The fragile environments of inexpensive CD4+ T-cell enumeration in the least developed countries: Strategies for accessible support

Abstract

With the advent of affordable antiretroviral treatment (ART), flow cytometry has ventured out of the exclusive realms of First World research to the resource-strapped clinical environment of developing countries (DCs). Flow cytometric instrumentation for ART has become more cost-efficient, thanks to simplified, yet accurate protocols and smart technologies. These positive developments have, however, not taken shape without problems, as health care in DCs remains weak due to chronic underfunding of their primary health systems. In addition, the multiplicity of donors has created parallel infrastructures that are difficult to manage and may undermine the responsibilities of public services. Hence, there is a prevailing lack of attention to maintenance, support, and human resource development. Not uncommonly, the procurement of high-value equipment is guided by nontechnical interests with mixed results. As conventional service contracts are unpopular, the sustainability of equipment is under serious threat after warranty periods, with environmental factors such as dust and unreliable power supplies being well-known culprits. Reagent supplies and servicing constitute further challenges, where a combination of short reagent shelf life, cold-box shipping, huge distances across poor infrastructures, rigid accounting procedures, and erratic customs requirements cause significant delays and extra costs. Although excellent, highly trained or trainable local staff is available, it is frequently diverted by brain drain from the government sector to privately funded hospitals, research facilities, and overseas postings. Despite these challenges, corporate service management has commonly remained loyal to its roots in the developed world.

A number of propositions address the current situation: “Reagent-rental” agreements represent an attractive alternative to service contracts, while smart instrument design has started to make inroads into more robust device concepts. To avoid logistical bottlenecks, reagents call for lyophilization and increased heat stability. Newly designed remote diagnostic tools are expected to save costs on service visits. Furthermore, web-based customer-relationship management and enterprise resource planning software is expected to ease the existing complex communication- and logistics issues. In addition, a public-private partnership is proposed that involves government, manufacturers, and local distributors with field application specialists. The latter operate crossbrand as independent subcontractors to manufacturers under a nationally endorsed cost-capping and quality assurance agreement to service all cytometric devices common in the region. These locally run networks may serve as “templates” for improved laboratory services in general, in collaboration with CD4 counting, haematology and infectious disease diagnostics. © 2008 Clinical Cytometry Society

The follow-up of clinical events by modern laboratory methods poses considerable difficulties in the process of rolling-out antiretroviral treatment (ART) across Africa (1, 2). Remarkably, the governments of the least developed countries (LDCs) are committed to establish programs that improve laboratory testing capacity, and have required their respective national reference laboratories to ascertain the quality of all HIV-related assays used both at the central and peripheral levels of the national laboratory network (3). Among these tests, measurement of CD4+ T-cells is essential for staging patients infected with the human immunodeficiency virus (HIV), determining their need for ART, and monitoring the course ofinfection (4, 5). While absolute CD4+ counts are adequate for adult patients, CD4+ T-cell percentages of total lymphocytes are a prerequisite for paediatric care (6–8). Still, most conventional instruments for CD4+ T-cells enumeration are expensive, as are the related reagents, and tend to demand considerable operator and maintenance skills. They are hence, in their unmodified format, unsuitable for resource-poor settings (9–11).

