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

Abstract

Background: Artemisinin-based combinations differ in their impact on gametocyte prevalence and density. This study assessed female and male gametocyte dynamics after treating children with uncomplicated Plasmodium falciparum malaria with either pyronaridine-artesunate (PA) or artemether-lumefantrine (AL).

Methods: Kenyan children with uncomplicated Plasmodium falciparum malaria were included and randomly assigned to PA or AL treatment. Filter paper blood samples were collected as a source of RNA for quantitative reverse-transcription PCR (qRT-PCR) and nucleic acid sequence based amplification (QT-NASBA) to detect female gametocytes (targeting Pfs25 mRNA). Male gametocytes were detected by qRT-PCR (targeting PfMGET mRNA). Duration of gametocyte carriage, the female and male gametocyte response and the agreement between qRT-PCR and QT-NASBA were determined.

Results: The mean duration of female gametocyte carriage was significantly longer for PA (4.9 days) than for AL (3.8 days) as estimated by QT-NASBA (P = 0.036), but this difference was less clear when determined by Pfs25 qRT-PCR (4.5 days for PA and 3.7 for AL, P = 0.166). qRT-PCR based female gametocyte prevalence decreased from 100% (75/75) at baseline to 6.06% (4/66) at day 14 in the AL group and from 97.7% (83/85) to 13.9% (11/79) in the PA group. Male gametocyte prevalence decreased from 41.3% (31/75) at baseline to 19.7% (13/66) at day 14 in the AL group and from 35.3% (30/85) to 22.8% (18/79) in the PA group. There was good agreement between Pfs25 qRT-PCR and QT-NASBA female gametocyte prevalence (0.85, 95% CI 0.82-0.87).

Conclusions: This study indicates that female gametocyte clearance may be slightly faster after AL compared to PA. Male gametocytes showed similar post-treatment clearance between study arms. Future studies should further address potential differences between the post-treatment transmission potential after PA compared to AL. Trial registration This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1.

Keywords: Artemether–lumefantrine; Gametocytes; Plasmodium falciparum; Pyronaridine–artesunate.

Fig. 1

Participant flow. Schematic presentation of patient screening, inclusion and follow-up for the present study

Fig. 2

Female gametocytes by Pfs25 QT-NASBA and qRT-PCR. a Gametocyte prevalence determined by QT-NASBA. b Gametocyte density determined by QT-NASBA. c Gametocyte prevalence determined by qRT-PCR. d Gametocyte density determined by qRT-PCR. 95% confidence intervals are presented for prevalences. Density is presented as median (IQR) for gametocyte-positive individuals only. Samples were considered negative if gametocyte levels were < 0.02/µl. AL artemether–lumefantrine, PA pyronaridine–artesunate

Fig. 3

Duration of female gametocyte carriage and gametocyte circulation time. Rounds represent the mean duration of female gametocyte carriage (in days) and their error bars the upper and lower limit of the 95% CI. Triangles represent the mean female gametocyte circulation time (in days) and their error bars the upper and lower limit of the 95% CI. AL artemether–lumefantrine, PA pyronaridine–artesunate

Fig. 4

Male gametocytes by PfMGET qRT-PCR. a Gametocyte prevalence, including 95% confidence intervals. b Gametocyte density, presented as median (IQR) for gametocyte-positive individuals only. Samples were considered negative if gametocyte levels were < 0.02/µl. AL artemether–lumefantrine, PA pyronaridine–artesunate