Cost-effectiveness analysis of rapid diagnostic test, microscopy and syndromic approach in the diagnosis of malaria in Nigeria: implications for scaling-up deployment of ACT

Malaria is the number one cause of mortality and morbidity in Nigeria and accounts for 25 and 30% of infant and childhood deaths, respectively and 11% maternal mortality [1]. Most victims of malaria still die because the disease is not diagnosed in time by health workers [2]. The diagnosis of malaria has traditionally relied on the clinical presentation of malaria symptoms [3, 4] and microscopical examination of Giemsa-stained blood films. Diagnosis based on symptoms alone is unreliable because the symptoms of malaria are non-specific, overlapping with other febrile diseases [5]. Studies in Africa have shown that more than 50% of patients clinically diagnosed with malaria have illnesses attributable to some other causes [6‐8]. This results in over-diagnosis of malaria [9], over-prescription of anti-malarial drugs, under-diagnosis and inappropriate treatment of non-malarial febrile illnesses (NMFI) [10‐14]. It is also costly and associated with side-effects [6] and ultimately contributes to the development and spread of drug resistance [7, 15, 16].

Although microscopy is considered to be the gold standard for malaria diagnosis [16, 17], in many malaria-endemic areas like Nigeria, there is lack of trained microscopists and reliable equipment [18].

As anti-malarial drug costs increase, diagnostic methods are becoming a crucial component of malaria control and prevention. Treating all fevers with anti-malarial medications will no longer hold with the introduction of a higher-priced artemisinin-based combination therapy (ACT), which was introduced in Nigeria in 2005 as the first-line anti-malarial drug, as a result of extensive resistance to chloroquine and sulphadoxine-pyrimethamine (SP) [19]. It has been noted that the cost of ACT is up to ten times more than chloroquine [20]. Although the prices of ACT have reduced recently, the recommended ACT (artemether-lumefantrine) in Nigeria is still sold at $6 to $8. Thus with the high cost of treatment for malaria, there is an increased need to ensure that malaria is correctly diagnosed prior to treatment [21].

Developments in rapid diagnostic tests (RDTs) based on the demonstration of parasite antigens have opened new possibilities for improved remote malaria diagnosis that is independent of microscopic diagnosis [18, 22‐25]. Several commercially available tests are sensitive, specific, and stable under operational conditions [14, 26, 27]. WHO recommended 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 [28]. RDTs can be performed close to home in settings with no sophisticated infrastructure, and they do not require much skill although some level of training is needed in order for RDTs to be used properly.

In spite of these advances, there is paucity of cost-effectiveness data of RDTs in highly malaria endemic countries like Nigeria. Although studies have investigated the cost-effectiveness of RDT in Africa [14, 28‐30], little is known on its cost-effectiveness in Nigeria. This paper reports an economic evaluation carried out to determine whether the use of RDT for diagnosis of malaria is cost-effective, when compared with clinical diagnosis and microscopy-based diagnosis of malaria. The cost-effectiveness analysis is based on the model by Shillcutt et al [28], with data on cost and malaria epidemiology obtained from south-east Nigeria. The information generated by this study will help design policy measures to strengthen the diagnosis and treatment components of the national malaria control strategy especially in the light of the introduction of ACT in Nigeria.

The study demonstrates the cost-effectiveness of RDTs over microscopy and syndromic approach. The results are consistent with results from a previous study [28], which showed that RDTs are cost-effective relative to syndromic approach and microscopy. Also the results of the present study are similar with a study in lower level health facilities in Zambia, which was conducted within the actual malaria context using field-based data in a malarious population [30]. Surprisingly, microscopy malaria diagnosis was less effective than expected which goes to challenge the fact that microscopy is the gold standard for malaria diagnosis [32].

More than 50% of patients who were diagnosed as having malaria through the syndromic approach, and who may have received anti-malarials, turned out to be parasite-negative. Thus this study demonstrated that over-diagnosis and, therefore, over-prescription of anti-malarials, may be reduced through the use of RDTs among this population at health centres. Malaria over-diagnosis is still a major public health problem in Africa with studies suggesting between 50% and 99% of those prescribed anti-malarials being test-negative, depending on endemicity in the clinical setting [8, 33‐35]. The ability to rule out malaria can also lead to more opportune diagnosis and treatment of other causes of fever, such as acute respiratory infection, typhoid fever and meningitis and avoidance of the exposure of those without malaria to any side-effects of the drug and the restriction of anti-malarials to true test-positives.

