Malaria treatment and prophylaxis in endemic and

nonendemic countries: evidence on strategies and their

cost-effectiveness

Abstract
TranslateAbstract
Artemisinin combination treatment is currently the preferred treatment strategy to combat malaria.
However, the drug costs are considerably higher than for previously used therapies. This review
discusses the cost-effectiveness of current malaria treatment and prophylaxis in endemic and
nonendemic countries. For endemic countries, a systematic search for economic evaluations (i.e.,
cost-effectiveness, cost-utility and cost-benefit analyses) was conducted, looking at the use of
Artemisinin combination treatments in children, pregnant women and other adults. In total, 24 studies
were identified investigating the cost-effectiveness of malaria treatments with the focus on
uncomplicated malaria, severe or prereferral treatment, all in combination with adequate diagnosis,
and malaria prevention by intermittent preventive treatment, respectively. In areas with both
Plasmodium falciparum and Plasmodium vivax transmission, artemether-lumefantrine and
dihydroartemisinin-piperaquine, respectively, are currently the most cost-effective treatment options.
Treatment of severe malaria with artesunate is more cost effective compared with treatment with
quinine. For patients that live more than 6 h away from an appropriate healthcare facility, prereferral
treatment proved to be more cost-effective compared with no prereferral intervention. Cost-
effectiveness of intermittent preventive treatment in pregnant women (IPTp) was dependent an
clinical attendance. IPT in infants with sulphadoxine-pyrimethamine (SP) is cost effective in sites with
high malaria transmission. IPT in children with artesunate (AS + SP), amodiaquine (AQ) + SPQ or
SP alone is a cost effective and safe intervention for reducing the burden of malaria in children in
areas with markedly seasonal malaria transmission. Although there is a need for it, little is known
about the cost-effectiveness of current approaches to malaria therapy in nonendemic countries and
the cost-effectiveness of antimalarial chemoprophylaxis.

Full Text
TranslateFull text

Figure 1. Malaria treatment and prophylaxis options in endemic and nonendemic countries. ACT:
Artemisinin combination treatment; IPT: Intermittent preventive treatment; IPTs: IPT in school
children; IPTi: IPT in infants; IPTp: IPT in pregnant women.
(Figure omitted. See article PDF.)

Health impact of malaria in endemic countries

Currently, 109 countries are considered as malaria-endemic, with the whole of sub-Saharan Africa
(SSA) and 45% of the southeast-Asian (SEA) population at risk. Yearly, malaria results in nearly one
million deaths, caused directly or indirectly by the parasite. 96% of the deaths caused by malaria
occur in low-income countries, and 87% of these children are younger than 5 years of age [1], most
of them in SSA. Indeed, the whole SSA region is at risk of malaria, while the risk profiles for SEA
countries vary, with areas of stable, unstable and no malaria risk [2]. Plasmodium
falciparum and Plasmodium vivax are the most common species causing malaria, withP.
falciparum being responsible for approximately 90% of the malaria cases; 94% in SSA and 57% in
SEA [2,101]. P. falciparum causes uncomplicated malaria and severe malaria.

Uncomplicated malaria: P. falciparum

Uncomplicated malaria presents as a febrile disease, with symptoms such as fever, headache,
muscle pain and vomiting [3]. If left untreated, it may develop into severe malaria with complications
and eventually lead to death [4].

Severe malaria: P. falciparum

Severe malaria can be defined as a malaria episode with signs and symptoms of organ dysfunction
or high levels of parasitemia [102]. It usually manifests with one or more of the following symptoms:
lactic acidosis, severe anemia, hypoglycemia, acute renal failure and coma (cerebral malaria).
Without quick and appropriate treatment, it can progress to death. The case fatality rate of treated
patients at this stage is approximately 10-20% [102]. In highly endemic areas, partial acquired
immunity in older children and adults lowers the risk of developing severe malaria.

Accurate diagnosis

Accurate diagnosis is becoming more important in preventing over-treatment and misdiagnoses of

malaria patients, and improving the efficient use of costly artemisinin combination treatment (ACT).

Three main methods are currently used to diagnose malaria, as is shown in Table 1. First, malaria
can be diagnosed based on clinical presentation of symptoms and signs; a history of fever or a
temperature of 37.5C (measured nonaxillary) or higher would confirm a malaria diagnosis [5]. This
method has a very poor specificity, as many nonmalaria febrile patients are considered malaria
cases. This leads to significant misdiagnosis and over-treatment [6]. Second, when microscopy
facilities are available, a blood sample can be analyzed. However, the accuracy of the test depends
on the expertise of the personnel, and not all healthcare centers have laboratory facilities for
adequate microscopic use [5]. Thirdly, rapid diagnostic tests (RDT) can also be used to confirm the
diagnosis of malaria. Currently, there are two major different antigen detection methods available,
sensitive to two principal antigens of the malaria parasite: HRP-2 to identify P. falciparum , and pLDH
to detect all four human malaria parasites [7]. HRP-2 can be combined with a plasmodium-specific
aldolase (the so-called pan-malarial antigen), which has a limited capacity to detect all four
'classic'species pathogenic to man, if not also Plasmodium knowlesi infections. Although multiple
limitations apply, such as limited sensitivity to non-falciparumspecies with the HRP-2/aldolase system
and high sensitivity with the pLDH system being limited to P. vivax detection, those RDTs are easy to
administer correctly, compared with microscopy where much expertise is needed [5].

Economic impact of malaria in endemic countries

Malaria imposes substantial direct and indirect financial losses on individuals and families; for
example in terms of missed schooling, welfare and income losses, as well as for travel expenses and
treatment. On a larger scale, this also applies to governmental bodies, for example for forging
country-specific intervention strategies against malaria and implementing them; and for initiating and
maintaining surveillance systems. A decade ago, Gallup and Sachs, and Malaney described the
negative impact malaria has on economic growth [8,9].

Range of treatment strategies available

Treatment of uncomplicated malaria

A range of drugs are available for P. falciparum therapy, but drug resistance is becoming an
increasing subject of concern [102]. Resistance to chloroquine (CQ) treatment has been reported in
all African countries, and also resistance to sulfadoxine-pyrimethamine (SP), the once-successor to
CQ as first-line treatment in vast parts of SSA, is increasing [10]. To that end, the WHO replaced CQ
and SP by ACTs as preferred first-line treatment [102]. Artemisinin derivates are yielding the most
rapid clinical improvement and clearance of the parasite. Furthermore, the transmission of the
parasite is reduced by decreasing the gametocyte carriage in the peripheral blood [11,12]. By using
combination therapies, the rate of resistance to a particular regimen will be slowed down, which is
another advantage of the ACTs. After the introduction of ACT a decline in malaria burden, mortality,
morbidity and treatment failure was shown [13].

The WHO guidelines recommend ACT as treatment for uncomplicated malaria to attain the optimal
therapeutic effect. Table 2 details the five ACTs that are currently used [102]. Malaria treatment
guidelines recommend that treatment for uncomplicated malaria should be restricted to people with
positive malaria results on the parasitological test, at least for nonpregnant adults and children over
the age of 5 years [14].

Treatment of severe malaria

Although recent studies showed that artesunate functions better than quinine as treatment for severe
malaria, quinine still remains the official first-line treatment in most countries [15,16]. Case fatality
rate of quinine was set at 11%, based on a study done in African children younger than 15 years
[15]. As quinine is not easy to administer with a narrow therapeutic ratio, the advantage of artesunate
is even greater [17].

When people cannot take the drugs orally, injections have to be given, which can only be done at a
healthcare facility. However, it may take much time to reach a clinic, by which time the disease may
have already progressed too far to be treated successfully [18]. Recent studies showed that
artesunate given rectally to children can reduce the more severe symptoms of the disease by
reducing the parasite density, and allowing more time to reach a clinic for further treatment [18]. The
success of prereferral treatment depends on the promptness in seeking care, as solely rectal
artesunate is not enough and further treatment is crucial for recovery [19]. Rectal artesunate takes 6-
12 h to produce a change in the parasite count [19]. When patients lived within a 6 h distance to the
clinic, the prereferral treatment had no additional effects on the health outcome. However, when it
took patients over 6 h to reach the clinic, the prereferral treatment had a significant beneficial impact
on the health outcome [18]. Presumably, the longer the time to reach the clinic was, the greater the
importance of prereferral treatment. It seemed that for patients in Africa, it took longer to access a
health clinic, whereas patients in Asia quickly got intravenous quinine and hospital care. When
subdivided by age, it suggests that young children especially can benefit from this intervention, with
a reduction in mortality of 49% [18]. It has been hypothesized that repeated prehospital rectal
artesunate can further reduce malaria mortality [20].

