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


Autoři: Rebecca E. Watts aff001;  Anand Odedra aff001;  Louise Marquart aff001;  Lachlan Webb aff001;  Azrin N. Abd-Rahman aff001;  Laura Cascales aff001;  Stephan Chalon aff002;  Maria Rebelo aff001;  Zuleima Pava aff001;  Katharine A. Collins aff001;  Cielo Pasay aff001;  Nanhua Chen aff003;  Christopher L. Peatey aff003;  Jörg J. Möhrle aff002;  James S. McCarthy aff001
Působiště autorů: QIMR Berghofer Medical Research Institute, Brisbane, Australia aff001;  Medicines for Malaria Venture, Geneva, Switzerland aff002;  Australian Army Malaria Institute, Brisbane, Australia aff003
Vyšlo v časopise: Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia. PLoS Med 17(8): e32767. doi:10.1371/journal.pmed.1003203
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003203

Souhrn

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).

Klíčová slova:

Adverse events – Antimalarials – Malaria – Malarial parasites – Parasitic diseases – Parasitic life cycles – Pilot studies – Plasmodium


Zdroje

1. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371: 411–423. doi: 10.1056/NEJMoa1314981 25075834

2. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361: 455–467. doi: 10.1056/NEJMoa0808859 19641202

3. Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505: 50–55. doi: 10.1038/nature12876 24352242

4. Straimer J, Gnädig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347: 428–431. doi: 10.1126/science.1260867 25502314

5. Stanisic DI, McCarthy JS, Good MF. Controlled human malaria infection: applications, advances, and challenges. Infect Immun. 2018;86: e00479–00417. doi: 10.1128/IAI.00479-17 28923897

6. McCarthy JS, Baker M, O'Rourke P, Marquart L, Griffin P, Hooft van Huijsduijnen R, et al. Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers. J Antimicrob Chemother. 2016;71: 2620–2627. doi: 10.1093/jac/dkw174 27272721

7. McCarthy JS, Lotharius J, Rückle T, Chalon S, Phillips MA, Elliott S, et al. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect Dis. 2017;17: 626–635. doi: 10.1016/S1473-3099(17)30171-8 28363636

8. McCarthy JS, Ruckle T, Djeriou E, Cantalloube C, Ter-Minassian D, Baker M, et al. A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study. Malar J. 2016;15: 469. doi: 10.1186/s12936-016-1511-3 27624471

9. McCarthy JS, Sekuloski S, Griffin PM, Elliott S, Douglas N, Peatey C, et al. A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. PLoS ONE. 2011;6: e21914. doi: 10.1371/journal.pone.0021914 21887214

10. Pawliw R, Farrow R, Sekuloski S, Jennings H, Healer J, Phuong T, et al. A bioreactor system for the manufacture of a genetically modified Plasmodium falciparum blood stage malaria cell bank for use in a clinical trial. Malar J. 2018;17: 283. doi: 10.1186/s12936-018-2435-x 30081913

11. Rockett RJ, Tozer SJ, Peatey C, Bialasiewicz S, Whiley DM, Nissen MD, et al. A real-time, quantitative PCR method using hydrolysis probes for the monitoring of Plasmodium falciparum load in experimentally infected human volunteers. Malar J. 2011;10: 48. doi: 10.1186/1475-2875-10-48 21352599

12. Collins KA, Wang CY, Adams M, Mitchell H, Rampton M, Elliott S, et al. A controlled human malaria infection model enabling evaluation of transmission-blocking interventions. J Clin Invest. 2018;128: 1551–1562. doi: 10.1172/JCI98012 29389671

13. Marquart L, Baker M, O'Rourke P, McCarthy JS. Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrob Agents Chemother. 2015;59: 4249–4259. doi: 10.1128/AAC.04942-14 25963983

14. Konstantopoulos S, Hedges LV. Analysing effect sizes: Fixed-effects models. In: Cooper H, Hedges LV, Valentine JC, editors. The Handbook of Research Synthesis and Meta-Analysis. Second ed. New York: Russell Sage Foundation; 2009. p. 279–294.

