Background
Although malaria remains a major global health issue with nearly half the world’s population still at risk and ongoing transmission in 91 countries, substantial progress has been made towards reducing the burden of the disease [
1]. The incidence of malaria declined by 21% between 2000 and 2015 [
1], and the proportion of global disability adjusted life years attributable to malaria fell from 3.5 to 2.3% over same period representing a drop in ranking relative to other causes from 7th to 14th [
2]. This improvement reflects more effective vector control and case management [
1].
Artemisinin-based combination therapy (ACT) is the World Health Organization (WHO) recommended first-line treatment for uncomplicated malaria [
1]. Five different artemisinin-based combinations, artemether–lumefantrine (AL), artesunate–amodiaquine, artesunate–mefloquine, dihydroartemisinin–piperaquine (DHA–PQP) and artesunate–sulfadoxine–pyrimethamine, currently meet the stringent WHO regulatory standards for prequalification with the choice of ACT based, at least in part, on local parasite drug resistance [
1]. The incorporation of ACTs into malaria control programmes has contributed to the global decline in malaria-related mortality and morbidity, but effective therapy remains a challenge in geo-epidemiological settings where there is transmission of multiple
Plasmodium species [
3]. Papua New Guinea (PNG) is a case in point. In 2011, PNG national malaria treatment guidelines were modified to include AL as first-line treatment for uncomplicated
Plasmodium falciparum and
Plasmodium vivax infections [
4]. These changes reflected WHO contemporary recommendations and were underpinned by the results of a randomized clinical trial that demonstrated that AL was the most efficacious [
5] and cost-effective [
6] ACT for falciparum malaria in PNG. Although DHA–PQP was more efficacious in vivax malaria, the cost and complexity of having different first-line treatments for cases of falciparum and vivax malaria, meant that it was included as an alternative second-line regimen [
4,
5]. Given that potentially preventable morbidity and mortality due to vivax malaria despite AL therapy remained a concern [
7], a search for more broadly effective and affordable formulations of ACT was recommended [
5].
Of the few potential alternative ACT, artemisinin–naphthoquine (AN) was one candidate. This ACT was already available in the private sector in PNG as single-dose treatment for uncomplicated malaria despite not being prequalified. Preliminary pharmacokinetic and safety studies in PNG children provided good evidence that the recommended single AN dose given daily for 3 days (a duration recommended by the WHO for all ACT medicines to increase cure rates and reduce the development of parasite resistance [
8]) would be safe, well tolerated and efficacious treatment for uncomplicated malaria [
9,
10], with the long elimination half-life of naphthoquine (t
1/2 = 23 days) [
10] likely to provide more extended suppression of late post-treatment
P. vivax emergence than the piperaquine component of DHA–PQP.
A randomized comparative safety and efficacy trial of AL and AN was, therefore, performed in young PNG children with uncomplicated
P. falciparum and
P. vivax infections in coastal Madang Province [
11]. The results showed that AN was non-inferior to AL for falciparum malaria with the same high cure rate, but that it was superior to AL for vivax malaria. However, the cost of using three times the recommended dose of a non-subsidized ACT is likely to be relatively high [
12,
13], which would be an impediment to its uptake in developing countries with similar epidemiology to that in malaria-endemic areas of PNG. The aim of the present study was, therefore, to assess the relative cost-effectiveness of AL and AN for the treatment of uncomplicated malaria in Melanesian children aged 0.5–5.9 years.
Discussion
This is the first economic analysis of AN for treatment of uncomplicated malaria in an area of intense transmission of multiple
Plasmodium species. The present data show that, while a 3-day course of AN had superior overall efficacy in uncomplicated paediatric malaria, the recommended first-line AL remained the more cost-effective treatment. In PNG children with falciparum malaria, AN was equally efficacious but far more costly than AL. In the case of vivax malaria, AN was significantly more efficacious than AL but only slightly more costly in the usual care setting. The most significant contributor to the difference in costs between AN and AL is the fact that AL is a subsidized prequalified first-line therapy provided with financial assistance from a Global Fund Affordable Medicines Facility Grant [
13], while AN can only be purchased over-the-counter at pharmacy-determined commercial cost. The availability of donated or subsidized drugs and willingness to pay will, therefore, determine the choice of regimen by the consumer outside the public health system.
