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

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

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://ichgcp.net/clinical-trials-registry/NCT02411994?term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1.

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

Figures

Fig. 1
Fig. 1
Participant flow. Schematic presentation of patient screening, inclusion and follow-up for the present study
Fig. 2
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
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
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

References

    1. Bhatt S, Weiss DJ, Cameron E, Bisanzio D, Mappin B, Dalrymple U, et al. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. 2015;526:207–211. doi: 10.1038/nature15535.
    1. Maude RJ, Pontavornpinyo W, Saralamba S, Aguas R, Yeung S, Dondorp AM, et al. The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J. 2009;8:31. doi: 10.1186/1475-2875-8-31.
    1. Maude RJ, Socheat D, Nguon C, Saroth P, Dara P, Li G, et al. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance. PLoS ONE. 2012;7:e37166. doi: 10.1371/journal.pone.0037166.
    1. Nosten F, van Vugt M, Price R, Luxemburger C, Thway K, Brockman A, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet. 2000;356:297–302. doi: 10.1016/S0140-6736(00)02505-8.
    1. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. NEJM. 2014;371:411–423. doi: 10.1056/NEJMoa1314981.
    1. Fairhurst RM, Dondorp AM. Artemisinin-resistant Plasmodium falciparum malaria. Microbiol Spectr. 2016;4:El10-0013-2016.
    1. Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SSS, et al. Efficacy and safety of a fixed-dose oral combination of pyronaridine–artesunate compared with artemether–lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet. 2010;375:1457–1467. doi: 10.1016/S0140-6736(10)60322-4.
    1. Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, et al. Pyronaridine–artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS ONE. 2011;6:e14501. doi: 10.1371/journal.pone.0014501.
    1. Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Ph D, et al. Pyronaridine–artesunate versus mefloquine plus artesunate for malaria. NEJM. 2012;366:1298–1309. doi: 10.1056/NEJMoa1007125.
    1. Kayentao K, Doumbo OK, Pénali LK, Offianan AT, Bhatt KM, Kimani J, et al. Pyronaridine–artesunate granules versus artemether–lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial. Malar J. 2012;11:364. doi: 10.1186/1475-2875-11-364.
    1. Duparc S, Borghini-fuhrer I, Craft JC, Arbe-barnes S, Miller RM, Shin C, et al. Safety and efficacy of pyronaridine–artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J. 2013;12:70. doi: 10.1186/1475-2875-12-70.
    1. Sagara I, Beavogui AH, Zongo I, Soulama I, Borghini-fuhrer I, Fofana B, et al. Safety and efficacy of re-treatments with pyronaridine–artesunate in African patients with malaria: a substudy of the WANECAM randomised trial. Lancet Infect Dis. 2016;16:189–198. doi: 10.1016/S1473-3099(15)00318-7.
    1. Chavalitshewinkoon-Petmitr P, Pongvilairat G, Auparakkitanon S, Wilairat P. Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro. Parasitol Int. 2000;48:275–280. doi: 10.1016/S1383-5769(99)00028-8.
    1. Adjalley SH, Johnston GL, Li T, Eastman RT, Ekland EH, Eappen AG, et al. Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue. Proc Natl Acad Sci USA. 2011;108:E1214–E1223. doi: 10.1073/pnas.1112037108.
    1. Delves MJ, Ruecker A, Straschil U, Lelièvre J, Marques S, López-Barragán MJ, et al. Male and female Plasmodium falciparum mature gametocytes show different responses to antimalarial drugs. Antimicrob Agents Chemother. 2013;57:3268–3274. doi: 10.1128/AAC.00325-13.
    1. Lelièvre J, Almela MJ, Lozano S, Miguel C, Franco V, Leroy D, et al. Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence “transmission blocking” assay. PLoS ONE. 2012;7:e35019. doi: 10.1371/journal.pone.0035019.
    1. Kumar N, Zheng H. Stage-specific gametocytocidal effect in vitro of the antimalaria drug qinghaosu on Plasmodium falciparum. Parasitol Res. 1990;76:214–218. doi: 10.1007/BF00930817.
    1. Targett G, Drakeley C, Jawara M, von Seidlein L, Coleman R, Deen J, et al. Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae. J Infect Dis. 2001;183:1254–1259. doi: 10.1086/319689.
    1. White NJ. The role of anti-malarial drugs in eliminating malaria. Malar J. 2008;7(Suppl 1):S8. doi: 10.1186/1475-2875-7-S1-S8.
    1. WWARN Gametocyte Study Group Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Med. 2016;14:79. doi: 10.1186/s12916-016-0621-7.
    1. Schneider P, Bousema T, Omar S, Gouagna L, Sawa P, Schallig H, et al. (Sub)microscopic Plasmodium falciparum gametocytaemia in Kenyan children after treatment with sulphadoxine-pyrimethamine monotherapy or in combination with artesunate. Int J Parasitol. 2006;36:403–408. doi: 10.1016/j.ijpara.2006.01.002.
    1. Schneider P, Schoone G, Schallig H, Verhage D, Telgt D, Eling W, et al. Quantification of Plasmodium falciparum gametocytes in differential stages of development by quantitative nucleic acid sequence-based amplification. Mol Biochem Parasitol. 2004;137:35–41. doi: 10.1016/j.molbiopara.2004.03.018.