Fortunately, two separate developments have set the stage for significant cost reductions. First, simplified yet accurate protocols such as primary CD4-gating (9), CD45 PanLeucogating (10–13), and the Blantyre count (14) have been introduced to run on existing high-throughput instruments in countries with infrastructures suited to feed their samples through centralized laboratories. Second, relatively simple flow-based technologies have recently become available, ostensibly designed to assist resource-poor nations in their plight. They include the CyFlow SL® (15, 16), CyFlow SL_3® (17, 18) and CyFlow Counter® (19, 20) (Partec, Münster, Germany), the Guava PCA® (Guava Technologies, Hayward) (21, 22), the AuRICA® (23) and PointCARE Now® (PointCARE, Marlborough) (24), and the FACSCount® (Becton Dickinson, San José) (25) flow cytometers. Although the latter was launched >15 years ago, it is still considered for simplified operation due to its accuracy and stability despite the fact that its running costs, in comparison with most of the other systems (26), can no longer be considered to be low. These instruments provide answers, at least on a temporary basis, by a significant cost reduction when compared to conventional instrumentation. Since the roll-out of increasingly affordable first-line ART in developing countries (DCs) in the early 2000s, coverage rates have slowly, but steadily increased to 19% in South East Asia, 27% in sub-Saharan Africa, and 61% in the Latin American and Caribbean region (27–31). Nevertheless, as ART is penetrating deeper into the less accessible corners of the DCs, it has become clear that the long-term viability of each installation remains subject to a number of major challenges. These “teething problems,” and their complexity in interaction with a variety of socioeconomical factors, are the subject of this review.

THE CHAOTIC LANDSCAPE OF AID

As levels of development aid topped United States Dollars (USD) 100 billion in 2005 (32), there has been an ever-growing focus on the effectiveness of ART, stressing donor alignment, harmonization, and mutual accountability (33). However, health systems in many DCs remain weak and tend to fail to function efficiently within the realms of both primary and secondary care. Health systems in DCs are commonly fashioned along a “hub and spoke” design, where a district hospital as “hub” has access to more highly trained staff than the more peripheral health centers and health posts, i.e. the “spokes” located in communities and staffed by health workers providing primary care services. In an ideal setting, district hospitals are able to provide comprehensive in- and out-patient care, including advanced laboratory facilities such as CD4+ T-cell enumeration, for those referred by primary care providers. In turn, they refer patients in need of more specialized care to regional or national-level health facilities. Primary health care systems in DCs, with district hospitals at their apex, have, however, commonly failed to receive the sustained attention and resources that their importance deserves, although they are, in close collaboration with subordinate health centers and health posts, ideally disposed to battle the prevalent causes of death and ill-health, including HIV/AIDS and tuberculosis (34).

At the same time, and despite the honorable intentions of the Paris Declaration (33), the multiplicity of donor support of international, bilateral, nongovernmental, faith-based, and academic nature tend to create parallel infrastructures that may duplicate, replace, or even contradict the core responsibilities of governmental service providers (35, 36). The resulting “chaotic landscape of aid” (37) has not infrequently corrupted pre-existing lines of command within the health system as a whole (38), and poses a serious challenge to the functional, sustainable implementation of ART, including CD4−-related cytometry (39, 40). Consequently, the reality on the ground does more often than not show a picture different from the one that the investors of goodwill originally envisaged. Well-meant efforts invested in laboratory excellence commonly settle in a handful of reference laboratories or academic centers that enjoy top-heavy international involvement and easy access to plentiful resources. While the focus of their day-to-day activities is related to the research of diseases prevailing in the region, they commonly lack a functional “translational” link to local hard-core clinical activities. Given this well-funded academia-centered setup with primary international links, it comes as no surprise that such institutions attract the scientific elite drawing it away from the more “mundane” clinical environments.

At a second level, there are clinical facilities that enjoy (co-)funding by third-party institutions, e.g. private and mission hospitals that may be variably involved in ongoing international research programs. In these settings, a significant donor involvement safeguards adequate resources and a functional working environment, which in turn tends to attract competent clinicians and thus renders them, again, unavailable to the under-funded governmental sector.

Thus, the governmental sector finds itself at the bottom of the funding hierarchy, and generally suffers from an exhausted and dispirited management of already scarce resources. In addition to the internal brain drain mentioned above, this sector experiences significant external brain drain, both of which may, especially in LDCs, add up to a fatal flow of events (41) in an environment, where the virtually complete lack of funds for modern technology, maintenance, and human resource development meets the bulk of the clinical work load (42, 43).

