Optimal Treatments for Severe Malaria and the Threat Posed by Artemisinin Resistance.
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ABSTRACT: Background
Standard treatment for severe malaria is with artesunate; patient survival in the 24 hours immediately posttreatment is the key objective. Clinical trials use clearance rates of circulating parasites as their clinical outcome, but the pathology of severe malaria is attributed primarily to noncirculating, sequestered, parasites, so there is a disconnect between existing clinical metrics and objectives.Methods
We extend existing pharmacokinetic/pharmacodynamic modeling methods to simulate the treatment of 10000 patients with severe malaria and track the pathology caused by sequestered parasites.Results
Our model recovered the clinical outcomes of existing studies (based on circulating parasites) and showed a "simplified" artesunate regimen was noninferior to the existing World Health Organization regimen across the patient population but resulted in worse outcomes in a subgroup of patients with infections clustered in early stages of the parasite life cycle. This same group of patients were extremely vulnerable to resistance emerging in parasite early ring stages.Conclusions
We quantify patient outcomes in a manner appropriate for severe malaria with a flexible framework that allows future researchers to implement their beliefs about underlying pathology. We highlight with some urgency the threat posed to treatment of severe malaria by artemisinin resistance in parasite early ring stages.
SUBMITTER: Jones S
PROVIDER: S-EPMC6452316 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)
| S-EPMC3495232 | biostudies-literature
Project description:BackgroundInformation regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa.MethodsWe conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes.ResultsThe PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups).ConclusionsArtemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).
| S-EPMC5117004 | biostudies-literature
Project description:Evolving resistance to artemisinin-based compounds in SE Asia threatens to derail attempts to control and eliminate malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) from the blood following treatment. We used a two-phase approach to identify the genes underlying this ongoing selective event. Comparison of geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from western Cambodia, western Thailand and Laos identified 33 strongly selected genome regions. We screened SNPs and microsatellites within these genome regions in 718 parasites from western Thailand, and identified a 35kb region of chr 13 showing strong association (P=10-6 to 10-11) with slow CR. This region contains several compelling candidate loci, such as HSP70, for assessment by transfection. These results illustrate the efficacy of targeted association for identifying the genetic basis of adaptive traits. 91 malaria parasite isolates assayed for single nucleotide polymorphisms across 45K loci
2012-04-30 | E-GEOD-33002 | biostudies-arrayexpress
Project description:Evolving resistance to artemisinin-based compounds in SE Asia threatens to derail attempts to control and eliminate malaria. Resistance has been confirmed in western Cambodia, has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CR) from the blood following treatment. We used a two-phase approach to identify the genes underlying this ongoing selective event. Comparison of geographical differentiation and haplotype structure at 6,969 polymorphic SNPs in 91 parasites from western Cambodia, western Thailand and Laos identified 33 strongly selected genome regions. We screened SNPs and microsatellites within these genome regions in 718 parasites from western Thailand, and identified a 35kb region of chr 13 showing strong association (P=10-6 to 10-11) with slow CR. This region contains several compelling candidate loci, such as HSP70, for assessment by transfection. These results illustrate the efficacy of targeted association for identifying the genetic basis of adaptive traits.
2012-05-01 | GSE33002 | GEO
Project description:Influenza pandemics, defined as global outbreaks of the disease due to viruses with new antigenic subtypes, have exacted high death tolls from human populations. The last two pandemics were caused by hybrid viruses, or reassortants, that harbored a combination of avian and human viral genes. Avian influenza viruses are therefore key contributors to the emergence of human influenza pandemics. In 1997, an H5N1 influenza virus was directly transmitted from birds in live poultry markets in Hong Kong to humans. Eighteen people were infected in this outbreak, six of whom died. This avian virus exhibited high virulence in both avian and mammalian species, causing systemic infection in both chickens and mice. Subsequently, another avian virus with the H9N2 subtype was directly transmitted from birds to humans in Hong Kong. Interestingly, the genes encoding the internal proteins of the H9N2 virus are genetically highly related to those of the H5N1 virus, suggesting a unique property of these gene products. The identification of avian viruses in humans underscores the potential of these and similar strains to produce devastating influenza outbreaks in major population centers. Although highly pathogenic avian influenza viruses had been identified before the 1997 outbreak in Hong Kong, their devastating effects had been confined to poultry. With the Hong Kong outbreak, it became clear that the virulence potential of these viruses extended to humans.
| S-EPMC88966 | biostudies-literature
Project description:BACKGROUND:Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS:Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS:The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS:Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).
| S-EPMC4143591 | biostudies-literature
Project description:Objective:To assess the public health risk to Singapore posed by the emergence of artemisinin-resistant (ART-R) malaria in the Greater Mekong Subregion (GMS). Methods:We assessed the likelihood of importation of drug-resistant malaria into Singapore and the impact on public health of its subsequent secondary spread in Singapore. Literature on the epidemiology and contextual factors associated with ART-R malaria was reviewed. The epidemiology of malaria cases in Singapore was analysed. The vulnerability and receptivity of Singapore were examined, including the connectivity with countries reporting ART-R malaria, as well as the preparedness of Singaporean health authorities. Sources of information include international journals, World Health Organization guidelines, data from the Singapore Ministry of Health and National Public Health Laboratory of the National Centre for Infectious Diseases, and the International Air Transport Association. Results:The importation of ART-R malaria into Singapore is possible given the close proximity and significant travel volume between Singapore and the GMS countries reporting artemisinin resistance. Singapore's vulnerability is further enhanced by the presence of foreign workers from neighbouring endemic countries. Nonetheless, the overall likelihood of such an event is low based on the rarity and decreasing trend of imported malaria incidence.?: With the presence of Anopheles vectors in Singapore, imported cases of drug-resistant malaria could cause secondary transmission. Nevertheless, the risk of sustained spread is likely to be mitigated by the comprehensive surveillance and control system in place for both infected vectors and human cases. Discussion:This risk assessment highlights the need for a continued high degree of vigilance of ART-R malaria locally and globally to minimize the risk and public health impact of drug-resistant malaria in Singapore.
| S-EPMC6831961 | biostudies-literature
Project description:Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10(-6) to 10(-12)) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.
| S-EPMC3355473 | biostudies-literature
Project description:RNAseq data profiling two heatshock-sensitive P. falciparum piggyBac mutants with and without exposure to febrile temperatures.
2021-06-14 | GSE177479 | GEO
Project description:Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.
| S-EPMC4417027 | biostudies-literature