Health workers might have altered their normal practice as a result of the study (Hawthorne effect), thus obeying test results and prescribing ACT only to those who are RDT positive. In real practice (absence of the research team), this may not be so, as studies have shown that anti-malarials are prescribed by health workers even if test results are negative [9, 13]. Undoubtedly, this will affect the cost-effectiveness of RDTs. Therefore, it is important that policy makers make effort to encourage health workers to use the test results as a guide for treatment decisions.

The sensitivity analysis at various levels of prevalence stresses the relevance of RDT under a low prevalence level. However, as has been noted the better health outcome with RDT compared to presumptive treatment does not mean improved treatment of true malaria cases, since sensitivity of presumptive treatment is higher than that of RDT [28]. Instead, it demonstrates improvement on treatment of bacterial non-malarial febrile infection that could be treated inappropriately with ACT using presumptive treatment. Bacterial diseases are an important cause of avoidable deaths in children in Africa [36‐38].

At higher probability levels RDT also showed to be more cost-effective compared to presumptive treatment and microscopy. The reason for this could be explained by the fact that higher NMFI implies low malaria prevalence, which in turn provides strong reason for diagnostic test before treatment. It also implies that if careful diagnosis is not carried out, there could be higher probability of giving malaria treatment to a patient with NMFI. This in turn has high cost implication, especially when the cost of ACT is considered. Again, at a low probability level of NMFI, presumptive treatment proves to be more cost-effective than RDT, while microscopy is dominated at all levels of NMFI cases. This implies that at low malaria prevalence, the probability that non-malarial febrile infection is bacterial should be important to decision makers.

Cost-effectiveness of RDT and other diagnostic tools also has much to do with adherence. The reason is because when someone adheres to treatment there will be less chances of going for second treatment option even though the cost implication in the case of NMFI may not be so much. NMFI also has cost-effectiveness impact on RDT treatment based on the fact that presumptive treatment may lead to antibiotics being given when a patient actually has malaria. Policy makers should, therefore, know that cost-effectiveness of RDT can be greatly reduced if there is poor ACT adherence level. In this study, patients adhered to ACT treatment up to 80% level. Improvement on this will further ensure a more effective result while relapse will negatively affect the gains of RDT over presumptive treatment and microscopy. In Nigeria, ACT is delivered free to children under five years in public health facilities and this is likely to ensure that adherence level to ACT is increased. However, it is worth noting that ACT adherence can decrease as result of patients' and caretakers forgetting to give the dose on certain days. They may also have incomplete dose if they perceive that they are cured after the initial few doses as have been noted in the past, when chloroquine was being used as the first-line anti-malarial drug [39]. Because of poverty, they may stop taking the drugs after one or two doses, to save tablets for later use by other members of the family.

A doubling of the cost of RDT made it less preferable to presumptive treatment. The implication of this is that policy makers should be more careful in choosing any policy that will cause an increase in the cost of RDT as consumers might become less willing to pay for the marginal increase in the cost. Again, a rise in the cost of RDT that is not checked by a corresponding decrease in the cost of ACT is likely to result in presumptive treatment being preferred over RDT and microscopy. In a low prevalence setting, such a situation could further worsen the challenges associated with inappropriate use of drugs including risk of resistance, further disease progression and consequent depletion of income. Thus, strategies must be in place to prevent increase in the cost of RDT if it is to remain cost-effective over other strategies especially at a declining prevalence level.

If the price of ACT rises at the current malaria prevalence level, treatment for malaria will be costly even for presumptive treatment with the cost of ACT significantly driving the cost-effectiveness of RDT. Such a finding has been noted elsewhere [28]. This calls for careful decision in fixing the price of ACT by any authority, as this could overshoot the societal ability and willingness to pay, and as well elude the cost containment of RDT. Considering the fact that Nigeria has a significant rural population, increasing the cost of ACT will make it further difficult for people to seek treatment at the appropriate time. It could also encourage presumptive treatment for two reasons: 1) RDT would no longer be affordable, and 2) microscopy with its high cost will not be affordable and available especially in the remote villages.

As cost of ACT is currently high, unnecessary spending on treatment that is not malaria can be avoided if RDT is used to ascertain the true health condition. This will enable health workers to treat malaria appropriately and at the same time avoid extra burden of second-line treatment cost.

On the other hand, a reduction in the cost of ACT which made presumptive treatment more cost-effective than the other options implies that consumers might end up preferring presumptive treatment strategy. Such a situation was prevalent in the era of chloroquine use, a very cheap anti-malarial drug. This means that with falling prices of ACT, efforts must be made to keep consumers informed of all the benefits of appropriate diagnosis of malaria, including the fact that ACT could face the same fate as chloroquine, if used inappropriately.