Intermittent preventive treatment

Intermittent preventive treatment (IPT) of malaria is a public health intervention aiming at treating and
preventing malaria. It involves the delivery of treatment doses of an antimalarial to a target
population, at regularly scheduled intervals, regardless of the plasmodial infection state, hence no
diagnostic tool is applied prior to drug administration [21]. It has been shown that after
discontinuation of IPT, clinical episodes did not increase in most settings; in addition, presumptive
treatment did not show a significant rebound effect in terms of an increase of clinical malaria
episodes after discontinuation of treatment [22]. Previous studies showed that IPT is an effective
strategy in the fight against malaria, especially in areas with seasonal transmission of malaria [23].
IPT has been endorsed by the WHO as a potential intervention to reduce malaria morbidity and
mortality in pregnant women (IPTp) and infants (IPTi). More recent studies have also shown IPT in
children (IPTc) to be a potentially valuable tool that can contribute to the control of malaria in areas
with markedly seasonal transmission [24]. IPT in school children (IPTsc) also appears to be a
strategy of value, particularly in areas of unstable malaria transmission with high seasonality, where
children are in school and able to receive continuous prophylaxis for the months during the rainy
season [25]. IPTp, IPTi and IPTsc all benefit from already existing health programs to aid their
delivery. The WHO recommends giving all pregnant women at risk of P. falciparum infection at least
two doses of SP, at the first and second scheduled antenatal care visits (at least 1 month apart),
except for HIV-positive mothers. Infants should receive three doses of SP delivered alongside the
Expanded Programme on Immunisation [102]. In Mozambique and Tanzania, the Expanded
Programme on Immunisation yields high compliance, with more than 92% of the children receiving
three doses of vaccines against DTP; thus offering an opportunity for malaria treatment as well.

In summary, in malaria-endemic areas, prompt and effective treatment with appropriate antimalarial
drugs will, for decades to come, remain central to successful malaria control [11,26], given the fact
that a malaria vaccine facilitating significant reductions in morbidity and mortality is not currently
available and will not be in the nearer future at least. The correct use of appropriate diagnostic tools
(RDTs or microscopy) is also important. In addition, IPT strategies exist to reduce morbidity and
mortality in pregnant women, infants and children in endemic areas and in areas of high-risk for
malaria.

Health & economic impact of malaria in nonendemic countries

In nonendemic countries, malaria is still known as an "imported disease"[27,28]. Treatment of

uncomplicated and severe malaria in returning travelers has its costs. Chemoprophylaxis can be,
depending on the regimen chosen and travel duration, quite expensive on a personal level. The
presence of ongoing local malaria transmission, identified through local surveillance and reported to
regional WHO offices, forms the basis of national and international chemoprophylaxis
recommendations in Western countries.

This article identifies strategies and discusses what has been published regarding cost-effectiveness
of malaria treatment and prophylaxis in endemic and nonendemic countries with prior application of
an appropriate diagnostic tool (RDTs or microscopy).

Figure 1 depicts the framework of malaria treatment options and prophylaxis in endemic and
nonendemic areas.

Methods

Data search

A systematic search for economic evaluations (i.e., cost-effectiveness, cost-utility and cost-benefit
analyses) was conducted comparing ACTs to other malaria therapies and prevention strategies in
children, pregnant women and other adults, in combination with prior application of an appropriate
diagnostic tool (RDTs or microscopy) in endemic countries. The language was restricted to English.
Published studies were identified though electronic searches of PUBMED and Embase (via OvidSP).
The reference list of the included studies was also searched. Publications of the WHO regarding
treatment guidelines and general information about malaria were found on the websites of the WHO
and the Center of Disease Control and Prevention (CDC). The cut-off date was set at January 2005
and the search was conducted in March 2011, spanning a publication period of just over 6 years.
The following search terms were used:

*Cost effectiveness malaria treatment

*Cost AND effectiveness AND malaria AND treatment

*Cost effectiveness antimalarial(s)

In selecting the articles, first titles and abstracts were screened and the final selection was based on
reading full papers that had passed the first selection.

A selection of articles, published since January 2005 about chemoprophylaxis strategies and cost-
effectiveness in nonendemic areas were used, however, they were not mentioned in the study
selection.

Study selection

In total, 206 articles were found in the first selection round. After screening of the titles and abstracts
of the articles, 54 articles remained to be assessed for eligibility. After assessment of the full paper,
24 articles were included. Of the 30 excluded articles, 17 articles were not evaluating ACT treatment
and 13 articles did not conduct a full economic evaluation of malaria treatment. The included articles
were subdivided according to the malaria stage or type of intervention strategy; 15 studies examined
uncomplicated malaria, three studies examined severe malaria and six studies examined IPT.

Risk of bias assessment

The Consensus Health Economic Criteria (CHEC) list was used for risk of bias assessment of the
economic analysis [29]. Table 3 shows the list, with studies that were analyzed using the CHEC list.

Perspective

Economic evaluations can be conducted from a provider or a societal perspective. The provider
perspective most often focuses on the public healthcare system and includes the costs of the health
facilities (i.e., drugs, personnel, medical examination, hospital fees, materials, administrative and
equipment overheads and building space). The societal perspective includes provider and household
direct and indirect costs (i.e., costs of healthcare facilities), but also costs of time lost due to caring
for a sick child, out-of-pocket expenses, transport and working absenteeism due to a sick child,
because of travelling to the hospital and waiting time for receiving treatment [15]. Since the majority
of articles described the cost-effectiveness from the provider's perspective, this is also the focus in
this review.

Cost-effectiveness threshold
An economic evaluation compares both costs and effects of two or more alternatives. The outcome
of an economic evaluation is the incremental cost-effectiveness ratio (ICER). As a formula, the ICER
can be defined as:

(Figure omitted. See article PDF.)

The effects of an intervention or disease can be expressed as life years saved, quality-adjusted life
years or disability-adjusted life years (DALYs). In cost-effectiveness studies of malaria treatment in
endemic countries, DALY is the most common term used to express the health effects. It describes
the overall disease burden expressed as the number of years lost due to ill-health, disability or early
death.

Cost-effectiveness can be measured by estimating the numbers of DALYs or deaths averted by the
intervention. Over the years, different criteria have been used to assess the cost-effectiveness of
different interventions [30]. When using DALYs averted to estimate the cost-effectiveness of an
intervention, an intervention can be considered cost effective if it was 'dominant'(i.e., if it yielded a
better effect at lower cost), or if it had an incremental cost per DALY under US $150 in 1993. A year
of life lost was assigned a cost of $150, based on the Ad Hoc Committee on Health Research
Priorities'recommendations [12,30,31]. Alternatively, an intervention was assumed to be cost-
effective when the cost per DALY averted was less than the gross domestic product (GDP) per head,
or if the cost was less than one-to-three-times, the GDP per capita, as estimated by the Commission
on Macroeconomics and Health [19].

Cost-effectiveness based on deaths averted can be estimated by making use of a threshold between
US $575 and 3450 (1993) per death averted [32]. These numbers are based on the willingness to
pay to avert the loss of a DALY, multiplied by the average patient age and life expectancy at death
and discounted with 3% [17]. Another method is the use of GDP as a threshold; as the mean cost
per death averted is below the GDP per capita, the intervention can be considered as being cost
effective [17].

Results

It is noted that studies are difficult to compare because of differences in methodology as mentioned
earlier. Differences in calculated cost-effectiveness between studies and its implications for policy
recommendations have been mentioned in the following sections. In the future the cost of resistance
should definitely be introduced in economic evaluations

Endemic countries: treatment strategies & their cost-effectiveness

Uncomplicated malaria
As effectiveness and costs differ for treatment of uncomplicated malaria for children and adults and
for infections with both P. falciparum and P. vivax , a distinction is made for those groups (Table 4).
The cost-effectiveness of treatment of uncomplicated malaria for adults is depicted, followed by
treatment of uncomplicated malaria for children in areas with P. falciparum only. Finally, cost-
effectiveness of malaria treatment interventions in areas with both P. falciparum and P.
vivax transmission is described.

Adults

Three cost-effectiveness studies of uncomplicated malaria treatment were conducted in Tanzania.

