Primaquine or other 8-aminoquinolines for reducing Plasmodium falciparum transmission

Abstract

Background The 8‐aminoquinoline (8AQ) drugs act on Plasmodium falciparum gametocytes, which transmit malaria from infected people to mosquitoes. In 2012, the World Health Organization (WHO) recommended a single dose of 0.25 mg/kg primaquine (PQ) be added to malaria treatment schedules in low‐transmission areas or those with artemisinin resistance. This replaced the previous recommendation of 0.75 mg/kg, aiming to reduce haemolysis risk in people with glucose‐6‐phosphate dehydrogenase deficiency, common in people living in malarious areas. Whether this approach, and at this dose, is effective in reducing transmission is not clear. Objectives To assess the effects of single dose or short‐course PQ (or an alternative 8AQ) alongside treatment for people with P. falciparum malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; and the WHO International Clinical Trials Registry Platform (ICRTP) portal using ‘malaria*', ‘falciparum', ‘primaquine', ‘8‐aminoquinoline', and eight 8AQ drug names as search terms. We checked reference lists of included trials, and contacted researchers and organizations. Date of last search: 21 July 2017. Selection criteria Randomized controlled trials (RCTs) or quasi‐RCTs in children or adults, adding PQ (or alternative 8AQ) as a single dose or short course alongside treatment for P. falciparum malaria. Data collection and analysis Two authors screened abstracts, applied inclusion criteria, and extracted data. We sought evidence on transmission (community incidence), infectiousness (people infectious and mosquitoes infected), and potential infectiousness (gametocyte measures assessed by microscopy or polymerase chain reaction [PCR]). We grouped trials into artemisinin and non‐artemisinin treatments, and stratified by PQ dose (low, 0.2 to 0.25 mg/kg; moderate, 0.4 to 0.5 mg/kg; high, 0.75 mg/kg). We used GRADE, and absolute effects of infectiousness using trial control groups. Main results We included 24 RCTs and one quasi‐RCT, comprising 43 arms. Fourteen trials evaluated artemisinin treatments (23 arms), nine trials evaluated non‐artemisinin treatments (13 arms), and two trials included both artemisinin and non‐artemisinin arms (three and two arms, respectively). Two trial arms used bulaquine. Seven PQ arms used low dose (six with artemisinin), 11 arms used moderate dose (seven with artemisinin), and the remaining arms used high dose. Fifteen trials tested for G6PD status: 11 excluded participants with G6PD deficiency, one included only those with G6PD deficiency, and three included all, irrespective of status. The remaining 10 trials either did not test or did not report on testing. No cluster trials ev...

Plasmodium falciparum: Multidrug resistance

“…Primaquine, an 8-aminoquinoline, was first used in 1926 (Foley & Tilley, 1998) introduced from 1950s, the only drug that targets the gametocyte stage of the P. falciparum (Gamo, 2014;Kaur et al, 2010;Paloque, Ramadani, Mercereau-Puijalon, Augereau & Benoit-Vical, 2016) and also arrests the parasite at the hypnozoite stages of P. vivax and P. ovale (Foley & Tilley, 1998;Graves, Gelband & Garner, 2014;Paloque et al, 2016;Petersen et al, 2011;World Health Organization, 2017). This drug targets the dormant stage of the parasite, mediating radical cure by treating parasite relapses (Foley & Tilley, 1998).…”

“…Artemisinin is a natural antimalarial drug extracted from Chinese medicinal herb Artemisia annua (Graves et al, 2014;Petersen et al, 2011;Wongsrichanalai & Sibley, 2013). It is also termed as Qinghaosu, a sesquiterpene lactone compound that targets almost all the forms of asexual as well as sexual stages of the parasite, in the 1970s (Gamo, 2014;Kaur et al, 2010).…”

“…Recently, new combination of OZ277 and arterolane-piperaquine (marketed as Synriam) is under clinical development (Ashley & Phyo, 2018;Blasco et al, 2017;Straimer et al, 2017;Wells et al, 2015). These combination therapies inhibit the multiple stages of the parasite by activating the endoperoxide bridge with a series of chemical reactions (Graves et al, 2014;Sugiarto et al, 2017). The endoperoxide bridge gets activated through iron-catalyzed endoperoxide bond with parasite-digested hemoglobin.…”

Early transmission of sensitive strain slows down emergence of drug resistance in Plasmodium vivax

“…On the other hand, 176 treatment plus primaquine (PQ) declined the proportion of humans with latent parasites but it accelerated the emergence 177 of resistant strain because PQ avoids the transmission of sensitive parasites after-treatment. This result challenges the 178 suggestion of PQ-dose to avoid the transmission of resistant parasites and P. vivax relapses can explain the underestimate 179 resistance induced by PQ effect [53,54].…”

ELQ-331 as a prototype for extremely durable chemoprotection against malaria

“…Although recent studies indicate the safety and efficacy of some 8-aminoquinoline dosages in some patients with G-6-PD deficiency (15), LAI-C would result in months of continuous oxidative stress making it almost certain that G-6-PD testing would be required prior to use, and likely that G-6-PD deficiency would be a contraindication for 8-aminoquinoline LAI-C. Furthermore, 8-aminoquinolines could be ineffective in the small but significant proportion of the population lacking adequate CYP 2D6 to form active metabolites (16).…”