Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.
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SUBMITTER: van der Pluijm RW
PROVIDER: S-EPMC8204272 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe use of drug combinations, including non-artemisinin-based and artemisinin-based combination therapy (ACT), is a novel strategy that enhances therapeutic efficacy and delays the emergence of multidrug-resistant Plasmodium falciparum. Its use is strongly recommended in most sub-Saharan African countries, namely Cameroon, where resistance to chloroquine is widespread and antifolate resistance is emerging.MethodsStudies were conducted in Cameroonian children with acute uncomplicated P. falciparum malaria according to the standard World Health Organization protocol at four sentinel sites between 2003 and 2007. A total of 1,401 children were enrolled, of whom 1,337 were assigned to randomized studies and 64 were included in a single non-randomized study. The proportions of adequate clinical and parasitological response (PCR-uncorrected on day 14 and PCR-corrected on day 28) were the primary endpoints to evaluate treatment efficacy on day 14 and day 28. The relative effectiveness of drug combinations was compared by a multi-treatment Bayesian random-effect meta-analysis.FindingsThe results based on the meta-analysis suggested that artesunate-amodiaquine (AS-AQ) is as effective as other drugs (artesunate-sulphadoxine-pyrimethamine [AS-SP], artesunate-chlorproguanil-dapsone [AS-CD], artesunate-mefloquine [AS-MQ], dihydroartemisinin-piperaquine [DH-PP], artemether-lumefantrine [AM-LM], amodiaquine, and amodiaquine-sulphadoxine-pyrimethamine [AQ-SP]). AM-LM appeared to be the most effective with no treatment failure due to recrudescence, closely followed by DH-PP.ConclusionAlthough AM-LM requires six doses, rather than three doses for other artemisinin-based combinations, it has potential advantages over other forms of ACT. Further studies are needed to evaluate the clinical efficacy and tolerance of these combinations in different epidemiological context.
| S-EPMC2834703 | biostudies-literature
Project description:The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coadministered with a longer-acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine [DHA-PPQ-MQ]) for use in South-East Asia, where DHA and PPQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at various degrees of DHA and PPQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PPQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PPQ, the administration of three 6.7-mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by World Health Organization (WHO) guidelines. As a result, three 8.3-mg/kg doses of MQ, the current WHO-recommended dosing regimen for MQ, combined with DHA-PPQ, has the potential to produce high cure rates in regions where resistance to DHA-PPQ has emerged.
| S-EPMC6201091 | biostudies-literature
Project description:Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.
| S-EPMC4873939 | biostudies-literature
Project description:Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance.Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient.A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR?=?1.34, 95% CI 1.20-1.50, p?<?0.001), having a temperature ?38.0°C vs?<?37.0°C (RR?=?1.19, 95% CI 1.05-1.35, p?=?0.007) and having a parasite density >20,000/?L vs <4,000/?L (RR?=?3.37, 95% CI 2.44-4.49, p?<?0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected.Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy.Current Controlled Trials Identifier NCT00527800.
| S-EPMC3909240 | biostudies-literature
Project description:The first-line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamic and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an in vitro high-throughput process for measuring the drug concentration-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against 15 parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification of plasmepsin II/III, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.
| S-EPMC7737215 | biostudies-literature
Project description:Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance.
