Malaria Treatment Landscape: Current Trends and Future Directions

Abstract

Malaria control relies partly on effective case treatment, with Artemisinin-based combination therapy (ACT) being a cornerstone strategy. ACTs have revolutionized malaria treatment by offering remarkable efficacy and bolstering disease control efforts. They demonstrate exceptional effectiveness against both falciparum and non-falciparum malaria, rendering them suitable for all malaria variants. However, a declining malaria transmission rate introduces a new concern, a heightened risk of severe malaria among the elderly due to fading premunition. An important advancement in malaria management is the deployment of artesunate for severe cases. Given the decreasing transmission rates, a comprehensive control package encompassing disease control and elimination is essential. Primaquine has proven to be effective in curtailing malaria transmission, positioning it as a key component in elimination strategies. In pursuit of malaria eradication, optimization of integrated tools for mass drug administration and chemoprevention initiatives targeting vulnerable populations is crucial. As the development of new antimalarial drugs remains uncertain, securing the longevity of ACTs necessitates innovative approaches and substantial investments. Looking forward, addressing pivotal challenges such as drug resistance, sub-optimal plasma drug exposure, diagnostic insensitivity, and sub-standard medications is paramount. By tackling these challenges head-on, the global community can bolster malaria control and work toward its eventual eradication.

1. Introduction

Malaria remains a significant global health concern, particularly in the tropical and subtropical regions of Africa. Six species of Plasmodium parasites are known to cause malaria in humans transmitted through the bites of infected Anopheles mosquitoes [1]. Plasmodium falciparum is the predominant causative agent of the disease in Africa and the most virulent species. Other species are less virulent and commonly found in Southeast Asia and Western Pacific. The global burden of malaria has substantially declined as compared to the levels at the beginning of the new millennium in the year 2000 [2]. The malaria control achievements were contributed by financial investments and innovative approaches fueled by the Millennium Development Goals and later Sustainable Development Goals (SDGs) [3, 4]. Despite the substantial decline, hundreds of millions of people are still affected by malaria each year, leading to hundreds of thousands of deaths globally [5].

Malaria treatment is a vital component among the efforts for the control and elimination of the disease. Effective treatment is crucial not only for reducing morbidity and mortality but also for controlling the spread of the disease. The treatment of malaria involves a multi-faceted approach, including the use of antimalarial medications, supportive care, and preventive strategies. The cornerstone of malaria management is the use of antimalarial drugs, which directly target the Plasmodium parasite. The choice of antimalarial drugs depends on various factors, including the severity of the infection, the type of Plasmodium species, the patient’s age, the likely pattern of susceptibility to antimalarial drugs, the cost, availability of such drugs, and geographical location. For this reason, recommendations vary according to geographic region and are usually under constant review.

Artemisinin which forms the current mainstay of antimalarial treatment is derived from the leaves of a Chinese herb known as Artemisia annua [6]. Its derivatives include dihydroartemisinin, artesunate, and artemether. Artemisinin-based combination therapies (ACTs) are the first-line treatment for uncomplicated falciparum malaria [7]. ACTs combine an artemisinin derivative, which rapidly reduces the parasite load, with a long-acting partner drug that clears the remaining parasites from the bloodstream. The long-acting partner drugs belong to synthetic 4-aminoquinoline (amodiaquine and piperaquine), aryl amino alcohol (mefloquine, lumefantrine, and halofantrine), and aminoacridine (pyronaridine). The combination of these drugs helps to prevent the development of drug resistance and ensures a higher cure rate. ACTs or chloroquine are equally effective in the treatment of infections caused by non-falciparum species [7]. Plasmodium vivax and Plasmodium ovale can form dormant liver-stage parasites referred to as hypnozoites [8]. To prevent relapses due to hypnozoites, additional drugs like primaquine or tafenoquine are used to target these latent forms after ACT or chloroquine [9].

Chemoprevention has emerged as a promising strategy to complement existing global malaria control strategies and proved to be effective, especially in vulnerable populations. In Africa, where P. falciparum is still sensitive, dihydroartemisinin-piperaquine (DHP) is explored for use in chemoprevention approaches targeting the elimination of malaria, though caution needs to be taken to prevent resistance development. However, resistance to DHP is widespread in the Great Mekong region, Southeast Asia [10]. Innovative researches are needed to generate further evidence on the optimal regimes, especially among the existing tools for effective chemoprevention.

