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Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia.
- Source :
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PLoS medicine [PLoS Med] 2020 Aug 21; Vol. 17 (8), pp. e1003203. Date of Electronic Publication: 2020 Aug 21 (Print Publication: 2020). - Publication Year :
- 2020
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Abstract
- Background: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria.<br />Methods and Findings: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ART-S infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants experienced transient severe falls in white cell counts and/or elevations in liver transaminase levels which were considered related to malaria. Additionally, 2 participants developed ventricular extrasystoles that were attributed to unmasking of a predisposition to benign fever-induced tachyarrhythmia. In the comparative study, parasite clearance half-life after AS was significantly longer for ART-R infected participants (n = 13, 6.5 hours; 95% confidence interval [CI] 6.3-6.7 hours) compared with ART-S infected participants (n = 9, 3.2 hours; 95% CI 3.0-3.3 hours; p < 0.001). The main limitation of this study was that the ART-R and ART-S parasite strains did not share the same genetic background.<br />Conclusions: We developed the first (to our knowledge) human model of ART-R malaria. The delayed clearance profile of ART-R parasites after AS aligns with field study observations. Although based on a relatively small sample size, results indicate that this model can be safely used to assess new drugs against ART-R P. falciparum.<br />Trial Registration: The studies were registered with the Australian New Zealand Clinical Trials Registry: ACTRN12617000244303 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372357) and ACTRN12617001394336 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373637).<br />Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: REW, AO, LM, LW, ANA, LC, MR, ZP, KAC, CP, and JSM are employees of the study sponsor QIMR Berghofer Medical Research Institute; SC and JJM are employees of Medicines for Malaria Venture which provided funding for the study.
- Subjects :
- Adolescent
Adult
Animals
Anti-Infective Agents adverse effects
Anti-Infective Agents pharmacology
Antimalarials adverse effects
Antimalarials pharmacology
Artemisinins adverse effects
Artemisinins pharmacology
Artesunate adverse effects
Artesunate pharmacology
Artesunate therapeutic use
Australia epidemiology
Female
Headache chemically induced
Healthy Volunteers
Humans
Malaria, Falciparum epidemiology
Male
Nausea chemically induced
Parasites metabolism
Pilot Projects
Young Adult
Anti-Infective Agents therapeutic use
Antimalarials therapeutic use
Artemisinins therapeutic use
Malaria, Falciparum blood
Malaria, Falciparum drug therapy
Plasmodium falciparum metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1549-1676
- Volume :
- 17
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PLoS medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32822347
- Full Text :
- https://doi.org/10.1371/journal.pmed.1003203