Background

For many years, CD4 count testing has been a key diagnostic tool to identify HIV positive patients eligible for antiretroviral therapy (ART) and monitoring patient responses to treatment. Recently, in light of new evidence supporting early treatment [1], there is a movement in policy recommendation and practice towards CD4-independent ART initiation and a number of countries have already approved treatment for all HIV infected individuals regardless of their CD4 count. However, in the near future, CD4 counts still remain an important and practical part of HIV care particularly in decision making around ART initiation, clinical management and treatment monitoring in many countries where access to viral load monitoring remains limited [2].

Availability and access to CD4 count testing has been identified as a major barrier for increasing access to ART particularly in low-resource settings where laboratory based CD4 monitoring is not always available or easy to access [3]. The lack of reliable and affordable tests in these settings leads to missed opportunities of early ART initiation and significant patient loss-to-follow up [4].

Point-of-care (POC) CD4 testing has been introduced as an approach to overcome this challenge, possessing major advantages as compared to standard laboratory-based CD4 testing by flow cytometry in primary healthcare settings that lack infrastructure support and absence of well-functioning patient and/or sample referral systems [5]. Results from recent field studies suggest that POC CD4 tests are reliable [6–8], can help to increase the likelihood of an infected person having their CD4 T-cell count measured and receive the result [9], reduce time from HIV testing to ART initiation [10, 11], facilitate rapid (same day) ART initiation among patients eligible for treatment [12, 13], reduce loss to follow up [11], and most importantly, provide an immediate CD4 count which can significantly improve patient retention on care [14].

However, there is lack of synthesis of available evidence regarding operation and implementation of POC technologies in field settings. We conducted a systematic review to assess acceptability and feasibility of currently available or prototype commercial POC CD4 tests and to identify evidence gaps from field evaluations with a geographical focus in resource-constrained settings.

Methods

Literature search strategy

This review was conducted following the requirements of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). A literature search using established search terms was first conducted in Medline to identify any study describing POC CD4 tests conducted in low and middle income countries (LMICs) published between Jan 2005 – Jan 2015 in English (see Additional file 1). The search strategy was then adapted by using the appropriate subject thesauri where available and modifying the search syntax to the relevant software platforms, and was undertaken across other electronic databases including: Embase, CENTRAL, Cinahl, PsycINFO, Biological Abstracts, Scopus and Web of Science. Searches were also conducted in grey literature resources and hand-searching of reference lists and citation was performed to identify relevant studies.

Study selection

Study inclusion criteria were defined using PICO (participants, interventions, comparisons, outcomes) format [15]. Participants (P) included HIV positive, HIV negative and unknown HIV status persons aged ≥ 12 months. For intervention (I), any of the following six commercially available POC CD4 testing platforms listed in the UNITAID “2014 HIV/AIDS Diagnosis Technology Landscape” report [16] were included: (1) PointCare NOW™ (PointCare Technology Inc, Marlborough, MA, USA); (2) Pima™ CD4 (Alere Inc, Waltham, MA, USA); (3) Daktari™ CD4 Counter (Daktari Diagnostics Inc, Cambridge MA, USA); (4) CyFlow® CD4 miniPOC (Partec, Munich, Germany); (5) BD FACSPresto™ (BD Biosciences, San Jose, CA, USA); and (6) MyT4™ CD4 Test (Zyomyx Inc, Fremont, CA, USA). Comparators/controls (C): Laboratory based CD4 test (Flow Cytometry) if applicable with outcomes (O) of interest containing information on acceptability, feasibility of POC CD4 testing in field settings (Fig. 1).

Fig. 1
figure 1

Selection process of included study for a systematic review of POC CD4 test

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Data extraction and data synthesis

A pre-constructed electronic data extraction form was developed, pre-tested and finalized by consensus among authors. Data extraction was conducted by one reviewer and verified by the second using the data extraction form with 20 % duplicate extraction (Five papers were randomly selected and data extracted independently by 2 reviewers and compared to identify discrepancies if any). Quality of included studies was assessed using either the QUADAS tool for quality assessment of diagnostic studies included in systematic review [17], the EPHPP quality assessment tool for quantitative studies [18], or a specific tool for quality assessment of qualitative studies [19].

The following data items were extracted: author (s) and year of publication, intervention (name of POC CD4 technology, training for test operators where mentioned), comparison (if applicable), population (age, gender, HIV status), study setting (types of facility, location/country), study design and sample size, and key study outcomes of interest.

