REVIEW

10.1111/j.1469-0691.2010.03280.x

Economic evaluation of point-of-care diagnostic technologies for infectious diseases

S. Loubiere1,2,3 and J.-P. Moatti1,2,3 1) INSERM, U912 (SE4S), 2) Universite Aix Marseille, IRD, UMR-S912 and 3) ORS PACA, Observatoire Regional de la Sante Provence Alpes Cote dAzur, Marseille, France

Abstract
We review the growing number of economic evaluations of individual point-of-care (POC) tests for diagnosis of infectious diseases in resource-limited settings that use either cohort studies or mathematical models. We focus on studies that evaluate POC diagnostic tests for the control of human immunodeciency virus (HIV) and malaria, tools that are central to the WHO prevention guidelines for infectious diseases in developing countries. Although rapid diagnostic tests for HIV and malaria seem to be cost-effective in these standard analyses, these do not take into account the reduction in patients waiting time and the number of clinic visits required to receive results, or future benets from the reduction in antimalarial drug pressure. Those additional cost reductions would be considerably greater with POC rapid tests, and the cost-effectiveness of POC tests would therefore be improved. Findings from cost-effectiveness analyses suggest that, despite the relatively small additional cost incurred, decision-makers should strongly consider using POC tests throughout or during parts of HIV and malaria epidemics, where this is feasible in terms of local human resources and logistical conditions. Keywords: Cost-effectiveness, HIV/AIDS, malaria, point-of-care testing, review
Clin Microbiol Infect 2010; 16: 10701076

Corresponding author and reprint requests: S. Loubiere, INSERM U912-ORS PACA, 23, rue Stanislas Torrents, 13006 Marseille, France E-mail: sandrine.loubiere@inserm.fr

Introduction
Recent gures from the WHO [1] suggest that 33 million individuals are living with HIV infection worldwide, more than two-thirds in developing countries with limited resources. The scale-up of antiretroviral therapy (ART) in low-income and middle-income countries has been unprecedented, with more than 4 million people estimated to have had access to ART at the end of 2008 [1]. Despite the global effort to control the AIDS pandemic, human immunodeciency virus (HIV) infection continues to spread relatively unabated in many parts of the world. The transmission rate for HIV-infected individuals unaware of their infection is up to 3.5-fold higher than that for those who are aware [2]. Identifying those who are acutely HIV-infected is a rst priority in order to reduce transmission rates through the use of both behavioural interventions and effective treatment programmes. Expansion of HIV testing is therefore urgently required, and mechanisms must be developed to ensure that

HIV diagnosis occurs early on in the course of disease, at affordable costs, especially for people living in resource-limited countries. The same holds true for malaria. Its diagnosis has traditionally relied on the clinical presentation of disease symptoms and microscopic examination of Giemsa-stained blood lms [3]. Diagnosis based on symptoms alone is unreliable, because the symptoms of malaria are non-specic, overlapping with those of other febrile diseases [4]. Studies in Africa have shown that between 50% and 99% of those clinically diagnosed with malaria and then prescribed antimalarial drugs have illnesses attributable to some other cause, depending on endemicity in the clinical setting [5,6]. This results in overdiagnosis of malaria and overprescription of antimalarial drugs, as well as underdiagnosis and inappropriate treatment of non-malarial febrile illnesses [7,8]. In addition, antimalarial drug pressure ultimately contributes to the development and spread of drug resistance [9]. Most victims of malaria still die because the disease is not diagnosed in time by health workers [10].

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It appears that existing diagnosis technologies are poorly adapted for use in resource-limited settings. Current technologies are very expensive and require delicate instruments, cold chain, and stable electricity, which are not available in areas where the majority of the patients reside [11]. In addition, when testing is carried out in centralized laboratories, turn-around times are of the order of several months for specimens sent from rural areas in developing countries [12,13]. How can high-quality test results be provided in the most cost-effective way? One solution is the use of point-of-care (POC) tests. These are diagnostic tests performed close to the patient. They require less laboratory infrastructure, are potentially cheaper, and can be designed to be easy to use and interpret [1416]. These advantages can help reduce the workload for laboratories and streamline care in settings where large numbers of patients are treated daily. In addition to improving the standard of care, a test that can be performed while the patient is at the clinic means that fewer patients are lost to follow-up and the burden on patients is reduced [11]. Because the procedures are very simple (the need for equipment such as centrifuges and electricity being eliminated), involve a limited number of steps, and do not require high precision, they can be used outside traditional laboratory settings by staff with no formal laboratory training. In the face of economic constraints, it is critically important to evaluate how best to utilize available resources [17,18]. Cost-effectiveness analysis is a well-established methodology for understanding, prioritizing and optimizing healthcare services. By comparing testing alternatives in terms of their relative advantages and costs, cost-effectiveness analysis can serve as one key element to inform decision-makers, in order to dene public health policy [19]. In this article, we review the growing number of economic evaluations of individual POC tests for diagnosis of infectious diseases in resource-limited settings that use either cohort studies or mathematical models. We focus on studies that evaluate POC diagnostic tests for the control of HIV and malaria, tools that are central to the WHO prevention guidelines for infectious diseases in developing countries.

