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Resistance to antimalarial drugs is a threat to global efforts to eliminate malaria by 2030. Currently, treatment for vivax malaria uses chloroquine or ACT for uncomplicated P. vivax whereas primaquine is given to eliminate latent liver stage infections (a method known as radical cure). Studies on P. vivax resistance to antimalarials and the molecular basis of resistance lags far behind the P. falciparum as in vitro cultivation of the P. vivax has not yet been established. Therefore, data on the P. vivax resistance to any antimalarial drugs are generated through in vivo studies or through monitoring of antimalarial treatments in mixed species infection. Indirect evidence through drug selective pressure on the parasites genome, as evidenced by the presence of the molecular marker(s) for drug resistance in areas where P. falciparum and P. vivax are distributed in sympatry may reflect, although require validation, the status of P. vivax resistance. This review focuses on the currently available data that may represent the state-of-the art of the P. vivax resistance status to antimalarial to anticipate the challenge for malaria elimination by 2030.
Eijkman Institute for Molecular Biology, Indonesia
Din Syafruddin*
Eijkman Institute for Molecular Biology, Indonesia
Hasanuddin University Medical Research Centre, Indonesia
Department of Parasitology, Faculty of Medicine, Hasanuddin University, Indonesia
*Address all correspondence to: din@eijkman.go.id
1. Introduction
Plasmodium vivax presents a major challenge to achieving the global effort to eliminate malaria by 2030. The global distribution and factors that are associated with P. vivax occurrence in wider geographic regions in tropical, subtropical and temperate zones have extensively been reviewed recently [1, 2]. The ability of this species to undergo dormancy in the form of single-celled hypnozoites in the human liver, a safe haven from immune attack during the long mosquito-free cold seasons contributed to this phenomenon (Figure 1) [3]. Currently, P. vivax is present in 51 countries across Central and South America, the horn of Africa, Asia and the Pacific islands. Global malaria control and elimination programme successfully brought down the malaria incidence from 238 million cases in 2000 to 229 millions in 2019. The proportion of P. vivax cases declined from 7% in 2000 to 3% in 2019 [4]. Between 2000 and 2015, global malaria case incidence declined by 27%, and between 2015 and 2019 it declined by less than 2%, indicating a slowing of the rate of decline since 2015. Different from other human malaria, P. vivax uses Duffy antigen as its receptor in human to invade exclusively the young red blood cell (reticulocytes). Therefore, individuals who do not express the Duffy antigen are considered to be genetically resistant to P. vivax infection and this is particularly true in the majority of African sub-saharan population [5]. However, evidence for P. vivax infections in Duffy negative patients raise the possibility of an alternative invasion mechanism to Duffy [6, 7].
Figure 1.
Plasmodium vivax life cycle [3].
Plasmodium vivax in most geographic regions is distributed in sympatry with P. falciparum. This situation requires special attention during diagnosis and before prescription of drugs to the infected people. The biological characteristic of the P. vivax exhibit multiple exoerythrocytic cycle (relapses) from a single mosquito inoculation, and coupled with the very early emergence of gametocytes in the course of blood-stage infection, perhaps enables parasite survival and transmit to mosquito vector silently despite relatively low probability of propagation in blood. This propensity presents a unique challenge to the chemotherapeutic intervention against vivax malaria cases in which radical cure to block the reactivation of hypnozoites should be given in addition to blood schizontocide. Although P. vivax has been known to be less severe than P. falciparum, a growing body of evidence indicates that severe and fatal outcome also occurred in many P. vivax cases and necessitate the importance of reversing the historic neglect of this infection [8, 9, 10].
Treatment of P. vivax currently relies on either chloroquine or ACTs, supplemented both with 14 days primaquine as anti-hypnozoites. The only available drug for radical cure is primaquine but its use in vivax endemic region is limited by its potential serious complication among the people who inherit glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency.