Definitions and assessment of acceptability and feasibility

Acceptability and feasibility are closely linked and affect each other but they are not identical. Acceptability focuses on individual factors (provider and patient’s perspectives) while feasibility takes other system factors (infrastructure, human resource, policy) into account. Thus, one test could be acceptable to both provider and patient, but may not be feasible to be deployed in a specific setting (for example if a test device requires constant electricity supply or dedicated, well trained technicians to operate them). To assess acceptability and feasibility of POC CD4 testing in field settings, a conceptual framework initially developed to explore the feasibility, acceptance and use of a rapid diagnostic test for malaria [20] has been adapted for use in this study. From the service provider’s perspective, acceptability is assessed by the ability to understand how to correctly perform a POC CD4 test, their willingness to carry out the test when necessary as part of their daily work and their belief that the test is relevant to their work and test result is accurate. From patient’s perspective, acceptability is influenced by their willingness to have the test performed on themselves, their belief that the test is convenient to take and relevant in determining their CD4 count. Feasibility depends on acceptability and the presence or absence of supporting system factors such as training, monitoring/supervision, supplies, infrastructure such as space, light, water etc. that enable the implementation of POC CD4 testing in the field.

Based on this concept, the following pre-defined measurements were used to assess acceptability (1) uptake of POC CD4 testing: the proportion of individuals who accept a POC CD4 test (having blood samples drawn for POC CD4 test) of the total number of individuals who have been confirmed HIV positive and offered CD4 testing; (2) reported attributes of the POC CD4 test relating to day-to-day field operation from the relevant stakeholders’ perspectives (clients/patients, service providers, health manager/policy makers). For assessing feasibility the following measurements were used: (1) reported system factors associated with or having effect on acceptability and feasibility of POC CD4 test in the field, and (2) locally specific context and operational issues affecting the deployment of POC CD4 testing.

Results

Study characteristics

The search identified 12 studies that reported information and data on the outcomes of interest (acceptability and feasibility) including 11 articles and one abstract, 11 of which were conducted in Sub-Saharan countries and used Pima as a single intervention or as part of an intervention program to improve HIV testing uptake and linkage to care (Table 1). Overall, the quality of included studies was considered between moderate and strong. The QUADAS score ranged from 7 to 12 (of a maximum score of 14) with most of the studies scoring between 10 and 12. Using the EPHPP tool, two studies were ranked as “moderate” and one as “strong”. One study deployed both quantitative and qualitative methods, and addressed most of the essential criteria listed in the tool for appraising the quality of qualitative research.

Table 1 Characteristics of studies included in the review
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Acceptability and feasibility of POC CD4 test

Only one of the included studies, presented as a conference abstract, aimed to assess acceptability of a POC CD4 test from the healthcare workers’ perspective. All other studies primarily assessed accuracy and/or effect of POC CD4 on HIV program or patient related outcomes, and provided additional data related to acceptability and feasibility of POC CD4 testing under field conditions (Table 2).

Table 2 Acceptability and feasibility of POC CD4 test
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Patient perspectives

Available data suggest that the Pima test was highly acceptable across study settings. Acceptance rates ranged from 90 % to 100 % when offered either at the home, via mobile HIV counseling and testing or in permanent voluntary counseling and testing settings [21–23]. Patients appreciated having on-site CD4 testing availability. One participant reported: “They used to collect our blood and send it somewhere, hence that will take some days but as for now there is a big difference, we now receive our results there and then” [24]. In terms of preference regarding the method of blood sampling, the findings of one study in India [25] suggested that study participants prefer to give venous blood samples versus finger-prick because of the requirement for other blood tests (which can only be performed with venous blood) and fear of being subjected to the discomfort of multiple pricks with more pain if sufficient volume is not obtained in one prick.