Replacement of presumptive treatment by HRP-2 RDTs reduced the overall drug and diagnostic
costs by 10 and 15% in high- and low-transmission areas, respectively. This was mainly due to the
reduction in malaria treatment costs, since ACTs are expensive, and with accurate diagnostics only
true malaria cases were treated [33]. In low-transmission settings (10% malaria prevalence), the use
of HRP-2 RDTs or microscopy became more attractive with an adherence (or response rate) of 20%
or above [34]. In these settings, despite the fairly high sensitivity of HRP-2 RDTs, the advantage over
microscopy was moderate. In high-transmission settings (60% malaria prevalence), both HRP-2
RDTs and microscopy incurred higher costs than presumptive treatment when the adherence rate
was below 65%. Above an adherence rate of 65%, HRP-2 RDTs use prior to treatment with ACTs
(RDT-ACT) yielded an advantage over presumptive treatment. This study assumed that only febrile
patients are tested, but in reality also patients with no history of fever were also tested [34]. By
replacing microscopy by HRP-2 RDTs, the percentage of correctly treated patients would increase to
95%, possibly resulting in a higher cost-effectiveness ratio of HRP-2 RDTs. However, there are
limitations to this study, in particular the fact that it used "cost/case correctly treated", for which there
is no clear threshold to classify HRP-2RDTs as cost effective [34]. The ICER of HRP-2 RDTs would
be US $25.2 per correctly treated patient in comparison with microscopy. In high-transmission
settings the sensitivity of the test will be slightly lower, resulting in an ICER of US $7.0 per correctly
treated patient, which is still considered to be cost effective [14].

Two studies regarding cost-effectiveness of ACTs were conducted in Zambia [5,14]. In the context of
low coverage of prevention strategies, the cost-effectiveness of treatment with Artemether-
lumefantrine Artemether-lumefantrine (AL) was compared with SP treatment. These studies showed
that the average cost of treating patients with AL was almost 20% higher than with SP. However,
although SP was less expensive, AL was more cost effective due to a reduction of need for hospital
care. In this study, diagnostic methods were not included [10]. When taking diagnostic methods into
account, HRP-2 RDT proved to be the most cost-effective option. The estimated ICER per correctly
diagnosed patient of HRP-2 RDTs, with clinical diagnosis used as baseline, was found to be lower
than microscopy (US$2.6 vs $9.6), meaning HRP-2 RDTs being the most cost-effective diagnostic
method. The personnel costs for HRP-2 RDTs and clinical diagnosis showed to be similar, while the
costs for microscopy were almost twice as high, as more expertise and time is needed for diagnosis
using microscopy [5].
As the costs vary with malaria prevalence and ACT use, a cost-effectiveness analysis was conducted
at three different prevalence levels (prevalence of 25, 50 and 75%) and using either AS + AQ or AL
as therapy. One study showed that RDT-ACT was more cost effective when the costs of the ACTs
were higher; as AL is more expensive than AS + AQ, using AL increases the cost-effectiveness of
HRP-2 RDTs as diagnostic method [6]. By increasing the costs of the treatment, the use of a test will
become more cost effective. Another study examined the cost-effectiveness of AS + AQ in
combination with microscopy or HRP-2 RDTs, including only the direct costs [7]. This study did not
show that using HRP-2 RDTs was cheaper. It did, however, confirm the high accuracy of the HRP-2
RDTs, but also showed the risk of false-positive results as transmission increases, which could lead
to misdiagnosis [7]. However, the authors concluded that in the absence of microscopy, HRP-2 RDTs
is a good alternative for the diagnosing of malaria with reduction of the over-prescription of
antimalarials [7].

By incorporating the consequences of diagnosis and total costs of treatment, a cost-effectiveness

analysis was conducted for outpatients in Uganda. By calculating only the direct costs for the
treatment of adults, HRP-2 RDTs was preferred at low (3%) and medium (30%) prevalence level.
When incorporating health outcomes, both HRP-2 RDTs and pLDH RDTs were more cost effective
than presumptive treatment. The highest cost savings were estimated at low-transmission sites [35].

When using the antimalarial AS + SP, HRP-2 RDTs were shown to be cost effective when 25% of the
febrile patients are positive for malaria, compared with clinical diagnosis in a holoendemic malaria
transmission area of Mozambique [36]. However, when more than 33.3% of the patients are malaria-
positive, clinical diagnosis, instead of HRP-2 RDTs, proved to be most cost effective. When using AL,
which is more expensive than AS + SP, HRP-2 RDTs will be cost effective when 50% or less of the
patients are tested positive. However, in this analysis it was assumed that all treatments were
successful, as a high treatment success rate is likely due to the high effectiveness of the treatments
[36].

Another estimation of cost-effectiveness of HRP-2 RDTs were based on findings from a high-
transmission area in Nigeria [37]. At a malaria prevalence level of 43.1%, the ICER of HRP-2 RDTs
was US $221 per death averted, as compared with presumptive treatment using DHA + PQ. At all
malaria prevalence levels of 40% or less, HRP-2 RDTs proved to be cost effective. As the ICER was
sensitive to HRP-2 RDTs cost changes, a rise in the HRP-2 RDTs price of US $0.76-1.14 resulted in
a reduction of the cost-effectiveness of HRP-2 RDTs compared with presumptive treatment (at a
malaria prevalence rate of 40%). Considering various prevalence levels, HRP-2 RDTs was found to
be less cost effective when malaria prevalence levels were above 30%. The ICER was also sensitive
to a rise in the costs of ACTs: with a 50% rise in costs of ACT, the HRP-2 RDT still remained cost-
effective at 40% prevalence with an ICER of 51.008 per death averted. However, with a reduction in
the costs of ACT and at a prevalence level of 40%, presumptive treatment will become more cost
effective [37].
Children less than 5 years of age

In Tanzania, a cost-effectiveness study of ACT for children compared with the monotherapy AQ was
conducted. In this study, three different ACTs (AQ + SP, AL and AQ + AS) were compared with AQ or
SP, using microscopy as a diagnostic tool. Only patients with confirmed malaria received treatment
[38]. The indirect cost (e.g., time lost due to care for a sick child) proved to be the largest component
of the costs for malaria treatment. Although AL is the most expensive antimalarial, it also turned out
to be the most cost-effective antimalarial compared with the other four (AQ + SP, AQ + AS, SP, AQ),
because of the high resistance of malaria against SP and AQ resulting in a reduction in need for
further treatment [38]. A modeling study in 2004 also showed that ACTs are extremely likely to be
cost effective under most conditions unless resistance to monotherapies or SP is very low [39].
When incorporating the health outcomes in areas with 3 and 30% transmission in Uganda, the HRP-
2 RDT showed to be the most cost-effective option compared with microscopy and presumptive
treatment. At a transmission level of 70%, presumptive treatment was shown to be more cost
effective [35]. When using HRP-2 RDTs in moderate-transmission areas for the diagnosis of children,
this resulted in a cost-saving of 7% (in case of HRP-2 RDT = US$1) to 12% (in case of HRP-2 RDT =
US$0.50). However, the use of HRP-2 RDTs was only cost-saving if ACT costs more than US$0.63.
In low-transmission sites, HRP-2 RDTs showed to be cost-saving if the costs for ACT were more than
US$0.50 [33].