The present review focuses on the recent progress that has been achieved to try to circumvent the problem of drug resistance in P. vivax. The global spread of chloroquine-resistant P. vivax has forced some countries to adopt artemisinin-based combination therapy (ACTs) to replace chloroquine as the first line drug to treat uncomplicated P. vivax and this policy change also impact the use of primaquine, the sole agent for anti-relapse. Many studies and reviews have been exclusively focused to elucidate the basic mechanism(s) of drug resistance in the malarial parasite using P. falciparum or other rodent and avian plasmodia as model while P. vivax, as usual, is consistently neglected. In discussing the topic, we will review all antimalarial drugs that used to be used or have been used to treat vivax malaria since the early development of quinine to date. Rapid development of resistance to the antimalarial drug mainstays from the early days to date will also be discussed to provide better perspectives for circumventing the problem of antimalarial drug resistance. The global extent of the drug-resistant P. vivax will also be reviewed to determine the appropriate measures based on drug policies that have been adopted by World Health Organisation (WHO) and implemented on local setting by member countries.
2. Challenges in the validation of drug resistance in Plasmodium vivax
2.1 Detection of hypnozoites
Historically, until to date, very few, if any, progress that has been achieved with regard to the biology of hypnozoites. Owing to its relatively “benign” clinical manifestation, the need for developing a more effective and less side effect radical cure have been hindered by our inability to detect the presence of hypnozoites in the liver cells. The occurrence of relapses in P. vivax after primaquine therapy would be assumed to be the most reliable indication of resistance. Nevertheless, recurrent parasite following primary attack may originate from failed therapy against asexual blood stages (recrudescence), biting infectious anopheline mosquitoes (reinfection), and reactivation of hypnozoites (relapse).
Since parasite arising from relapse may be genetically heterologous [11, 12, 13], distinguishing these events using molecular technologies is not yet possible, and this imposes limitations in estimating primaquine efficacy against relapse or resistance. Our inability to detect the presence of hypnozoite lead us to the assumption that every acute attack of P. vivax shall also harbour hypnozoites in the liver cell and this is supported by the fact that without prescription of anti-relapse, almost all acute attack will experience relapse within a year [14, 15]. Recent studies have tried to identify any protein (s) that are released by hypnozoites during its dormancy and some progress have been achieved in this endeavour. Although the finding is still a proof-of-principle, the presence of human arginase-I and an uncharacterized P. vivax protein in plasma-derived exosomes deserves further exploration on the potential to identify biomarkers of hypnozoite infection [16].
2.2 In vitro cultivation of Plasmodium vivax
Studies on P. vivax resistance to drugs used either as blood schizontocide or radical cure lags far behind P. falciparum. The absence of in vitro culture system for propagating the blood stage of P. vivax has made the in vivo test is the only way to determine the P. vivax drug response to any antimalarial drugs [17]. Advance in molecular and cellular biology within the last few decades have contributed significantly to the progress in the establishment and refinement of ex vivo drug test and repeatable in vitro cultivation in P vivax [18, 19, 20]. It has long been known that P. vivax invade exclusively young erythrocyte (reticulocytes) of Duffy antigen positive vertebrate host for asexual development in human and non human primate [21]. Recent progress have identified more specifically that Plasmodium vivax preferentially invade stage I reticulocytes CD71highTOhigh) [22]. Other progress also showed the success for long term cultivation, including cryopreservation and re-cultivation of P. vivax using blood of certain non-human primate [23]. With the aforementioned evidence, ex vivo and in vitro drug testing platform of P. vivax for novel drug development is now workable.
3. History of antimalarial drug use in vivax malaria
3.1 Quinine
Originally extracted from a Peruvian tree bark in South America, quinine was initially named cinchona in 1742 by Linnaeus. In 1820, two French chemists isolated quinine from the cinchona bark and this compound became a treatment of reference for intermittent fever throughout the world [24, 25] until the resistance of P. falciparum was first reported in Brazil in 1910 [26]. Quinine is also used for malaria prophylaxis. It was not clear as to whether the resistance rendered complete inefficacy of quinine to cure the falciparum malaria nor that it also occurred in other species, including P. vivax but it was evident that quinine was still widely used as the antimalarial mainstay until the second world war when the new antimalarial, chloroquine was introduced. As the advance in parasite biology provide more insight into parasite species diversity in human and other primates, the resistance phenomenon has attracted attention to investigate in animal model but the results were not conclusive [27]. At the end of 1930s, pamaquine, a new compound targeted at P. vivax liver stage was introduced, but 20 years later it was replaced by primaquine, a new 8-aminoquinoline compound. Primaquine is also still used until now as anti-hypnozoites for P. vivax [28] and malaria prophylactic [29] and anti-gametocyte drug for P. falciparum [30].
