Single low-dose primaquine to reduce malaria transmission
Authors: Richard W Steketee, Feiko ter Kuile
Journal: The Lancet Infectious Diseases (2013)

The WHO Evidence Review Group's August, 2012 report about the safety and effectiveness of a single dose of primaquine as a Plasmodium falciparum gametocytocide1WHOWHO Evidence Review Group: The safety and effectiveness of single dose primaquine as a P. falciparum gametocytocide. Pullman Hotel, Bangkok, Thailand, 13–15 August 2012.http://www.who.int/malaria/mpac/sep2012/primaquine_single_dose_pf_erg_meeting_report_aug2012.pdfGoogle Scholar and WHO's new policy recommendation about low-dose primaquine2WHOUpdated WHO policy recommendation (October 2012): single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. October, 2012. World Health Organization, Geneva2012Google Scholar, 3WHO Malaria Policy Advisory Committee and SecretariatMalaria Policy Advisory Committee to the WHO: conclusions and recommendations of September 2012 meeting.Malar J. 2012; 11: 424Crossref PubMed Scopus (56) Google Scholar generated much interest for malaria control programmes seeking additional methods to reduce malaria transmission, especially in settings in which elimination of malaria is pursued. A single dose of primaquine at 0·75 mg base per kg has long been recommended as an adjunct therapy to reduce malaria transmission of P falciparum. However, the drug is often not used because of concerns about dose-dependent haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and the low availability of G6PD tests in the field. WHO's expert review group reviewed the available scientific literature, which suggested that one low dose of 0·25 mg base per kg of primaquine could be used widely and safely in people with malaria infection, including those with G6PD deficiency,1WHOWHO Evidence Review Group: The safety and effectiveness of single dose primaquine as a P. falciparum gametocytocide. Pullman Hotel, Bangkok, Thailand, 13–15 August 2012.http://www.who.int/malaria/mpac/sep2012/primaquine_single_dose_pf_erg_meeting_report_aug2012.pdfGoogle Scholar to help reduce the duration of circulating late-stage gametocytes (the sexual transmissible stage of the parasite) by roughly half and contribute to malaria transmission reduction. The authors of the report noted that additional effectiveness and safety evidence would be welcome to characterise the optimum dose and help countries to establish policies and strategies for single low-dose primaquine.1WHOWHO Evidence Review Group: The safety and effectiveness of single dose primaquine as a P. falciparum gametocytocide. Pullman Hotel, Bangkok, Thailand, 13–15 August 2012.http://www.who.int/malaria/mpac/sep2012/primaquine_single_dose_pf_erg_meeting_report_aug2012.pdfGoogle Scholar In The Lancet Infectious Diseases, Alice Eziefula and colleagues describe the results of the first formal dose-finding study to assess the P falciparum gametocytocidal efficacy (measured as duration of gametocyte carriage) of a single dose of primaquine when given with artemisinin combination therapy.4Eziefula AC Bousema T Yeung S et al.Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial.Lancet Infect Dis. 2013; (published online Nov 11.)http://dx.doi.org/10.1016/S1473-3099(13)70268-8PubMed Google Scholar The study included 468 Ugandan children younger than 10 years with normal G6PD function and uncomplicated malaria who received standard doses of artemether–lumefantrine and one low dose of primaquine at doses of 0·75 mg/kg, 0·4 mg/kg, and 0·1 mg/kg. The aim was to establish the lowest efficacious dose in people with normal G6PD enzyme function. All doses of primaquine were safe and very well tolerated. The 0·4 mg/kg dose and the standard 0·75 mg/kg regimen had similar gametocytocidal efficacy (mean duration of gametocyte carriage: 6·6 days in the 0·75 mg/kg group and 6·3 days in the 0·4 mg/kg group), but an efficacy gradient was apparent from 0·4 mg/kg to 0·1 mg /kg to placebo. As Eziefula and colleagues note, this work preceded the choice of 0·25 mg/kg in the WHO report,2WHOUpdated WHO policy recommendation (October 2012): single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. October, 2012. World Health Organization, Geneva2012Google Scholar but the WHO-recommended dose falls between the 0·4 mg/kg and 0·1 mg/kg doses assessed. In malaria control programme settings, children are likely to receive a specific number of tablets within prespecified age or bodyweight bands, whereby actual doses will range above and below the intended target dose of 0·25 mg/kg (eg, 0·15–0·35 or 0·1–0·4 mg/kg).5Taylor W Terlouw DJ Olliaro PL White NJ Brasseur P ter Kuile FO Use of weight-for-age-data to optimize tablet strength and dosing regimens for a new fixed-dose artesunate-amodiaquine combination for treating falciparum malaria.Bull World Health Organ. 