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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

How Point-of-Care Testing Could Drive Innovation in Global Health

Ilesh V. Jani, M.D., Ph.D., and Trevor F. Peter, Ph.D., M.P.H.

The investment in health services in low- and mid- dle-income countries has increased substantially in recent years.1 Such investment has been led by unprecedented efforts to combat major diseases, enabled by the availability of lower-cost and effec- tive drug regimens for treatment and prophylaxis, along with improved vector control. As health services have expanded, so has the demand for diagnostic tests that are essential in identifying patients, determining prognosis, monitoring treat- ment, and assessing the efficacy of prevention.2

Classic diagnostic technologies are not well suited to meeting the expanded testing needs. Laboratory tests require complex infrastructure, skilled technicians, and a stable supply of elec- tricity, all of which are scarce, particularly in nonurban areas. Traditional testing is usually performed in remote laboratories, which increas- es the cost and inconvenience of accessing health care and leads to a high number of patients who leave the system before a diagnosis is established.3 These limitations are a critical barrier to equity in health services. Microscopy requires less in- frastructure and is more widely available, but it can be inaccurate (e.g., sputum tests for tubercu- losis) or slow and underutilized (e.g., smear tests for malaria, schistosomiasis, and other parasitic infections).4-6 Many patients with tuberculosis or malaria are simply treated on the basis of a pre- sumptive clinical diagnosis. Although convention- al laboratory testing and microscopy will still be needed, it is expected that faster and more ac- curate point-of-care diagnostic tests that do not require laboratory infrastructure will play an in- creasing role in expanding health care in low- and middle-income countries.7

T h e S h if t t o w a r d P o in t- o f - C a r e T e s t in g

Rapid point-of-care testing for diabetes, anemia, pregnancy, human immunodeficiency virus (HIV),

and malaria have long been available and have be- come common diagnostic tools in both high- and low-income countries (Fig. 1). The first generation of point-of-care testing relied on easy-to-detect biomarkers, such as antibodies, antigens, and sim- ple biochemical reactions. Such biomarkers are also increasingly used in point-of-care tests for a wide range of infectious diseases (e.g., syphilis, hepatitis, measles, schistosomiasis, and tricho- moniasis) and for applications such as blood typing.8-11

A second generation of point-of-care diagnos- tics is now on the horizon, partly because of re- cent industry and donor investment. These tests detect more complex and less accessible biomark- ers, such as nucleic acids and cell-surface markers, and take advantage of advances in microfluidics, microelectronics, optical systems, and laboratory- on-a-chip nucleic acid test (NAT)–based amplifi- cation and detection techniques.12,13 The first applications of these technologies have included enumeration of CD4+ T cells, NAT-based diagno- sis of tuberculosis and drug-resistance screening, and testing of HIV viral load.14-16 Additional ap- plications are in the pipeline for other blood- borne and respiratory infections.

A third generation of technologies will enable simultaneous detection of multiple targets (multi- plexing) and will use more accurate biomarkers. Advances in engineering and test chemistry will produce devices that are smaller, simpler to op- erate, and potentially instrument-free,17 enabling reliable home-based testing or self-testing. These technologies will extend a wider range of diag- nostics from the laboratory into clinics and com- munities.

Point-of-care testing can have a transforma- tive effect on health care. Rapid HIV tests cata- lyzed increased rates of case finding that have driven global efforts in HIV prevention and treat- ment.18 Malaria rapid tests have been instrumen- tal in raising testing rates in Africa for suspected

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Detection targets Antibodies Antigens Simple biochemical reactions

Typical samples

Test cartridges Sample (e.g., capillary blood, oral fluid, or urine) is inserted into disposable test cartridge

Samples Capillary blood, oral fluid, urine, breath, and other samples

Multiple test formats Handheld lab-on-a-chip devices Disposable tests (no instruments) Doctor’s office desk-based devices