In response to the resistance to quinine in 1910 [26], scientists across the globe explore to find alternative treatment. Mepacrine was first synthesised in 1931 at Bayer, Germany. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine. Mepacrine (Atabrine) was used extensively during the second World War by Allied forces fighting in North Africa and the Far East to prevent malaria. This compound is also used for the treatment of giardiasis (an intestinal parasite) and has been researched as an inhibitor of phospholipase A2. Establishment of mepacrine-resistant strain in rodent plasmodia model indicated that the drug interfere with the haemozoin formation as that of quinine-resistant and primaquine-resistant strain [31]. The major breakthrough achieved during this period is the establishment of testing platform to raise drug-resistant malarial parasites in rodent model [32].
3.2 Primaquine (8-aminoquinoline)
Primaquine has long been used for radical cure to prevent relapse of malaria due to P. vivax and P. ovale. Primaquine kills hypnozoites, the dormant liver stage of the parasite. However, primaquine is known to cause severe haemolysis in patients with G6PD deficiency, a genetic disorder present in approximately 8% of the population in malaria endemic countries [33]. To prevent relapses, the World Health Organisation recommends the co-administration of CQ and standard- (total, 3.5 mg/kg) or high-dose PQ (total, 7.0 mg/kg) distributed over 14 days to patients aged >6 months with normal G6PD activity who are neither pregnant nor breastfeeding [34]. Nevertheless, adherence to such prolonged course in malaria endemic areas is poor and coupled with the fear of G6PD deficiency, prescription of this drug is mostly inadequate. Following reports of primaquine resistance in P. vivax in several geographic areas [35, 36, 37, 38, 39, 40]. Collins and Jeffrey in1996 conducted a review and concluded that the data on the efficacy of primaquine as an anti relapse remains few and inconclusive. Therefore, the need for a standardised tool to determine primaquine resistance status should be developed [41, 42]. Primaquine is also known to possess blood schizontocidal activity as well as gametocytocidal activity in P. falciparum. In the context of anti-relapse activity in P. vivax, it is important to distinguish as to whether the observed recurrent parasite following a radical cure indeed originates from reactivated hypnozoites or recrudescence. Attempts to prescribe safer and shorter dose of primaquine rendered several improvements but dependence on G6PD screening could not be excluded [34]. Review on primaquine use in P. vivax concluded that the currently suggested indications in relation to vivax malaria, namely; causal prophylaxis, terminal prophylaxis, and radical cure is still highly effective [43, 44]. With regard to primaquine treatment failure in some areas, the presence of host genetic factors, such as single nucleotide polymorphisms (SNPs) in the gene encoding enzyme involved in primaquine metabolism, CYP2D6, may also be considered before claiming primaquine resistance [45, 46].
A new compound of 8-aminoquinoline class, tafenoquine was introduced following clinical trials in several countries [47, 48]. Despite single dose prescription, tafenoquine did not show any superiority to primaquine [49]. Therefore, development of a novel compound for anti-hypnozoites that does not depend on G6PD status still has to be prioritised.
3.3 Aminoquinoline antimalarials
Chloroquine was discovered in 1934, by Hans Andersag and co-workers at the Bayer laboratories. Research by German scientists to discover a substitute for quinine led to the synthesis in 1934 of Resochin (chloroquine) and Sontochin (3-methyl-chloroquine). After the war, chloroquine have for decades been the mainstays for malaria treatment and prevention during the global malaria eradication campaign by WHO in 1950s. This safe and inexpensive 4-aminoquinoline compound is believed to exert its antimalarial property through accumulation in the food vacuole [50]. The mechanisms by which chloroquine selectively accumulates may include protonation and ion trapping of the chloroquine due to the low pH of the food vacuole, active uptake of chloroquine by a parasite transporter(s), and/or binding of chloroquine to a specific receptor in the food vacuole [51, 52, 53, 54, 55].