Provider perspectives

One study which employed qualitative research methods in 35 maternal and new-born child health (MNCH) settings in Zimbabwe [24] reported health personnel expressed a preference toward performing POC CD4 testing (Pima) as it was efficient in resource use, user-friendly and responded well to patients’ needs: the machine “used fewer resources (syringes and needles), and less technical expertise was needed” to run the test and it was “catering for all types of clients”; finger-prick sampling was reported as “less traumatizing to the patients as less blood is taken for immediate use” and “no suspicion that blood was used for other purposes”. The Pima machine was reported as portable, compact, easy-to-use, battery operated with 3–4 h backup providing feasibility for use in non-laboratory settings [21, 25–27] and by non-laboratory technicians [23, 28]. However, relatively low throughput capacity, frequent error codes, cartridge rejection before expiration date and increased technical breakdown after one year of operation at a busy site were also reported as limitations of the Pima technology [24]. Healthcare workers also noted that a full blood count is required to identify type of antiretroviral drugs patients can be prescribed and this cannot be done with a finger-prick sample; also problems with test errors may lead to multiple pricks being required [24]. In another study conducted at five Prevention of Mother to Child Transmission (PMTCT) and HIV/AIDS care and treatment clinics in Tanzania, 73 % (8/11) of health care workers who were interviewed named venous blood as their preferred sample collection method and 100 % (11/11) trusted Pima-venous test results [29].

Influencing factors

Human resource shortage is a major factor that influences feasibility and acceptability of POC CD4 in field settings. It was suggested that the introduction of onsite POC CD4 testing would increase the workload of health personnel at clinical settings and this could be considered the most prominent challenge in terms of feasibility and acceptability in the context of no financial incentives or additional staffing could be provided [24, 28]. Training for health care staff on POC CD4 testing was reported as another factor that might influence acceptability and feasibility. In addition to training of test operators, training for health managers is also required. Senior health staff reported that it was not feasible for them to monitor test operators on a test on which they were not trained: “it’s difficult for me to supervise something I don’t know about” and “it’s downgrading to received instruction from a junior” [24]. The internal quality control and performance monitoring were also reported as critical factors to ensure on-going reliability and acceptability of POC CD4 testing in clinic settings where external quality control is a challenge because of the remoteness of the sites [27, 30, 31].

Discussion

The findings of our review show that there is relatively limited data on acceptability and feasibility of POC CD4 testing, with data only available for the Pima test; no other current commercially available POC CD4 tests [32] have published data on acceptability and feasibility in field settings. For Pima, the available data consistently demonstrates that it is feasible to deploy for decentralization of CD4 testing through different models of service delivery. However, there are some issues related to the implementation of Pima that might influence acceptability and feasibility of the test that remain unanswered. From the patient’s perspective no qualitative data were available to capture the willingness of patients to choose a POC CD4 test over a standard flow cytometric CD4 test when offered, or the patient’s belief in the accuracy or relevance of POC CD4 testing in identifying treatment eligibility or response to treatment. One study [22] reported 10 % of patients declined the offer of POC CD4 testing and chose standard CD4 testing at referral clinics but reasons for their preference was not studied. From the health service provider’s perspective, a number of issues need to be addressed in terms of acceptability and feasibility to provide insights into future implementation of the test. Although the device was reported as being easy-to-use, a reported high error rate and frequent test operator errors raised questions about the health workers’ ability to correctly perform the test in their daily working environment. Information on the training and supervision of test operators that would allow assessment of their capacity to follow testing procedure and perform the test correctly is lacking. The preference of health workers toward venous blood collection for CD4 testing also needs further studies to identify if this preference is due to the health workers’ belief in the validity of the test, difficulties involved with capillary blood sampling or other logistic issues related to blood testing in field settings. Lastly, human resources shortage represents a major challenge. The introduction of POC CD4 testing at primary healthcare level has been reported to be associated with increased work-load for health staff and while the provision of this service may well response to patients’ needs and improve quality of HIV treatment and care, the question remains is how to provide effective and sustainable POC CD4 testing service in busy primary clinic settings without overburdening the already strained healthcare providers. All these are important issues that need to be studied and factored into the planning process to guide future implementation of the test in remote and disadvantaged areas.