P. falciparum & P. vivax transmission

In Papua New Guinea, a study was conducted among children (6-60 months) regarding the cost-
effectiveness of three ACT combinations (AS + SP, DHA + PQ and AL) compared with the
conventional treatment of CQ + SP [1]. The study was focused on the societal costs (e.g., the costs
of traveling between home and the health clinic) plus the direct costs of healthcare (i.e., medication
costs, visits to health clinics and clinical tests). The ICER per treatment success for P.
falciparum treatment with DHA + PQ was estimated at US$12.00, and US$10.37 for treatment with
AL. The ICER of AL relative to DHA + PQ was US$10.60 [1]. The increased life expectancy per 1000
cases treated with AL was 16.4 years (or 12.8 years when discounted at 3% as recommended by
Gold et al. , 1996), compared with CQ + SP [1]. By calculating the ICER for the treatment of P. vivax ,
it was estimated that DHA + PQ was the most cost-effective therapy compared with CQ + SP [1].
Although the ACTs were more expensive in routine healthcare settings, DHA + PQ and AL proved to
be cost effective for treatment of P. vivax and P. falciparum respectively, compared with CQ + SP,
with AL being the most effective [1]. However, treatment compliance has not been considered in this
analysis, and also the costs of time parents took off work when looking after a sick child were not
included [1]. A study conducted in the Amazon region in Brazil compared the cost-effectiveness of
RDT detecting pLDH (OptiMal ) and microscopy, with both P. falciparum and P. vivax present [40].
In this study, all components of malaria diagnosis were included: personnel, equipment,
maintenance, training and transportation; however, treatment costs and the societal perspective were
excluded. It showed that microscopy was more cost-effective than pLDH RDTs in remote endemic
areas when a high sensitivity (92-95%) and specificity (100%) for microscopy diagnosis were
maintained. When microscopic sensitivity and specificity for P. vivax were 90% and 98%,
respectively, and when its sensitivity for P. falciparum was 83%, pLDH RDTs were more cost-effective
than microscopy, indicating that very high microscopy accuracy levels are needed for microscopy to
be more cost-effective than pLDH RDTs. However, in this study the costs of the antimalarials were
not included [40]. Another study conducted in the Amazon region showed that in remote areas HRP-
2 RDT was cost-saving compared with microscopy; however, accuracy parameters were not used in
this model [41]. True accuracy of microscopy-diagnostic techniques in field settings is generally
unknown in most endemic countries, which makes it difficult to determine the real sensitivity and
specificity of microscopy [40]. In Ethiopia, malaria is seasonal with two transmission seasons, and
both P. falciparum and P. vivax are present, causing 60 and 40% of the malaria cases respectively. P.
vivax is treated with CQ, while P. falciparum is treated with AL. When calculating the ICER for pLDH-
over HRP-2 RDTs, the incremental costs were estimated at US$0.59 per case correctly treated.
However, this applies to an area with both P. vivaxand P. falciparum prevalence; therefore, diagnostic
and treatment strategies differ from those in areas with only P. falciparum [42].

Severe malaria

The articles used in the analysis of the cost-effectiveness of treatment for severe malaria are listed in
Table 5.

As shown in a study conducted in SEA, the mortality rate of patients treated with artesunate was
considerably lower than that of patients treated with quinine, but the costs of treatment with
artesunate were slightly higher [17]. The ICER of artesunate versus quinine were shown to be the
highest in India, with an ICER of US$358.90 per DALY averted, and the lowest in Myanmar with an
ICER of US$104.80 per DALY averted. If decision makers are willing to pay US$575 to avert the loss
of a life, artesunate will be cost effective up to costs of US$4.20 per vial, which is more than the
current selling price. When the willingness-to-pay threshold is US$3.450, the costs will be cost
effective up to US$24.40 per vial. The pooled ICER of averting a death using artesunate is
approximately US$140. However, the costs of administering the drug, costs of equipment and
potential side effects were not included in the analysis. These excluded costs can reduce the cost-
effectiveness of artesunate, but the costs per death averted demonstrate that it remains a highly
attractive intervention [17]. Further evidence has been provided on the cost-effectiveness of
artesunate [43].

Prereferral rectal treatment

A recent study was conducted in a high-transmission area of SSA to examine the cost-effectiveness
of rectal artesunate given together with an antibiotic with the intention of improving health outcomes
for both malaria and non-malarial illnesses, in a period of 5 years, from a provider's perspective [19].
Presumptive treatment based on the clinical symptoms and signs of severe malaria in high endemic
areas, had an estimated specificity of 74.6% and was assumed to have perfect sensitivity. Costs in
local currency units are converted to international dollars using purchasing power parity exchange
rates. A purchasing power parity exchange rate is the number of units of a country's currency
required to buy the same amounts of goods and services in the domestic market as the North
American dollar would buy in the USA [103]. The ICER per DALY over 5 years was estimated, with a
range from IS$14,001 (14% referral compliance) to IS$86,316 (100% referral compliance). When
uptake and compliance was both low (25%), the intervention was estimated to avert 19 DALYs at
IS$1,173 per DALY averted. Under full uptake and compliance (100%) the intervention should avert
967 DALYs at IS$77 per DALY averted. Applying the GDP of 2008 threshold of $1546 for the SSA
region, prereferral artesunate treatment proved to be highly cost effective [19]. Another study
evaluated the health effects on the population and the costs of prereferral antimalarials in both SEA
and SSA. In this study the treatment failure rates were set at 26% (for 5 years and older) and 6% (<5
year); treatment failures were adjusted for healthcare access within 6 h and after 6 h. The costs for
HRP-2 RDTs were included in the analysis. Compared to usual practice, full coverage with rectal
antimalarials would avoid 238,428 deaths in SSA and 6873 deaths in SEA annually, with costs of
$35 million and 30 million, respectively, in SSA and SEA. Costs per death avoided were US$148 in
SSA and US$4429 in SEA, with a cost per DALY averted of US$5 in SSA and US$177 in SEA.
Highest changes in ICER were observed when healthcare access rates were varied. However, the
household costs of seeking care were not included and also the costs for delivery were unclear,
which probably depends on intervention implementation and geographical region [2].

Endemic countries: "drug"prevention strategies and their cost-effectiveness

IPT

The articles used in the analysis of the cost-effectiveness of IPT are listed in Table 6.

IPT: pregnant women

A study in Mozambique evaluated the incremental effect of IPTp in addition to insecticide-treated bed
nets. The costs included in the analysis were intervention costs (costs and administration of drugs
and training), recurrent costs (personnel and supplies) and household costs (transportation, food,
and income and welfare losses) [31]. Calculating the ICER per DALY averted, IPTp-SP was cost
effective in reducing both maternal clinical malaria and neonatal death when the clinical attendance
was higher than 37.5%, protective efficacy more than 15%, malaria incidence greater than 0.15
person-year at risk, case fatality rate greater than 0.15%, at a cost of SP per dose less than
US$0.57, or personnel cost for each dose delivered less than US$0.60 [31]. A study conducted in
Uganda compared the cost-effectiveness of IPTp at healthcare centers and IPTp by community-
based delivery. It showed that the compliance with the new delivery system was much higher and
also the access and use was increased [44]. However, the costs of the community based delivery
system were higher, due to the costs of training and the purchase of bicycles for the community
based resource person. The ICER of cost per DALY averted was US $1068, which is considered
cost effective [44].
IPT: infants

Previous studies showed that IPTi has efficacy rates ranging from 22.6% in Mozambique to 63.2% in
Tanzania when using SP as the antimalarial [22]. The great range in degree of efficacy could be
because of the increasing drug resistance to SP. The health effects were based on the efficacy
results and the malaria incidence of previous trials. With IPTi implementation, the malaria incidence
was reduced by 63.2% in Tanzania and 22.2% in Mozambique. Both the financial (budgetary) and
the nonfinancial costs (opportunity costs, e.g., switching of health resources from one use to
another) were included in the economic costs. The economic costs included all costs involved in the
implementation; policy change, behavior change, and all costs involved with drugs and drug
administration. The dropout rate of 23 and 19% for Tanzania and Mozambique, respectively, was
also included in the analysis. The number of DALYs averted was estimated at 118.9 per 1000 infants
in Tanzania and 47.6 per 1000 infants in Mozambique. With a pooled efficacy for SP of 30% and a
pooled cost-effectiveness ratio, the costs per DALY averted were US$8.1, with the cost per malaria
episode averted being US$3.4, and cost per malaria death averted US$221.9 [22]. IPTi using SP
and alternative antimalarials, delivered alongside the Expanded Programme on Immunisation across
five African countries, in most cases yielded a major reduction in malaria cases [21]. In sites where
IPTi had a significant effect on reducing malaria, it proved to be cost effective in all the sites, ranging
from US$2.90 (Ifakara, Tanzania with SP) to US$39.63 (Korogwe, Tanzania with mefloquine) per
DALY averted, which is considered to be cost effective (Table 7). However, in low-transmission sites,
the intervention was not cost effective [21].