Effective malaria treatment relies on early diagnosis and the use of appropriate antimalarial drugs. Prompt and accurate diagnosis ensures timely administration of drugs, reduces the severity of the disease, and prevents complications and deaths. In endemic regions, rapid diagnostic tests (RDTs) have revolutionized malaria diagnosis by providing quick and reliable results without the need for sophisticated laboratory equipment. Nevertheless, lower sensitivities [11] and deletion of P. falciparum histidine- rich protein 2 and 3, the target proteins in RDTs [12] challenge the effective diagnosis and treatment of malaria. Other challenges like drug resistance, limited healthcare access, co-infections, and socioeconomic factors pose significant obstacles in combatting malaria effectively [13]. Strengthening malaria treatment efforts will make significant strides toward eliminating the global burden of this devastating disease. This chapter provides a comprehensive insight into the current approaches for the management of malaria focusing on key therapeutics and chemoprophylaxis options, as well as challenges and future direction for strengthening the treatment and control strategies toward malaria eradication.

2. Malaria treatment approaches

Before 2006, malaria treatment regimens consisted of monotherapies. During that time, chloroquine and amodiaquine were widely used against infections caused by all types of parasite species. In some endemic areas, chloroquine is now less effective due to widespread resistance [14]. However, it is still utilized in other areas where the Plasmodium species are susceptible to their action, especially against the non-falciparum species. Amodiaquine is still available as a partner drug in combination therapy. The antifolate sulfadoxine-pyrimethamine (SP) was an effective and well-tolerated antimalarial drug given as a single dose. SP is also a partner drug in combination therapy although the widely spread resistance limits its use for malaria treatment in some areas. However, it is recommended for malaria intermittent preventive treatment (IPT) in endemic areas [15].

Following the WHO’s first edition of the Guidelines for malaria treatment in 2006 [16], many countries changed the malaria treatment regimen from monotherapy to combination therapy. ACTs are highly effective in treating uncomplicated malaria caused by Plasmodium falciparum [17] and non-falciparum malaria infections [18]. The combination offers several advantages over monotherapies. ACTs achieve faster parasite clearance and reduce the risk of treatment failure compared to monotherapy. Combining artemisinin derivatives with a partner drug that has a different mechanism of action, help to delay the development of drug resistance. The combination of artemisinin with another antimalarial drug often enhances the overall therapeutic effect thus providing a synergistic effect. The partner drug may have a longer half-life, ensuring continuous parasite clearance and reducing the chances of recrudescence [19]. By rapidly reducing the number of parasites in the blood, ACTs contribute to reduce the transmission and prevalence of malaria in communities.

2.1 Types of ACTs

The World Health Organization (WHO) recommends six ACTs for the treatment of uncomplicated falciparum malaria [7] namely:

1. Artemether-lumefantrine

2. Artesunate-mefloquine

3. Artesunate-amodiaquine

4. Artesunate-sulfadoxine-pyrimethamine

5. Dihydroartemisinin-piperaquine

6. Artesunate-pyronaridine

2.2 Mechanism of action for antimalarial drugs

Artemisinin and its derivatives exhibit potent antimalarial activity by targeting the Plasmodium parasites during their asexual blood stage. The mode of action involves the production of reactive oxygen species, which damage the parasite’s cellular components, leading to its death [20]. Artemisinin derivatives have a rapid onset of action, reducing the parasite load quickly.

The partner drugs in ACTs have a longer half-life and eliminate the remaining parasites. They target blood stage parasites although the exact mechanism is unknown. The current knowledge suggests that lumefantrine acts by forming a complex with hemin and inhibits β-hematin formation and consequently inhibits nucleic acid and protein synthesis. Aminoquinoline, aminoacridine, and bisquinoline partner drugs are hypothesized to have a similar mechanism through binding to heme and arrest the polymerization of a toxic haematin resulting in its accumulation in the erythrocytes destroying the parasites [21]. The antifolates antimalarial drugs work through the inhibition of key enzymes involved in the folate pathways. Sulfadoxine inhibits dihydropteroate synthase (DHPS), an important enzyme in folate synthesis by the parasites [22]. On the flip side, pyrimethamine competitively inhibits a key enzyme for the production of tetrahydrofolate, dihydrofolate reductase (DHFR) which is a crucial co-factor needed by the parasites for the biosynthesis of nucleotides and proteins [23].

