes and is cost-effective compared to CLIN. In urban settings, viral load has the greatest clinical benefit and is cost-effective compared to biannual POC-CD4 or LAB-CD4. Tailoring ART monitoring strategies to specific settings with different available resources can improve clinical outcomes while remaining economically efficient.

Co-financing for viral load monitoring during the course of antiretroviral therapy among patients with HIV/AIDS in Vietnam: A contingent valuation survey.

BACKGROUND: Viral load testing is considered the gold standard for monitoring HIV treatment; however, given its high cost, some patients cannot afford viral load testing if this testing is not subsidized. Since foreign aid for HIV/AIDS in Vietnam is rapidly decreasing, we sought to assess willingness to pay (WTP) for viral load and CD4 cell count tests among HIV-positive patients, and identified factors that might inform future co-payment schemes. METHODS: A multi-site cross-sectional survey was conducted with 1133 HIV-positive patients on antiretroviral therapy (ART) in Hanoi and Nam Dinh. Patients' health insurance coverage, quality of life, and history of illicit drug use were assessed. A contingent valuation approach was employed to measure patients' WTP for CD4 cell count and viral load testing. RESULTS: HIV-positive patients receiving ART at provincial sites reported more difficulty obtaining health insurance (HI) and had the overall the poorest quality of life. Most patients (90.9%) were willing to pay for CD4 cell count testing; here, the mean WTP was valued at US$8.2 (95%CI = 7.6-8.8 US$) per test. Most patients (87.3%) were also willing to pay for viral load testing; here, mean WTP was valued at US$18.6 (95%CI = 16.3-20.9 US$) per test. High income, high education level, and hospitalization were positively associated with WTP, while co-morbidity with psychiatric symptoms and trouble paying for health insurance were both negatively related to WTP. CONCLUSIONS: These findings raise concerns that HIV-positive patients in Vietnam might have low WTP for CD4 cell count and viral load testing. This means that without foreign financial subsidies, many of these patients would likely go without these important tests. Treating psychiatric co-morbidities, promoting healthcare services utilization, and removing barriers to accessing health insurance may increase WTP for monitoring of HIV/AIDS treatment among HIV+-positive Vietnamese patients.

POC CD4 Testing Improves Linkage to HIV Care and Timeliness of ART Initiation in a Public Health Approach: A Systematic Review and Meta-Analysis.

BACKGROUND: CD4 cell count is an important test in HIV programs for baseline risk assessment, monitoring of ART where viral load is not available, and, in many settings, antiretroviral therapy (ART) initiation decisions. However, access to CD4 testing is limited, in part due to the centralized conventional laboratory network. Point of care (POC) CD4 testing has the potential to address some of the challenges of centralized CD4 testing and delays in delivery of timely testing and ART initiation. We conducted a systematic review and meta-analysis to identify the extent to which POC improves linkages to HIV care and timeliness of ART initiation. METHODS: We searched two databases and four conference sites between January 2005 and April 2015 for studies reporting test turnaround times, proportion of results returned, and retention associated with the use of point-of-care CD4. Random effects models were used to estimate pooled risk ratios, pooled proportions, and 95% confidence intervals. RESULTS: We identified 30 eligible studies, most of which were completed in Africa. Test turnaround times were reduced with the use of POC CD4. The time from HIV diagnosis to CD4 test was reduced from 10.5 days with conventional laboratory-based testing to 0.1 days with POC CD4 testing. Retention along several steps of the treatment initiation cascade was significantly higher with POC CD4 testing, notably from HIV testing to CD4 testing, receipt of results, and pre-CD4 test retention (all p<0.001). Furthermore, retention between CD4 testing and ART initiation increased with POC CD4 testing compared to conventional laboratory-based testing (p = 0.01). We also carried out a non-systematic review of the literature observing that POC CD4 increased the projected life expectancy, was cost-effective, and acceptable. CONCLUSIONS: POC CD4 technologies reduce the time and increase patient retention along the testing and treatment cascade compared to conventional laboratory-based testing. POC CD4 is, therefore, a useful tool to perform CD4 testing and expedite result delivery.

How Will New Guidelines Affect CD4 Testing in Veterans With HIV?