HARDWARE ISSUES

Procurement

The procurement of cytometric equipment, like that of any other costly biomedical instrumentation, is a multifaceted process (44) that involves a series of factors, which do not always relate to technical and/or managerial aspects (45) and may occasionally blur the informed decision-making process. There are important unrelated factors, such as national evaluation requirements (that may be rigidly linked to exacting and often costly requirements set to resemble those of the developed world), regional dominance of certain models and existing governmental predilections. At the same time, cytometric technology is far from stagnant, and modifications of diagnostics can lead to more accurate, yet less expensive technology. Such novel instrumentation may present a difficult choice, especially when no ascertained information is available on its performance, reliability, and field installation requirements to obtain optimal results. Consequently, the above process is not always an entirely rational one—and may well become delayed, sometimes with unfortunate consequences (46, 47).

Instrument Support

Manufacturers commonly grant a 1-year warranty period to cover parts and labor without any extra costs in case of instrument failure. A review of tender documents reveals that in recent years there has been a call for extended warranty periods of up to 3 years, though not all manufacturers are equally conscientious to meet such requests.

Thereafter, most installations in the developed world subscribe to maintenance agreements (48, 49). In contrast, most installations in DCs operate without any service contract or protective shield. Service contracts carry a price tag of several thousand USD per annum and are perceived as poor value for money, due to a commonly overly optimistic assessment of the risk of instrument failure by the owner. Given the complexity of even the simple flow cytometers—and the exposed operating conditions (see below)—instrument failures are, however, unavoidable. It is near impossible to accurately predict the lifetime of an instrumentation as complex as a flow cytometer under conditions prevalent in DCs. Nevertheless, experience from the field allows an estimate that unless covered by a service contract, even simple flow cytometers rarely happen to see through a lifetime of three times the warranty—i.e. <50% of their anticipated lifespan. The different fates of equipment with (A) and without (B) appropriate service contract are illustrated in Figure 1.

Figure 1. Instrument lifespan with (A) and without (B) service contract. Diagrams do not imply any specific time scale.

Environmental Factors

The vast majority of cytometric equipment was originally designed for deployment in the developed world. It is known that dust exerts a detrimental effect to computing equipment (50). Similarly, biomedical instrumentations are electromechanical devices that suffer from vulnerability to small particulates. Apart from regular cleaning in accordance with the adage “a clean lab is a happy lab,” a critical determinant to life span is whether or not the cytometric equipment is located inside a closed dust-free room or not. Translated into (sub) tropical settings, this does imply the costly installation of air conditioning, to avoid overheating of both operators and instrumentation.

As soon as there is a need for refrigeration, the energy issue takes wider dimensions, as fridges demand predictable electricity or fuel supplies. The everyday menu of power variations in many DCs, and certainly most LDC, consists not only of plain blackouts, but also short-term drop-outs, minor variations in peak voltage (so-called swells and saps), abrupt surges (including those caused by lightning), dips and spikes due to sudden external load changes, and long-term under-voltage brownouts, all of which are prone to cause damage to sensitive equipment (51). Even without permanent damage to the equipment itself, power variations cause significant secondary damage, as they do not only disrupt any assay(s) in process, but also lead to the loss of productive hours of up to several days per week, as well as high opportunity costs for air conditioning, which demands the presence of a generator with related fuel expenses. The installation of alternative energy sources—such as mains-powered rechargeable batteries or solar systems that in turn feed inverters—helps reduce the time of power outages. Our experience has however shown that these measures are not a cure-all, and are known for load-dependent power variations given the internal resistance of the inverter setup, as well as harmonics and, depending on the quality of the installation, variable voltage reductions.

Knocks sustained during instrument transport and storage, as well as day-to-day vibrations created by innocuous-looking vortex mixers placed on the same resonating working surface as the cytometers are known culprits of misalignments of even the low-maintenance instruments.