2.3 Treatment regimens for uncomplicated malaria

Artemether-lumefantrine (ALu) is the first-line treatment policy in most African countries. It is the most commonly used ACT available in a fixed-dose combination. Each tablet contains 20 mg of artemether and 120 mg of Lumefantrine. The recommended dose is 1.4–4 mg/kg for artemether and 10–16 mg/kg for lumefantrine. However, it is conveniently administered in a pre-defined weight band. Patients weighing 5–14 kg receive one tablet (20 mg artemether/120 mg Lumefantrine), 15–24 kg receive two tablets, 25–34 kg receive three tablets, and > 34 kg receive four tablets given twice daily for three consecutive days [24]. One tablet formulation containing 80 mg of artemether and 480 mg of lumefantrine is also available for patients weighing >34 kg to reduce pill burden. Formulations for pediatric patients are also available in the form of dispersible tablets [25]. The first dose is usually administered at the health facility as a direct observed therapy (DOT). Recent evidence indicates that ALu is safe in pregnancy and is recommended in all trimesters [26] making one regimen for the general population, children, and pregnant women.

DHP is also one of the first-line treatment policies in some African countries. It is very well-tolerated and available in a fixed dose combination containing 40 mg dihydroartemisinin and 320 mg piperaquine per tablet. Pediatric formulations are available in a strength of 20 mg dihydroartemisinin and 160 mg piperaquine per tablet. The dose regimen for children weighing <25 kg is 4 mg of dihydroartemisinin per kg body weight and 24 mg of piperaquine per kg body weight given once daily for three consecutive days. For children weighing ≥25 kg and adults, the dose is 4 mg of dihydroartemisinin per kg body weight and 18 mg of piperaquine per kg body weight given once daily for three consecutive days [27]. However, in resource-limited countries, weight-based dosing is a challenge, thus adults receive a three-day course of three tablets daily. Resistance to DHP is widely spread in the Great Mekong region and necessitated the removal of this regimen as the first-line policy [10].

In Southeast Asia, the first-line policy is artesunate-amodiaquine (AS-AQ) which is also the first-line policy in some West African countries. AS-AQ is available in a fixed dose formulation containing different strengths of 25/67.5, 50/135, and 100/270 mg of artesunate/amodiaquine, respectively [28]. Artesunate 50 mg and amodiaquine 135 mg are also available as separate formulations. AS-AQ is given once daily for three consecutive days at a dose of 4 mg/kg for artesunate and 10 mg/kg of amodiaquine. For convenient dosing, AS-AQ is also given in weight bands where, children weighing between 4.5 to <9 kg receive one tablet (25/67.5 mg) once daily for 3 days, 9 to <18 kg receive one tablet (50/135 mg), 18 to <36 kg receive one tablet (100/270 mg) once daily for 3 days and those weighing ≥36 kg and adults receive two tablets (100/270 mg) once daily for 3 days [28].

Artesunate mefloquine is available in a separate formulation. One formulation contains 50 mg of artesunate and the other 250 mg of mefloquine base. The recommended dose is 4 mg/kg/day for artesunate given once daily for 3 days and 25 mg/kg of mefloquine divided over 2 days as 15 mg/kg and 10 mg/kg given on the second and third days [29]. Artesunate-SP is available on a separate tablet. However, due to widespread resistance to SP, this regimen is not used in some countries. Artesunate-pyronaridine is a recently introduced ACT regimen available in a fixed dose formulation containing 60 mg of artesunate and 180 mg of pyronaridine as a salt. The fixed-dose formulation is indicated for children with 20 kg body weight and above. Patients weighing 20 to <24 kg receive one tablet, 24 to <45 kg receive two tablets, 45 to <65 kg receive three tablets, and ≥ 65 kg receive four tablets once daily for 3 days. For children with <20 kg body weight, the granular pediatric formulation is available in a sachet packaging containing 20 mg of artesunate and 60 mg of pyronaridine tetraphosphate [30]. Children weighing 5 to <8 kg receive one sachet, 8 to <15 kg receive two sachets, and 15 to <29 kg receive three sachets. Nevertheless, the deployment of Artesunate-pyronaridine has not been expanded in many countries. It is essential to follow the prescribed dosage and complete the full course of treatment to ensure effectiveness and reduce the risk of developing drug resistance.