Devices will fully automate testing and analysis or display of results

Transmission of results Devices are likely to have wireless connectivity to transmit result data

Small instruments process and read results

Common test formats

First generation of POC diagnostic testing

Examples Rapid test strips and dipsticks (HIV antibody and antigen, malaria antigen, urine biochemistry, and pregnancy tests) Simple instruments (glucometers and hemoglobin meters)

Detection targets Whole cells DNA or RNA using PCR or other nucleic acid detection method

Examples CD4-cell count HIV viral load Tuberculosis diagnosis and potential drug resistance

Potential detection targets Nucleic acid sequencing Advanced protein analysis (proteomics)

Examples Antiviral and antibiotic drug-resistance screening Differential diagnosis (e.g., viral rash and fever, childhood diseases, antenatal tests) Home-based self-testing

Second generation of POC diagnostic testingB

Next generation of POC diagnostic testingC

Urine

Automated reading

Manually read cartridge- based strips

Manually read dipsticks

Oral fluid

Capillary blood

Lateral-flow test

Vertical-flow test

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cases from below 5% in 2000 to 45% in 2010,19 thereby reducing inappropriate antimalarial treat- ment and improving community-based manage- ment of fever and health outcomes.20 New point- of-care tests also show promise. In Mozambique, the use of such testing for CD4+ T cells at primary health care clinics doubled the rate of initiation of antiretroviral therapy and halved the time until treatment initiation.21 Rapid, cost-effective NAT- based testing for tuberculosis increased the rate of case detection by up to 50% and reduced the time until treatment initiation by a factor of 10.22,23 Other opportunities exist for point-of-care testing to improve access to appropriate medical services and thus patient outcomes. An accurate test for preeclampsia may enable earlier diagno- sis and appropriate care for a major cause of ma- ternal death,24 and NAT or antigen testing for HIV may improve the rate of pediatric case detec- tion and treatment coverage, which is currently below 50% in many low- and middle-income countries.25

However, weak health systems limit the effect of such testing programs. The initial adoption of promising new diagnostics is hampered by slow regulatory approval and uncertainty over how to deploy new tests relative to existing technology.

This may lead to either inappropriate use or over- use. After deployment, inventories of testing sup- plies often run low, and the reliability of point- of-care testing in real-life nonlaboratory settings may be low.26 In addition, the use of such tests has not always improved patient outcomes. For example, rapid antenatal syphilis testing reduced treatment delays but did not lead to higher treat- ment rates or a reduction in perinatal mortality.27 The use of rapid tests for malaria has not always improved the prescribing behavior of clinicians.28 Access to rapid tests for HIV did not improve the uptake of same-day testing at antenatal clinics.29 Despite widespread use of rapid tests for HIV, only 40% of HIV-infected persons know their sta- tus, and 40% of those with positive test results do not access follow-up care and may be at increased risk for death or complications because of delayed therapy.3

Study data suggest similar challenges with new point-of-care technologies. Despite the avail- ability of point-of-care testing for CD4+ T cells at primary health care clinics in Mozambique, only 30% of patients underwent same-day test- ing, and 20% were not tested at all.21 Of those tested and eligible for antiretroviral therapy, 40% were lost to follow-up while undergoing addi- tional testing and counseling before treatment. The benefit of new point-of-care tests cannot be taken for granted.

N e e d e d C h a n g e s in H e a lt h S y s t e m s

Health systems have been designed around ei- ther syndromic management or diagnostic test- ing performed in the laboratory and are not well adapted to the use of point-of-care testing. The coming wave of such technologies demands changes to health systems. We propose four key areas where change is needed (Fig. 2).

First, testing policies need to be updated. The World Health Organization (WHO) and other normative bodies should provide recom- mendations on how to use point-of-care tests (including guidance on risks, benefits, and cost- effectiveness), how to select the right products, and where and how to deploy new technologies in relation to existing tests. Even if such tests are cost-effective, their use may incur additional costs to health budgets, especially for new and more sophisticated tests, and these implications

Figure 1 (facing page). Evolution of Point-of-Care (POC) Diagnostic Testing.