After a decade of its use, chloroquine resistant P. falciparum arose in four separate locations, starting with the Thai-Cambodian border around 1957; in Venezuela and parts of Colombia around 1960; in Papua New Guinea in the mid-1970s and in Africa in 1978 in Kenya and Tanzania [56]. Resistance of P. falciparum to chloroquine changed the treatment policy to use several drugs such as halofantrine, lumefantrine, pyronaridine, mefloquine, and sulfadoxine-pyrimethamine (SP), while chloroquine and primaquine remain effective to treat P. vivax until few decades.
Resistance by P. vivax to chloroquine was unknown until 1989, when Australians repatriated from Papua New Guinea failed routine treatment [57]. Subsequent reports affirmed that finding and CQ-resistant P. vivax (CRPV) was reported from Indonesia [58] and Guyana [59]. A review and meta-analytic study evaluating chloroquine clinical trials performed during the period of 1960 to 2014 found out a contrasting evidence, indicating chloroquine sensitivity as shown by elimination of the asexual parasite by day 3 [60]. Although in some studies, a high degree of resistance was confirmed, the trials exhibited heterogeneity in study design and the presence of confounding factors such as interpretation of a recurrent parasites to distinguish relapse or recrudescence. In addition, technical issues on the quality and the dose of chloroquine used may also play role as the chloroquine possesses a wide therapeutic windows that enable to increase the dose. A therapeutic efficacy study to determine the efficacy of chloroquine in uncomplicated vivax malaria was conducted in Papua, Indonesia in 2007 isolated few recurrent parasites that survive chloroquine at blood concentration ranged from 100 ng/ml to 516 ng/ml [61]. Other study performed in vitro chloroquine sensitivity assay on either freshly collected or cryopreserved P. vivax isolates collected from Papua and Thailand [62]. The global spread of chlroquine-resistant P. vivax was later summarised in 2016 [63], as shown in Figure 2.
Figure 2.
Chloroquine -resistant P. vivax infections. Source: World Wide Antimalarial Resistance Network (WWARN), available at: http://www.wwarn.org/vivax/surveyor/#0 and [64].
The absence of reliable, robust, sensitive methods for detection and monitoring of antimalarial drug efficacy in P. vivax has almost certainly contributed to the delayed recognition of this emerging problem [57]. Other factors include the relatively small parasite biomass in P. vivax infections, concomitant medication, such as primaquine to kill hypnozoites, early transmission due to the early presence of gametocytes, and high genetic diversity in natural population of P. vivax [64]. This delay has had important public health implications in areas where high-grade chloroquine-resistant P. vivax is prevalent (such as Indonesia and Oceania), partly effective drug treatments and consequent recurrent infections are an important contributing factor to severe anaemia from P. vivax malaria [65].
3.4 Resistance to antifolate and sulpha drugs
Proguanil, also known as chlorguanide and chloroguanide, is the first antifolate used to treat malaria. Proguanil is converted by the liver to its active metabolite, cycloguanil. The success of proguanil in treating human malaria led to further study of its chemical class and to the development of pyrimethamine in 1952. Resistance to the monotherapies of proguanil or pyrimethamine developed rapidly (within one year in the case of proguanil). A clear cut resistance to antifolate was proven in P. falciparum, P. vivax and P. malariae [66, 67, 68]. Sulfones and sulfonamides were then combined with proguanil or pyrimethamine in hopes of increasing efficacy and preventing or delaying resistance. By 1953, P. falciparum resistance had already been noted in Tanzania. When Sulfadoxine-pyrimethamine (SP) was introduced in Thailand in 1967, resistance appeared in the same year and spread quickly throughout South-East Asia. Resistance to SP in Africa remained low until the late 1990s but since then it has spread rapidly [69]. The SP has never been recommended for P. vivax treatment but evidence suggest that this compound is also effective to treat uncomplicated P. vivax [70, 71]. In response to resistance to SP and chloroquine, a combination of proguanil with a new class antimalarial compound, atovaquone, was introduced in 1999 by Glaxo-Smith Kline [72]. Nevertheless, prior to its introduction, resistance to atovaquone has been rapidly selected up in rodent plasmodia and P. falciparum [73, 74]. Since 2011, atovaquone-proguanil is available as a generic drug.