Chloroquine is recommended for the treatment of blood stage uncomplicated infection with a non-falciparum parasite. Chloroquine is formulated in tablet form with a strength of 250 mg per tablet. The prescribed dosage regimen for adults involves an initial dose of four tablets (250 mg per tablet), followed by two tablets after 6 hours, followed by a maintenance dose of two tablets daily for 2 days [31]. For pediatric patients, the recommended chloroquine dosage involves an initial dose of 10 mg base/kg then, a follow-up dose of 5 mg base/kg after 6 hours, followed by a maintenance dose of 5 mg base/kg once daily for 2 days. Children aged 1–4 years receive an initial dose of one tablet, followed by half a tablet after 6 hours, and then half a tablet once daily for 2 days. Children aged 5–8 years receive two tablets for the initial dose, followed by one tablet after 6 hours, and then one tablet once daily for 2 days. Children aged 9–14 years should take three tablets initially, followed by one and a half tablets after 6 hours, and then one and a half tablets once daily for 2 days [31].

ACTs have demonstrated good efficacy and safety for non-falciparum infections [18] and are used for the treatment of the same making one therapeutic approach for all Plasmodium infections. Infections with P. vivax and P. ovale exist as hypnozoites that survive in the liver and may result in relapse. Since most antimalarial drugs act on the blood stage of the parasite, primaquine given at a dose of 0.25 mg/kg daily for seven or 14 days is recommended to eliminate hypnozoites in the liver after a full course of chloroquine or ACT [32]. The risk of recrudescence is lower with DHP than ALu and decreases with additional primaquine [33]. Recently, tefenoquine a long-acting and well-tolerated member of 8-aminoquinoline given as a single dose proved to be an alternative to primaquine as it outweighs adherence problems [34]. A low dose of primaquine is also effective against the transmissibility of falciparum mature gametocytes interrupting malaria transmission, especially in areas of low transmission intensities requiring elimination [35]. A single dose of 0.25 mg/kg primaquine for falciparum infections after a three-day course of ACT reduces gametocytemia thus blocking the transmission of the disease [35]. Primaquine is known to cause hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, making testing for G6PD deficiency important before administering the drug. In resource-constrained countries, G6PD testing is not feasible in routine settings. However, recent evidence indicates that a single dose of primaquine as recommended by the WHO is safe even among G6PD-deficit patients with minimal reduction in Hemoglobin [36, 37]. The availability of simple and cost-effective G6PD tests for routine use in the future will aid in the safe management of malaria.

2.4 Treatment regimens and management of severe malaria

Severe malaria is a life-threatening medical emergency caused primarily by the P. falciparum parasite. It is a significant public health concern, particularly in regions with high malaria transmission rates. With the decreasing burden of malaria, cases of severe malaria are also rare although, may be problematic in the older population as primunition wanes. Prompt and appropriate treatment is essential to reduce mortality and morbidity associated with severe malaria. Management of severe malaria aims immediately to reduce the parasite load, manage the symptoms, manage the associated complications, and proper supportive care.

Artesunate, a water-soluble drug can rapidly reduce parasite load and improve survival rates in patients with severe malaria and is the first-line treatment for severe malaria [7]. It can be administered intravenously or intramuscularly for critically ill patients and is available in both parenteral and rectal formulations for use in resource-limited settings. Following initial treatment with intravenous or intramuscular artesunate, a full course of ACT is given to clear any remaining parasites and to complete the treatment. ACTs, such as ALu or AS-AQ , are highly effective and help to prevent the development of drug resistance. The choice of ACT may depend on local drug resistance patterns and individual patient factors.