describes the methodological features of each analysis that evaluates the cost-effectiveness of POC diagnostic tests for HIV disease and malaria.

Cost-effectiveness of Rapid POC Diagnostic Tests for the Control of HIV

In 1992, the Global Programme on AIDS and the WHO rst recommended the use of testing strategies based on combinations of screening tests (including simple, rapid tests) for blood screening, surveillance, and diagnosis, instead of the enzyme immunoassay and western blot techniques previously used [20]. Although these recommendations were revised as the range of antibody tests expanded, they were still intended for serum or plasma testing. Instead, recently developed rapid tests detect HIV antibodies in whole blood specimens, making it possible to evaluate the performance and the cost-effectiveness of POC HIV testing in settings with limited laboratory facilities and where the demand for voluntary counselling testing is likely to increase. For several reasons, the expanded use of POC rapid HIV testing promises to play an important role in HIV prevention, both in developed and in developing countries. First, access to immediate HIV test results could improve the application of prophylactic regimens to reduce vertical transmission when used intrapartum or postpartum [2123]. In line with this objective, Menzies et al. [24] studied the cost-effectiveness of initiating diagnosis with a rapid HIV test to screen out HIV-uninfected infants. The comparator that they used was the current diagnosis-testing algorithm DNA-PCR. The study population comprised HIV-exposed children <18 months of age attending two postnatal screening programmes in Uganda between 2005 and 2006. The authors used a decision-analytical model to compare the DNA-PCR and rapid HIV test approaches, and found that the former identied 94.3% (91.894.7%) of HIV-infected infants, as compared with 87.8% (79.490.5%) for the latter. Moreover, the total cost of the POC testing programme was about 40% less than that of DNA-PCR ($59 vs. $38 per infant aged 69 months). The rapid POC test is therefore more costeffective than the comparator, as the incremental cost per HIV-infected infant correctly diagnosed using the latter ranges from $559 (95% CI $261$2702) with low compliance to $7165 (95% CI: $332220 127) with perfect compliance. Second, as several studies indicate that persons who are aware of their HIV infection more frequently adopt behaviours to reduce the likelihood of transmission [2527], the use of rapid tests as a tool for prevention strategies promoting the need for awareness of ones own and ones partners

Review of Recent Studies on the Costeffectiveness of ART

We used the Medline database to conduct a literature search of articles published between 2006 and 2010. We then reviewed citation and reference lists to identify additional studies. Table 1 provides a summary of the results and

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TABLE 1. Cost-effectiveness of rapid POC test for the diagnosis of HIV and malaria
Cost measure Results Effectiveness measure Time horizon Discount Strategy Compared rate Perspective number interventions Sensitivity analysis

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References

Setting Methods

Menzies et al. Uganda 2009 [25] S2 None S2 Health care provider S1 Reference group

Decision tree Medical with Monte costs Carlo simulations care Ng/Ct cases None averted and HIV cases averted

care HIV-positive None infants correctly diagnosed

None

Provider

S1

$1489/infected infant correctly diagnosed Reference group

HIV prevalence, HIV incidence, sensitivity and specicity and costs Costs and sensitivity of POC test

Vickerman et al. 2006 [40]

Benin

Dynamic Medical mathematical costs model; data from SIDA2 project

Pre-test counseling + DNAPCR Pre-test counseling + Rapid HIV test + DNA-PCR Currently used syndromic approach to diagnosis Modied syndromic management including POC tests

Sanders et al. US 2010 [34] S2 Extended dominance; Extended dominance

Randomized trial; Markov statetransition model

Medical costs

care Life-years saved; quality-adjusted life-years

Lifetime

3%

Societal

S1

$81.0/HIV infection averted for a test costing $1, $151.4 for a test costing $2, $221.8 for a test costing $3, $292.2 for a test costing $4 Reference group