POST-SALES ISSUES

Reagent Supplies

The fast and efficient provision of essential consumables continues to cause considerable problems given the poorly developed communication, transport and customs clearance infrastructure in many parts of the developing world. The analysis of the common ordering pathway for supplies (Fig. 2) assumes that the consumables are ordered from locations outside the end-user's country—as is usually the case. Order processing times are stated in calendar days, and are (favorable) estimates based on extensive field-based experience. There are four common bottlenecks. It tends to be difficult for laboratory staff to mobilize funds from within their institution's accounting department, due to restrictive bureaucratic in-house procedures (arrow A). The next bottleneck (arrow B) constitutes the majority of distributors' and manufacturers' demand for prepayment. Credit cards do not constitute an easily accessible payment option within the context of LDCs, as they are not widely available and subject to tight scrutiny on international payments. Distributors and manufacturers do not usually regard a receipt of an effected telegraphic transfer issued by the originating bank as sufficient proof of payment, but insist on awaiting the arrival of funds at their company accounts before making preparations for shipment of goods. The same holds true for check payments done nationally, to be cleared first before goods are released. Further unavoidable delays incur by shipping (arrow C): Evidently, the further away stocks are held from the end-user's laboratories, the higher the shipping charges, and the more days are required. Finally, customs clearance (arrow D) represents a highly variable limitation amounting from days to weeks, depending on the friendliness of the excise authorities.

Figure 2. Common work flow of consumables ordering and delivery process in DCs: Numbers present favourable estimates of average cumulative processing time in calendar days till step completion. Note bottlenecks highlighted by arrows, including client's accounting procedures (A), advance payment requirements (B), shipping (C), and customs clearance (D).

Reagent Shelf Life

The minimum order frequency is dictated by the reagent shelf-life. However, the more often supplies have to be shipped, the more often they hit the time-consuming and costly bottlenecks outlined above. With the exception of PointCare (52), all the current suppliers of flow-based CD4+ test kits such as Beckman Coulter (53, 54), Becton Dickinson (55), Guava Technologies (56, 57), and Partec (58, 59) provide perishable supplies that depend on an intact cold chain—a cold box shipping with extra charges that not uncommonly outweigh the costs of the goods ordered. Therefore, when coupled with cold chain requirements, the reagents' shelf life represents a capricious factor in countries with sluggish customs clearance procedures.

Moreover, in cases of prolonged instrument downtimes, reagents may expire. If under service contract, the manufacturer will have to replace expired reagents free of charge. Otherwise, the end-user will need to incur the expenses of both lost functionality and reagent loss.

Service Visits

Service visits for maintenance, troubleshooting and repairs constitute the second major component of after-sales services. While routine maintenance service visits are fairly straightforward (notwithstanding the poorly developed infrastructure necessitating prolonged car or bus journeys over bone-rattling roads), the issues encountered above with reagent supplies are further amplified (Fig. 3). As before, laboratory staff tends to have problems in mobilizing funds (arrow A), followed by the next bottleneck (arrow B), prepayment requirements. With minor and common errors, the servicing will be completed with the first visit (marker line X), resulting in a fully functioning instrument. In more severe cases, however, the diagnosis, only, is established during the first visit—to be followed by the ordering of spares and a second “curative” visit. Thus the client's accounting department will have to get involved once more (arrow C), followed by another payment (arrow D). Shipping (arrow E) and customs clearance (arrow F) create further delays. The time frame is ≥10 days for simple one-visit repairs, and ≥26 days for repeat visits. Manufacturers may strive to reduce downtimes by furnishing a loaner unit while repairing a defective device off-site. Unfortunately, the provision of a loaner commonly involves repeated shipping and customs clearance. Finally, even an exemplary well-coordinated service visit may become a sad farce due to prolonged power outages at the laboratory facility at the time of the visit.

Figure 3. Common work flow of “curative” service visits in DCs without service contract: Numbers present favourable estimates of average cumulative processing time in calendar days till step completion. Note bottlenecks highlighted by arrows, including client's accounting procedures (A), advance payment requirements (B), repeat clearance by client's accounting department (C), repeat advance payment requirements (D), shipping (E), and customs clearance (F). Simple repairs may be done in one visit, and the work flow terminates as indicated by marker line (X).