3.5 Artemisinin-based combination therapy (ACTs)
Artemisinin is a sesquiterpene lactone, containing the peroxide group, extracted and isolated from the leaves of Artemisia annua. by Chinese scientists in 1972 [75]. The drug and its derivatives play a role in killing Plasmodium falciparum by inhibiting the activity of phosphatidylinositol-3-kinase (PfPI3K) [76]. Initially, it was used as monotherapy to treat uncomplicated malaria but due to high recrudescence rate, a combination therapy was advised. Artemisinin-based Combination Therapy (ACTs), particularly artesunate-mefloquine, was introduced in Thailand during the early 1990s [77]. Since 2001, artemisinin (ART) combination therapy (ACT) has been recommended as the first-line treatment in the national treatment guidelines of most malaria endemic countries and have played an important role in reducing global malaria-associated mortality and morbidity [78].
Resistance to artemisinin was first detected in the Greater Mekong Subregion (GMS) region in 2008 [79]. Since then, ART resistance has spread and/or emerged in other areas of the GMS [80, 81, 82, 83]. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years, and the availability of substandard artemisinin, have probably been the main driving force in the selection of the resistant phenotype in the region. ART resistance is defined as the parasite clearance half-life of >5 h or presence of parasites in patients 3 days after treatment but has been more challenging to define, mostly because artemisinin act potently and rapidly clear parasites from the bloodstream by a unique mechanism involving the spleen [84, 85].
Currently, several drugs have been recommended (Table 1) for the treatment of severe and uncomplicated vivax malaria [34, 63, 86, 87, 88, 89, 90] and WHO is considering the use of artesunate-pyronaridine, in areas where other ACTs are failing. In the absence of resistance, all six partner drugs would be highly efficacious as monotherapies at the dose used in the ACTs. Two injectable treatments, artesunate and artemether, are recommended for the treatment of severe malaria and should be followed by an ACTs once the patient can tolerate oral therapy [34].
Drugs
Severe
1
Artesunate
2
Artemether
3
Quinine
Uncomplicated
1
Artesunate - Amodiaquine
2
Artemether - Lumefantrine
3
Artesunate - Mefloquine
4
Artesunate - Pyronaridine
5
Artesunate – Sulfadoxine/Pyrimethamine
6
Dihydroartemisinin - Piperaquine
7
Chloroquine
Antirelapse
1
Primaquine
2
Tafenoquine
Table 1.
Antimalarial drugs for the treatment of Plasmodium vivax malaria.
Studies to monitor the efficacy of the ACTs on both P. falciparum and P. vivax have been conducted since the introduction of this drug in 2001. Evidence to date revealed that resistance of P. falciparum to artemisinin so far is not only confined to the Greater Mekong Subregion (GMS). Recent evidence indicated that P. falciparum isolates carrying the kelch13 C580Y mutation has been found in Papua New Guinea [91]. The finding is quite worrying as both PNG and Indonesia shared terrestrial border and the mutations may have spread to Indonesia. Therapeutic efficacy studies (TES) conducted during the period of 2009–2018 in various sites in Indonesia, including the Indonesia-PNG border documented no cases of either P. falciparum and P. vivax resistance nor treatment failure associated with artemisinin in Indonesia [92, 93, 94, 95, 96]. Nevertheless, recurrent parasite at late observation day was reported and this recurrence certainly nothing to do with artemisinin but rather with partner drug.