Improvements in POC technology will lead to increas- ingly complex tests run on devices that are smaller and easier to use than the current generation of devices. Panel A shows first-generation POC tests, which are conducted with the use of simple chemical analyses and devices. Most tests are lateral- or vertical-flow devices that allow the specimen to flow across or through the solid surface of the test strip past a reac- tion area, resulting in a visual signal. Both manual and automated readings of test results are common. Panel B shows second-generation POC tests, which detect more difficult diagnostic targets with the use of more complex chemical analyses. Sophisticated, disposable microfluidic test cartridges automate sample prepara- tion and test processing. Cartridges are inserted into small, portable instruments that automatically process and read the results, which are displayed digitally. Pan- el C shows the next generation of POC tests, which will probably include more complex diagnostics for the si- multaneous targeting of multiple diseases with the use of instruments that are smaller and easier to use and disposable devices that fully automate sample process- ing, testing, and reporting of results. HIV denotes hu- man immunodeficiency virus, and PCR polymerase chain reaction.

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n engl j med 368;24 nejm.org june 13, 20132322

need to be made clear. For example, use of new NAT-based testing for tuberculosis in South Af- rica increased the cost of diagnosis by 55% and the cost of treatment by 8%.30 Guidance on clini- cal-management algorithms will also be needed. Point-of-care tests will provide health care work- ers, especially those in primary care and com- munity-based settings, with unprecedented diag- nostic information for guiding clinical decisions. Governments, with guidance from the WHO, have developed and implemented practical disease- management algorithms that are based on clini- cal judgment for primary health care settings in which routine laboratory diagnostics were not feasible or reliable. The increased availability of accurate test data in these settings will necessi- tate new clinical algorithms and guidance on how to interpret and use diagnostic information. In addition, point-of-care testing will increasingly

be used in the private health sector and in less formal settings, such as pharmacies, retail outlets, and homes. The increased availability raises con- cern about product quality and testing perfor- mance, and supportive but firm regulations on the use of such tests in these settings will be needed.

Second, innovation will be needed in the de- sign, operation, and workflow of clinics to ensure that testing is accessible and results are used in real time to guide treatment. Point-of-care test- ing may lengthen clinic visits and place extra de- mands on staffing and space. Bottlenecks at any stage can increase waiting times and result in extra visits by patients, and the benefits of on- site testing may be lost. Clinics may need to hire additional staff in key cadres, extend clinic hours or work shifts, and change the scheduling of pa- tients, clinic flow, and use of space in order to facilitate onsite testing and immediate delivery of follow-up care. Improved medical-record sys- tems that capture test results and make them available across different service departments may improve the tracking and follow-up of patients.31 Steps should also be taken to increase testing rates and reduce the effect of shortages in space or test operators (e.g., use of multiplex or parallel testing). The implementation of many of these initiatives in public health systems will require changes in government policy and resource al- location — for example, to facilitate the exten- sion of clinic operating times, hiring of addition- al staff, and improvements in data-management systems.

Third, systematic steps should be taken to effectively decentralize point-of-care testing and to improve the retention of patients both before and after testing. Policies that enable new models for expanded community-based testing and that facilitate safe and reliable self-diagnosis provide opportunities to better exploit such testing, as well as drive technology innovation. Addressing weaknesses in retention that persist despite on- site testing will require initiatives both upstream and downstream of the test to improve access to testing and ensure appropriate linkage to follow- up care. Interventions such as transportation and food allowances for clinic visits and mobile-phone reminders32 can help ensure that patients com- plete their treatment as well as promote adherence to clinical protocols among health care workers.33 Streamlining and integrating testing and related services can improve access to treatment. For

Revised policy and normative guidance Cost and cost-effectiveness of POC testing Decentralization of services Testing guidelines Clinical algorithms Community-based testing and self-testing

Improved operational systems

Product regulation Supply chain Training Quality assurance Maintenance

Streamlined clinic services New staff cadres and

shifts Space reassignment Patient scheduling Improved medical records Bundled procedures

Decentralization and retention initiatives

Community-based testing Self-testing Linkage to care Integrated services Patient-centric services Adherence tools

Figure 2. Health-System Improvements to Support Expanded POC Testing.

