Is low-dose tafenoquine combined with dihydroartemisinin-piperaquine a potential risk factor for Plasmodium vivax resistance to 8-aminoquinolines?
Authors: Temi Lampejo
Journal: The Lancet Microbe (2022)

In The Lancet Microbe, Will Stone and colleagues1Stone W Mahamar A Smit MJ et al.Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial.Lancet Microbe. 2022; (published online March 23.)https://doi.org/10.1016/S2666-5247(21)00356-6Summary Full Text Full Text PDF PubMed Google Scholar showed that administration of a single low-dose of tafenoquine (an 8-aminoquinoline derivative with an extended half-life of 15 days) in combination with dihydroartemisinin-piperaquine (an oral artemisinin combination therapy) accelerated Plasmodium falciparum gametocyte clearance in a dose-dependent manner and a significant transmission reduction at day 7 was observed with all doses of tafenoquine studied (0·42 mg/kg, 0·83 mg/kg, and 1·66 mg/kg) when compared with dihydroartemisinin-piperaquine alone.1Stone W Mahamar A Smit MJ et al.Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial.Lancet Microbe. 2022; (published online March 23.)https://doi.org/10.1016/S2666-5247(21)00356-6Summary Full Text Full Text PDF PubMed Google Scholar The 8-aminoquinoline class of compounds, of which primaquine is the most widely used, are an essential component of Plasmodium vivax malaria treatment to eliminate liver hypnozoites.2WHOWHO Guidelines for malaria. World Health Organization, Geneva2021Google Scholar Although fairly low rates of P vivax malaria are reported in Mali,2WHOWHO Guidelines for malaria. World Health Organization, Geneva2021Google Scholar where the study by Stone and colleagues1Stone W Mahamar A Smit MJ et al.Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial.Lancet Microbe. 2022; (published online March 23.)https://doi.org/10.1016/S2666-5247(21)00356-6Summary Full Text Full Text PDF PubMed Google Scholar was done, in certain other regions of the world P vivax and P falciparum are both highly prevalent; a large study in southeast Asia reported 1164 (11%) mixed P falciparum and P vivax infections among 10 549 individuals treated for P falciparum infection, and the cumulative risk of P vivax recurrence was significantly higher after mixed infection compared with after P falciparum monoinfection (49·3% vs 29·4%; p<0·001).3Douglas NM Nosten F Ashley EA et al.Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics.Clinl Infect Dis. 2011; 52: 612-620Crossref PubMed Scopus (103) Google Scholar Widespread use of low-dose 8-aminoquinolines for P falciparum malaria in such settings could affect P vivax susceptibility to these agents. Several reports of suspected P vivax primaquine resistance already exist; however, some data are confounded by an inability to discriminate between reinfection and relapse, or because of incomplete or underdosed therapy.4Thomas D Tazerouni H Sundararaj KGS Cooper JC Therapeutic failure of primaquine and need for new medicines in radical cure of Plasmodium vivax.Acta Trop. 2016; 160: 35-38Crossref PubMed Scopus (17) Google Scholar Additional barriers to the investigation of 8-aminoquinoline resistance are the absence of identifiable resistance mechanisms and the difficulty of propagation of P vivax in vitro.4Thomas D Tazerouni H Sundararaj KGS Cooper JC Therapeutic failure of primaquine and need for new medicines in radical cure of Plasmodium vivax.Acta Trop. 2016; 160: 35-38Crossref PubMed Scopus (17) Google Scholar WHO recommends a higher dose of primaquine (0·5 mg/kg per day) for the tropical, frequent relapsing P vivax stains prevalent in east Asia and Oceania, whereas a lower dose (0·25 mg/kg per day) is dose recommended for temperate strains, suggesting altered susceptibility of certain P vivax strains to primaquine.2WHOWHO Guidelines for malaria. World Health Organization, Geneva2021Google Scholar The doses of tafenoquine used for P falciparum malaria in the study by Stone and colleagues are substantially lower than the dose recommended for P vivax malaria (300 mg; equivalent to 5 mg/kg in a 60 kg adult). In co-endemic regions, frequent and prolonged exposure of P vivax strains to low levels of 8-aminoquinolines, particularly with tafenoquine in view of its prolonged half-life, could serve as a potential driver for P vivax 8-aminoquinoline resistance. The more chronic, relapsing nature of P vivax malaria, frequently characterised by undetected low-level parasitaemia, gives a greater theoretical predisposition to resistance under drug selection pressures, and the higher genetic diversity of P vivax compared with that of P falciparum suggests a greater evolutionary potential for the development of drug resistance.5Olliaro PL Barnwell JW Barry A et al.Implications of Plasmodium vivax biology for control, elimination, and research.Am J Trop Med Hyg. 2016; 95: 4-14Crossref PubMed Scopus (35) Google Scholar Should adjunctive low-dose tafenoquine use become commonplace for the treatment of P falciparum malaria in co-endemic settings, heightened vigilance and consideration for the potential emergence of 8-aminoquinoline-resistant P vivax strains are required. I declare no competing interests. Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trialTafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin–piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials. Full-Text PDF Open Access