    1. Mens PF, Sawa P, Van Amsterdam SM, Versteeg I, Omar SA, Schallig HDFH, et al. A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether–lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya. Malar J. 2008;7:237. doi: 10.1186/1475-2875-7-237.
    1. Stone W, Sawa P, Lanke K, Rijpma S, Oriango R, Nyaurah M, et al. A molecular assay to quantify male and female Plasmodium falciparum gametocytes: results from 2 randomized controlled trials using primaquine for gametocyte clearance. J Infect Dis. 2017;216:457–467. doi: 10.1093/infdis/jix237.
    1. White N, Ashley E, Recht J, Delves M, Ruecker A, Smithuis F, et al. Assessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria. Malar J. 2014;13:483. doi: 10.1186/1475-2875-13-483.
    1. Roth JM, Sawa P, Makio N, Omweri G, Osoti V, Okach S, et al. Pyronaridine–artesunate and artemether–lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a randomized controlled non-inferiority trial. Malar J. 2018;17:199. doi: 10.1186/s12936-018-2340-3.
    1. WHO. Child growth standards and the identification of severe acute malnutrition in infants and children. Geneva: World Health Organization; 2009. . Accessed 14 Dec 2017.
    1. WHO. Basic malaria microscopy—part I: Learner’s guide. 2 ed. Geneva: World Health Organization; 2010. . Accessed 12 Jan 2018.
    1. Lasonder E, Rijpma SR, Van Schaijk BCL, Hoeijmakers WAM, Kensche PR, Gresnigt MS, et al. Integrated transcriptomic and proteomic analyses of P. falciparum gametocytes: molecular insight into sex-specific processes and translational repression. Nucleic Acids Res. 2016;44:6087–6101. doi: 10.1093/nar/gkw536.
    1. Pett H, Gonçalves BP, Dicko A, Nébié I, Tiono AB, Lanke K, et al. Comparison of molecular quantification of Plasmodium falciparum gametocytes by Pfs25 qRT-PCR and QT-NASBA in relation to mosquito infectivity. Malar J. 2016;15:539. doi: 10.1186/s12936-016-1584-z.
    1. Bousema T, Okell L, Shekalaghe S, Griffin JT, Omar S, Sawa P, et al. Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar J. 2010;9:136. doi: 10.1186/1475-2875-9-136.
    1. Méndez F, Muñoz Á, Plowe C. Use of area under the curve to characterize transmission potential after antimalarial treatment. Am J Trop Med Hyg. 2006;75:640–644.
    1. Carrasco JL, King TS, Chinchilli VM. The concordance correlation coefficient for repeated measures estimated by variance components. J Biopharm Stat. 2009;19:90–105. doi: 10.1080/10543400802527890.
    1. Pan Y, Rose CE, Haber M, Ma Y, Carrasco JL, Stewart B, et al. Assessing agreement of repeated binary measurements with an application to the CDC’s anthrax vaccine clinical trial. Int J Biostat. 2013;9:19–32. doi: 10.1515/ijb-2012-0001.
    1. Sawa P, Shekalaghe SA, Drakeley CJ, Sutherland CJ, Mweresa CK, Baidjoe AY, et al. Malaria transmission after artemether–lumefantrine and dihydroartemisinin-piperaquine: a randomized trial. J Infect Dis. 2013;207:1637–1645. doi: 10.1093/infdis/jit077.
    1. Dicko A, Roh ME, Diawara H, Mahamar A, Soumare HM, Lanke K, et al. Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial. Lancet Infect Dis. 2018;18:30044–30046. doi: 10.1016/S1473-3099(18)30044-6.
    1. Bousema JT, Schneider P, Gouagna LC, Drakeley CJ, Tostmann A, Houben R, et al. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis. 2006;193:1151–1159. doi: 10.1086/503051.
    1. Bousema T, Drakeley C. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clin Microbiol Rev. 2011;24:377–410. doi: 10.1128/CMR.00051-10.
    1. Schneider P, Bousema JT, Gouagna LC, Otieno S, Van De Vegte-Bolmer M, Omar SA, et al. Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am J Trop Med Hyg. 2007;76:470–474.
    1. Eziefula AC, Bousema T, Yeung S, Kamya M, Owaraganise A, Gabagaya G, 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. 2014;14:130–139. doi: 10.1016/S1473-3099(13)70268-8.
    1. Gonçalves BP, Tiono AB, Ouédraogo A, Guelbéogo WM, Bradley J, Nebie I, et al. Single low dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission after artemether–lumefantrine in children with asymptomatic infection: a randomised, double-blind, placebo-controlled trial. BMC Med. 2016;14:40. doi: 10.1186/s12916-016-0581-y.
    1. Sowunmi A, Balogun ST, Gbotosho GO, Happi CT. Plasmodium falciparum gametocyte sex ratios in symptomatic children treated with antimalarial drugs. Acta Trop. 2009;109:108–117. doi: 10.1016/j.actatropica.2008.10.010.
    1. Gbotosho GO, Sowunmi A, Okuboyejo TM, Happi CT, Michael OS, Folarin OA, et al. Plasmodium falciparum gametocyte carriage, emergence, clearance and population sex ratios in anaemic and non-anaemic malarious children. Mem Inst Oswaldo Cruz. 2011;106:562–569. doi: 10.1590/S0074-02762011000500008.
    1. Koella JC, Lorenz L, Bargielowski I. Microsporidians as evolution-proof agents of malaria control? Adv Parasitol. 2009;68:315–327. doi: 10.1016/S0065-308X(08)00612-X.
    1. Okell LC, Cairns M, Griffin JT, Ferguson NM, Tarning J, Jagoe G, et al. Contrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis. Nat Commun. 2014;5:5606. doi: 10.1038/ncomms6606.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다