Primaquine for all: is it time to simplify malaria treatment in co-endemic areas?
Authors: Marcus V G Lacerda, Quique Bassat
Journal: The Lancet Infectious Diseases (2018)

In most areas endemic for malaria, the major species are Plasmodium falciparum and Plasmodium vivax. Falciparum malaria is more often lethal, develops resistance to drugs easily, and is responsible for most of the malaria burden in Africa. However, particularly in this second era of malaria elimination efforts,1Bassat Q Velarde M Mueller I et al.Key knowledge gaps for Plasmodium vivax control and elimination.Am J Trop Med Hyg. 2016; 95: 62-71Crossref PubMed Scopus (32) Google Scholar P vivax requires increasing attention2Bassat Q The importance of being vivax.J Trop Pediatr. 2014; 60: 335-337Crossref PubMed Scopus (4) Google Scholar because of the intrinsic challenges related to its control. This species can lead to severe or even life-threatening disease,3Siqueira AM Lacerda MV Magalhães BM et al.Characterization of Plasmodium vivax-associated admissions to reference hospitals in Brazil and India.BMC Med. 2015; 13: 57Crossref PubMed Scopus (46) Google Scholar can present variable evidence of resistance to chloroquine in relation to geographical area,4Siqueira AM Alencar AC Melo GC et al.Fixed-dose artesunate-amodiaquine combination vs chloroquine for treatment of uncomplicated blood stage P. vivax infection in the Brazilian Amazon: an open-label randomized, controlled trial.Clin Infect Dis. 2017; 64: 166-174Crossref PubMed Scopus (20) Google Scholar and has few drug options to prevent relapse. Prevention of relapse is essential because up to 80% of reported cases of P vivax malaria could result from hypnozoite-derived relapses, rather than from newly acquired infections.5Robinson LJ Wampfler R Betuela I et al.Strategies for understanding and reducing the Plasmodium vivax and Plasmodium ovale hypnozoite reservoir in Papua New Guinean children: a randomised placebo-controlled trial and mathematical model.PLoS Med. 2015; 12: e1001891Crossref PubMed Scopus (154) Google Scholar The triggers of relapse are not sufficiently understood, but 8-aminoquinolines (such as primaquine, or the newly registered tafenoquine) are the only effective drugs enabling radical cure. There are several sources of variation in relapse rates. Different strains of vivax have distinct relapse patterns,6Battle KE Karhunen MS Bhatt S et al.Geographical variation in Plasmodium vivax relapse.Malar J. 2014; 13: 144Crossref PubMed Scopus (178) Google Scholar and pharmacogenetics also seems to have a role in primaquine metabolism, which could affect relapse as primaquine only becomes active once metabolised (CYP 2D6 pathway) into its active metabolites.7Brasil LW Rodrigues-Soares F Santoro AB et al.CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study.Malar J. 2018; 17: 57Crossref PubMed Scopus (39) Google Scholar However, acute infections may also trigger relapses.8Shanks GD White NJ The activation of vivax malaria hypnozoites by infectious diseases.Lancet Infect Dis. 2013; 13: 900-906Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar Data showing possible P vivax relapses after P falciparum infection were obtained first in Thailand,9Looareesuwan S White NJ Chittamas S Bunnag D Harinasuta T High rate of Plasmodium vivax relapse following treatment of falciparum malaria in Thailand.Lancet. 1987; 2: 1052-1055Summary PubMed Scopus (119) Google Scholar but an analysis reported in The Lancet Infectious Diseases by Robert Commons and colleagues10Commons RJ Simpson JA Thriemer K et al.Risk of Plasmodium vivax parasitaemia after Plasmodium falciparum infection: a systematic review and meta-analysis.Lancet Infect Dis. 2019; 19: 91-101Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar provides statistical robustness regarding this observation. Their impressive meta-analysis, which included 31 262 patients from 153 studies done over more than four decades, supports that such relapses are not just local, but rather occur globally in all settings co-endemic for P vivax and P falciparum. The overall risk of P vivax parasitaemia by day 42 after P falciparum treatment was 5·6% (95% CI 4·0–7·4). Although the investigators found some short-term significant differences in the risk of recurrence depending on regional relapse periodicity and the half-lives of the drugs used to treat the initial P falciparum infection, the differential effect seemed to wane by day 63, when