Artemisinin-based Combination Therapy Regimens Research Articles

Putative molecular markers of Plasmodium falciparum resistance to antimalarial drugs in malaria parasites from Ghana.

Antimalarial drugs including artemisinin-based combination therapy (ACT) regimens and sulphadoxine-pyrimethamine (SP) are used in Ghana for malaria therapeutics and prophylaxis respectively. The genetic basis of Plasmodium falciparum development of drug resistance involves single nucleotide polymorphisms in genes encoding proteins for multiple cellular and metabolic processes. The prevalence of single nucleotide polymorphisms in nine P. falciparum genes linked to ACT and SP resistance in the malaria parasite population was determined. Archived filter paper blood blot samples from patients aged 9 years and below with uncomplicated malaria reporting at 10 sentinel sites located in three ecological zones for the Malaria Therapeutic Efficacy Studies were used. The samples used were collected from 2007-2018 malaria transmission seasons and mutations in the genes were detected using PCR and Sanger sequencing. In all 1,142 samples were used for the study. For falcipain-2 gene (pffp2), Sanger sequencing was successful for 872 samples and were further analysed. The prevalence of the mutants was 45% (392/872) with pffp2 markers V51I and S59F occurring in 15.0% (128/872) and 3.0% (26/872) of the samples respectively. Prevalence of other P. falciparum gene mutations: coronin (pfcoronin) was 44.8% (37/90); cysteine desulfurase (pfnfs) was 73.9% (68/92); apicoplast ribosomal protein S10 (pfarps10) was 36.8% (35/95); ferredoxin (pffd) was 8.8% (8/91); multidrug resistance protein-1 (pfmrp1) was 95.2.0% (80/84); multidrug resistance protein-2 (pfmrp2) was 91.4% (32/35); dihydrofolate reductase (pfdhfr) was 99.0% (84/85); dihydropteroate synthase (pfdhps) was 72% (68/95). The observation of numerous mutations in these genes of interest in the Ghanaian isolates, some of which have been implicated in delayed parasite clearance is of great interest. The presence of these genotypes may account for the decline in the efficacies of ACT regimens being used to treat uncomplicated malaria in the country. The need for continuous monitoring of these genetic markers to give first-hand information on parasite susceptibility to antimalarial drugs to inform policy makers and stakeholders in malaria elimination in the country is further discussed.

Differential Incidence of Malaria in Neighboring Villages in a High-Transmission Setting of Southern Mali.

ABSTRACT.Throughout a phase IIIb/IV efficacy study of repeated treatment with four artemisinin-based combination therapies, significant heterogeneity was found in the number of clinical episodes experienced by individuals during the 2-year follow-up. Several factors, including host, parasite, and environmental factors, may contribute to the differential malaria incidence. We aimed to identify risk factors of malaria incidence in the context of a longitudinal study of the efficacy of different artemisinin-based combination therapy regimens in Bougoula-Hameau, a high-transmission setting in Mali. Risk factors including age, residence, and treatment regimen were compared among individuals experiencing eight or more clinical episodes of malaria (“high-incidence group”) and individuals experiencing up to three clinical episodes (“low-incidence group”). Consistent with the known association between age and malaria risk in high-transmission settings, individuals in the high incidence group were significantly younger than individuals in the low-risk group (mean age, 7.0 years versus 10.6 years, respectively; t-test, P < 0.0001). Compared with individuals receiving artemether-lumefantrine, those receiving artesunate-amodiaquine had greater odds of being in the high-incidence group (odds ratio [OR], 2.24; 95% CI, 1.03 – 4.83, P = 0.041), while individuals receiving dihydroartemisinin-piperaquine had a lower odds of being in high incidence group (OR: 0.30, 95% CI, 0.11–0.85; P = 0.024). Individuals residing in the forested areas of Sokourani and Karamogobougou had significantly greater odds of being in the high-incidence group compared with individuals residing in the semi-urban area of Bougoula-Hameau 1 (Karamogobougou: OR, 3.68; 95% CI, 1.46–9.31; P = 0.0059; Sokourani: OR, 11.46; 95% CI, 4.49–29.2; P < 0.0001). This study highlights the importance of fine-mapping malaria risks even at sub-district levels for targeted and customized interventions.

Geographic expansion of artemisinin resistance.