BACKGROUND: Guidelines now recommend limited use of routine CD4 cell count testing in human immunodeficiency virus (HIV)-infected patients with successful viral control who are not immunocompromised. METHODS: CD4 and viral load tests for patients receiving HIV care from the US Department of Veterans Affairs during 2009-2013 were evaluated to determine trends in CD4 testing frequency and the number, cost, and results of CD4 tests considered optional under the guidelines. RESULTS: There were 28 530 individuals with sufficient testing to be included. At the time of the last CD4 test, 19.8% of the cohort was eligible for optional monitoring and 15.6% for minimal monitoring. CD4 testing frequency declined by 10.8% over 4 years, reducing the direct cost of testing by US$196 000 per year. Full implementation of new treatment guidelines could reduce CD4 testing a further 28.9%, an additional annual savings of US$600 000. CD4 tests conducted during periods of potentially reduced monitoring were rarely <200 cells/µL: 1.1% of the tests conducted when minimal monitoring was recommended and just 0.3% of tests conducted when optional monitoring was recommended were less than this value. CONCLUSIONS: Reduced CD4 monitoring of HIV-infected patients would result in modest cost savings and likely reduce patient anxiety, with little or no impact on the quality of care. Veterans Affairs has made substantial progress in reducing the frequency of optional CD4 testing, but further reductions may still be warranted.

Early Treatment in HIV Patients: A Cost-Utility Analysis from the Italian Perspective.

BACKGROUND AND OBJECTIVE: Highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections and mortality. Several recent studies show early antiretroviral therapy reduces the risk of AIDS and HIV-related disease. The aim of this study was to perform an economic analysis to estimate the cost-utility of early antiretroviral therapy in Italy for managing HIV-infected patients. METHODS: The incremental cost-utility analysis was carried out to quantify the benefits of the early-treatment approach in HIV subjects. A Markov simulation model including direct costs and health outcomes was developed from a third-party (Italian National Healthcare Service) payer's perspective for four CD4 strata. 5000 Monte Carlo simulations were performed on two distinct scenarios: Standard of care (SoC) in which 30% of patients started HAART with a CD4 count ≥500 cells/mm(3) versus the early-treatment scenario (ETS), where the number of patients starting HAART with a CD4 count ≥500 cells/mm(3) increased to 70%. A systematic literature review was carried out to identify epidemiological and economic data, which were subsequently used to inform the model. In addition, a one-way probabilistic sensitivity analysis was performed in order to measure the relationship between the effectiveness of the treatments and the number of patients to undergo early treatment. RESULTS: The model shows, in terms of the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY) gained, that early treatment appeared to be the most cost-effective option compared to SoC (ICER = €13,625) over a time horizon of 10 years. The cost effectiveness of ETS is more sustainable as it extends the time horizon analysis (ICER = €7526 per QALY to 20 years and €8382 per QALY to 30 years). The one-way sensitivity analysis on the main variables confirmed the robustness of the model for the early-treatment approach. CONCLUSION: Our model represents a tool for policy makers and health-care professionals to provide information on the cost effectiveness of the early-treatment approach in HIV-infected patients in Italy. Starting HAART earlier keeps HIV-infected patients in better health and reduces the incidence of AIDS- and non-AIDS-related events, generating a gain in terms of both patients' health and correct resource allocation.

Cost-effectiveness of population-level expansion of highly active antiretroviral treatment for HIV in British Columbia, Canada: a modelling study.

BACKGROUND: Widespread HIV screening and access to highly active antiretroviral treatment (ART) were cost effective in mathematical models, but population-level implementation has led to questions about cost, value, and feasibility. In 1996, British Columbia, Canada, introduced universal coverage of drug and other health-care costs for people with HIV/AIDS and and began extensive scale-up in access to ART. We aimed to assess the cost-effectiveness of ART scale-up in British Columbia compared with hypothetical scenarios of constrained treatment access. METHODS: Using comprehensive linked population-level data, we populated a dynamic, compartmental transmission model to simulate the HIV/AIDS epidemic in British Columbia from 1997 to 2010. We estimated HIV incidence, prevalence, mortality, costs (in 2010 CAN$), and quality-adjusted life-years (QALYs) for the study period, which was 1997-2010. We calculated incremental cost-effectiveness ratios from societal and third-party-payer perspectives to compare actual practice (true numbers of individuals accessing ART) to scenarios of constrained expansion (75% and 50% probability of accessing ART). We also investigated structural and parameter uncertainty. FINDINGS: Actual practice resulted in 263 averted incident cases compared with 75% of observed access and 676 averted cases compared with 50% of observed access to ART. From a third-party-payer perspective, actual practice resulted in incremental cost-effectiveness ratios of $23 679 per QALY versus 75% access and $24 250 per QALY versus 50% access. From a societal perspective, actual practice was cost saving within the study period. When the model was extended to 2035, current observed access resulted in cumulative savings of $25·1 million compared with the 75% access scenario and $65·5 million compared with the 50% access scenario. INTERPRETATION: ART scale-up in British Columbia has decreased HIV-related morbidity, mortality, and transmission. Resulting incremental cost-effectiveness ratios for actual practice, derived within a limited timeframe, were within established cost-effectiveness thresholds and were cost saving from a societal perspective. FUNDING: BC Ministry of Health, National Institute of Drug Abuse at the US National Institutes of Health.