nearly a quarter (24%) of all patients treated for P falciparum had developed a P vivax relapse, detectable in peripheral blood. Importantly, P vivax predominated among all parasite recurrences following P falciparum treatment, representing about 70% of recurrences at day 63. The mechanisms behind such relapses are still unknown, but one could argue, from a public health standpoint, that the time has come to propose an innovative move in the treatment of malaria, promoting the universal use of primaquine for both species in areas where they co-exist and remain prevalent. Indeed, the number of cases of P falciparum needed to treat with radical cure to prevent one P vivax recurrence by day 63—ranging between 4·7 and 5·0 as proposed by the study investigators—would seem to amply justify this radical change in malaria treatment. The additional P falciparum gametocidal effect that 8-aminoquinolines exert, which should also substantially reduce malaria transmission, might be another advantage of such a bold programmatic change. In areas where primaquine is routinely used for all patients with P vivax, such as Latin America,11Recht J Siqueira AM Monteiro WM Herrera SM Herrera S Lacerda MVG Malaria in Brazil, Colombia, Peru and Venezuela: current challenges in malaria control and elimination.Malar J. 2017; 16: 273Crossref PubMed Scopus (129) Google Scholar this change would not pose major difficulties, with the exception of ensuring adequate compliance for a usually 2-week treatment course. Nevertheless, in areas where glucose-6-phosphate dehydrogenase (G6PD) deficiency is prevalent, such as southeast Asia, primaquine use would need to be expanded carefully on account of the potential hazards that such a prohaemolytic drug might have in individuals lacking full functionality of the G6PD enzyme.12Thriemer K Bobogare A Ley B et al.Quantifying primaquine effectiveness and improving adherence: a round table discussion of the APMEN Vivax Working Group.Malar J. 2018; 17: 241Crossref PubMed Scopus (28) Google Scholar The availability of point-of-care tests to detect G6PD deficiency (ie, G6PD activity lower than 30%) might help the safe use of primaquine against both malaria species.13Brito MA Peixoto HM Almeida AC et al.Validation of the rapid test Carestart(tm) G6PD among malaria vivax-infected subjects in the Brazilian Amazon.Rev Soc Bras Med Trop. 2016; 49: 446-455Crossref PubMed Scopus (22) Google Scholar In the real world, however, the switch from a simple 3-day P falciparum treatment regimen with an artemisinin-based combination therapy (ACT) to a 14-day course including primaquine might be met with some reluctance among health providers and even the general population. In this respect, tafenoquine could be an exciting alternative to bypass these barriers, because it only requires a single dose, and is considered safe and efficacious for individuals with G6PD activity higher than 70%.14Llanos-Cuentas A Lacerda MV Rueangweerayut R et al.Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study.Lancet. 2014; 383: 1049-1058Summary Full Text Full Text PDF PubMed Scopus (192) Google Scholar Studies such as the one by Commons and colleagues highlight the relevance of meta-analytical approaches to answer questions that remain difficult to solve with single studies. The results of this study hint at the exciting potential of simplifying malaria treatment in areas co-endemic for P falciparum and P vivax. Use of an ACT plus primaquine (or tafenoquine) regimen irrespective of the underlying species could have huge operational advantages, but the overall impact of such an approach needs to be thoroughly evaluated. We declare no competing interests. QB is a member of the WHO Malaria Treatment Guidelines Group. This group produces global guidance on the treatment of malaria and this includes decisions about antimalarial drugs mentioned in this comment. The views expressed by the authors are personal opinions and do not represent the recommendations of WHO. Risk of Plasmodium vivax parasitaemia after Plasmodium falciparum infection: a systematic review and meta-analysisOur findings show a high risk of vivax parasitaemia after treatment of falciparum malaria, particularly in areas with short relapse periodicity and after rapidly eliminated treatment. In co-endemic regions, universal radical cure for all patients with uncomplicated malaria has the potential to substantially reduce recurrent malaria. Full-Text PDF Open Access