IPT: children

A study performed in Kenya showed that a therapeutic course of AQ + SP to school children,

regardless of their infection state, dramatically reduced parasitemia and anemia [45,46]. In these
settings, the treatment was delivered by the school teachers, with supervision provided by staff of the
District Health Office. The costs were calculated from the providers'perspective, including financial
(implementation and program) and economic (opportunity costs of using existing governmental staff)
costs. Costs to households were excluded since costs of accessing treatment at their own school
were considered negligible [45]. It showed that the delivery of IPTsc was associated with a 50%
reduction in the proportion of children that were anemic, when comparing it to the situation without
IPTc. Furthermore, the estimated prevalence of P. falciparum parasitemia was reduced by 88%. The
costs were primarily driven by the drug purchase price and cost of personnel. A decrease in those
costs is considered to increase the attractiveness of IPTc. The costs per case of anemia or
parasitemia averted were estimated at US$29.84 and $5.36, respectively. When including a one-way
sensitivity analysis, it showed that when changes in drug prices, personnel costs, drug wastage and
efficacy were taken into account, the costs per case of anemia or parasitemia averted varied
between US$24.60-40.32 and $4.20-7.24, respectively [45]. Studies in Senegal and Mali have
shown that IPTc with AS + SP, AQ + SPQ or SP alone is an efficacious and safe intervention for
reducing the burden of malaria in children in areas with high transmission with short transmission
periods [47,48]. Another study conducted in Ghana explored the effects of IPTc in areas with a more
prolonged transmission season, such as in Ghana [23]. When analyzing the cost-effectiveness of
IPTc for AS + AQ or SP, provider and direct household costs were included. The cost per malaria
case averted were estimated at US$98.39 for SP bimonthly, at US$61.00 for AS + AQ monthly and
for AS + AQ bimonthly at US$204.75 based on a small-scale clinical trial (the possibilities for
reducing costs further were modeled as the intervention was scaled up to the district level). Training,
drug delivery and supervision accounted for approximately 20-30% each of total unit costs. The most
significant difference in the economic and financial costs appeared in the training cost centers [23].

Nonendemic countries: treatment strategies & their cost-effectiveness

Returning travelers with uncomplicated & severe malaria

Malaria imported back to nonendemic areas by travelers remains a major cause of travel-related
morbidity and an important cause of travel-related hospitalizations. Even in so-called affluent
settings, cost of patient care for malaria patients in particular, is an issue in times of healthcare
funding constraints. Of note, and to the best of our knowledge, there is hardly any published data
available comparing cost-effectiveness of various treatment regimens of imported malaria. For the
first time, the MALTHER study comparing various treatment regimens of
uncomplicated falciparum malaria imported into Europe compared hospitalization rates and
durations across various settings in Europe, but systematically collected data are missing [Bouchaud
O, Mhlberger N, Parola P et al. Therapy of uncomplicated falciparum malaria in europe: MALTHER
a prospective observational multicentre study (2011), Submitted].

Nonendemic countries: "drug"prevention strategies and their cost-effectiveness

Malaria chemoprophylaxis comes with considerable cost as well as both perceived and objectifiable
adverse events. These are factors which contribute to under-usage if official current
recommendations are considered as a benchmark. The presence of ongoing local malaria
transmission, identified though local surveillance and reported to regional WHO offices, forms the
basis of national and international chemoprophylaxis recommendations in nonendemic countries.

A number of recent publications puts various current chemoprophylaxis 'dogmata'to the test by
revisiting the issue of individual risk to specific destinations including modeling [49-53]. For example,
Behrens et al. proposed using a threshold incidence of greater than one case per 100,000 visits to
consider targeted malaria prophylaxis recommendations to minimize use of chemoprophylaxis for
low-risk exposure during visits to SEA [54]. In some areas, chemoprophylaxis use was not a cost-
effective policy for travelers (e.g., Thailand or the Amazon region of Brazil), but was cost-effective for
travel to West Africa and for those staying in India and Indonesia for longer than 45 days. Policies,
therefore, need to be adjusted regularly to reflect the changing risk [55]. Future modeling efforts
should aim at specifying cost-effectiveness of malaria chemoprophylaxis, assuming various levels of
use of basic (nonchemoprophylactic) measures (i.e., the use of repellents and insecticide-treated
bed nets).

Of note, it has been shown that reimbursement of 80% of the cost of the cheapest effective malaria
chemoprophylaxis (mefloquine) for travelers from Switzerland to West Africa is highly effective in
terms of malaria cases averted and is cost effective to the Swiss health system [53].

Discussion

With malaria being one of the most significant causes of morbidity and mortality worldwide, effective
treatment is essential to reduce the malaria burden. As there are several treatment options available,
the effectiveness and costs of the treatment regimens need to be examined. Cost-effectiveness
analysis should be performed in order to inform the optimal malaria treatment. The WHO
recommends that malaria treatment should be restricted to malaria-positive patients. Therefore, the
availability and accurate use of diagnostic methods needs to be improved, to minimize over-
treatment. The standard treatment for severe malaria has changed to artesunate as this has recently
been tested with good results. The main focus in this article is about cost-effectiveness of malaria
patients in endemic areas treated therapeutically and using prophylaxis (IPT) when indicated. The
cost-effectiveness with respect to treatment of malaria in returning travelers and chemoprophylaxis
used by travelers is mentioned as well.

In the literature about the endemic countries there were, however, different outcome measures of
cost-effectiveness, which made it difficult to directly compare articles. Most articles used an ICER,
but this was calculated per DALY or death averted, or per correctly treated patients. We do not
recommend direct comparison across all the studies, as in addition to different outcome measures,
not all articles included the same expenditures; for example some studies included the drug
administration costs as well, while others only included the costs for the actual drug, and costs are
collected and presented in varying years. Each article does, however, include a cost-effectiveness
ratio, to which the level of cost-effectiveness of an intervention can be determined. The review
provides a summary of the evidence and is able to identify key themes. For example, results show
that the cost-effectiveness of treatment depends on several factors: malaria prevalence or
transmission, malaria severity, cost of drugs, accuracy of diagnosis and effectiveness of treatment
(although this is not always added to the analysis).

Over-treatment of malaria increases the drug costs, but it also has the danger of missing nonmalaria
cases. As malaria and bacterial infections can present with similar signs and symptoms,
misdiagnosis can, for example, lead to the development of severe bacterial infections that could have
been prevented with accurate diagnostics and treatment [56]. Therefore, accurate diagnosis is
important for therapeutic purposes [2]. The accuracy of RDTs is encouraging; however, recent
studies showed that healthcare workers did not always act in accordance with the outcome of the
diagnostic test. Patients with malaria did not always receive the appropriate treatment, and some
patients received antimalarials despite a negative test result. However, the outcome of the test did
have an effect on the antimalarial prescribed; when malaria was confirmed, it was more likely that AL
was prescribed [5]. Receiving antimalarials despite a negative test lowers the cost-effectiveness of
the intervention/treatment [57]. In countries where resistance to SP and AQ is low, the cost-
effectiveness of AL will be reduced. Especially in areas with low AQ resistance (west Africa), the
cost-effectiveness of the combination drugs with AQ will be higher [42].

The use of prereferral treatment is promising, but the importance of reaching the health clinic in time
should not be underestimated. Without attending a health clinic, the chance of survival is lower.
Regarding the cost-effectiveness outcomes of the study of Tozan et al. , several factors should be
taken into account [19]. First, access to healthcare facilities should be limited but not impossible.
Second, the likelihood of malaria should be high, as bacterial infections can present with similar
symptoms. And third, community workers should be in place for accurate follow-up treatment [19].
Without those preconditions, the cost-effectiveness of the intervention will be reduced.

Although there is a change in treatment policy and combination treatments are widely used, recently,
resistance to artemisinin has been confirmed in one area, the Cambodia-Thailand border [58,59].
With the increase of treatment resistance, the mortality and morbidity will increase again and this will
have a negative effect on the cost-effectiveness of the treatment. At present, the effectiveness of
ACTs is almost 100%, hence out-of-league compared with other failing treatment options, such as
CQ and SP. The emergence of artemisinin resistance shall increase the costs of treatment
enormously.

Regarding malaria chemoprophylaxis in nonimmune travelers to endemic countries, and due to

difficulty with determining exact risks, particularly as the level of use of nonchemoprophylactic
prevention methods is difficult to factor in, cost-effectiveness estimates remain crude.

Moreover, despite a growing need for optimizing cost structures in the often so-called affluent
(malaria nonendemic) countries, cost-effectiveness considerations are still in a fledgling state.

Conclusion

In general, the use of RDTs was more cost effective if the costs of the ACTs were higher and the
price of the RDT was low. As AL is the most effective antimalarial, by incorporating HRP-2 RDTs, this
is also the most cost-effective option. In areas with both P. falciparumand P. vivax transmission, AL
and DHA + PQ, respectively, are the most cost-effective treatment options. In particular, when
sensitivity and specificity of microscopy was moderate, HRP-2 RDT was the most cost-effective
option. In areas with mixed species transmission, the pLDH RDTs were most cost effective.

