Plasmodium falciparum gametocyte dynamics after pyronaridine–artesunate or artemether–lumefantrine treatment

Roth, Johanna; Sawa, Patrick; Omweri, George; Osoti, Victor; Makio, Nicodemus; Bradley, John; Bousema, Teun; Schallig, Henk D. F. H.; Mens, Pètra F.

doi:10.1186/s12936-018-2373-7

Cited by 11 publications

(9 citation statements)

References 43 publications

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“… 21 Our data from highly sensitive sex-specific RT-qPCR assays show near identical gametocyte circulation times for individuals treated with dihydroartemisinin–piperaquine or pyronaridine–artesunate, tentatively supporting earlier indications that pyronaridine–artesunate might be inferior to artemether–lumefantrine for gametocyte clearance. 22 , 23 Gametocyte kinetics might not reflect gametocyte infectivity, 24 and the effect of pyronaridine–artesunate on transmission to mosquitoes has not previously been studied. We assessed the infectivity of single infections up to 42 days after treatment, preventing re-infection by retreatment with dihydroartemisinin–piperaquine at day 21.…”

Section: Discussionmentioning

confidence: 99%

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

Stone

Mahamar²,

Sanogo³

et al. 2022

The Lancet Microbe

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Background Pyronaridine-artesunate is the most recently licensed artemisinin-based combination therapy. WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance. We aimed to determine the efficacy of pyronaridine-artesunate and dihydroartemisinin-piperaquine with and without single low-dose primaquine for reducing gametocyte density and transmission to mosquitoes. MethodsWe conducted a four-arm, single-blind, phase 2/3, randomised trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako (Bamako, Mali). Participants were aged 5-50 years, with asymptomatic P falciparum malaria mono-infection and gametocyte carriage on microscopy, haemoglobin density of 9•5 g/dL or higher, bodyweight less than 80 kg, and no use of antimalarial drugs over the past week. Participants were randomly assigned (1:1:1:1) to one of four treatment groups: pyronaridine-artesunate, pyronaridine-artesunate plus primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus primaquine. Treatment allocation was concealed to all study staff other than the trial pharmacist and treating physician. Dihydroartemisinin-piperaquine and pyronaridine-artesunate were administered as per manufacturer guidelines over 3 days; primaquine was administered as a single dose in oral solution according to bodyweight (0•25 mg/kg; in 1 kg bands). The primary endpoint was percentage reduction in mosquito infection rate (percentage of mosquitoes surviving to dissection that were infected with P falciparum) at 48 h after treatment compared with baseline (before treatment) in all treatment groups. Data were analysed per protocol. This trial is now complete, and is registered with ClinicalTrials.gov, NCT04049916. Findings Between Sept 10 and Nov 19, 2019, 1044 patients were assessed for eligibility and 100 were enrolled and randomly assigned to one of the four treatment groups (n=25 per group). Before treatment, 66 (66%) of 100 participants were infectious to mosquitoes, with a median of 15•8% (IQR 5•4-31•9) of mosquitoes becoming infected. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 48 h after treatment was 100•0% (IQR 100•0 to 100•0) for individuals treated with pyronaridineartesunate plus primaquine (n=18; p<0•0001) and dihydroartemisinin-piperaquine plus primaquine (n=15; p=0•0001), compared with -8•7% (-54•8 to 93•2) with pyronaridine-artesunate (n=17; p=0•88) and 50•4% (13•8 to 70•9) with dihydroartemisinin-piperaquine (n=16; p=0•13). There were no serious adverse events, and there were no significant differences between treatment groups at any point in the frequency of any adverse events (Fisher's exact test p=0•96) or adverse events related to study drugs (p=0•64). The most common adverse events were headaches (40 events in 32 [32%...

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Section: Discussionmentioning

confidence: 99%

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

Stone

Mahamar²,

Sanogo³

et al. 2022

The Lancet Microbe

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“…Initially P25 was routinely used as a generic gametocyte marker; however, it was later found to be highly enriched in female gametocytes (20,35). Male markers were subsequently included in the sex-specific gametocyte measurements (36)(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Novel Method for the Separation of Male and Female Gametocytes of the Malaria Parasite Plasmodium falciparum That Enables Biological and Drug Discovery

