The assessment of antimalarial drug efficacy in-vivo

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Abstract

Currently recommended methods of assessing uncomplicated falciparum malaria treatment work less well in high transmission than in low transmission settings. There is also uncertainty how to assess intermittent preventive therapies and seasonal malaria chemoprevention, and P. vivax radical cure. A “pharmacometric antimalarial resistance monitoring (PARM)” approach is proposed for slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e. recurrent parasitaemias in the presence of normally suppressive drug concentrations), and to characterise changes over time. PARM requires characterization of pharmacometric profiles but should be simpler and more sensitive than current methodologies. PARM does not require parasite genotyping, and can be applied to the assessment of both prevention and treatment.

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Spread of artemisinin resistance in Plasmodium falciparum malaria.

Elizabeth A Ashley, Mehul Dhorda, Rick Fairhurst … (2014)

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. 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. 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. 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.).

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Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination.

Teun Bousema, Chris Drakeley (2011)

Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.

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Determinants of relapse periodicity in Plasmodium vivax malaria

Nicholas J. White (2011)

Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

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Journal

Journal ID (nlm-journal-id): 100966034

Journal ID (nlm-ta): Trends Parasitol

Journal ID (iso-abbrev): Trends Parasitol

Title: Trends in parasitology

ISSN (Print): 1471-4922

ISSN (Electronic): 1471-5007

Publication date Nihms-submitted: 09 June 2022

Publication date (Print): August 2022

Publication date (Electronic): 06 June 2022

Publication date PMC-release: 01 August 2022

Volume: 38

Issue: 8

Pages: 660-672

Affiliations

[1 ]Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok Thailand

[2 ]Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK

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[* ]Correspondence: nickw@ 123456tropmedres.ac

Article

Manuscript ID: EMS145861

DOI: 10.1016/j.pt.2022.05.008

PMC ID: 7613059

PubMed ID: 35680541

SO-VID: a1a92685-8533-47a6-8075-09948d7c90cc

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This work is licensed under a CC BY 4.0 International license.

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The assessment of antimalarial drug efficacy in-vivo

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Malaria vaccine development

Most cited references 49

Spread of artemisinin resistance in Plasmodium falciparum malaria.

Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination.

Determinants of relapse periodicity in Plasmodium vivax malaria

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