Treatment of severe malaria with artesunate is cost-effective and especially for children that live
more than 6 h away from an appropriate healthcare facility, prereferral treatment was shown to be
cost effective. It needs to be noted that the WHO has changed their guidelines for the treatment of
severe malaria to artesunate for all age groups in all endemic settings, based on recently published
studies [43,102].

IPTi-SP is cost effective in sites with high malaria transmission. When clinical attendance was higher
than 37.5%, IPTp was estimated to be cost effective. IPTc with AS + SP, AQ + SPQ or SP alone is an
efficacious, safe and cost-effective intervention for reducing the burden of malaria in children in areas
with high transmission and short transmission periods.

Recommendations

There are many different methods to describe the cost-effectiveness of antimalarials. The selection
of the outcome measure(s) is most often dictated by the end points of the trial being costed and/or
the ability to model scenarios beyond the scope of a trial. Studies should aim to be consistent in their
approach. Preferably, the study should take into account both providers and societal costs, and
therefore include costs to health facilities and direct and indirect family costs, as was done by
Wiseman et al. [38]. Where possible, each study should describe the ICER as cost per DALY
averted, which then helps comparisons to other malaria and non-malaria health interventions. To
reflect uncertainty, sensitivity analyses should be presented, to include the main cost drivers and
costs that are particularly sensitive to change, such as drug cost and diagnostic tools. The cost of
resistance should be introduced in future economic evaluations.

Cost-effectiveness of malaria chemoprophylaxis in travelers and of treatment of imported malaria

requires further study.

Table 1. Malaria diagnosing strategies.

Specificit
Malaria diagnosis Characteristics Sensitivity
y

Temperature above
Clinical or presumptive treatment 37.5C; History of High Low
fever

Microscopy Blood slides 71-90% 76-93%

HRP-2,
Rapid diagnostic test detects Plasmodium 95% 93%
falciparum

pLDH detects Plasmodium 88-92% 85-99.5%

falciparum , Plasmodium
vivax ,Plasmodium
ovale , Plasmodium malariae

Data taken from [5,6,12,29].

Table 2. Five artemisinin-based treatment combinations as recommended by the WHO as first-

line treatment.

Artemisinin-based combination treatment Region

Sub-Saharan Africa &

Artemether combined with lumefantrine AL
southeast Asia

Artesunate combined with amodiaquine AS + AQ Sub-Saharan Africa

Artesunate combined with mefloquine AS + MQ South America

Artesunate combined with sulphadoxine-

AS + SP South America
pyrimethamine

Dihydroxy-artemsinin combined with DHA + PQ/AS +

Southeast Asia
piperaquine MQ

AL: Artemether-lumefantrine; AQ: Amodiaquine; AS: Artesunate; DHA: Dihydroartemisinin; PQ:

Piperaquine; SP: Sulphadoxine-pyrimethamine.

Data taken from [102].

Table 3. Quality assessment using the Consensus Health Economic Criteria list.

Article Year CHEC-list (/19) Ref.

Uncomplicated malaria

Rolland et al. 2006 17 [6]

Wiseman et al. 2006 17 [38]

Chanda et al. 2007 18 [10]

Lubell et al. 2007 17 [14]

Lubell et al. 2007 13 [34]

Lubell et al. 2008 14 [35]

Shillcutt et al. 2008 16 [30]

Zikusooka et al. 2008 18 [36]

Chanda et al. 2009 17 [5]

Uzochukwu et al. 2009 17 [37]

Mosha et al. 2010 16 [33]

de Oliveira et al. 2010 16 [40]

Ly et al. 2010 17 [7]

Davis et al. 2011 17 [1]

Lemma et al. 2011 18 [42]

Severe malaria

Lubell et al. 2009 17 [17]

Buchanan et al. 2010 17 [2]

Tozan et al. 2010 18 [19]

Intermittent preventive treatment

Temperley et al. 2008 17 [45]

Mbonye et al. 2008 18 [44]

Hutton et al. 2009 16 [22]

Conteh et al. 2010 17 [21]

Conteh et al. 2010 17 [23]

Sicuri et al. 2010 13 [31]

CHEC: Consensus Health Economic Criteria.

Table 4. Overview of analyzed articles about cost-effectiveness of uncomplicated malaria with

or without a diagnostic tool.

Outco
Comp Outco R
Countr Treatm me: P.
Article ared me:P. ef
y ent falcipa
to vivax .
rum

Adult
populatio
n

ICER
success
Chanda et fully
Zambia AL SP [7]
al. treated
case;
4.1

AL +
Chanda et Clinica
Zambia microsc ICER [12]
al. l
opy

AL + RDT 9.6; 2.6

 IC/corr
Lubell et Tanzan Microsc ectly
[19]
al. ia opy treated
case

25.2 vs
7.0
R (low vs
Tanz Micro
D high
ania scopy
T transmi
ssion);
ICER

10
RDT
.1

Cost
savings
;
Lubell et Tanzan Micros
RDT Probabi [16]
al. ia copy
lity
overvie
w

Cost
savings
Sub-
;
Lubell et Sahara Presu
; pLDH Transm [36]
al. n mptive
ission
Africa
depend
ent

Transm
ission
HRP-2
depend
ent

Senega AS+AQ Micros Cost

Ly et al. [11]
l +RDT copy savings

Mosha et Tanzan RDT Presu Cost [35]

al. ia mptive savings
 ; Low
transmi
ssion:
ACT
>US
$0.50;
High
transmi
ssion:
ACT
>US
$0.63

IC/fals
e
positiv
e
averted
Ethiopi ; ; -0.7,
Rolland et Presu
a and AL+RD -0.2, [10]
al. mptive
Sudan T +1.6
(Preval
ence
25%,
50%,75
%)

0.1,
+0.6,
+2.5
AS+AQ+ (preval
RDT ence
25, 50
and
75%)

Cost
savings
Sub-
;
Shilcutt et Sahara Micros
RDT Probabi [33]
al. n copy
lity
Africa
overvie
w
 IC per
Uzochukw ; AL + Presu death
Nigeria [39]
uet al. RDT mptive averted
$; -221

AL +
microscop 257
y

IC (=
cost
; AS + savings
Zikusooka Mozam Clinica
SP + ); [38]
et al. bique l
RDT <25%
pt pos
malaria

<50%
Clinica
AL + RDT pt pos
l
malaria

Child
populatio
n

Net CE
Provide
AQ +
r and
Wiseman Tanzan SP (+
AQ societal [40]
et al. ia microsc
; 4.92
opy)
and
-19.71

AQ + AS 1.57
(+ and
microscop -22.44;
y); AL (+ 0.17
microscop and
y) -22.35

Lubell et Sub- pLDH; Presu Cost [36]

al. Sahara savings
 ;
Transm
ission
depend
n
HRP-2 mptive ent;
Africa
Transm
ission
depend
ent

Cost
savings
; Low
transmi
ssion:
ACT
Mosha et Tanzan Presu >US
RDT [35]
al. ia mptive $0.50;
High
transmi
ssion:
ACT
>US
$0.63

P.
falciparui
mand P.
vivaxtran
smission

AS + ICER; ICER;
Papua
Davis et SP; CQ + 38.31; 2.21; [1
New
al. DHA + SP 12; -0.14; ]
Guinea
PQ; AL 10.37 13.83

Parascr
Lemma et Ethiopi Parach ICER; ICER; [4
een +
al. a eck 0.59 0.59 5]
AL

Oliveira et Brazil Microsc RDT ICER; [42]

al. opy US
$15.86-
 58.92

ACT: Artemisinin combination treatment; AL: Artemether-lumefantrine; AQ: Amodiaquine; AS:

Artesunate; CQ: Chloroquine; ICER: Incremental cost-effectiveness ratio; SP: Sulphadoxine-
pyrimethamine.

Table 5. Overview of analyzed articles about cost-effectiveness of severe malaria treatment.

Ref
Article Country Treatment Compared to Outcome
.

Myanmar, ICER; US$358.90-

Lubell et al. AS Quinine [17]
India $104.80

DALY averted;
Buchanan et SSA and Rectal Parenteral
US$5 (SSA) and [2]
al. SEA antimalarials antimalarial
US$177 (SEA)

Parenteral ICER; IS$14.001-

Tozan et al. SSA Prereferral AS [19]
antimalarial 86.316

AS: Artesunate; DALY: Disability adjusted life year; ICER: Incremental cost-effectiveness ratio; SEA:
Southeast Asia; SSA: Sub-Saharan Africa.

Table 6. Overview of analyzed articles about cost-effectiveness of intermittent preventive

treatment.

