Efficacy of low-dose primaquine plus artemether-lumefantrine or dihydroartemisinin-piperaquine for radical cure of Plasmodium vivax in the Solomon Islands: A randomised clinical trial

Robert James^1,2Thomas Obadia^3,4Lyndes Wini⁵Albino Bobogare⁵Sarah Charnaud^1,2Shazia Ruybal^1,2Caitlin Bourke^1,2Jacob Munroe^1,2Brioni Moore^6,7,8Madhu Page-Sharp^6,7Laurens Manning^8,9Urijah Liligeto⁵Sophie Georgina Zaloumis¹⁰J Kevin Baird^11,12Harin Karunajeewa¹³Ivo Mueller^1,2*

• ¹Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Parkville, Australia
• ²Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
• ³Institut Pasteur, Paris, Île-de-France, France
• ⁴Institut Pasteur, Université Paris Cité, G5 Infectious Disease Epidemiology and Analytics, Paris, France
• ⁵National Vector-Borne Control Centre, Ministry of Health and Medical Services, Solomon Islands Government, Honiara, Solomon Islands
• ⁶Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, Western Australia, Australia
• ⁷Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia
• ⁸Wesfarmers Centre of Vaccines & Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, Australia
• ⁹University of Western Australia, Perth, Western Australia, Australia
• ¹⁰Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Carlton, Victoria, Australia
• ¹¹Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, England, United Kingdom
• ¹²Oxford University Clinical Research Unit, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
• ¹³Department of Medicine, Western Health, University of Melbourne, Melbourne, Australia

Background: Primaquine (PQ) remains the only 8-aminoquinoline endorsed world-wide by the WHO for treatment of latent Plasmodium vivax liver stage parasites. It is a prodrug, with metabolism and therapeutic activity impacted by both inherent human CYP2D6 polymorphism and poorly understood interactions with variably co-administered blood schizontocidal therapies. Widespread chloroquine resistance in vivax malaria means that radical cure must now include one of many available artemisinin-combination therapies (ACTs).Methods: During September 2017 to February 2019, a clinical trial was conducted at Guadalcanal, Solomon Islands, examining the safety and efficacy of PQ (0.25mg/kg/d x 14d) concurrently administered with standard doses of either dihydroartemisinin-piperiquine (DP), or artemetherlumefantrine (AL). A relapse control arm received AL without PQ. The 384 enrolled subjects were followed for 180 days to estimate efficacy against relapse, along with CYP2D6 genotyping, methaemoglobin measurements along with those of PQ absorption and metabolism.Results: Both PQ treatment arms had significantly reduced rates of current P. vivax parasitaemia (PQ-AL: HR = 0.50, CI95[0.33-0.75], PQ-DP: HR=0.34, CI95[0.22-0.52] P < 0.001) relative to no PQ. Neither regimen provided adequate clinical efficacy (PQ-AL: 43.7%, PQ-DP: 34.1%). No significant differences in CYP2D6 genotype-predicted activity scores, methaemoglobin levels, nor concentrations of PQ or its metabolites (5,6-OQ and CPQ), were observed between the two PQ treatment arms at day 7 post-initiation of dosing.