In addition to antimalarial medications, supportive care plays a critical role in the management of severe malaria. Severe malaria often presents with complications including anemia, metabolic acidosis, and multi-organ dysfunction, which require specific interventions. Intravenous fluids and electrolyte management are essential to maintain hydration and correct any imbalances. Malaria-associated mortalities occur with admission of <3 g/dL of hemoglobin thus immediate blood transfusions may be necessary [37]. In resource-limited countries, health facilities in rural settings are not sufficient to provide blood transfusion services in addition to poor infrastructure for a quick referral system. This contributes to malaria-associated severe anemia causing mortalities, especially in children. Monitoring of vital signs, such as blood pressure, heart rate, and oxygen saturation, is vital to detect any deterioration promptly. Fever, discomfort, and pain are common symptoms of severe malaria requiring the use of antipyretics, such as paracetamol. Additionally, appropriate analgesics may be needed to manage pain and reduce distress in patients. Frequent monitoring of patients with severe malaria is crucial to assess treatment response and detect any potential complications. Parasitemia usually remains high for about 48 hours thus serial blood smears should be examined to evaluate the reduction in parasite density. Laboratory investigations, including complete blood count, liver and renal function tests, and coagulation profiles, should be performed regularly to identify and manage any adverse effects or complications. Cerebral malaria leading to seizures is a common complication of severe malaria, particularly in young children thus anticonvulsants, such as diazepam or phenobarbital are administered [38]. However, caution should be exercised with the use of diazepam to prevent respiratory depression, especially in critically ill patients. Severe malaria can lead to hypoglycemia, especially in children thus monitoring of blood glucose is also important. Intravenous glucose supplementation may be needed in managing and preventing life-threatening low blood sugar levels.

2.5 Efficacy of antimalarials and drug resistance

To inform policy decisions, WHO recommends regular monitoring of antimalarial drugs through therapeutic efficacy studies (TES). The outcomes of TES, include clinical and parasitological responses monitored for a minimum of 28 days for drugs with elimination half-lives of less than 7 days (lumefantrine, amodiaquine, and artemisinin derivatives). For antimalarial drugs with longer elimination half-lives such as piperaquine and mefloquine longer periods of at least 42 days are recommended [39]. Responses can be regarded as adequate clinical and parasitological responses characterized by the absence of parasitemia on day 28 (day 42) irrespective of axillary temperature. It can be also regarded as early treatment failure (ETF) defined by higher parasitemia on days 1, 2, and 3 as compared to the levels on day 0 with an axillary temperature of ≥37.5°C or late clinical failure (LCF) characterized by danger signs, presence of parasitemia between day 4 and day 28 (42) with the axillary temperature of ≥37.5°C. Additionally, late parasitological failure is characterized by the presence of parasitemia on any day between day 7 and day 28 (day 42). An efficacy rate of at least 90% for ACTs is deemed sufficiently acceptable in therapeutics [39].

Several TES from areas where resistance to ACTs has not been reported have consistently reported acceptable efficacy (≥90%). ALu is particularly effective in regions where P. falciparum is still sensitive and demonstrated an overall cure rate of about 98% in endemic regions [19]. In sub-Saharan Africa, few studies have reported ≥10% therapeutic failure for ALu in some countries [19]. Equally, AS-AQ has a high cure rate with an overall efficacy of 98.4% for uncomplicated malaria, making it an important tool in the fight against malaria in regions where drug-resistant strains are a concern. Similar to ALu and AS-AQ , DHP has a high cure rate with an overall efficacy of 99.4% for uncomplicated malaria [40]. It is well-tolerated by most patients and has been widely used in areas where malaria is endemic. It is important to note that the efficacy of antimalarial drugs can vary depending on the geographical location due to the development of drug-resistant strains of the malaria parasite. Therefore, it’s essential to monitor drug efficacy regularly and update treatment guidelines accordingly.

The efficacy of controlling malaria is jeopardized by the presence of antimalarial resistance. Therapeutic Efficacy Studies (TES) constitute one approach to track the development of resistance to antimalarial drugs. Elevated instances of treatment ineffectiveness resulting from diminished drug responsiveness might be linked to the emergence of resistance. Additional conventional methods encompass the surveillance of genetic markers linked to drug resistance. Mutation in PfKelch13 gene is associated with reduced parasite clearance and is used to monitor artemisinin resistance [41]. On the other hand, mutations occurring in the Pfcrt transporter, as well as in the Pfmdr gene, have led to the development of resistance against chloroquine and its structurally related antimalarials [42]. In the Pfcrt gene, mutations are prominent within positions 72–76 among most P. falciparum strains causing resistance to 4-aminoquinolines. An increase in Pfplasmepsin 2/3 copy numbers as well as mutations occurring in the Pfcrt transporter are associated with piperaquine resistance [42, 43]. Resistance to mefloquine and lumefantrine is largely associated with an increase in the copy number of the wild-type Pfmdr gene [43]. Meanwhile, resistance to atovaquone emerges readily due to mutations occurring in the mitochondrial multicopy cytochrome b gene specifically at position 268, commonly Y268S or Y268N [43]. The prevalence of PfKelch13 mutation associated with partial artemisinin resistance is high in Southeast Asia, particularly in the Great Mekong sub-regions of Myanmar and Cambodia, and is spreading to Papua New Guinea [44]. The widespread resistance to DHP led to change in the first-line treatment policy in this region [10]. In the African region, PfKelch13 mutations have emerged in Uganda, Eritrea and Rwanda [13]. Parasite resistance to antimalarial drugs is associated with reduced parasite clearance.