Corporate Service Management

The majority of manufacturers of diagnostic equipment for CD4+ T-cell enumeration are business entities that have grown over time into well-established companies within the developed world, and have segmented markets with the main focus on their nurturing resource-rich environments. Therefore, their client support management is heavily influenced by conventional, proprietary, and centralized infrastructures that are highly conscious of the relatively small and possibly volatile market share of DCs. As a result of the daunting—and expensive—logistics in DCs, end-users in resource-poor settings are commonly serviced by stripped-down versions of support systems that have originally been designed to serve more affluent environments. The ensuing bare-bones collaboration among manufacturers, distributors, and end-users is to highlight the huge gaps and challenges that remain in resource-limited settings, despite laudable achievements in some areas.

Human Resources

Fortunately, the workforce at hand in DCs, including LDCs, has been shown to be committed and enthusiastic, if appropriately trained and supported. Undoubtedly, the “ownership” of the diagnostic process and the ART environment as a whole is a matter of pride, which fosters an “I can do” attitude. This progress is however not a uniform phenomenon. HIV/AIDS is taking its toll among health workers (60–62), resulting in increased staff turnover. Understandably, there is poor staff retention in dysfunctional working environments, with inadequate support, and diminutive or missed salaries and cursory attention to staff development. The former are commonly encountered in governmental health care settings of LDCs, contributing to the aforesaid brain-drain (63). Given the impediments that junior staff has to overcome to acquire valuable skills, it is perceivable that such know-how may be jealously guarded, instead of establishing an open working atmosphere fostering skills-sharing (64). Consequently, capacity may well be lost with the resignation of senior staff, as no successors are trained, rendering skills retention a patchy affair. That is why operators are often not trained in even basic maintenance procedures, not to mention the troubleshooting of common errors.

STRATEGIES AND SOLUTIONS

Several approaches, some of them borrowed from different disciplines, are offered to address the gaps listed above. International workshops on HIV-related cytometry with a focus on resource-poor settings are suitable platforms to familiarize key stakeholders with current support issues, fair pricing and sustainability, beyond proprietary interests. These workshops emphasize the need for more efficient operations, where reductions in unit costs are associated with increased numbers of tests, and thus higher profits (65). These fora further delineate future logical developments that marry simplified technology with proof of its increased reliability, and hence help unlock a previously poorly explored mass market with a huge demand for affordable laboratory involvement.

Rental Agreements Linked to Service and Reagent Supply

The dynamics of this mass market call for a simplified business model for laboratory support that does away with the conventional dichotomy of hardware and consumables. Reagent-rental agreements are not unheard of in the developed world (66, 67), but they have only just started to take off in DCs. They offer a number of incentives: A unified pay-as-you-go (PAYG) pricing concept absorbs the total cost of ownership, including training, maintenance, repairs and reagent shipping, into the price paid per “test-kit,” thus reflecting risks related to usage intensity. Unrelated risks, such as poor power conditions, are to be catered for during device installation. This pricing model is not entirely without pitfalls: The advent of generic reagents by third-party manufacturers may diminish the revenue to manufacturers selling proprietary reagents under the PAYG scheme. Likewise, end-users purchasing generic reagents outside the PAYG package will expose themselves to the risks of instrument breakdown without cost control. To mitigate this paired risk, market forces will encourage instrument manufacturers to streamline production and to price reagents competitively, further driving existing cost-capping agreements with donor co-operations, especially in LDCs. In consequence, reagents under the PAYG scheme are expected to approximate USD 2.5–3.00 per test in countries with adequate, and USD 3.50–4.00 per test in countries with poor infrastructure. These prices are to decrease, as simpler, low-maintenance instrumentation enters the market (see below).

Smart Instrument Design

The current generation of simple(r) flow cytometers benefited significantly from the advent of smaller, cheaper, and less power-hungry lasers, which enabled biomedical engineers to fashion compact desktop units, do away with the need for regular laser adjustments, and reduce overall power consumption significantly (11, 15–18, 68–70). Low power consumption allows further improvements, such as fan-less designs, ideally with hermetically closed, dust-proof casings sporting external heat sinks, if required. These measures are expected to significantly reduce the number of dust-related incidents and service visits.