| S-EPMC5464640 | biostudies-literature
Project description:Artemisinin-based combination therapies (ACTs) resistance has emerged and could be diffusing in Africa. As an offshore island on the African continent, the island of Bioko in Equatorial Guinea is considered severely affected and resistant to drug-resistant Plasmodium falciparum malaria. However, the spatial and temporal distribution remain unclear. Molecular monitoring targeting the Pfcrt, Pfk13, Pfpm2, and Pfmdr1 genes was conducted to provide insight into the impact of current antimalarial drug resistance on the island. Furthermore, polymorphic characteristics, haplotype network, and the effect of natural selection of the Pfk13 gene were evaluated. A total of 152 Plasmodium falciparum samples (collected from 2017 to 2019) were analyzed for copy number variation of the Pfpm2 gene and Pfk13, Pfcrt, and Pfmdr1 mutations. Statistical analysis of Pfk13 sequences was performed following different evolutionary models using 96 Bioko sequences and 1322 global sequences. The results showed that the prevalence of Pfk13, Pfcrt, and Pfmdr1 mutations was 73.68%, 78.29%, and 75.66%, respectively. Large proportions of isolates with multiple copies of Pfpm2 were observed (67.86%). In Bioko parasites, the genetic diversity of Pfk13 was low, and purifying selection was suggested by Tajima's D test (-1.644, P > 0.05) and the dN/dS test (-0.0004438, P > 0.05). The extended haplotype homozygosity analysis revealed that Pfk13_K189T, although most frequent in Africa, has not yet conferred a selective advantage for parasitic survival. The results suggested that the implementation of continuous drug monitoring on Bioko Island is an essential measure. IMPORTANCE Malaria, one of the tropical parasitic diseases with a high transmission rate in Bioko Island, Equatorial Guinea, especially caused by P. falciparum is highly prevalent in this region and is commonly treated locally with ACTs. The declining antimalarial susceptibility of artemisinin-based drugs suggested that resistance to artemisinin and its derivatives is developing in P. falciparum. Copy number variants in Pfpm2 and genetic polymorphisms in Pfk13, Pfcrt, and Pfmdr1 can be used as risk assessment indicators to track the development and spread of drug resistance. This study reported for the first time the molecular surveillance of Pfpm2, Pfcrt, Pfk13, and Pfmdr1 genes in Bioko Island from 2017 to 2019 to assess the possible risk of local drug-resistant P. falciparum.
| S-EPMC9241599 | biostudies-literature
Project description: Not available
| S-EPMC8092484 | biostudies-literature
Project description:OBJECTIVES:To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda. DESIGN:Randomized single-blind controlled trial. SETTING:Tororo, Uganda, an area of high-level malaria transmission. PARTICIPANTS:Children aged one to ten years with confirmed uncomplicated P. falciparum malaria. INTERVENTIONS:Amodiaquine + artesunate or artemether-lumefantrine. OUTCOME MEASURES:Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS:Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens. CONCLUSIONS:Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.
| S-EPMC1488893 | biostudies-literature
Project description:BACKGROUND:Malaria is a major public health problem in endemic countries including Sudan, where about 75% of populations are at risk. Due to widespread of chloroquine-resistant strains of Plasmodium falciparum, artemisinin-based combination therapy (ACT) is currently treatment of choice for malaria in the vast majority of malaria-endemic countries. This systematic review and meta-analysis is performed to obtain an overall stronger evidence of the outcomes of ACT in the treatment of uncomplicated falciparum malaria from the existing literature in Sudan. METHODS:The preferred reporting items for systematic review and meta-analysis statement were used to select studies to be included in this review. A computerized systematic strategy was adopted to search articles from PubMed, Google Scholar and Science Direct databases. Unpublished materials were also included. Open Meta-Analyst software was used to perform the meta-analysis. Random effects model was used to combine the included studies and the heterogeneity of studies was assessed using Cochrane Q and I2 (χ2 = 73.05, df (19), P < 0.001 and I2 = 73.99). RESULTS:Twenty studies fulfilled the inclusion criteria (ACT in the treatment of uncomplicated falciparum malaria) and were included in the final analysis with a total number of 4070 participants. Malaria treatment outcome was assessed using World Health Organization guidelines. Adequate clinical and parasitological response was used to assess treatment success at the 28th day. Treatment success of all combined studies was 98% [(95% CI 97.2-98.8%), P < 0.001]. Treatment success was higher in malaria patients treated with artemether + lumefantrine (AL) than patients treated with artesunate + sulfadoxine-pyrimethamine (AS + SP) (98.9% (95% CI 98.4-99.4%) vs 97.1% (95% CI 95.5-98.6%), P < 0.001). Eleven studies reported adverse drug reactions (ADRs) to ACT (184 participants out of 3957 (4.65%). The ADRs were mild and resolved spontaneously. There was no severe ADRs or deaths. CONCLUSION:Based on this review, the overall malaria treatment success was high (98%). AL regimen showed higher efficacy compared to AS + SP. The overall regimens were associated with mild low rates ADRs.
| S-EPMC5850971 | biostudies-literature