Artemisinin-based combination therapy (ACT) is the global standard of care for uncomplicated falciparum malaria. First reports of ACT resistance came from western Cambodia and the Thailand-Cambodia border in 2002-2004. The subsequent emergence and expansion of Plasmodium falciparum strains resistant to the artemisinin component and ACT are now threatening the efficacy of falciparum malaria treatment. We performed a literature review on the history and the current degree of geographic expansion of artemisinin and ACT resistance. Resistance against artemisinins is defined as >5% of patients carrying PfKelch13 (K13) mutations, all of whom have been found to have persistent parasitaemia by microscopy on Day 3 after treatment. Several studies including the multi-centre Tracking Resistance to Artemisinin Collaboration study investigated artemisinin resistance in Southeast Asia and beyond and demonstrated increasing prevalence of P. falciparum infections with slow parasite clearance rates in the Greater Mekong Subregion (GMS). K13 mutations were strongly associated with delayed P. falciparum parasite clearance, and the prevalence of the mutation PfKelch13 C580Y is increasing in the GMS. Resistance to ACT regimens is now well established in western Cambodia and in eastern Thailand, southern Laos and southern Vietnam. Moreover, the prevalence of slow P. falciparum parasite clearance has continuously increased over the past 10-15years at the Thailand-Myanmar border, in nearly all regions of Myanmar, and at the Myanmar-China border. Multidrug resistant malaria is a rapidly increasing problem, but fortunately still limited to Southeast Asia, in particular to the GMS. In the long-term it may threaten global progress in malaria control but is not yet of concern with regards to malaria prophylaxis, as ACTs are not used for prevention in travellers, current ACT regimens are still effective in most malaria endemic areas outside the GMS and the preferred travellers' prophylaxis atovaquone-proguanil and doxycycline remain protective. However, artemsinin resistance in the GMS is of real concern to travellers as it will affect the choice of malaria treatment including standby-emergence treatment.

Differential infectivity of gametocytes after artemisinin-based combination therapy of uncomplicated falciparum malaria.

BackgroundMost malaria-endemic countries use artemisinin-based combination therapy (ACT) as their first-line treatment. ACTs are known to be highly effective on asexual stages of the malaria parasite. Malaria transmission and the spread of resistant parasites depend on the infectivity of gametocytes. The effect of the current ACT regimens on gametocyte infectivity is unclear.ObjectivesThis study aimed to determine the infectivity of gametocytes to Anopheles gambiae following ACT treatment in the field.MethodsDuring a randomised controlled trial in Bougoula-Hameau, Mali, conducted from July 2005 to July 2007, volunteers with uncomplicated malaria were randomised to receive artemether-lumefantrine, artesunate-amodiaquine, or artesunate-sulfadoxine/pyrimethamine. Volunteers were followed for 28 days, and gametocyte carriage was assessed. Direct skin feeding assays were performed on gametocyte carriers before and after ACT administration.ResultsFollowing artemether-lumefantrine treatment, gametocyte carriage decreased steadily from Day 0 to Day 21 post-treatment initiation. In contrast, for the artesunate-amodiaquine and artesunate-sulfadoxine/pyrimethamine arms, gametocyte carriage increased on Day 3 and remained constant until Day 7 before decreasing afterward. Mosquito feeding assays showed that artemether-lumefantrine and artesunate-amodiaquine significantly increased gametocyte infectivity to Anopheles gambiae sensu lato (s.l.) (p < 10−4), whereas artesunate-sulfadoxine/pyrimethamine decreased gametocyte infectivity in this setting (p = 0.03).ConclusionDifferent ACT regimens could lead to gametocyte populations with different capacity to infect the Anopheles vector. Frequent assessment of the effect of antimalarials on gametocytogenesis and gametocyte infectivity may be required for the full assessment of treatment efficacy, the potential for spread of drug resistance and malaria transmission in the field.

Efficacy and safety of artemisinin-based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial

BackgroundThere is general international agreement that the importance of vivax malaria has been neglected, and there is a need for new treatment approaches in an effort to progress towards control and elimination in Latin America. This open label randomized clinical trial evaluated the efficacy and safety of three treatment regimens using either one of two fixed dose artemisinin-based combinations or chloroquine in combination with a short course of primaquine (7–9 days: total dose 3–4.2 mg/kg) in Brazil. The primary objective was establishing whether cure rates above 90% could be achieved in each arm.ResultsA total of 264 patients were followed up to day 63. The cure rate of all three treatment arms was greater than 90% at 28 and 42 days. Cure rates were below 90% in all three treatment groups at day 63, although the 95% confidence interval included 90% for all three treatments. Most of the adverse events were mild in all treatment arms. Only one of the three serious adverse events was related to the treatment and significant drops in haemoglobin were rare.ConclusionThis study demonstrated the efficacy and safety of all three regimens that were tested with 42-day cure rates that meet World Health Organization criteria. The efficacy and safety of artemisinin-based combination therapy regimens in this population offers the opportunity to treat all species of malaria with the same regimen, simplifying protocols for malaria control programmes and potentially contributing to elimination of both vivax and falciparum malaria.Trial registration RBR-79s56s