4. Molecular basis of P. vivax resistance to antimalarial drugs
The advent of molecular and cellular parasitology within the last 4 decades have brought along a lot of substantial innovations in the antimalarial drug testing platforms, molecular assays to phenotype as well as genotype the malarial parasite, although it mainly attributed to P. falciparum. In P. vivax, attempts to develop a repeatable in vitro drug resistance test continue to elude us, although certain progress has been achieved [23]. As a consequence, progress on the studies to elucidate the molecular basis of the P. vivax resistance to antimalarial drugs, particularly chloroquine and artemisinin is lagged far behind P. falciparum. While studies on molecular basis of resistance to chloroquine and artemisinin successfully identified candidate gene (s) through a clear phenotypic and genotypic assay, similar progress in P. vivax could not be achieved. The molecular basis of Plasmodium resistance to antifolates and sulpha drugs had been well described [97, 98, 99]. This evidence also applies to P. vivax, and the underlying genetic polymorphisms in dhfr and dhps genes, conferring resistance to antifolates and sulpha drugs, respectively. Likewise, resistance to atovaquone, a partner drug of proguanil has been associated genetic polymorphisms in the cytb gene of the malarial parasite [73, 74].
Resistance to chloroquine, has long been subject for research in many laboratories around the globe. A yet unclear mechanism of action of this compound making it more attractive for elucidation using molecular tool. Initially the role of Plasmodium falciparum multidrug resistance 1 (pfmdr1), homologous to the mammalian multiple drug resistance (MDR) gene were incriminated [100, 101, 102]. The product of thePfmdr1gene, P-glycoprotein homolog 1 (Pgh1) has been localized to the membrane of the digestive vacuole of mature blood stage parasites. This model predicted that thePfmdr1gene would be amplified and/or over expressed in CQ-resistant isolates. Further study, however identified different mechanism for chloroquine resistance but support for the role of this pfmdr1 in other antimalarials such as mefloquine, halofantrine and quinine [103, 104, 105, 106]. Chloroquine-resistant parasites pump chloroquine out at 40 times the rate of chloroquine-sensitive parasites; the pump is coded by the P. falciparum chloroquine resistance transporter (PfCRT) gene [107, 108]. The natural function of the chloroquine pump is to transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit.
Several genetic polymorphisms at the PfCRT gene have been associated with resistance to chloroquine in a wide geographic regions of malaria endemic areas [108]. Nevertheless, attempts to prove this finding in CRPV still fail, primarily because the technical difficulties in proving the resistant phenotype in P. vivax. Molecular analysis of the P. vivax isolates that have been phenotypically determined to be resistant in a rigorous in vivo and limited in vitro tests did not reveal any polymorphisms in the PvCRT gene as that of PfCRT. Instead, amplification of Pvmdr1 and several SNPs in the pvmdr1 was found to associate with CRPV [62]. Recent evidence found out that increases in PvCRT copy number associated with the P. vivax resistance to chloroquine [109, 110, 111, 112, 113].
The molecular basis for artemisinin resistance in the malarial parasite have also been described recently. Since mammalian kelch proteins can detect oxidants and other stressors, mutations in K13-propeller were reasonably implicated in mediating resistance to artemisinin and have been proposed as molecular marker [114, 115, 116, 117]. Subsequent studies provided a more detail biochemical impact of the PfKelch13 mutations on the decreased abundance of PfKelch13 protein, decreased haemoglobin digestion, and enhanced glutathione production [118]. However, the finding on the interaction of dihydroartemisinin with phosphatidylinositol-3-phosphate kinase, and that elevated phosphatidyl-inositol-3 phosphate can be associated with resistance in the absence of PfK13 mutations suggested for other mechanism [119]. In line with this evidence, Tyagi et al [120] raised a clear-cut artemisinin resistant isolates of P. falciparum following artesunate drug pressure in humanised mouse and the molecular analyses of the ART-resistant isolates revealed no mutations in PfK13 gene. Instead, an obvious selective pressure on RAD5 gene. Interestingly, the ART-resistant isolates also exhibited concomitant resistance to quinine, a second line drug used for treating severe malaria cases. The association between mutations in RAD5 gene and the resistance to artemisinin require further confirmation through either reverse genetics or genetic gross in mosquito.