Mutations within the dhfr gene (S108N, N51I, C59R) that encodes the drug target dihydrofolate reductase, result in resistance to pyrimethamine in both P. falciparum and P. vivax, rendering the drug less effective against these parasites [45]. Similarly, the resistance of both P. falciparum and P. vivax to sulfadoxine is attributed to mutations accumulating in the dhps gene, which is responsible for encoding the drug target dihydropteroate synthase. Notable mutations within this gene include A437G, K540E, and A581G [45]. The combination of these mutations compromises the efficacy of SP. In the WHO eastern Mediterranean region, the widespread resistance to SP necessitated the change of policy to ALu from AS + SP. In addition, the widespread parasite resistance to SP in sub-Saharan Africa impedes the efficiency of SP to clear parasitemia and prevent new infections [46].

2.6 Safety profile of ACTs

Artemisinin derivatives, including artemether, dihydroartemisinin, and artesunate, have demonstrated a favorable safety profile. The most commonly reported adverse events are mild and self-limiting, including nausea, vomiting, dizziness, and headaches. These side effects are generally well-tolerated and rarely lead to treatment discontinuation [47]. However, some patients may experience more severe adverse reactions, such as allergic reactions or anaphylaxis, though these instances are exceedingly rare.

The safety profile of partner drugs in ACTs varies depending on the specific drug used. Lumefantrine, amodiaquine and piperaquine are among the most commonly used partner drugs. Lumefantrine is generally well-tolerated, with gastrointestinal disturbances (e.g., diarrhea) being the most commonly reported adverse events [48]. Concerns have been raised about cardiac safety, particularly in patients with pre-existing cardiac conditions or prolonged QT intervals, but these events are rare and often not directly attributed to lumefantrine [49]. Amodiaquine has a well-documented safety profile and is generally considered safe for use. However, it may cause adverse effects such as hepatotoxicity, which can be severe but is rare. Amodiaquine is known to cause hemolysis in individuals with G6PD deficiency. Piperaquine is well-tolerated, and its safety profile is generally favorable. However, there have been isolated reports of rare adverse events, including cardiovascular events and QT interval prolongation, especially when used at high doses [50].

The safety of ACTs in pregnant women and young children is of paramount importance. Studies have shown that ACTs are safe and effective during pregnancy when used as recommended [26]. Pregnant women with malaria are at an increased risk of drug-related adverse outcomes, but the benefits of treating malaria with ACTs outweigh the potential risks. Similarly, ACTs are equally safe and effective in treating malaria in children, contributing to the reduction of malaria-related mortality in this vulnerable population [51].

3. Chemoprevention of malaria

Chemoprevention involves the administration of a full course of antimalarial drugs to vulnerable populations as a preventive measure. The rationale behind chemoprevention lies in its ability to proactively target malaria parasites during their lifecycle, thereby preventing infection, reducing parasite reservoirs, and subsequently decreasing the risk of transmission. This approach is particularly valuable for high-risk populations, including pregnant women, young children, and travelers visiting malaria-endemic regions. Chemoprevention of malaria has demonstrated its potential as a complementary strategy to conventional malaria control measures. By effectively targeting high-risk populations and interrupting parasite transmission, chemoprevention holds the promise of reducing malaria-related morbidity and mortality.