2006; 84: 956-964Crossref PubMed Scopus (50) Google Scholar Eziefula and colleagues' study clarifies, for the first time, that doses greater than 0·4 mg/kg are not needed but, as the authors note, further attention should be given to the efficacy gradient between 0·4 mg/kg and 0·1 mg/kg, including the assessment of their safety in patients with G6PD deficiency to define the most efficacious and safest primaquine treatment regimen. Several studies are planned or in progress, and although protocol changes can be difficult, investigators should strongly consider including groups that would allow assessment of the dosing based on these new findings and WHO's recommendations. The investigators gave the primaquine dose to the participants on day 2, which is common practice.6White NJ Primaquine to prevent transmission of falciparum malaria.Lancet Infect Dis. 2013; 13: 175-181Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar Nevertheless, national malaria control programmes might be more inclined to give primaquine with the first dose of the ACT to ensure that both drugs are given under observation. Although the authors acknowledged the limitation of delaying the primaquine dose, this approach was used to minimise potential interference of the malaria-attributable haematological effects during the acute phase of illness. However, the optimum timing of the single dose deserves further study. Primaquine has a very short half-life and delay of its administration has been suggested to enhance its efficacy because gametocyte densities often peak several days after the start of artemisinin treatment.7Piyaphanee W Krudsood S Tangpukdee N et al.Emergence and clearance of gametocytes in uncomplicated Plasmodium falciparum malaria.Am J Trop Med Hyg. 2006; 74: 432-435PubMed Google Scholar, 8Lawpoolsri S Klein EY Singhasivanon P et al.Optimally timing primaquine treatment to reduce Plasmodium falciparum transmission in low endemicity Thai-Myanmar border populations.Malar J. 2009; 8: 159Crossref PubMed Scopus (39) Google Scholar Delayed dosing might also improve safety because the risk of haemolysis in G6PD-deficient patients could be lower in afebrile patients.9Al-Sweedan SA Jdaitawi H Khriesat WM Khader YY Al-Rimawi HS Predictors of severe hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency following exposure to oxidant stresses.Hematol Oncol Stem cell Ther. 2009; 2: 354-357Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar However, it is unclear whether this benefit is outweighed by the additional days of potential infectivity before primaquine administration6White NJ Primaquine to prevent transmission of falciparum malaria.Lancet Infect Dis. 2013; 13: 175-181Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar and the reduced opportunity to give primaquine under observation. A final programmatic consideration is the adherence to the full 3 day course of the artemisinin combination therapy. Artemether–lumefantrine, which resulted in clearance of the asexual parasites, was also an effective treatment for the sexual stage of the parasites, which is consistent with earlier studies with other artemisinin combination therapies.6White NJ Primaquine to prevent transmission of falciparum malaria.Lancet Infect Dis. 2013; 13: 175-181Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar A substantial decrease was recorded in the nucleic acid sequence-based amplification-measured gametocyte prevalence from roughly 82% at day 0 to roughly 40% at day 2 before primaquine administration, and to 15% by day 14 in participants who received artemether–lumefantrine plus placebo. Although complete gametocyte clearance was not achieved, this finding emphasises the importance of effective artemisinin combination therapy treatment, since slow or incomplete clearance of the asexual stages of the parasite could fuel gametocyte numbers and viability.6White NJ Primaquine to prevent transmission of falciparum malaria.Lancet Infect Dis. 2013; 13: 175-181Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 10Rieckmann KH McNamara JV Frischer H Stockert TA Carson PE Powell RD Gametocytocidal and sporontocidal effects of primaquine and of sulfadiazine with pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum.Bull World Health Organ. 1968; 38: 625-632PubMed Google Scholar Mass malaria treatment campaigns must focus on ensuring that full dosing of artemisinin combination therapy is achieved. To this end, we will all welcome a safe and highly effective single-dose treatment that can be combined with one dose of primaquine and can be given as directly observed treatment for malaria. We declare that we have no conflicts of interest. Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trialWe conclude that 0·4 mg/kg primaquine has similar gametocytocidal efficacy to the reference 0·75 mg/kg primaquine dose, but a dose of 0·1 mg/kg was inconclusive for non-inferiority. Our findings call for the prioritisation of further trials into the efficacy and safety of doses of primaquine between 0·1 mg/kg and 0·4 mg/kg (including the dose of 0·25 mg/kg recently recommended by WHO), in view of the potential for widespread use of the drug to block malaria transmission. Full-Text PDF Open Access