Monitoring of HIV treatment in seven countries in the WHO Region of the Americas.

OBJECTIVE: To determine the prevalence of adequate monitoring and the costs of measuring CD4+ T-lymphocytes (CD4+ cell) and human immunodeficiency virus (HIV) viral load in people receiving antiretroviral therapy (ART) in seven countries in the WHO Region of the Americas. METHODS: We obtained retrospective, longitudinal data for 14 476 adults who started a first ART regimen at seven HIV clinics in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru between 2000 and 2011. We estimated the proportion of 180-day periods with adequate monitoring, which we defined as at least one CD4+ cell count and one viral load measurement. Factors associated with adequate monitoring were analysed using regression methods. The costs of the tests were estimated. FINDINGS: The median follow-up time was 50.4 months; the proportion of 180-day periods with adequate CD4+ cell counts was 69% while the proportion with adequate monitoring was 62%. Adequate monitoring was more likely in participants who were older, who started ART more recently, whose first regimen included a non-nucleoside reverse transcriptase inhibitor or who had a CD4+ cell count less than 200 cells/µl at ART initiation. The cost of one CD4+ cell count ranged from 7.37 United States dollars (US$) in Argentina to US$ 64.09 in Chile; the cost of one viral load measurement ranged from US$ 20.34 in Brazil to US$ 186.28 in Haiti. CONCLUSION: In HIV-infected participants receiving ART in the WHO Region of the Americas, CD4+ cell count and viral load monitoring was often carried out less frequently than regional guidelines recommend. The laboratory costs of monitoring varied greatly.

Point-of-care CD4 testing to inform selection of antiretroviral medications in south african antenatal clinics: a cost-effectiveness analysis.

BACKGROUND: Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays. METHODS: We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO "Option A"): antenatal zidovudine (CD4 ≤350/µL) or ART (CD4>350/µL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/life-year saved). RESULTS: In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs. CONCLUSIONS: In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection.

Benefits of task-shifting HIV care to nurses in terms of health-related quality of life in patients initiating antiretroviral therapy in rural district hospitals in Cameroon [Stratall Agence Nationale de Recherche sur le SIDA (ANRS) 12110/Ensemble pour une Solidarité Thérapeutique Hospitalière en Réseau (ESTHER) substudy].

OBJECTIVES: The World Health Organization (WHO) recommends task-shifting HIV care to nurses in low-resource settings with limited numbers of physicians. However, the effect of such task-shifting on the health-related quality of life (HRQL) of people living with HIV (PLHIV) has seldom been evaluated. We aimed to investigate the effect of task-shifting HIV care to nurses on HRQL outcomes in PLHIV initiating antiretroviral therapy (ART) in rural district hospitals in Cameroon. METHODS: Outcomes in PLHIV were longitudinally collected in the 2006-2010 Stratall trial. PLHIV were followed up for 24 months by nurses and/or physicians. Six HRQL dimensions were assessed during face-to-face interviews using the WHO Quality of Life (WHOQOL)-HIV BREF scale: physical health; psychological health; independence level; social relationships; environment; and spirituality/religion/personal beliefs. The degree of task-shifting was estimated using a consultant ratio (i.e. the ratio of nurse-led to physician-led visits). The effect of task-shifting and other potential correlates on HRQL dimensions was explored using a Heckman two-stage approach based on linear mixed models to adjust for the potential bias caused by missing data in the outcomes. RESULTS: Of 1424 visits in 440 PLHIV (70.5% female; median age 36 years; median CD4 count 188 cells/µL at enrolment), 423 (29.7%) were task-shifted to nurses. After multiple adjustment, task-shifting was associated with higher HRQL level for four dimensions: physical health [coefficient 0.7; 95% confidence interval (CI) 0.1-1.2; P = 0.01], psychological health (coefficient 0.5; 95% CI 0.0-1.0; P = 0.05), independence level (coefficient 0.6; 95% CI 0.1-1.1; P = 0.01) and environment (coefficient 0.6; 95% CI 0.1-1.0; P = 0.02). CONCLUSIONS: Task-shifting HIV care to nurses benefits the HRQL of PLHIV. Together with the previously demonstrated comparable clinical effectiveness of physician-based and nurse-based models of HIV care, our results support the WHO recommendation for task-shifting.