The only formulation of AN currently available is that manufactured by KPC under the brand name ARCO
®. It satisfies WHO recommendations for universal combination therapy for uncomplicated malaria but has not yet met the WHO prequalification manufacturing standards [
20]. As a result, AN is not eligible for financial subsidy, inclusion on competitive pricing indices, or global distribution by International agencies including UNICEF, the Global Fund and Unitaid [
13,
20]. As KPC continues to distribute ARCO
® as a single-dose treatment, a regimen which is inconsistent with WHO recommendations for 3 days of ACT [
8], future prequalification appears unlikely. However, given that ARCO
® is marketed in the private sector in a range of countries in Africa, Asia and Oceania, it is important for the cost-effectiveness implications of this form of ACT to be assessed.
In PNG, ARCO
® can be purchased as a single-dose therapy across the counter at an average cost of $1.84 per tablet, which is significantly more expensive than subsidized AL therapy ($0.19 per tablet) that is usually widely available through government hospitals and clinics [
13,
15]. Even if AN were efficacious as single-dose therapy (as recommended by the manufacturer), its cost-effectiveness in comparison to a treatment course of AL would still be questionable. However, preliminary studies of the safety, efficacy and tolerability of AN in PNG children found unacceptable rates of treatment failure after a single dose [
9,
10]. Dose-ranging studies identified that a minimum of two daily doses was required for adequate Day 28 and Day 42 ACPR, while a 3-day treatment course was considered the most appropriate given WHO recommendations [
9].
For falciparum malaria in the present study, AN and AL had similar treatment efficacy (100 and 97.8% for AN and AL, respectively) but AL was significantly more cost-effective therapy with a mean cost of US$7.66 per patient (PP analysis) compared to US$17.28 per patient for AN therapy. This finding is consistent with other analyses of AL in a usual care setting. A cost-effectiveness study comparing DHA–PQP and AL for uncomplicated malaria in Tanzanian children completed in 2012 reported a mean cost of US$8.40 from the provider’s perspective for successful treatment of a clinical case of uncomplicated malaria [
21]. Considering currency inflation over a 5-year period, the present findings are also consistent with previous reports of the cost-effectiveness of AL for treatment of uncomplicated falciparum and vivax malaria in Papua New Guinean children in 2008 ($6.97 per treatment success) [
5]. A potential complication in determining cost-effectiveness analyses across different malaria-endemic regions is the relative lack of data from South-east Asia compared to the African continent where a number of different donation/subsidization schemes ensure availability to all in need [
13]. The maximum manufacturer prices for AL for children with uncomplicated malaria were recently set by the Global Fund at US$0.43–$1.22 per treatment course [
12,
13] but these data are predominantly from African countries and it is not known how many other malaria endemic nations received subsidized anti-malarials under the Affordable Medicines Facility malaria (AMFm) scheme.
A further consideration for countries such as PNG is that, despite a decline in the prevalence of falciparum malaria, the prevalence of
P. vivax has increased by 13–36% [
22‐
24] to the point where it has become the predominant
Plasmodium species causing infection and illness in young PNG children [
25]. Primaquine cannot be given for routine radical cure of
P. vivax mainly because of the risk of haemolysis due to the relatively high prevalence of glucose-6-phosphatase deficiency in PNG. In this situation, selection of an ACT with a long half-life component is desirable so that there is an extended period of prophylaxis against relapses from hypnozoites during recovery [
26]. In the present study, AL was efficacious in only 30% of children with vivax malaria compared with 100% after treatment with AN [
11]. This rate of AL treatment failure is similar to that reported in other studies conducted in similar geo-epidemiological settings [
27‐
29]. It is the most likely reason why the present analysis found AN to be similarly cost-effective to AL in