Compared
Article Country Treatment Outcome Ref.
to

Huttonet Tanzania and No

IPTi DALY averted; US$8.1 [22]
al. Mozambique treatment

Contehet Sub-Saharan No DALY averted;

IPTi [21]
al. Africa treatment US$2.90-39.63

Mbonyeet Uganda IPTp IPTp at ICER; US$1.068 [44]

al. community- clinic
based
 delivery

Sicuri et No DALY averted;

Mozambique IPTp [31]
al. treatment US$1.02

Anemia averted;
Temperlyet No
Kenya IPTc US$29.84; Parasitemia [45]
al. treatment
averted; US$5.36

Malaria case averted;

IPTc-AS + US$61.00
Contehet No
Ghana AQ; IPTc- (monthly)/US$204.75 [23]
al. treatment
SP (bimonthly); US$98.39
(bimonthly)

AS: Artesunate; DALY: Disability adjusted life year; ICER: Incremental cost-effectiveness ratio; IPTc:
Intermittent preventive treatment in children; IPTi: Intermittent preventive treatment in infants; IPTp:
Intermittent preventive treatment in pregnant women; SP: Sulphadoxine-pyrimethamine.

Table 7. Costs per disability adjusted life years averted using intermittent preventive treatment
in infants.

Location Cost per DALY averted Antimalarial

Ifakara, Tanzania US$2.90 SP

Ifakara, Tanzania US$7.9 SP

Korogwe, Tanzania US$39.63 MQ

Manhica, Mozambique US$8.3 SP

DALY: Disability adjusted life year; SP: Sulphadoxine-pyrimethamine.

Executive summary

*With malaria being one of the most significant causes of morbidity and mortality worldwide, prompt
and effective treatment is essential to reduce the malaria burden.
*As there are several treatment options available, the effectiveness and costs of the treatment
regimens need to be examined.

*Cost-effectiveness analyses should be performed in order to inform the national malaria control
programs.

*The availability and accurate use of diagnostic methods needs to be improved to minimize
overtreatment.

*The standard treatment for severe malaria has changed to artesunate as this has recently been
tested with good results.

*The methodology of calculated cost-effectiveness should be similar and, therefore, its implications
for policy recommendations could be comparable in the future.

*Future modeling efforts should aim at specifying cost-effectiveness of malaria chemoprophylaxis

assuming various levels of use of basic (nonchemoprophylactic) measures (i.e., the use of repellents
and insecticide-treated bed nets).

*Cost-effectiveness of malaria chemoprophylaxis in travelers and of treatment of imported malaria

requires further study as well.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or materials discussed in the
manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References
1 Davis WA, Clarke PM, Siba PM et al. Cost-effectiveness of artemisinin combination therapy for
uncomplicated malaria in children: data from Papua New Guinea. Bull. World Health Organ. 89(3),
211-220 (2011).

2 Buchanan J, Mihaylova B, Gray A, White N. Cost-effectiveness of pre-referral antimalarial,

antibacterial, and combined rectal formulations for severe febrile illness. PLoS ONE 5(12), e14446
(2010).

3 Grobusch MP, Kremsner PG. Uncomplicated malaria. Curr. Trop. Microbiol. Immunol. 295, 83-104
(2005).
4 Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin-based combination therapy for
treating uncomplicated malaria.Cochrane Database Syst. Rev. 3, CD007483 (2009).

5 Chanda P, Castillo-Riquelme M, Masiye F. Cost-effectiveness analysis of the available strategies

for diagnosing malaria in outpatient clinics in Zambia. Cost Eff. Resour. Alloc. 7, 5 (2009).

6 Rolland E, Checchi F, Pinoges L, Balkan S, Guthmann JP, Guerin PJ. Operational response to
malaria epidemics: are rapid diagnostic tests cost-effective? Trop. Med. Int. Health 11(4), 398-408
(2006).

7 Ly AB, Tall A, Perry R et al. Use of HRP-2-based rapid diagnostic test for Plasmodium
falciparum malaria: assessing accuracy and cost-effectiveness in the villages of Dielmo and Ndiop,
Senegal. Malar. J. 9, 153 (2010).

8 Gallup JL, Sachs JD. The economic burden of malaria. Am. J. Trop. Med. Hyg. 64(Suppl. 1-2), 85-
96 (2001).

9 Sachs J, Malaney P. The economic and social burden of malaria. Nature 415(6872), 680-685
(2002).

10 Chanda P, Masiye F, Chitah BM et al. A cost-effectiveness analysis of artemether lumefantrine for

treatment of uncomplicated malaria in Zambia. Malar. J. 6, 21 (2007).

11 Price R, Nosten F, Simpson JA et al. Risk factors for gametocyte carriage in uncomplicated
falciparum malaria. Am. J. Trop. Med. Hyg. 60(6), 1019-1023 (1999).

12 Targett G, Drakeley C, Jawara M et al. Artesunate reduces but does not prevent posttreatment
transmission of Plasmodium falciparum to Anopheles gambiae . J. Infect. Dis. 183(8), 1254-1259
(2001).

13 Giha HA. Artemisinin derivatives for treatment of uncomplicated Plasmodium falciparum malaria
in Sudan: too early for too much hope. Parasitol. Res. 106(3), 549-552 (2010).

14 Lubell Y, Reyburn H, Mbakilwa H et al. The Cost-effectiveness of parasitologic diagnosis for

malaria-suspected patients in an era of combination therapy. Am. J. Trop. Med. Hyg. 77(Suppl. 6),
128-132 (2007).

15 Dondorp AM, Fanello CI, Hendriksen IC et al. Artesunate versus quinine in the treatment of
severe falciparum malaria in African children (AQUAMAT): an open-label, randomised
trial. Lancet 13, 376(9753), 1647-1657 (2010). *This study demonstrated the superiority of
artesunate compared with quinine in the treatment of severe malaria in addition to perfoming cost
analysis.
16 Jones KL, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe
malaria. Cochrane Database Syst. Rev. 4, CD005967 (2007).

17 Lubell Y, Yeung S, Dondorp AM et al. Cost-effectiveness of artesunate for the treatment of Severe
malaria. Trop. Med. Int. Health14(3), 332-337 (2009). *This study demonstrated the superiority of
artesunate compared with quinine in the treatment of severe malaria in addition to perfoming cost
analysis.

18 Gomes MF, Faiz MA, Gyapong JO et al. Pre-referral rectal artesunate to prevent death and
disability in severe malaria: a placebo-controlled trial. Lancet. 14, 373(9663), 557-566 (2009).

19 Tozan Y, Klein EY, Darley S, Panicker R, Laxminarayan R, Breman JG. Prereferral rectal
artesunate for treatment of severe childhood malaria: a cost-effectiveness analysis. Lancet 4,
376(9756), 1910-1915 (2010). *This study demonstrated the superiority of artesunate compared with
quinine in treatment of severe malaria in addition to perfoming cost analysis.

20 Grobusch MP. Early rectal artesunate administration: a life-saver in remote areas? Future
Microbiol. 4(4), 397-400 (2009).

21 Conteh L, Sicuri E, Manzi F et al. The cost-effectiveness of intermittent preventive treatment for
malaria in infants in sub-Saharan Africa. PLoS ONE 5(6), e10313 (2010).

22 Hutton G, Schellenberg D, Tediosi F et al. Cost-effectiveness of malaria intermittent preventive

treatment in infants (IPTi) in Mozambique and the United Republic of Tanzania. Bull. World Health
Organ. 87(2), 123-129 (2009).

23 Conteh L, Patouillard E, Kweku M, Legood R, Greenwood B, Chandramohan D. Cost

effectiveness of seasonal intermittent preventive treatment using amodiaquine & artesunate or
sulphadoxine-pyrimethamine in Ghanaian children. PLoS ONE 5(8), e12223 (2010).

24 Wilson AL; IPTc Taskforce. A systematic review and meta-analysis of the efficacy and safety of
intermittent preventive treatment of malaria in children (IPTc). PLoS ONE 6(2), e16976 (2011).

25 Bojang KA, Akor F, Conteh L et al. Two strategies for the delivery of IPTc in an area of seasonal
malaria transmission in the Gambia: a randomised controlled trial. PLoS Med. 8(2), e1000409
(2011).

26 Lubell Y, Mills AJ, Whitty CJ, Staedke SG. An economic evaluation of home management of
malaria in Uganda: an interactive Markov model. PLoS ONE 5(8), e12439 (2010).