HIV prevalence; sensitivity and specicity; costs

S3

$16,259/LY; $10,660/QALY

Shillcutt et al. SubDecision tree; 2008 [35] Saharan Monte Carlo Africa simulations

Direct medical care costs and variable costs

Disability-adjusted None life years

None

Provider and patients

S1 S2

Traditional counseling and testing Nurse-initiated routine screening with traditional HIV testing and counseling Nurse-initiated routine screening with rapid HIV testing and streamlined counselling Presumptive treatment Microscopy diagnosis

Malaria prevalence; adherence to treatment; costs

Clinical Microbiology and Infection, Volume 16 Number 8, August 2010

2010 The Authors Journal Compilation 2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 10701076 S3 Rapid diagnostic tests (RDTs) None None 14 days None follow-up Consumer S1 and provider S2 S3 Provider S1 S2 Presumptive treatment Microscopy diagnosis Rapid diagnostic tests (RDTs) Clinical diagnosis (CD) Clinical diagnosis + Rapid diagnostic tests (CD + RDT) Malaria prevalence; sensitivity; adherence to ACT; costs None None None Provider S1 S2 Clinical diagnosis Clinical diagnosis + Rapid diagnostic tests Reference group 95% certain that microscopy is cost-effective at prevalence <41% and not cost-effective at prevalence >83% 95% certain that RDTs are cost-effective at prevalence <62% and not cost-effective at prevalence >90%; 85% certain that RDTs are costeffective relative to microscopy across all level of prevalence Reference group $257/death averted $-221/death averted Outcomes better in the CD + RDT group CD + RDT is cost saving in patients >15 years, when ACT is reduced to <20% of fever patients Reference group In high malaria prevalence: 178 over-treatment errors averted and 82 undertreatment errors averted/ 1000 outpatients; a cost savings of $-13/1000 outpatients. In low malaria prevalence: 54 over-treatment errors averted and 5 under-treatment errors averted/1000 outpatients; an additional cost of $+241/1000 outpatients Malaria prevalence; sensitivities and specicities; costs

Uzochukwu et al. 2009 [39] Msellem et al. 2009 [27]

Nigeria

Decision tree model

Zurovac et al. 2008 [46]

Direct medical Deaths averted and non medical costs Zanzibar A non randomized Direct medical Prescription of clinical trial and non medical ACT; costs prescription of antibiotics; re-attendance rate Kenya Randomized Medical care AL treatment clinical trial; costs errors Decision tree

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infection status could considerably reduce HIV sexual transmission. Vickerman et al. [28] studied the impact of combined Neisseria gonorrhoeae/Chlamydia trachomatis rapid POC tests on the transmission of HIV or sexually transmitted infections among female sex workers, their clients and the general population in Cotonou, Benin. Using a deterministic model and data from the SIDA2 trial [29], the authors showed that rapid POC tests constitute a cost-effective use of resources for increasing the impact of treatment interventions for sexually transmitted infections in resource-poor settings, even though they cost up to $4 per test. The rapid POC tests resulted in 10% of N. gonorrhoeae/C. trachomatis cases being averted and 6% of HIV cases being averted, the incremental cost per HIV infection averted being $292.2 (95% CI 224.7472.6), and the initial test costing $4. However, the authors argued that they used the lower cost range for the combined N. gonorrhoeae/C. trachomatis test on the grounds that more expensive tests would no longer be cost-effective. Failing to explore the potential impact of the higher costs possibly biased their results in favour of POC testing, making it appear more cost-effective than it may actually be in practice. Third, POC tests considerably reduce patient anxiety, the adverse effects of waiting for ones test results, and also the risk of loss to follow-up [30,31]. In a recent study conducted in the USA, Sanders et al. [32] examined the costs and benets of three strategies to improve HIV testing and receipt of results among primary-care patients with unknown HIV status: (i) traditional HIV counselling and testing; (ii) nurse-initiated routine screening with traditional counselling and testing; and (iii) nurse-initiated routine screening with streamlined counselling and rapid HIV testing. On the basis of a Markov model, data from randomized controlled trials, and assumptions when necessary, the authors showed that nurse-initiated routine screening with traditional counselling and testing increased rates of testing and improved receipt of test results, and was also costeffective as compared with traditional HIV-testing strategies. With rapid testing by nurses, life-expectancy was increased by 0.87 years or 0.63 quality-adjusted life-years as compared with traditional counselling and testing. Including the benets from reduced transmission, the additional gains in health benet with rapid testing cost $10 660/QALY. Although rapid diagnostic tests for HIV seem to be costeffective in these standard analyses, these do not take into account the reduction in patient waiting time and the number of clinic visits required to receive results. Those additional costs would be considerably reduced with POC rapid tests, and the cost-effectiveness of POC tests for HIV would therefore be improved.