Reliable and accurate CD4+ T cell count and percent by the portable flow cytometer CyFlow MiniPOC and "CD4 Easy Count Kit-Dry", as revealed by the comparison with the gold standard dual platform technology.

BACKGROUND: An accurate and affordable CD4+ T cells count is an essential tool in the fight against HIV/AIDS. Flow cytometry (FCM) is the "gold standard" for counting such cells, but this technique is expensive and requires sophisticated equipment, temperature-sensitive monoclonal antibodies (mAbs) and trained personnel. The lack of access to technical support and quality assurance programs thus limits the use of FCM in resource-constrained countries. We have tested the accuracy, the precision and the carry-over contamination of Partec CyFlow MiniPOC, a portable and economically affordable flow cytometer designed for CD4+ count and percentage, used along with the "CD4% Count Kit-Dry". MATERIALS AND METHODS: Venous blood from 59 adult HIV+ patients (age: 25-58 years; 43 males and 16 females) was collected and stained with the "MiniPOC CD4% Count Kit-Dry". CD4+ count and percentage were then determined in triplicate by the CyFlow MiniPOC. In parallel, CD4 count was performed using mAbs and a CyFlow Counter, or by a dual platform system (from Beckman Coulter) based upon Cytomic FC500 ("Cytostat tetrachrome kit" for mAbs) and Coulter HmX Hematology Analyzer (for absolute cell count). RESULTS: The accuracy of CyFlow MiniPOC against Cytomic FC500 showed a correlation coefficient (CC) of 0.98 and 0.97 for CD4+ count and percentage, respectively. The accuracy of CyFlow MiniPOC against CyFlow Counter showed a CC of 0.99 and 0.99 for CD4 T cell count and percentage, respectively. CyFlow MiniPOC showed an excellent repeatability: CD4+ cell count and percentage were analyzed on two instruments, with an intra-assay precision below ± 5% deviation. Finally, there was no carry-over contamination for samples at all CD4 values, regardless of their position in the sequence of analysis. CONCLUSION: The cost-effective CyFlow MiniPOC produces rapid, reliable and accurate results that are fully comparable with those from highly expensive dual platform systems.

Routine CD4 cell count monitoring seldom contributes to clinical decision-making on antiretroviral therapy in virologically suppressed HIV-infected patients.

OBJECTIVES: In Australia, CD4 cell count is monitored approximately every 6 months in HIV-infected patients during antiretroviral therapy (ART). The aim of this study was to determine if routine CD4 monitoring contributed to decisions on changes to ART, and to estimate how reduced CD4 monitoring could contribute to cost savings in Australia. METHODS: We conducted a retrospective cohort analysis investigating all HIV-infected patients who attended the Melbourne Sexual Health Centre (MSHC) in Australia from 1 April 2011 to 1 October 2013. We reviewed the electronic medical records of all patients who changed or stopped antiretroviral regimens during this time period to determine whether CD4 cell count could have contributed to this clinical decision. RESULTS: Among 1004 patients with HIV infection on ART, none [95% confidence interval (CI) 0-2.3%] of the 162 clinical decisions to change or stop treatment were influenced by CD4 cell counts. Reducing the current biannual CD4 monitoring strategy to annually could potentially save ∼AU$ 1.5 million (US$ 1.4 million) each year in Australia [i.e. ∼AU$ 74 700 (US$ 67 700) could be saved per 1000 HIV-infected patients during ART]. CONCLUSIONS: Routine CD4 monitoring in HIV-infected patients during ART could be reduced from biannually to annually, as it rarely influences clinical decisions in patients' management. Not only could this avoid patients being unnecessarily anxious about normal fluctuations in their CD4 counts but it would also result in cost savings.