To empower the end-user to partake in guided repair attempts in a rational and safe manner, future cytometric designs should consider features that are already standard with today's desktop and notebook computers. Modular bay design, with pluggable tubing and wiring arranged in functional blocks that can be exchanged in the case of malfunction, could avoid the tedious, costly shipping of entire pieces of equipment and also help toward a faster road to instrument recovery. The modular bay structure should be enhanced by an on-board self-diagnostic system found, for instance, in today's washing machines.

Pipetting is an important source of error, and is complicated by the need of regular pipette calibrations. Instrument manufacturer or distributors are advised to assist in this procedure, as most sites in DCs do not avail of the required analytical balance. It is preferred to reduce pipetting steps as much as possible, and ideally do away with them entirely.

It is desirable to retain an open-platform, two-color concept, in order to accommodate relative CD4+ counts, as well as upcoming assays, e.g. for HIV mRNA, opportunistic infections and tuberculosis, all of which are currently devoid of an affordable, accurate and precise testing platform. It is anticipated that future developments will produce further, radical simplification of cytometry, without loosing out on assay precision and accuracy (70).

Universal Power Supplies

The reliable supply of electricity is one of the major challenges in DCs. Extensive field experience has shown that the safest and most cost efficient way to connect is via a fast switching power supply with a range of 70–280 V, which constitutes a slightly wider range than those found in notebook computers. Assisted with a professional surge protector, this setup is capable of providing adequate power conditioning for a wide range of environments, including erratic mains, solar and battery/inverter combination supply settings. At the same time, there should be a stabilized power inlet for 12 V direct current, in order to hook the unit straight on to a car battery without the need for an inverter. Finally, as external power is prone to fail, the unit should boast integrated backup power made with standard AA NiMH cells that are automatically charged, whenever the equipment has access to external power.

Long-Life Reagents

Lyophilized reagents are preferable to their liquid counterparts, as they tend to have an extended shelf life. These reagent should be heat-stable and not require cold chain at any time, combining the benefits of less frequent ordering requirements with the obsolesce of cold-box shipping and refrigeration.

Remote Instrument Diagnostics and Trouble-Shooting

A series of technological innovations that have lately found their way into a growing number of LDCs have rendered internet-based remote instrument diagnostics a realistic, and cost-efficient option: Second (2G) and third (3G) Generation wireless telephone technology, including general packet radio service (GPRS), enhanced data rates for global system for mobile communication (GSM) evolution (EDGE) and high-speed downlink packet access (HSPDA), to name but a few protocols, have revolutionized the internet access in many LDCs. These are more cost efficient than leased lines or satellite links, with transfer costs of under USD 0.50 per MByte, without contract. This service is expanding fast and presents an attractive option for low-volume connections to the internet from wherever there is mobile phone cover. The required hardware includes a GPRS-enabled mobile phone or a <USD 100 dedicated modem for computer connection (71). The second crucial technology is OpenVPN, a free, open-source virtual private network (VPN) package for creating encrypted point-to-point communication channels between two computers connected to the internet (72). Provided the troubled cytometer features a data port that permits attachment of a computer with wireless internet technology and VPN software enabled, a remote field application specialist (FAS) can connect to the computer on site, visualize the screen and use the keyboard of the operator on site. Both the operator in the laboratory and the remote FAS can communicate via chat software and by watching the results on screen. This greatly simplifies instrument diagnostics, preparations for one single “curative” service visit and thus reduces the need for second follow-up visits. Furthermore VPN software facilitates remote software (re-)installation, updates and training.

Enterprise Resource Planning and Customer Relationship Management Systems

One of the most commonly heard complaints by operators and owners alike is the poor communication of manufacturers and/or distributors with the end-users. Internet-based customer relationship management (CRM) systems allow the end-user and owning institution to follow-up on orders and service requests in real-time. The manufacturer/distributor can also use the CRM component as an integral part of a broader web-based enterprise resource planning (ERP) environment to keep customer data up-to-date, follow-up payments and orders, maintain an inventory on installations and spares, etc. There are many different versions CRM and ERP systems available, some of which are web-based, royalty free and open-source.