Sensitivity analysis

Clinical diagnosis + Rapid diagnostic tests with a revised practice for artemetherlumefantrine (AL)

Strategy number

Compared interventions

Perspective

S3

Discount rate

Time horizon

Effectiveness measure

Cost measure

TABLE 1. (Continued )

References

Lubell et al. 2008 [21]

Tanzania

Setting

Randomized clinical trial; Decision tree

Methods

Medical care costs

Life-years lost

None

None

Societal

S1 S2

Presumptive treatment Microscopy diagnosis Rapid diagnostic tests (RDTs)

In high malaria prevalence: 144 over-treatment errors averted and 13 undertreatment errors averted/ 1000 outpatients; a costsavings of $-222/1000 outpatients. In low malaria prevalence: 37 over-treatment errors averted and 7 under-treatment errors averted/1000 outpatients; an additional cost of $+109/1000 outpatients Results depend on prevalence, response rate (see original paper)

Results

Cost of life year lost; Microscopy sensitivity

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Cost-effectiveness of Rapid POC Diagnostic Tests in the Diagnosis of Malaria

As antimalarial drug costs increase, diagnostic methods are becoming a crucial component of malaria control and prevention, and there is an increased need to ensure that malaria is correctly diagnosed prior to treatment. For example, in 39 African countries, as a result of extensive resistance to chloroquine and sulphadoxinepyrimethamine [33], artemisinin-based combination therapy (ACT) has been the rst-line antimalarial treatment since 2007. Although prices have been reduced recently, ACT still costs up to ten times more than chloroquine [34,35]. As regards diagnosis of the disease, the WHO [10] guidelines recommend that parasite-based diagnosis should be used in all cases of suspected malaria, with the possible exception of children in high-prevalence areas and in certain other situations. With a presumptive antimalarial treatment strategy, diagnostic sensitivity is maximized, and the case management algorithm is greatly simplied. However, presumptive treatment has serious disadvantages, because of its very poor specicity (that is, many febrile cases are diagnosed as malaria even though they have a different pathology) [36,37]. In contrast, rapid diagnostic POC tests can be performed in settings with no sophisticated infrastructure, as they require only a minimum level of training for community health workers in charge of diagnosis and prescription. Despite these advances, there is a scarcity of cost-effectiveness data on rapid POC tests in countries with high malaria endemicity [38]. This review reports results from economic evaluations carried out in developing countries to determine whether the use of rapid POC tests for diagnosis of malaria is cost-effective when compared with clinical and microscopy-based diagnosis. Using a decision tree model, Shillcutt et al. [39] conducted a cost-effectiveness analysis in different sub-Saharan settings to compare presumptive, eld standard microscopy and rapid POC tests in the diagnosis of malaria. They showed that these latter have the potential to be cost-effective in most parts of sub-Saharan Africa, and that appropriate management of malaria and non-malarial febrile illnesses is required to reap the full benets of this type of testing. However, the authors acknowledged that little is known about the impact of introducing new diagnostics on patients behaviour, especially in terms of facility use and adherence to therapy. One limit of this model, as reported by the authors, is that it considers formal outpatient facilities only, whereas in many settings a high proportion of care-seekers obtain drugs from private, informal pharmacies. Further