27 Rodriguez AJ, Ferrer MV, Barrera MA, Pacheco M, Daza V, Franco-Paredes C. Imported cases of
malaria admitted to two hospitals of Margarita Island, Venezuela, 1998-2005. Travel Med. Infect.
Dis. 7(1), 44-48 (2009).
28 Zoller T, Naucke TJ, May J et al. Malaria transmission in non-endemic areas: case report, review
of the literature and implications for public health management. Malar. J. 8, 71 (2009).

29 Evers S, Goossens M, de Vet H, van Tulder M, Ament A. Criteria list for assessment of
methodological quality of economic evaluations: Consensus on Health Economic Criteria. Int. J.
Technol. Assess. Health. Care 21(2), 240-245 (2005).

30 Shillcutt S, Morel C, Goodman C et al. Cost-effectiveness of malaria diagnostic methods in sub-

Saharan Africa in an era of combination therapy. Bull. World Health Organ. 86(2), 101-110 (2008).

31 Sicuri E, Bardaji A, Nhampossa T et al. Cost-effectiveness of intermittent preventive treatment of

malaria in pregnancy in southern Mozambique. PLoS ONE 5(10), e13407 (2010).

32 Jamison DT, Breman JG, Measham AR et al. Disease Control Priorities in Developing Countries .
Oxford University Press, Oxford, UK (1993).

33 Mosha JF, Conteh L, Tediosi F et al. Cost implications of improving malaria diagnosis: findings
from north-eastern Tanzania. PLoS ONE 5(1), e8707 (2010). *Accurate diagnosis and its costs are
very important.

34 Lubell Y, Reyburn H, Mbakilwa H et al. The impact of response to the results of diagnostic tests
for malaria: cost-benefit analysis.BMJ 336(7637), 202-205 (2008). *Accurate diagnosis and its costs
are very important.

35 Lubell Y, Hopkins H, Whitty CJ, Staedke SG, Mills A. An interactive model for the assessment of
the economic costs and benefits of different rapid diagnostic tests for malaria. Malar. J. 7, 21 (2008).

36 Zikusooka CM, McIntyre D, Barnes KI. Should countries implementing an artemisinin-based

combination malaria treatment policy also introduce rapid diagnostic tests? Malar. J. 7, 176 (2008).

37 Uzochukwu BS, Obikeze EN, Onwujekwe OE, Onoka CA, Griffiths UK. 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. Malar. J. 8, 265 (2009).

38 Wiseman V, Kim M, Mutabingwa TK, Whitty CJ. Cost-effectiveness study of three antimalarial
drug combinations in Tanzania. PLoS Med. 3(10), e373 (2006). *For future studies we aim for a
consistent approach and this study has taken that into account, for example for both providers and
social costs.

39 Coleman PG, Morel C, Shillcutt S, Goodman C, Mills AJ. A threshold analysis of the cost-
effectiveness of artemisinin-based combination therapies in sub-saharan Africa. Am. J. Trop. Med.
Hyg. 71(Suppl. 2), 196-204 (2004).
40 de Oliveira MR, de Castro GA, Toscano CM. Cost effectiveness of OptiMal(R) rapid diagnostic
test for malaria in remote areas of the Amazon Region, Brazil. Malar. J. 9, 277 (2010).

41 Rosas Aguirre AM, Llanos Zavalaga LF, Trelles de BM. Cost-effectiveness ratio of using rapid
tests for malaria diagnosis in the Peruvian Amazon. Rev. Panam. Salud. Publica. 25(5), 377-388
(2009).

42 Lemma H, San SM, Lofgren C, Barnabas G. Cost-effectiveness of three malaria treatment

strategies in rural Tigray, Ethiopia where both Plasmodium falciparum and Plasmodium vivax co-
dominate. Cost Eff. Resour. Alloc. 9, 2 (2011).

43 Lubell Y, Riewpaiboon A, Dondorp AM, et al.Cost-effectiveness of parenteral artesunate for

treating children with severe malaria in sub-Saharan Africa. Bull. World Health Organ. 89(7), 504-
512. (2011)

44 Mbonye AK, Hansen KS, Bygbjerg IC, Magnussen P. Intermittent preventive treatment of malaria
in pregnancy: the incremental cost-effectiveness of a new delivery system in Uganda. Trans. R. Soc.
Trop. Med. Hyg. 102(7), 685-693 (2008).

45 Temperley M, Mueller DH, Njagi JK et al. Costs and cost-effectiveness of delivering intermittent
preventive treatment through schools in western Kenya. Malar. J. 7, 196 (2008).

46 Clarke SE, Jukes MC, Njagi JK et al. Effect of intermittent preventive treatment of malaria on
health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled
trial. Lancet 372(9633), 127-138 (2008).

47 Dicko A, Mantel C, Thera MA et al. Risk factors for malaria infection and anemia for pregnant
women in the Sahel area of Bandiagara, Mali. Acta Trop. 89(1), 17-23 (2003).

48 Cisse B, Sokhna C, Boulanger D et al. Seasonal intermittent preventive treatment with artesunate
and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised,
placebo-controlled, double-blind trial. Lancet 367(9511), 659-667 (2006).

49 Massad E, Behrens RH, Burattini MN, Coutinho FA. Modelling the risk of malaria for travelers to
areas with stable malaria transmission. Malar. J. 8, 296 (2009).

50 Behrens RH, Carroll B, Beran J et al. The low and declining risk of malaria in travellers to Latin
America: is there still an indication for chemoprophylaxis? Malar. J. 6, 114 (2007).

51 Behrens RH, Bisoffi Z, Bjrkman A et al. Malaria prophylaxis policy for travellers from Europe to
the Indidan sub continent. Malar. J.5, 7 (2006).
52 Pistone T, Schwarzinger M, Chauvin P et al. Reimbursement of malaria chemoprophylaxis for
travellers from Europe to sub-Saharan Africa: cost-effectiveness analysis from the perspective of the
French national health insurance system. Health Policy 88(2-3), 186-199 (2008).

53 Widmer LL, Blank PR, Van Herck K, Hatz C, Schlagenhauf P. Cost-effectiveness analysis of
malaria chemoprophylaxis for travellers to west-Africa. BMC Infect. Dis. 10, 279 (2010).

54 Behrens RH, Carroll B, Hellgren U et al. The incidence of malaria in travellers to South-East Asia:
is local malaria transmission a useful risk indicator? Malar. J. 9, 266 (2010).

55 Massad E, Behrens BC, Coutinho FA, Behrens RH. Cost risk benefit analysis to support
chemoprophylaxis policy for travellers to malaria endemic countries. Malar. J. 10, 130 (2011).

56 Rolland E, Checchi F, Pinoges L, Balkan S, Guthmann JP, Guerin PJ. Operational response to
malaria epidemics: are rapid diagnostic tests cost-effective? Trop. Med. Int. Health 11(4), 398-408
(2006).

57 Reyburn H, Mbatia R, Drakeley C et al. Overdiagnosis of malaria in patients with severe febrile
illness in Tanzania: a prospective study. BMJ 329(7476), 1212 (2004).

58 Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant

malaria in western Cambodia. N. Engl. J. Med. 359(24), 2619-2620 (2008). *Resistance to
artesunates will have grave consequences for malaria therapy in the absence of equally effective
alternatives.

59 Dondorp AM, Nosten F, Yi P et al. Artemisinin resistance in Plasmodium falciparum malaria. N.

Engl. J. Med. 361(5), 455-467 (2009). *Resistance to artesunates will have grave consequences for
malaria therapy in the absence of equally effective alternatives.

101 WHO. World Malaria Report (2010).

http://www.who.int/malaria/world_malaria_report_2010/en/index.html

102 WHO. Guidelines for the treatment of malaria. Second edition 2010.
http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html

103 WHO. Malaria publications. www.who.int/malaria/publications

AuthorAffiliation
Michle Van Vugt, 1 Infectious Diseases, Center for Tropical Medicine & Travel Medicine, Division of
Internal Medicine, AIGHD, Academic Medical Center, University of Amsterdam, Meibergdreef 9, PO
Box 22660, 1100 DD Amsterdam, The Netherlands
Elisa Sicuri, 3 Barcelona Centre for International Health Research (CRESIB), Hospital Clnic-
Universitat de Barcelona, Barcelona, Spain

Anne Van Beest, Maurits Van Tulder, 2 Department of economics, VU University Medical Center,
Amsterdam, The Netherlands

Martin P Grobusch, ** Author for correspondence, m.p.grobusch@amc.uva.nl