Estimating implementation and operational costs of an integrated tiered CD4 service including laboratory and point of care testing in a remote health district in South Africa.

BACKGROUND: An integrated tiered service delivery model (ITSDM) has been proposed to provide 'full-coverage' of CD4 services throughout South Africa. Five tiers are described, defined by testing volumes and number of referring health-facilities. These include: (1) Tier-1/decentralized point-of-care service (POC) in a single site; Tier-2/POC-hub servicing processing < 30-40 samples from 8-10 health-clinics; Tier-3/Community laboratories servicing ∼ 50 health-clinics, processing < 150 samples/day; high-volume centralized laboratories (Tier-4 and Tier-5) processing < 300 or > 600 samples/day and serving > 100 or > 200 health-clinics, respectively. The objective of this study was to establish costs of existing and ITSDM-tiers 1, 2 and 3 in a remote, under-serviced district in South Africa. METHODS: Historical health-facility workload volumes from the Pixley-ka-Seme district, and the total volumes of CD4 tests performed by the adjacent district referral CD4 laboratories, linked to locations of all referring clinics and related laboratory-to-result turn-around time (LTR-TAT) data, were extracted from the NHLS Corporate-Data-Warehouse for the period April-2012 to March-2013. Tiers were costed separately (as a cost-per-result) including equipment, staffing, reagents and test consumable costs. A one-way sensitivity analyses provided for changes in reagent price, test volumes and personnel time. RESULTS: The lowest cost-per-result was noted for the existing laboratory-based Tiers- 4 and 5 ($6.24 and $5.37 respectively), but with related increased LTR-TAT of > 24-48 hours. Full service coverage with TAT < 6-hours could be achieved with placement of twenty-seven Tier-1/POC or eight Tier-2/POC-hubs, at a cost-per-result of $32.32 and $15.88 respectively. A single district Tier-3 laboratory also ensured 'full service coverage' and < 24 hour LTR-TAT for the district at $7.42 per-test. CONCLUSION: Implementing a single Tier-3/community laboratory to extend and improve delivery of services in Pixley-ka-Seme, with an estimated local ∼ 12-24-hour LTR-TAT, is ∼ $2 more than existing referred services per-test, but 2-4 fold cheaper than implementing eight Tier-2/POC-hubs or providing twenty-seven Tier-1/POCT CD4 services.

Multisite evaluation of point of care CD4 testing in Papua New Guinea.

Laboratory-based CD4 monitoring of HIV patients presents challenges in resource limited settings (RLS) including frequent machine breakdown, poor engineering support and limited cold chain and specimen transport logistics. This study assessed the performance of two CD4 tests designed for use in RLS; the Dynal assay and the Alere PIMA test (PIMA). Accuracy of Dynal and PIMA using venous blood was assessed in a centralised laboratory by comparison to BD FACSCount (BD FACS). Dynal had a mean bias of -50.35 cells/µl (r(2) = 0.973, p<0.0001, n = 101) and PIMA -22.43 cells/µl (r(2)= 0.964, p<0.0001, n = 139) compared to BD FACS. Similar results were observed for PIMA operated by clinicians in one urban (n = 117) and two rural clinics (n = 98). Using internal control beads, PIMA precision was 10.34% CV (low bead mean 214.24 cells/µl) and 8.29% (high bead mean 920.73 cells/µl) and similar %CV results were observed external quality assurance (EQA) and replicate patient samples. Dynal did not perform using EQA and no internal controls are supplied by the manufacturer, however duplicate testing of samples resulted in r(2) = 0.961, p<0.0001, mean bias =  -1.44 cells/µl. Using the cut-off of 350 cells/µl compared to BD FACS, PIMA had a sensitivity of 88.85% and specificity of 98.71% and Dynal 88.61% and 100%. A total of 0.44% (2/452) of patient samples were misclassified as "no treat" and 7.30% (33/452) "treat" using PIMA whereas with Dynal 8.91% (9/101) as "treat" and 0% as "no treat". In our setting PIMA was found to be accurate, precise and user-friendly in both laboratory and clinic settings. Dynal performed well in initial centralized laboratory evaluation, however lacks requisite quality control measures, and was technically more difficult to use, making it less suitable for use at lower tiered laboratories.

Effect of management strategies and clinical status on costs of care for advanced HIV.

