Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria

Abstract

Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.)

Pyronaridine–artesunate or dihydroartemisinin–piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a four-arm, single-blind, phase 2/3, randomised trial

“… 6 Patients treated with artemether–lumefantrine or dihydroartemisinin–piperaquine can still harbour infectious gametocytes and these can persist after treatment. 7 The duration of gametocyte infectivity to mosquitoes following ACT treatment is so far poorly defined and has not been assessed beyond the first week after treatment. Primaquine has potent gametocytocidal activity, with studies showing that a single low dose of 0·25 mg/kg is sufficient to neutralise infectivity to mosquitoes within 48 h. 8 , 9 This dose is considered safe in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD), who are at risk of transient haemolysis after treatment with oxidative compounds including primaquine.…”

Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data

“…Two of these studies used 0.25 mg/kg of primaquine with DP as part of mass drug administration activities reaching over 10,000 individuals in Zanzibar [16], and 8445 participants in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, although Cambodian participants were not given primaquine for regulatory reasons [17]. Two Cambodian studies have since been published; however, one efficacy study (109 participants) [18] and one open randomised trial on primaquine tolerability (109 participants, 12 were G6PD-deficient with the Viangchan variant) show a 0.25 mg/kg dose of primaquine to be reasonably safe (in 11 G6PD-deficient patients, day 7 haemoglobin concentration dropped from 8.2 to 7.5g/dL in one participant, for two remained below 8g/dL with small changes [6.9-6.4, 7.4-7.4 g/dL], and stayed above 8g/dL for the remaining nine). This informed the Cambodian national decision to deploy 0.25 mg/kg of primaquine with ACTs nationwide in 2018 [19].…”

“…17 Laboratory of Medical Microbiology and Immunology, Rijnstate Hospital, Arnhem, The Netherlands. 18 Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. 19 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.…”

Is it time for Africa to adopt primaquine in the era of malaria control and elimination?

“…When coadministered with effective schizontocidal drugs i.e. artemisinin-based combination therapy (ACT), a single 0.25 mg base/kg dose gives maximal transmission-blocking effect [11][12][13][75][76][77][78], thus accelerating malaria elimination strategy and reducing the rate of emergence of artemisinin-resistant malaria parasites [24]. SLD primaquine has also proven to be well-tolerated and safe in various settings with different G6PD deficiency variants [10-14, 75, 76, 79].…”