Ridgway

Shea

Cihalova

et al. 2020

mSphere

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We developed a flow-cytometry-based method to separate and collect cocultured male and female Plasmodium falciparum gametocytes responsible for malaria transmission. The purity of the collected cells was estimated at >97% using flow cytometry, and sorted cells were observed by Giemsa-stained thin-smear and live-cell fluorescence microscopy. The expression of validated sex-specific markers corroborated the sorting strategy. Collected male and female gametocytes were used to confirm three novel sex-specific markers by quantitative real-time PCR that were more enriched in sorted male and female gametocyte populations than existing sex-specific markers. We also applied the method as a proof-of-principle drug screen that allows the identification of drugs that kill gametocytes in a sex-specific manner. Since the developed method allowed for the separation of male and female parasites from the same culture, we observed for the first time a difference in development time between the sexes: females developed faster than males. Hence, the ability to separate male and female gametocytes opens the door to a new field of sex-specific P. falciparum gametocyte biology to further our understanding of malaria transmission. IMPORTANCE The protozoan Plasmodium falciparum causes the most severe form of human malaria. The development of sexual forms (so-called gametocytes) is crucial for disease transmission. However, knowledge of these forms is severely hampered by the paucity of sex-specific markers and the inability to extract single sex gametocytes in high purity. Moreover, the identification of compounds that specifically affect one sex is difficult due to the female bias of the gametocytes. We have developed a system that allows for the separation of male and female gametocytes from the same population. Applying our system, we show that male and female parasites mature at different rates, which might have implications for transmission. We also identified new sex-specific genes that can be used as sex markers or to unravel sex-specific functions. Our system will not only aid in the discovery of much needed gametocidal compounds, but it also represents a valuable tool for exploring malaria transmission biology.

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“…Recently, studies have shown that the transmission-reducing effect differs among artemisinin-based combinations [7–10]. However, it is still unclear whether AL and DP are the most appropriate choice for reducing community-wide transmission of P. falciparum in a high malaria-endemic setting [9, 11].…”

Section: Introductionmentioning

confidence: 99%

Gametocyte clearance in children, from western Kenya, with uncomplicated Plasmodium falciparum malaria after artemether–lumefantrine or dihydroartemisinin–piperaquine treatment

Omondi¹,

Burugu²,

Matoke-Muhia³

et al. 2019

Malar J

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BackgroundThe efficacy and safety of artemether–lumefantrine (AL) and dihydroartemisinin–piperaquine (DP) against asexual parasites population has been documented. However, the effect of these anti-malarials on sexual parasites is still less clear. Gametocyte clearance following treatment is essential for malaria control and elimination efforts; therefore, the study sought to determine trends in gametocyte clearance after AL or DP treatment in children from a malaria-endemic site in Kenya.MethodsChildren aged between 0.5 and 12 years from Busia, western Kenya with uncomplicated Plasmodium falciparum malaria were assigned randomly to AL or DP treatment. A total of 334 children were enrolled, and dried blood spot samples were collected for up to 6 weeks after treatment during the peak malaria transmission season in 2016 and preserved. Plasmodium falciparum gametocytes were detected by qRT-PCR and gametocyte prevalence, density and mean duration of gametocyte carriage were determined.ResultsAt baseline, all the 334 children had positive asexual parasites by microscopy, 12% (40/334) had detectable gametocyte by microscopy, and 83.7% (253/302) children had gametocytes by RT-qPCR. Gametocyte prevalence by RT-qPCR decreased from 85.1% (126/148) at day 0 to 7.04% (5/71) at day 42 in AL group and from 82.4% (127/154) at day 0 to 14.5% (11/74) at day 42 in DP group. The average duration of gametocyte carriage as estimated by qRT-PCR was slightly shorter in the AL group (4.5 days) than in the DP group (5.1 days) but not significantly different (p = 0.301).ConclusionThe study identifies no significant difference between AL and DP in gametocyte clearance. Gametocytes persisted up to 42 days post treatment in minority of individuals in both treatment arms. A gametocytocidal drug, in combination with artemisinin-based combination therapy, will be useful in blocking malaria transmission more efficiently.

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Plasmodium falciparum gametocyte dynamics after pyronaridine–artesunate or artemether–lumefantrine treatment

Cited by 11 publications

References 43 publications

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

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

Novel Method for the Separation of Male and Female Gametocytes of the Malaria Parasite Plasmodium falciparum That Enables Biological and Drug Discovery

Gametocyte clearance in children, from western Kenya, with uncomplicated Plasmodium falciparum malaria after artemether–lumefantrine or dihydroartemisinin–piperaquine treatment

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