Shown are four key areas of improvement in health systems — revised policy and normative guidance, improved operational systems, streamlined clinic ser- vices, and decentralization and retention initiatives — that will require strengthening in order to increase the effect of POC testing. In these areas, the use of POC testing may prompt system improvements that may eventually extend beyond diagnostics to other areas of health care.

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example, the integration of outpatient services and HIV therapy in Zambia resulted in increased rates of case finding,31 and point-of-care testing for CD4+ T cells in HIV screening clinics in South Africa increased linkage to care.34 Other opportunities exist across disease programs, such as point-of-care tuberculosis testing in HIV screening clinics or therapy centers.35 However, the feasibility and cost-effectiveness of these in- terventions need further investigation. Many health-system innovations exist only in pilot form. Translating useful pilots into policy and routine practice is a challenge that requires in- creased attention from both governments and development partners.

Fourth, operational challenges to implement- ing point-of-care testing need to be overcome. Weaknesses in supportive services — including product regulation, supply chain, human resourc- es and training, quality assurance, and equipment maintenance — are widespread and systemic.36 In particular, new in-service and preservice ini- tiatives in training and retention of clinic staff will be needed to ensure that new technologies are used appropriately. Initiatives to improve these areas are under way and can benefit other areas of health care delivery.37 In addition, rational planning for product uptake is necessary to en- sure that the investment in point-of-care diag- nostics is cost-effective and sustainable and that tests are widely accessible.

D r i v in g t h e In n o v at i o n in H e a lt h S y s t e m s

The rise of point-of-care testing is expected to expand access to medical services, improve health outcomes, and facilitate the sustainability of dis- ease-control programs in low- and middle-income countries. Although such technologies were ini- tially focused on HIV, tuberculosis, and malaria, they will be used in the diagnosis and treatment of other diseases, and their deployment at scale will require substantial investment. However, such testing may not be cost-effective if the diagnos- tic innovation is not matched with innovation in health systems.

As point-of-care testing becomes more com- mon in diagnostic medicine, it could drive this innovation in health systems in at least three ways. First, the supply of point-of-care tests will

directly induce changes, such as improved patient flow within clinics. Second, the new technologies tend to increase testing rates substantially, and as more patients are tested, the demand for as- sociated services will increase and existing sys- temic weaknesses will be highlighted. This in- creased pressure on health services will motivate local and international initiatives to seek ways to address such limitations. Finally, the enthusi- asm for new point-of-care technologies among public health practitioners, scientists, and the pri- vate sector should elicit proactive efforts in re- solving health-system bottlenecks so that the tests can be successfully used.

There are many examples of system innovation that have been prompted by the use of point-of- care testing, such as the use of provider-initiated HIV testing to increase diagnostic rates and im- prove patient retention,38 wireless networks that capture test data from remote sites and monitor quality,39 and the “Test, Track, and Treat” pro- gram for malaria, an international initiative of the WHO designed to scale up malaria testing linked to treatment and disease surveillance.19 However, more is needed to address the chal- lenges described above. Commitment from gov- ernments and global-health actors is necessary, and strengthening of initiatives should be evi- dence-based, drawing on operational research to identify high-priority and cost-effective interven- tions.40 The investment in developing new point- of-care diagnostics has started to yield fruit. Now health systems need to evolve to reap the benefits.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

From the Instituto Nacional da Saúde, Maputo, Mozambique (I.V.J.); and Clinton Health Access Initiative, Boston (T.F.P.).

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DOI: 10.1056/NEJMsb1214197

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