Although data was only available for Pima POC CD4 testing, some lessons could be learned for future planning and implementation of POC CD4 testing in LMICs. First, like other rapid diagnostic tests the validity or accuracy of POC CD4 test as perceived by the end users (health care provider and patient), will affect acceptance and use of the test in the field [20]. As accuracy and efficacy of the test are influenced by the test operators’ practical skills, the importance of quality training on POC CD4 testing for health professionals, both test operator and supervisor, must be recognized and infrastructure to support this should be adequately addressed before introduction and scale up of any POC CD4 technology [33]. This remains true for all POC tests that could be considered “quick” and “easy” but often require comprehensive training and supervision to ensure diagnostic test accuracy under field conditions [34, 35]. Without standardized quality training packages delivered to health workers in these clinics, ensuring competency standards are obtained by all test operators and their supervisors, and without on-going internal quality assurance systems in place it is impossible to rule out any potential operator-induced bias. Second, the preference toward a specific type of blood sample may also influence the acceptability and feasibility of a POC CD4 test. This preference may come from either the health service provider’s or patient’s views including challenges with one type of blood sampling, the need for a large amount of blood for other blood tests, or the health worker’s belief in accuracy of the test with one type of blood over the other. For POC CD4 tests that can be used with either type of blood sample, this would require further study to identify technical and programmatic solutions for extending test applicability in the field. Third, POC technologies are designed to be user friendly and be easily operated by low-to-middle level healthcare cadres. In addition to the importance of training for health staff, discussed above, their workload upon introduction of POC CD4 testing is an important issue to consider. The reality is that in some of the highest volume clinics in low-resource settings, it is the nurses, midwives and counselors who have the highest workload. Therefore, it is recommended that patient and staff work flow should be thoroughly studied and work load issues appropriately addressed through additional incentives, staffing or task shifting to ensure the effectiveness, efficacy and sustainability of POC technology when introduced into busy clinical settings.

The future role and impact of CD4 testing in general and POC CD4 testing in particular need to be considered from both technical and programmatic perspectives. In order to achieve the newly proposed sustainable development goal of ending the HIV/AIDS epidemic by 2030 [36], and with evidence showing positive clinical impact of ART for patients with CD4 count > 500 cells/μl [37], a policy shift toward recommendation of ART initiation for all HIV infected individuals regardless of CD4 count has recently been announced by WHO [38]. However, scaling up of ART programs in low-resource settings may risk low adherence and retention to care rates if critical health system factors such as well-trained health staff, well-functioning patient monitoring and appropriate support systems are not in place [39]. A successfully scaled up treatment program, therefore, will require innovative and effective models of service delivery (such as integration and decentralization of care), strong procurement and supply chain management, sufficient laboratory and/or point-of-care diagnostic services to monitor clinical treatment outcomes, HIV viral load and drug resistance and antiretroviral drug toxicities. Most of these systems are not currently in place in those LMICs mostly affected by the HIV epidemic and could only be achieved through a gradual process of health system strengthening. Therefore, in countries where treatment for all is not currently feasible with the available resources and current health system capacity, CD4 testing is required to prioritize treatment eligibility likely for those patients whose CD4 count is less than 350 cells/μl. Going forward, CD4 testing will still play an important role in identifying patients who present late to care for clinical management, for initiation and cessation of prophylaxis and for management of patient responses to ART even in countries where CD4-independent ART initiation is being introduced.

This review has some limitations that should be considered in interpretation of the findings. First, assessment of acceptability and feasibility was not the primary objective of any of the included studies and in a number of studies POC CD4 testing was only a part of a more comprehensive program intervention. This carries a risk of introducing bias as impact of the POC CD4 test and its acceptability and feasibility could be influenced by other interventions or implementation strategies. Second, we included only published studies in English and this inclusion may overlook data from studies published in other languages or unpublished data from evaluations conducted by government agencies, local reference facilities or research institutions. All but one of the included studies reporting outcomes of interest use Pima as the index test and this presents challenges in terms of generalizing the findings of the review to other POC CD4 tests, as specific technical and operational characteristics of each test will significantly impact feasibility and acceptability of the test from both service provider and patient perspectives. Of note, these limitations cannot be overcome until more data from field studies of different POC CD4 technologies are available.

Conclusions

Data is available for one of the POC CD4 tests on the market, the Alere Pima CD4, and suggests that it could be feasible to implement point-of-care CD4 testing in non-laboratory settings in low and middle income countries. Further studies using other currently or newly available POC CD4 tests in different geographical regions are needed to inform in-country decision making regarding the selection and adoption of a suitable test. Qualitative studies on feasibility and acceptability are needed to explore end users’ beliefs on the value of and preference toward POC CD4 testing. Evidence regarding supporting system factors such as training, monitoring, supplies, and facility requirements should be available and inform the planning process for the introduction and scaling up of POC CD4 tests at primary health care levels in low-resource settings.

Abbreviations

ART, Antiretroviral therapy; HBCT, home based counseling and testing; LMICs, Low and middle income countries; LTFU, Loss to follow up; MNCH, Maternal and new born child health; PICO, participants, interventions, compactors/controls, outcomes; POC, point-of-care; PRISMA, Preferred reporting items for systematic review and meta-analysis