Pregnant women, in particular, are at increased risk of malaria and adverse pregnancy outcomes due to pregnant-associated immune modulation and the preferential of falciparum parasites to the placenta [52]. Most of the infected women at their first antenatal care clinic have asymptomatic parasitemia [53]. Chemoprevention is therefore a vital intervention to protect both maternal and fetal health. Intermittent Preventive Treatment in Pregnancy (IPTp) involves the administration of a full treatment course of an antimalarial drug during antenatal care visits, irrespective of whether the pregnant woman shows symptoms or has a confirmed infection. SP has been the mainstay for IPTp due to its safety profile and effectiveness against the adverse effects of malaria in pregnancy [54]. The efficiency of SP in the prevention of parasitemia and placental malaria is compromised due to widespread parasite resistance to the drug [46]. However, taking at least three doses of SP during pregnancy is associated with improved birth weight [55] which is explained by the non-malaria effects of SP [56]. IPTp with DHP has recently shown superior efficacy against parasitemia and placental malaria than SP [57]. Future studies need to explore the efficacy and safety of combined DHP and SP for IPTp. IPT with SP has also been recommended to children considering the feasibility of providing it with a routine expanded program for immunization. In addition, Seasonal Malaria Chemoprevention (SMC) using AQ with SP is effectively implemented in endemic areas with high seasonal malaria transmission [58]. In eastern Africa where SP resistance is widespread, SMC with DHP is explored [58, 59].

Mass Drug Administration (MDA) involves administering antimalarial drugs to entire populations in high-transmission settings, regardless of individual infection status. This approach aims to reduce the overall parasite burden in the community and consequently, interrupt transmission. While MDA has shown promising results, its implementation requires careful consideration of factors such as drug resistance and feasibility. With the longest half-life of piperaquine which provides extended prophylaxis, DHP is an ideal option for elimination strategies including MDA [60]. In target areas for elimination, MDA with ACTs demonstrated lower incidences and prevalence of parasitemia [61]. Travelers to malaria-endemic regions can take prophylactic antimalarial medications to prevent infection. Several antimalarial medications, such as mefloquine, atovaquone-proguanil, doxycycline, and primaquine, may be prescribed depending on the specific circumstances, including the region of travel and drug resistance patterns.

While a chemopreventive drug regimen is crucial for malaria control and elimination strategies, consistent adherence to the drug is the main challenge for its effectiveness. Non-adherence can reduce the protective effect and contribute to the emergence of drug resistance. The future of malaria chemoprevention control is promising. Ongoing research should focus on optimizing existing strategies and exploring new drug combinations and delivery methods. Additionally, advancements in molecular diagnostics and genetic surveillance will enable real-time monitoring of drug resistance, allowing for timely adjustments to treatment regimens. Furthermore, targeted chemoprevention based on individual risk profiles may become a reality as we gain a better understanding of the host-parasite interactions that drive severe disease outcomes.

4. Disposition of antimalarial drugs

Understanding the pharmacokinetics of antimalarial drugs is crucial for optimizing treatment regimens, ensuring therapeutic efficacy, successful outcomes in malaria management, and preventing drug resistance. The disposition of antimalarial drugs is a complex process that significantly influences their therapeutic effectiveness and the development of drug resistance. In addition, consideration of individual patient factors and potential drug interactions is essential for tailoring antimalarial therapy and reducing the global burden of malaria effectively. Most commonly, antimalarial drugs are administered orally, and their bioavailability is influenced by factors such as food intake and the presence of drug transporters in the gastrointestinal tract [61, 62]. ACTs taken with fatty meal especially milk has been shown to improve their systemic exposure [63]. The extensive distribution of some antimalarial, like chloroquine, contributes to their ability to target malaria parasites in various tissues. The knowledge of antimalarial drug disposition allows the design of appropriate dosing regimens.

The liver primarily carries out the metabolism of many antimalarial drugs through various enzymatic pathways, including cytochrome P450 enzymes. Artemisinin, artesunate, and artemether are metabolized by various CYP enzymes to a potent active metabolite dihydroartemisinin (Figure 1). These enzymes are polymorphic and genetic variations in these enzymes can lead to inter-individual differences in drug metabolism, influencing drug efficacy and toxicity [64]. The role of genetic variations in CYP3A4 the main metabolic pathway for most antimalarial drugs on their dispositions has not been documented. Genetic variation in CYP3A5 is associated with lower lumefantrine plasma concentrations and treatment failure [65]. Sub-optimal drug concentrations due to poor adherence or altered pharmacokinetics may provide selective pressure for the emergence of drug-resistant malaria parasites. Continued research in this field will contribute to the development of more effective and targeted antimalarial treatment strategies.