P. vivax infections in contrast to the marked disparity in the case of
P. falciparum infections. The excess cost per treatment success with AN was $14.83 for
P. vivax versus $436.82 for
P. falciparum.
There are population data from PNG detailed enough to provide estimates of the benefit of ACT regimens. In 2009, 1,431,395 suspected malaria cases were treated in PNG with a reported 604 malaria-attributable deaths. This represents 21.3% of the total PNG population assuming no multiple presentations. Furthermore, a study of febrile patients presenting at five sentinel health facilities across PNG in 2008 reported a malaria slide positivity rate ranging from 2.2 to 74.9% [
30]. The clinical trial data, on which this analysis is based, showed that 79% of uncomplicated cases were due to
P. falciparum only, 14% to
P. vivax only, and 6% to mixed
P. falciparum and
P. vivax infections. Projecting the trial PP usual care cost-effectiveness analysis to the general PNG population of 7,154,870 in 2012, and assuming that all suspected cases were confirmed as a worst case scenario, 213,358 and 28,499 more cases of
P. vivax and
P. falciparum, respectively, could be treated successfully every year if AN were used instead of AL, costing an extra US$14,663,345 per year. However, these estimates may have to be revised as, since the trial was conducted in 2012, two rounds of countrywide distributions of long lasting insecticide treated nets have resulted in a 6.7% reduction in the overall prevalence of malaria [
31,
32]. It was estimated that the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted). This may not be cost-effective and affordable given that the gross national income
per capita in PNG in 2012 was $1820 [
33,
34], unless the cost of AN is reduced considerably.
The present study had limitations. The analysis did not consider treatment compliance. All treatments are given over 3 days but AL requires two doses per day and the medication should be taken with supplementary fat (usually milk or biscuits), aspects which might reduce compliance. Although all children allocated AL in the trial had a therapeutic plasma lumefantrine concentration on Day 7, consistent with all six doses having been administered successfully [
11], a cost-effectiveness study of ACTs in sub-Saharan Africa estimated compliance with ACTs to be only 30–60% compared with 85–95% for sulfadoxine–pyrimethamine [
35]. As conventionally recommended in cost-effectiveness analyses, estimates were based on the primary endpoints of the intervention trial. In the usual care situation in countries such as PNG, diagnosis and response to treatment are not underpinned by PCR. In addition, microscopy and/or rapid diagnostic tests (RDTs) may not be available or reliable in areas of PNG and in other resource-poor tropical countries. A national cross-sectional survey conducted prior to the implementation of the revised PNG national malaria treatment programme found that that RDTs or functional microscopy was utilized in only 15% of health facilities [
36]. As a result, presumptive treatment based on presenting symptoms is most likely to occur, as shown in the same survey where 96.4% of fever presentations received anti-malarial treatment including 82% of patients who tested negative for malaria by either RDT or microscopy [
36]. Recent PNG surveys assessing 88 health centres across PNG in 2012 showed a substantial increase in the use of RDTs and microscopy across all health facilities between 2010 and 2012 (16.2% vs. 68.3%) [
37]. Although an economic analysis of the impact of these changes was beyond the scope of the present study, the data suggest that a progressive reduction in RDT costs in parallel with increased availability may improve diagnostic accuracy in countries such as PNG, and thus reduce inappropriate treatment.
Other potential limitations were that, while uncertainty has been accounted for in the outcomes of the trial via bootstrapping, the estimates of cost per life year are meant to be indicative and so a probabilistic model that would allow quantification of uncertainty around these estimates was not built. The current analysis also did not consider the cost implications of the mixed Plasmodium infections but these were a minor component of the burden of disease (6.5% of total cases). Post-treatment gametocyte carriage and consequent malaria transmission was also not factored into the analyses. Opportunity costs, such as the time taken off work by parents needing to look after their sick child including transportation to the clinic or hospital, have not been addressed. Treatment that accelerates recovery might allow parents to return to work more quickly. Finally, there are sometimes unpredictable shortages of government supplies of approved drugs such as AL in PNG which means that parents have to fill prescriptions at commercial pharmacies at increased cost.