Evaluation of artemisinin-based combination therapy (ACT) to uncomplicated falciparum malaria patients in Purworejo District, Central Java, Indonesia

Artemisinin-based Combination Therapy (ACT) to treat uncomplicated Plasmodium falciparum malaria has been applied in Purworejo District, Central Java, Indonesia, since 2004. However evaluation of the two ACT regimens used ie: Artesunate Amodiaquine (AAQ) and Dihydroartemisinin-Piperaquine (DHP) co-administered with Primaquine (PQ) has not been performed. This study aims to evaluate the efficacy and side effects of AAQ+PQ and DHP+PQ treatment in uncomplicated falciparum malaria in Purworejo. In this descriptive and observational study, 46 Pf infected patients who fullfill the inclusion and exclusion criterias were recruited from December 2010 to August 2011. Standard ACT treatment were given to the patients followed by WHO drug efficacy evaluation for 28 days. The clinical symptoms and adverse events was also evaluated over the course of the treatment. From all recruited subjects, 37 patients received DHP+PQ and 9 patients received AAQ+PQ. On the DHP+PQ treated patient, all subjects were free of asexual and sexual parasites by Day-3 while on AAQ+PQ treated patient, this parasite clearance was achieved faster as early as on D-2 at the latest. On the otherhand, the disappearance of fever was also last longer in DHP+PQ treated patient which in one patient last on D-14, while in AAQ+PQ treated patient, the symptom of fever dissappeared by D-2 at the latest. No Early or Late Treatment Failures were found on either DHP+PQ or AAQ+PQ treatment as well as clinical and parasitological failures. However, the presence of adverse events cause by both drugs should not be ignored to ensure drug compliance.

Adherence to artemisinin-based combination therapy for the treatment of malaria: a systematic review of the evidence

BackgroundIncreasing access to and targeting of artemisinin-based combination therapy (ACT) is a key component of malaria control programmes. To maximize efficacy of ACT and ensure adequate treatment outcomes, patient and caregiver adherence to treatment guidelines is essential. This review summarizes the current evidence base on ACT adherence, including definitions, measurement methods, and associated factors.MethodsA systematic search of the published literature was undertaken in November 2012 and updated in April 2013. Bibliographies of manuscripts were also searched and additional references identified. Studies were included if they involved at least one form of ACT and reported an adherence measurement.ResultsThe search yielded 1,412 records, 37 of which were found to measure adherence to ACT. Methods to measure adherence focused on self-report, pill counts and bioassays with varying definitions for adherence. Most studies only reported whether medication regimens were completed, but did not assess how the treatment was taken by the patient (i.e. timing, frequency and dose). Adherence data were available for four different ACT formulations: artemether-lumefantrine (AL) (range 39-100%), amodiaquine plus artesunate (AQ + AS) (range 48-94%), artesunate plus sulphadoxine-pyrimethamine (AS + SP) (range 39-75%) and artesunate plus mefloquine (AS + MQ) (range 77-95%). Association between demographic factors, such as age, gender, education and socio-economic status and adherence to ACT regimens was not consistent. Some evidence of positive association between adherence and patient age, caregiver education levels, drug preferences, health worker instructions, patient/caregiver knowledge and drug packaging were also observed.ConclusionsThis review highlights the weak evidence base on ACT adherence. Results suggest that ACT adherence levels varied substantially between study populations, but comparison between studies was challenging due to differences in study design, definitions, and methods used to measure adherence. Standardising methodologies for both self-report and bioassays used for evaluating adherence of different formulations across diverse contexts would improve the evidence base on ACT adherence and effectiveness; namely, specific and measurable definitions for adherence are needed for both methodologies. Additionally, further studies of the individual factors and barriers associated with non-adherence to ACT are needed in order to make informed policy choices and to improve the delivery of effective malaria treatment.

Artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria.

The World Health Organization strongly recommends artemisinin-based combination therapy (ACT) regimens for the treatment of uncomplicated Plasmodium falciparum malaria cases in endemic areas. Among the combinations of compounds that are available at present, excellent results have been obtained for the artemisinin derivative artemether, in a combination galenic preparation with lumefantrine (artemether-lumefantrine, AL). Here, the pharmacological properties and the therapeutic options of both substances are briefly reviewed and a cursory overview is given on recent trials that have compared the therapeutic effects of AL in the standard 6-dose regimen with other antimalarials and combinations. In order to ensure the most achievable and reliable adherence and compliance of children in the treatment of malaria, a dispersible formulation of AL is now attainable. Recent reports on the emergence of resistance to ACT regimens in Asia, however, are alarming.