15. Simpson JA, Aarons L, Collins WE, Jeffery GM, White NJ. Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection. Parasitology. 2002;124: 247–263. doi: 10.1017/s0031182001001202 11922427

16. Wockner LF, Hoffmann I, Webb L, Mordmüller B, Murphy SC, Kublin JG, et al. Growth rate of Plasmodium falciparum: analysis of parasite growth data from malaria volunteer infection studies. J Infect Dis. 2020;221: 963–972. doi: 10.1093/infdis/jiz557 31679015

17. Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, et al. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012;12: 851–858. doi: 10.1016/S1473-3099(12)70181-0 22940027

18. Sá JM, Kaslow SR, Krause MA, Melendez-Muniz VA, Salzman RE, Kite WA, et al. Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model. Proc Natl Acad Sci U S A. 2018;115: 12513–12518. doi: 10.1073/pnas.1813386115 30455312

19. Hastings IM, Kay K, Hodel EM. How robust are malaria parasite clearance rates as indicators of drug effectiveness and resistance? Antimicrob Agents Chemother. 2015;59: 6428–6436. doi: 10.1128/AAC.00481-15 26239987

20. Giao PT, Binh TQ, Kager PA, Long HP, Van Thang N, Van Nam N, et al. Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy? Am J Trop Med Hyg. 2001;65: 690–695. doi: 10.4269/ajtmh.2001.65.690 11791958

21. Cheng Q, Kyle DE, Gatton ML. Artemisinin resistance in Plasmodium falciparum: a process linked to dormancy? Int J Parasitol Drugs Drug Resist. 2012;2: 249–255. doi: 10.1016/j.ijpddr.2012.01.001 23420506

22. Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q. Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis. 2010;202: 1362–1368. doi: 10.1086/656476 20863228

23. Reuling IJ, de Jong GM, Yap XZ, Asghar M, Walk J, van de Schans LA, et al. Liver injury in uncomplicated malaria is an overlooked phenomenon: an observational study. EBioMedicine. 2018;36: 131–139. doi: 10.1016/j.ebiom.2018.09.018 30243492

24. The West African Network for Clinical Trials of Antimalarial Drugs (WANECAM). Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet. 2018;391: 1378–1390. doi: 10.1016/S0140-6736(18)30291-5 29606364

25. Woodford J, Shanks GD, Griffin P, Chalon S, McCarthy JS. The dynamics of liver function test abnormalities after malaria infection: a retrospective observational study. Am J Trop Med Hyg. 2018;98: 1113–1119. doi: 10.4269/ajtmh.17-0754 29436349

26. Nieman AE, de Mast Q, Roestenberg M, Wiersma J, Pop G, Stalenhoef A, et al. Cardiac complication after experimental human malaria infection: a case report. Malar J. 2009;8: 277. doi: 10.1186/1475-2875-8-277 19958549

27. van Meer MP, Bastiaens GJ, Boulaksil M, de Mast Q, Gunasekera A, Hoffman SL, et al. Idiopathic acute myocarditis during treatment for controlled human malaria infection: a case report. Malar J. 2014;13: 38. doi: 10.1186/1475-2875-13-38 24479524

28. Hingorani P, Karnad DR, Rohekar P, Kerkar V, Lokhandwala YY, Kothari S. Arrhythmias seen in baseline 24-hour Holter ECG recordings in healthy normal volunteers during Phase 1 clinical trials. J Clin Pharmacol. 2016;56: 885–893. doi: 10.1002/jcph.679 26626443

29. Stinson JC, Pears JS, Williams AJ, Campbell RW. Use of 24 h ambulatory ECG recordings in the assessment of new chemical entities in healthy volunteers. Br J Clin Pharmacol. 1995;39: 651–656. doi: 10.1111/j.1365-2125.1995.tb05724.x 7654483

30. Kobasa T, Talundzic E, Sug-Aram R, Boondat P, Goldman IF, Lucchi NW, et al. Emergence and spread of kelch13 mutations associated with artemisinin resistance in Plasmodium falciparum parasites in 12 Thai Provinces from 2007 to 2016. Antimicrob Agents Chemother. 2018;62: e02141–02117. doi: 10.1128/AAC.02141-17 29378723

31. WWARN K13 Genotype-Phenotype Study Group. Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis. BMC Med. 2019;17: 1. doi: 10.1186/s12916-018-1207-3 30651111

32. Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, et al. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N Engl J Med. 2016;374: 2453–2464. doi: 10.1056/NEJMoa1513137 27332904


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2020 Číslo 8

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