Resistance of P. vivax to artemisinin so far has never been reported in areas where ACTs have long been used as first line drug for P. vivax malaria in South and Southeast Asia and the Pacific islands to replace chloroquine. This evidence, however, has to be carefully considered as P. vivax perhaps has long experienced with artemisinin pressure as that of P. falciparum, particularly in the GMS region where both species are distributed in sympatry and undetectable mixed species infection are common [121]. In support of this assumption, molecular analysis of P. vivax isolate from the GMS region revealed a high diversity and ex vivo analysis indicate reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartemisinin [122, 123]. In this context, regular monitoring of the antimalarial treatment as well as genomic surveillance of the PvK12 gene, orthologues of the PfK13, in P. vivax and other relevant gene (s) should be conducted to monitor the emergence of artemisinin-resistant P. vivax and to contain the spread of the resistance to other regions [124, 125].
Reports of P. vivax resistance to primaquine and chloroquine have been well documented. Nevertheless, attempts to validate the resistance status of primaquine rendered an equivocal results. With the current limitation in testing platform both in vivo and in vitro, the use of primaquine as anti-relaps compound is still recommended. Therefore, factors that may limit its use in P. vivax endemic setting such as G5PD deficiency should be excluded by deploying a cheap, easy to use Point-of-Care (PoC) G6PD test.
Plasmodium vivax resistance to chloroquine present different burden to each geographic areas. Therefore, the use of alternative drug ACTs should be tailored following the degree of resistance to chloroquine, as well as therapeutic response to any available ACTs.
Plasmodium vivax resistance to artemisinin has never been found in any of the P. vivax isolates examined from different geographic regions but resistance to partner drug such as amodiaquine, piperaquine, lumefantrine, mefloquine and pyronaridine should be regularly monitored to safeguard our arsenal for achieving malaria elimination by 2030.
Resistance of P. vivax to the antimalarial drug mainstays, chloroquine and primaquine poses a serious challenge to achieving the global malaria elimination that has been set up in 2030. Despite ambiguous evidence on both of this drug, chloroquine and primaquine deserve further exploration on its efficacy in different geographic setting before being side lined. To ensure the safe provision of primaquine treatment in P. vivax, local capacity to determine the existence host genetic factors such as G6PD deficiency as well as CYP2D6 allelic frequency should be established to mitigate the treatment failure that potentially increasing the risk of severe and fatal outcome.
Recent progress on the in vitro cultivation of P. vivax renew our interest to carefully validate the clinical phenotype of P. vivax isolates to the antimalarial drug mainstays, chloroquine, ACT and primaquine as well as the association with the genotype through genome-wide association study. In this context, progress achieved in P. falciparum certainly provide guidance to circumvent the limitations in P. vivax.
The proven efficacy of ACTs to vivax malaria in general and CRPV in particular, also support for our readiness to circumvent the problem of P. vivax resistance toward the remaining years ahead. Although the ACT is hastily paired with primaquine, evidence to date is still supportive.
Apart from our readiness to cope in turn the chemotherapeutic issue in combating P. vivax, efforts to mitigate the transmission through vector control should also be encouraged. A regular vector surveillance and control around the dwelling areas should be promoted to prevent the silent transmission of the parasite to Anopheles vector.
We gratefully acknowledge Prof. Amin Soebandrio MD, Ph.D, Clin. Microbiol, Chairman of the Eijkman Institute for Molecular Biology for his encouragement and advice and Prof. dr. Budu, Ph.D., Sp.M (K), M.Med.Ed, Dean of the Faculty of Medicine, Hasanuddin University for the support to DS. Therapeutics efficacy studies (TES) for period 2012–2021 in Eijkman Institute are supported by Government of Indonesia (Ministry of Research and Technology/National Research and Innovation Agency and Ministry of Health) and World Health Organisation.
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Written By
Puji Budi Setia Asih and Din Syafruddin
Submitted: 28 February 2021Reviewed: 18 March 2021Published: 13 May 2021
Open access peer-reviewed chapter
