Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia

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.

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.

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.

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).

Author summary

Why was this study done?

• Malaria resistance to artemisinin combination therapies is spreading in the Greater Mekong subregion; therefore, new antimalarial drugs are needed to control malaria.

• Malaria volunteer infection studies (VIS), in which healthy volunteers are infected with malaria parasites, have been used to test antimalarial drugs in development.

• We sought to develop a human model of artemisinin-resistant (ART-R) malaria that could be used to evaluate the efficacy of antimalarial drugs against ART-R malaria.

What did the researchers do and find?

• We conducted 2 malaria VIS. In a pilot study, 2 healthy participants were infected with ART-R parasites. In a comparative study, participants were randomised to be infected with either ART-R (13 participants) or artemisinin-sensitive (ART-S; 9 participants) parasites. In both studies, participants were given a single dose of an artemisinin derivative (artesunate[AS]) 8 or 9 days after infection.

• Malaria was well tolerated in the pilot study (36 adverse events reported) and the comparative study (277 adverse events reported); no serious adverse events were reported in the studies. Common adverse events included headache, pyrexia, myalgia, nausea, and chills.

• In the comparative study, parasites took significantly longer to clear from the blood of participants after AS administration for participants infected with ART-R parasites (6.5 hours) compared with participants infected with ART-S parasites (3.2 hours).

What do these findings mean?

• We have developed the first (to our knowledge) human model of ART-R malaria, the results of which, although based on a relatively small sample size, indicate potential to be safely used to assess the efficacy of new drugs against ART-R parasites.

• The longer time to clear ART-R parasites from the blood of participants after AS administration is comparable with the observations from studies conducted in the Greater Mekong subregion, which suggests that the findings from this human model of ART-R malaria are relevant for clinical malarial patients.