analysis of the cost-effectiveness of rapid POC tests at these informal providers is warranted. In the same way, Uzochukwu et al. [40] compared the cost-effectiveness of rapid POC testing with syndromic diagnosis and microscopy in a hypothetical population of 100 000 patients with a history of fever or of non-specic symptoms or signs suggestive of malaria and clinically diagnosed as having malaria by health workers in urban and rural districts of Nigeria. The same decision tree used by Shillcutt et al. was employed, and the analysis was further stratied by age group. The incremental cost-effectiveness ratio of rapid POC tests vs. presumptive treatment was $221 per death averted, and microscopy was a dominated strategy (i.e. less effective and more costly). With a malaria prevalence in the hypothetical population of 43.1% or less, the rapid POC test is cost-effective when compared with other diagnostic strategies for malaria treatment. The authors concluded that policy-makers and healthcare providers should be aware of the upper limit of malaria prevalence for which the use of rapid POC tests brings about cost savings. Similarly, Zurovac et al. [41] questioned the impact of malaria prevalence on the cost-effectiveness of diagnostic strategies. They found that in an area of Kenya with a high rate of malaria transmission (between 30% and 50%), rapid POC tests would improve malaria treatment by reducing the percentage of overtreatment errors, with lower costs. In an area with a low prevalence of malaria (about 1.5% of all patients above 5 years of age), rapid POC tests would yield minor reductions in overtreatment errors, but with higher costs. According to the authors, the limited benets obtained in low-prevalence areas result from the underuse of ACT following the recent introduction of a new treatment policy [42]. A follow-up evaluation in Zambia showed that the frequency of ACT prescriptions increased over 2 years, and that this increase coincided with the expansion of rapid POC test capacity [43]. Similar changes in Kenya in the future would inevitably change the current overtreatment and costs. Msellem et al. [44] studied the inuence of rapid POC tests for malaria diagnosis on drug prescriptions, health outcomes and costs in primary healthcare settings in Zanzibar, and compared this intervention with symptom-based clinical diagnosis alone. The authors wanted to test the hypothesis that prompt testing of febrile patients would lead to better patient healthcare through both improved use of ACT and prescription of more appropriate treatments, including antibiotics, to nonmalaria patients. A total of 1887 patients of all ages with reported fever were enrolled in a non-randomized, four-centre clinical trial, and followed up for 14 days. Outcomes were analysed with a multilevel modelling approach, although primary outcome and costs were not combined in the form of a

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cost-effectiveness ratio. The results showed an overall twofold reduction in the prescription of antimalarial drugs and reattendance of patients because of illness during the 2-week follow-up period in patients within the POC group. Overall costs were, however, similar in the POC and clinical diagnosis groups, despite a signicant reduction of costs among the adult patients after rapid POC testing. In addition, the introduction of rapid POC testing resulted in cost savings in patients aged over 15 years (malaria treatment being reduced to less than 20% of febrile patients in this population). An important piece of information added by this study is that the false-negative results with POC testing (i.e. patients detected by microscopy but not detectable by POC testing) did not develop any severe manifestations during the 2 weeks of follow-up. This supports the general recommendation for consistency in not treating rapid POC test-negative patients. Obviously, retesting is required if the illness remains and becomes aggravated. In this study, nurses and patients showed great condence in the POC test results as a guide to the choice of treatment to be prescribed. Strong compliance by prescribers with practice guidelines, when rapid diagnostic test results prove to be negative, was also reported in a recent study conducted in mainland Tanzania [45]. These ndings are in contrast, however, to those from other studies showing that care providers, although willing to perform diagnostic tests, do not always comply with recommended practices [6,9,46]. As demonstrated by Lubell et al. [47], using an economic evaluation and taking into account clinicians responses to test results, this would affect the cost-effectiveness of rapid diagnostic tests. Therefore, it is important that policy-makers make efforts to encourage health workers to use the test results as a guide for treatment decisions. Although these models do not address what potential interventions would be needed to improve healthcare providers behaviours (e.g. training, supervision, strengthening of drug and rapid diagnostic test supplies, and additional personnel) and the costs of such interventions, these analyses nonetheless provide better information about their potential impacts. Further work is needed to determine what future benets can be obtained from the reduction in antimalarial drug pressure. Such benets include a deceleration in the development of antimalarial resistance and improved antibiotic drug prescription thanks to enhanced specicity of malaria diagnosis.

receive their test results. It can also immediately provide the test results needed to make decisions about treatment. Highly sensitive and specic POC diagnostic tests, given their ease of use and interpretation, could potentially be deployed at a peripheral level in epidemics, if a minimal degree of personnel training, logistics and quality assurance is guaranteed [48]. From the nancial standpoint, the public health improvement inherent in the deployment of POC diagnostic tests might result in either additional immediate expenditures (because of the cost of testing) or signicant long-term savings (because of effective control of HIV and malaria). Further data are required to more accurately dene costefcacy-type models, especially when evaluating the clinical and economic consequences of misdiagnosis. Findings from cost-effectiveness analyses suggest that, despite the relatively small additional cost incurred, decision-makers should strongly consider using POC tests throughout or during parts of HIV and malaria epidemics, where this is feasible in terms of local human resources and logistical conditions.

Transparency Declaration
Both authors declare that they have no conicts of interest.

References
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Conclusions
Over the past decade, POC testing has become increasingly accessible in areas with limited laboratory facilities, resulting in a great reduction in the number of persons who do not

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2010 The Authors Journal Compilation 2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 10701076