Figure 1.

Metabolic pathways for artemisinin derivatives. Source: https://www.pharmgkb.org/pathway/PA165378192.

5. Challenges and future perspective in the management of malaria

Although progress has been made in malaria control efforts over the years, numerous challenges persist, hindering the effective treatment and management of the disease. One of the most critical challenges in malaria treatment is the emergence and spread of drug-resistant strains of the malaria parasite, particularly P. falciparum, which is responsible for the majority of malaria-related deaths. Resistance to antimalarial drugs like chloroquine and SP has been documented in many regions worldwide, limiting treatment options and compromising treatment efficacy. Resistance to artemisinin forming the current treatment regimen has also surfaced in Southeast Asia [66]. Delayed parasite clearance and treatment failures have been observed in some regions. The emergency of artemisinin resistance has been reported in some African countries [13]. The threat of further drug resistance underscores the urgency of developing and deploying new antimalarial drugs. Regular monitoring of drug resistance is essential for maintaining treatment efficacy. Several approaches for mitigating antimalarial resistance are warranted. The availability of different types of ACTs provides an opportunity for further research aiming to mitigate resistance development. Future studies should generate evidence on the effectiveness of multiple first-line drugs and the use of triple artemisinin combination treatments, (TACTs) which combine artemisinin derivatives with two slowly eliminated antimalarial drugs for mitigating drug resistance [67].

Sub-optimal antimalarial plasma exposure resulting in treatment failure is another challenge facing the effective treatment of malaria. Sub-optimal drug concentrations occur in pregnant women possibly due to pregnancy-related increased CYP enzyme activity [68]. Children also have higher clearance of antimalarial drugs leading to sub-therapeutic concentrations [69, 70]. The existence of high-efficacy ACTs provides a chance for further optimization of dosage regimens. Future studies should evaluate the effectiveness of increasing doses or dosing durations, especially in children and pregnant women. Furthermore, the burden of sub-standard drugs in sub-Saharan Africa is underestimated but contributes to sub-optimal plasma drug exposure and compromises the treatment of malaria. In sub-Saharan Africa, it is estimated that about 19% of antimalarial drugs are falsified or sub-standard with an estimated economic burden of more than US 10 billion [71]. The weak control of pharmaceuticals in low- and middle-income countries underscores the need to strengthen drug regulation and post-market surveillance [72].

Effective malaria treatment relies on accurate and timely diagnosis. Conventional microscopy-based diagnosis, while reliable, is labor-intensive and may not be feasible in resource-limited settings. RDTs have been instrumental in improving access to diagnostics, but they have limitations, including the potential for false-negative results and difficulty in detecting low-level infections. Furthermore, parasites have developed deletion of histidine-rich protein, the target proteins in RDTs [12]. The deployment of new highly sensitive RDTs will ensure effective diagnosis and treatment of malaria [73]. Effective combating of malaria also requires addressing the social determinants of health to ensure equitable access to treatment for all. However, low socioeconomic status especially in developing countries, including poverty and lack of education, can exacerbate malaria treatment challenges. Poor communities may face financial barriers in accessing healthcare services and purchasing antimalarial medications. ACTs are generally more expensive than older antimalarial drugs, which can present a barrier to their widespread implementation in resource-limited settings. Furthermore, emerging diseases such as COVID-19 affect the supply and distribution of malaria consumables including medicines and diagnostics. International collaborations and funding initiatives are needed to increase access and affordability.

6. Conclusion

Artemisinin-based combination therapies (ACTs) are safer and remain to be key for malaria control and elimination strategies. DHP and primaquine are promising options for malaria elimination strategies. Malaria treatment faces numerous challenges, from drug resistance to healthcare access limitations and diagnostic difficulties. Addressing these challenges requires a multi-pronged approach, including the development of new antimalarial drugs, strengthening healthcare systems in endemic regions, enhancing diagnostic capabilities, and addressing social and environmental determinants of malaria. Collaboration among governments, international organizations, researchers, and communities is essential to overcome these challenges and ultimately achieve the goal of malaria elimination, improving the health and well-being of millions worldwide.

Conflict of interest

The author declares no conflict of interest.

Notes/thanks/other declarations

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