Low-Cost Service Cascade Business Model

It is essential to realize that laboratory support in environments with low spending power and difficult access does not constitute a financially attractive service rendering opportunity for manufacturers. For the end-user, it is, however, crucial to keep downtimes to an absolute minimum, as channeling of samples to alternative sites is bound to be prohibitively expensive or entirely impractical, leading to the total breakdown of clinical services. Hence, it will be necessary to establish decentralized reagent and service supply structures that are strategically located to support end-users more efficiently. Total cost of ownership will need to be reduced by a decentralized, quality-controlled, smart framework for cost-efficient, reliability-centered maintenance (RCM, as opposed to routine preventive maintenance) and repairs. RCM will be rendered feasible by means of internal device checks with self-diagnostic facility designed to be part of the instruments. Such simple circuits alert the operator of impending irregularities well in advance, and prompt for a service visit.

A public-private partnership (PPP) can be created between the respective government and manufacturers as key stake holders to cover these activities. Nongovernmental and academic institutions with key expertize in laboratory support will be able to collaborate with manufacturers to further instrumentation for both flow and nonflow technologies, and for training. Standard good laboratory procedures, including RCM, will become essential parts of the curriculum—leading to a decentralized, cost-efficient maintenance network that accommodates ranked levels of expertize. Experienced laboratory technicians are expected to be trained up to carry out simple repairs, from dusting mirrors and changing blocked tubing to replacing modular parts of cytometers on instruction. More complex issues will be diagnosed, and possibly resolved, remotely by regionally deployed FASs, accessing remote installations via VPN, followed by visits for corrective intervention. Manufacturers will be able to outsource FAS services to local, independent third-party firms that may serve a range of different brands. Pricing on spares and modular parts will be agreed upon to ascertain minimal downtimes. Quality control of maintenance services will be judged by customer satisfaction, call-to-job completion time and quality of maintenance and repair outcomes measured by instrument performance (73).

Further support to FASs will be made available directly in real-time from the respective manufacturer's headquarters, using the same internet-based technology. The above data will be captured and kept up-to-date by manufacturers, FASs and clients alike by means of an open-source, free, web-based CRM/ERP system as outlined above. The more attention manufacturers pay to creating smart and easy-to-maintain instrumentation, the less overheads they will incur.

The suggested approach is based on the recognition that support to health care in resource-poor settings cannot be adequately delivered by First World corporations and charities alone. Instead, essential health care involves empowerment with technology and skills transfer to the local and national level, in order to secure essential laboratory support, including CD4+ T-cell enumeration. The suggested PPP is a proven vehicle to translate the existing monopoly on service delivery held by instrument manufacturers into the empowerment of locally owned companies, under the auspices of a governmental body for quality control and enforcement of pricing agreements. Sustainability is maximized, as manufacturers benefit from the newly opened up mass market, while support and maintenance are provided locally for an affordable fee by expertise built up locally in a conjoint effort by all stakeholders.

Scenario I: CD4+ T-Cell Enumeration at National/Regional Centers

With the availability of international external quality assessment (EQA) schemes, national flow cytometry laboratories are already in operation in a number of DCs, where the infrastructure allows centralized processing in a few easily accessible test centers (74, 75). These centers of excellence have successfully supervised the large scale roll-out of CD4+ T-cell enumeration, after having modified their CD4 counting technology to be at least as precise/accurate as the one seen in more affluent countries, but considerably more cost-effective (13,76–78). Under their influence, further laboratories are presently established countrywide (79, 80), in order to accommodate the use, and to observe the precision of the performance of even simpler CD4 counting assays, as they arrive to serve the more dispersed rural communities.