An incremental effect value that fluctuated drastically at the 40% prevalence level, which is close to the prevalence of 43.1% noted in this study, gives a clear picture of what was obtained in Nigeria before the change in malaria treatment regime. Before 2005, chloroquine was the first-line drug for malaria treatment. Given the low cost of chloroquine, people were given presumptive treatment on the assumption that an average Nigerian has malaria parasites. The regime change made the cost of treatment to rise, which simultaneously brought about the need to ensure that one has malaria parasite before treatment so as to avoid giving the costly ACT drug incorrectly. The analysis however shows the need for a reduced cost of ACT given that most people cannot afford the treatment cost. It also shows that lower price of ACT will go a long way to improving the treatment-seeking pattern of the people, especially the poor and vulnerable.

Although studies have investigated the cost-effectiveness of RDT in Africa [14, 28‐30], this study provides, the first estimates of the cost-effectiveness of RDT in Nigeria. A particular strength of this analysis is that costs are based on relevant information from the study. However, the results are also subject to a number of assumptions. The sensitivity analysis showed, that the overall cost-effectiveness of RDT is relatively robust to these assumptions. In terms of extrapolation to parts of Nigeria, Enugu east LGA is representative of areas of stable perennial malaria transmission in Nigeria.

The primary limitation of the study is that effectiveness was estimated from the results of the study where the study team delivered ACT treatment free of charge. In practice, availability of ACT may influence cost-effectiveness because patients may not be able to purchase ACT as a result of its high costs. However, this may not be necessarily so for under-fives, that are officially given free ACT in public facilities in Nigeria.

Secondly, all patients that were negative for malaria parasites were not given ACT. But in practice, health workers may not adhere strictly to this as evidence has shown that health workers are reluctant to refrain from treating for malaria after a negative test [9, 16, 40, 41], a practice that is likely to reduce the cost-effectiveness of RDTs.

Thirdly, patients who were negative on microscopy or RDT received amoxicillin systematically. Realizing that not all these patients would require amoxicillin, they were subsequently refereed for further investigations and management and may have gotten proper treatment for their illnesses. This may have made RDTs more cost-effective and thus biased the cost-effectiveness estimates. However, the proportion of NMFI was too small as to have contributed to RDTs being more cost effective. Nevertheless, in actual practice, health workers may prescribe antibiotics to patients who are negative within the concept of integrated management of childhood illnesses and when this happens, it will even make RDTs more cost-effective.

Fourthly, clinical outcome rather than parasitological clearance was used to assess effectiveness of treatment. It is possible that parasitological clearance does not occur following treatment despite the non-recurrence of fever and this can influence the measure of effect since patients recorded as having recovered could still have malaria parasites. However, it is noteworthy that since fever is the major symptom that makes individuals seek health care, those who do not have fever within 21 days of treatment are unlikely to seek further care or incur additional expenditure on treatment, thus limiting the potential bias arising from use of clinical outcome for this analysis.

Finally, patients who reported prior anti-malarial drug intake were not included in the study as this could cause a possible bias considering the fact that having taken an anti-malarial drug, their test results may have read negative implying that they don't have malaria, whereas they may have had malaria prior to coming to the health centre. However, in this study, there were not a significant number of them.

At the prevalence level of 43.1%, RDT was a cost effective strategy for diagnosis of malaria in Nigeria. Policy makers and healthcare providers can be confident that at the prevalence level of malaria in Nigeria, that it will be cost saving to use RDTs rather than a syndromic approach and microscopy. There is, therefore, increased opportunity for cost savings if RDTs are introduced in health facilities especially in rural communities where microscopic examination for malaria diagnosis is not readily available. RDTs decreased the number of false positive patients who would have received unnecessary medication and thus helped to prevent the erroneous treatment of fever caused by other infections, and may reduce the drug resistance of malaria. There are compelling reasons to justify the implementation of RDTs in Nigeria. Most of the health centres that serve the Nigerian poor do not have microscopes or trained technicians to examine blood films. Therefore, the reliance on these rapid tests, which are reliable, cheap, and simple enough to be used by non-laboratory staff, is likely to greatly contribute to an effective control of malariaThe wide application of RDT in Nigeria is also likely to avoid the treatment of patients with bacterial disease with the costly ACT and thus provide appropriate anti-bacterial treatment for those with bacterial infection.