OBJECTIVES: To determine the association between preexisting characteristics and current health and the cost of different types of advanced human immunodeficiency virus (HIV) care. METHODS: Treatment-experienced patients failing highly active antiretroviral treatment (ART) in the United States, Canada, and the United Kingdom were factorial randomized to an antiretroviral-free period and ART intensification. Cost was estimated by multiplying patient-reported utilization by a unit cost. RESULTS: A total of 367 participants were followed for a mean of 15.3 quarters (range 1-26). Medication accounted for most (61.8%) of the $26,832 annual cost. Cost averaged $4147 per quarter for ART, $1981 for inpatient care, $580 for outpatient care, and $346 for other medications. Cost for inpatient stays, outpatient visits, and other medications was 171% higher (P <.01) and cost of ART was 32% lower (P <.01) when cluster of differentiation 4 (CD4) count was <50 cells/µL compared with periods when CD4 count was >200 cells/µL. Some baseline characteristics, including low CD4 count, high viral load, and HIV from injection drug use with hepatitis C coinfection, had a sustained effect on cost. CONCLUSIONS: The association between health status and cost depended on the type of care. Indicators of poor health were associated with higher inpatient and concomitant medication costs and lower cost for ART medication. Although ART has supplanted hospitalization as the most important cost in HIV care, some patients continue to incur high hospitalization costs in periods when they are using less ART. The cost of interventions to improve the use of ART might be offset by the reduction of other costs.

The clinical and economic impact of point-of-care CD4 testing in mozambique and other resource-limited settings: a cost-effectiveness analysis.

BACKGROUND: Point-of-care CD4 tests at HIV diagnosis could improve linkage to care in resource-limited settings. Our objective is to evaluate the clinical and economic impact of point-of-care CD4 tests compared to laboratory-based tests in Mozambique. METHODS AND FINDINGS: We use a validated model of HIV testing, linkage, and treatment (CEPAC-International) to examine two strategies of immunological staging in Mozambique: (1) laboratory-based CD4 testing (LAB-CD4) and (2) point-of-care CD4 testing (POC-CD4). Model outcomes include 5-y survival, life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs). Input parameters include linkage to care (LAB-CD4, 34%; POC-CD4, 61%), probability of correctly detecting antiretroviral therapy (ART) eligibility (sensitivity: LAB-CD4, 100%; POC-CD4, 90%) or ART ineligibility (specificity: LAB-CD4, 100%; POC-CD4, 85%), and test cost (LAB-CD4, US$10; POC-CD4, US$24). In sensitivity analyses, we vary POC-CD4-specific parameters, as well as cohort and setting parameters to reflect a range of scenarios in sub-Saharan Africa. We consider ICERs less than three times the per capita gross domestic product in Mozambique (US$570) to be cost-effective, and ICERs less than one times the per capita gross domestic product in Mozambique to be very cost-effective. Projected 5-y survival in HIV-infected persons with LAB-CD4 is 60.9% (95% CI, 60.9%-61.0%), increasing to 65.0% (95% CI, 64.9%-65.1%) with POC-CD4. Discounted life expectancy and per person lifetime costs with LAB-CD4 are 9.6 y (95% CI, 9.6-9.6 y) and US$2,440 (95% CI, US$2,440-US$2,450) and increase with POC-CD4 to 10.3 y (95% CI, 10.3-10.3 y) and US$2,800 (95% CI, US$2,790-US$2,800); the ICER of POC-CD4 compared to LAB-CD4 is US$500/year of life saved (YLS) (95% CI, US$480-US$520/YLS). POC-CD4 improves clinical outcomes and remains near the very cost-effective threshold in sensitivity analyses, even if point-of-care CD4 tests have lower sensitivity/specificity and higher cost than published values. In other resource-limited settings with fewer opportunities to access care, POC-CD4 has a greater impact on clinical outcomes and remains cost-effective compared to LAB-CD4. Limitations of the analysis include the uncertainty around input parameters, which is examined in sensitivity analyses. The potential added benefits due to decreased transmission are excluded; their inclusion would likely further increase the value of POC-CD4 compared to LAB-CD4. CONCLUSIONS: POC-CD4 at the time of HIV diagnosis could improve survival and be cost-effective compared to LAB-CD4 in Mozambique, if it improves linkage to care. POC-CD4 could have the greatest impact on mortality in settings where resources for HIV testing and linkage are most limited. Please see later in the article for the Editors' Summary.