Scenario II: CD4+ T-Cell Enumeration at the District Level

Not all DCs offer the needed transportation and political environment to back highly centralized CD4+ T-cell enumeration. Besides, predominant good governance policies push for decentralization, which in turn tends to antagonize any attempts to bundle testing sites. The ensuing decentralized testing environment does not necessitate sophisticated, high-throughput instrumentation, but comprises of target sites, such as district and provincial hospitals, that are perfect candidates for the new generation of simplified flow cytometers mentioned above, with a close link to a national reference laboratory for EQA and training purposes as a highly desirable addendum.

Scenario III: CD4+ T-Cell Enumeration at the Grassroots Level

For rural and remote settings, there tend to be two lines of thought: The first is to have a cytometer at hand at every outpost required. Given the immense logistic challenges, ranging from complete lack of electrical power to bad connections to the nearest district or provincial capital, the very same technology soon becomes a hindrance, as reagent supplies run short, the equipment starts to fail or unreliable data are generated. With supplies, maintenance and support commonly weeks away, prolonged downtimes are unavoidable, as well as exorbitant costs in furnishing the former. For the most common setting of that kind, the governmental sector, there is a pragmatic alternative, which involves the use of blood fixatives that, like TransFix®, keep samples stabilized for at least 5–10 days at ambient temperatures (80). When community health workers, equipped with suitable means of transport, visit hamlets (81, 82) they draw blood into tubes prefilled with water-free concentrates of TransFix® in a process that does not require any pipetting. These samples are then sent by comparatively easily available and affordable public transport to the next district or provincial hospital, where they are analyzed, followed by transmission of results back to the peripheral level by short message service (SMS).

OUTLOOK

With flow cytometry becoming firmly established in resource-poor settings, there are new, challenging developments that range from simplified, innovative technologies to the possible involvement of key stakeholders in the collaborative network of a PPP. These efforts provide a chance to intensify collaborations across different specialities, and foster a pragmatic multidisciplinary approach to HIV/AIDS beyond all divisions. Affordable laboratory support could thus be scaled up to include other tests for infectious disease diagnosis, including tuberculosis and opportunistic infections, as well as other assays essential for ART monitoring.

The final conclusions are therefore threefold: First, it is a misconception to assume that the well-standardized technologies routinely used in developed countries can be “transplanted” to DCs without sensible modifications—for the simple reason that in DCs every single unnecessary complication has to be exponentially paid for, in terms of service difficulties, equipment downtime and rocketing costs. Second, these countries would be better served, if more grants were deployed through established channels within the existing health system, thus minimizing the exposure to bottle-necks in ordering and service arrangements, without duplicating or even counteracting established efforts for basic health care. Third, the truly exciting new trends that are slowly developing in both Africa and South East Asia may, in terms of unified laboratory services for infectious disease management, serve as progressive models even for the developed countries, where these services may frequently remain compartmentalized in separate specialist laboratories for hematology, immunology, microbiology, and clinical chemistry.

Acknowledgements

The author wishes to thank the German Development Cooperation (GTZ) in Ethiopia, Rwanda, Uganda, and Vietnam for opportunities to help shape health policy and ART provision issues. He is indebted to Dr. Joseph Wakana and Dr. Eugène Rurangwa of the Great Lakes Initiative on HIV/AIDS (GLIA) in Burundi, the Democratic Republic of the Congo, Kenya, Rwanda, Tanzania, and Uganda for their advice on highly mobile populations afflicted by HIV/AIDS in the region. The author thanks Dr. Amandua Jacinta of the Uganda Ministry of Health, Prof. Harriet Manyanja-Kizza and Prof. Jürgen Freers of Makerere University Medical School (Uganda), Action Medeor (Germany), and Krisana Kraisintu (Thailand) for their insight into the realities of access to ART in Africa. The author also thanks Dr. Frank Mandy (Health Canada), the Carribean Cytometric and Analytical Society, Dr. Jeff Harvey as well as Grave Manyeki, Wanjugu Wambugu and Peter Leposo for technical advice, and Prof. Kovit Pattanapanyasat of Siriraj Hospital, Bangkok (Thailand) for his help with the use of generic reagents on proprietary platforms. Prof. George Janossy (UCL, London) has critically read the manuscript.