Effectiveness of antimalarial drug combinations in treating concomitant urogenital schistosomiasis in malaria patients in Lambaréné, Gabon: A non-randomised event-monitoring study

Rella Zoleko-Manego, Dearie G Okwu, Christian Handrich, Lia B Dimessa-Mbadinga, Malick A Akinosho, Wilfrid F Ndzebe-Ndoumba, Saskia D Davi, Daniel Stelzl, Luzia Veletzky, Andrea Kreidenweiss, Tamara Nordmann, Ayola A Adegnika, Bertrand Lell, Peter G Kremsner, Michael Ramharter, Ghyslain Mombo-Ngoma, Rella Zoleko-Manego, Dearie G Okwu, Christian Handrich, Lia B Dimessa-Mbadinga, Malick A Akinosho, Wilfrid F Ndzebe-Ndoumba, Saskia D Davi, Daniel Stelzl, Luzia Veletzky, Andrea Kreidenweiss, Tamara Nordmann, Ayola A Adegnika, Bertrand Lell, Peter G Kremsner, Michael Ramharter, Ghyslain Mombo-Ngoma

Abstract

Background: Urogenital schistosomiasis is prevalent in many malaria endemic regions of sub-Saharan Africa and can lead to long-term health consequences if untreated. Antimalarial drugs used to treat uncomplicated malaria have shown to exert some activity against Schistosoma haematobium. Here, we explore the efficacy on concomitant urogenital schistosomiasis of first-line recommended artemisinin-based combination therapies (ACTs) and investigational second-generation ACTs when administered for the treatment of uncomplicated malaria in Gabon.

Methods: Microscopic determination of urogenital schistosomiasis was performed from urine samples collected from patients with confirmed uncomplicated malaria. Egg excretion reduction rate and cure rate were determined at 4-weeks and 6-weeks post-treatment with either artesunate-pyronaridine, artemether-lumefantrine, artesunate-amodiaquine or artefenomel-ferroquine.

Results: Fifty-two (16%) out of 322 malaria patients were co-infected with urogenital schistosomiasis and were treated with antimalarial drug combinations. Schistosoma haematobium egg excretion rates showed a median reduction of 100% (interquartile range (IQR), 17% to 100%) and 65% (IQR, -133% to 100%) at 4-weeks and 6-weeks post-treatment, respectively, in the artesunate-pyronaridine group (n = 20) compared to 35% (IQR, -250% to 70%) and 65% (IQR, -65% to 79%) in the artemether-lumefantrine group (n = 18). Artesunate-amodiaquine (n = 2) and artefenomel-ferroquine combination (n = 3) were not able to reduce the rate of eggs excreted in this limited number of patients. In addition, cure rates were 56% and 37% at 4- and 6-weeks post-treatment, respectively, with artesunate-pyronaridine and no cases of cure were observed for the other antimalarial combinations.

Conclusions: Antimalarial treatments with artesunate-pyronaridine and artemether-lumefantrine reduced the excretion of S. haematobium eggs, comforting the hypothesis that antimalarial drugs could play a role in the control of schistosomiasis.

Trial registration: This trial is registered with clinicaltrials.gov, under the Identifier NCT04264130.

Conflict of interest statement

The authors have declared that no competing interests exist.

Copyright: © 2022 Zoleko-Manego et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Figures

Fig 1. Participants flow.
Fig 1. Participants flow.
Abbreviation: Tx: treatment.
Fig 2. Schistosoma egg excression before and…
Fig 2. Schistosoma egg excression before and posttreatment.

References

    1. WHO | What is schistosomiasis? [Internet]. WHO. [cited 19 May 2020]. Available on:
    1. Wikman-Jorgensen PE, Henríquez-Camacho CA, Serrano-Villar S, Pérez-Molina JA. The role of artesunate for the treatment of urinary schistosomiasis in schoolchildren: a systematic review and meta-analysis. Pathog Glob Health. Nov 2012;106(7):397–404. doi: 10.1179/2047773212Y.0000000038
    1. Schistosomiasis [Internet]. [cited 19 May 2020]. Available on:
    1. Adegnika AA, Ramharter M, Agnandji ST, Ateba Ngoa U, Issifou S, Yazdanbahksh M, et al.. Epidemiology of parasitic co-infections during pregnancy in Lambaréné, Gabon. Trop Med Int Health TM IH. oct 2010;15(10):1204–9. doi: 10.1111/j.1365-3156.2010.02598.x
    1. Dejon-Agobé JC, Edoa JR, Honkpehedji YJ, Zinsou JF, Adégbitè BR, Mbong Ngwese, et al.. Schistosoma haematobium infection morbidity, praziquantel effectiveness and reinfection rate among children and young adults in Gabon [published correction appears in Parasit Vectors. 2021 Jun 21;14(1):329]. Parasit Vectors. 2019;12(1):577. Published 2019 Dec 10. doi: 10.1186/s13071-019-3836-6
    1. Jäckle MJ, Blumentrath CG, Zoleko RM, Akerey-Diop D, Mackanga J-R, Adegnika AA, et al.. Malaria in pregnancy in rural Gabon: a cross-sectional survey on the impact of seasonality in high-risk groups. Malar J. 2013;12:412. doi: 10.1186/1475-2875-12-412
    1. Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis. 2008. Dec;21(6):659–67. doi: 10.1097/QCO.0b013e328318978f
    1. Cioli D, Pica-Mattoccia L, Basso A, Guidi A. Schistosomiasis control: praziquantel forever? Mol Biochem Parasitol. 2014. Jun;195(1):23–9. doi: 10.1016/j.molbiopara.2014.06.002
    1. Botros S, Pica-Mattoccia L, William S, El-Lakkani N, Cioli D. Effect of praziquantel on the immature stages of Schistosoma haematobium. Int J Parasitol. 2005. Nov;35(13):1453–7. doi: 10.1016/j.ijpara.2005.05.002
    1. Sabah AA, Fletcher C, Webbe G, Doenhoff MJ. Schistosoma mansoni: chemotherapy of infections of different ages. Exp Parasitol. 1986. Jun;61(3):294–303. doi: 10.1016/0014-4894(86)90184-0
    1. Inyang-Etoh PC, Ejezie GC, Useh MF, Inyang-Etoh EC. Efficacy of a combination of praziquantel and artesunate in the treatment of urinary schistosomiasis in Nigeria. Trans R Soc Trop Med Hyg. 2009. Jan;103(1):38–44. doi: 10.1016/j.trstmh.2008.08.002
    1. Boulanger D, Dieng Y, Cisse B, Remoue F, Capuano F, Dieme JL, et al.. Antischistosomal efficacy of artesunate combination therapies administered as curative treatments for malaria attacks. Trans R Soc Trop Med Hyg. 2007. Feb;101(2):113–6. doi: 10.1016/j.trstmh.2006.03.003
    1. Adedoja AA, Akanbi AA, Oshodi AJ. Effect of artemether-lumefantrine treatment of falciparum malaria on urogenital schistosomiasis in co-infected School Aged Children in North Central of Nigeria. Int J Biol Chem Sci. 2015. Jun;9(1):134–40.
    1. Utzinger J, N’Goran EK, N’Dri A, Lengeler C, Xiao S, Tanner M. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet. 2000. Apr 15;355(9212):1320–5. doi: 10.1016/s0140-6736(00)02114-0
    1. N’Goran EK, Utzinger J, Gnaka HN, Yapi A, N’Guessan NA, Kigbafori SD, et al.. Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am J Trop Med Hyg. 2003. Jan;68(1):24–32.
    1. Li YS, Chen HG, He HB, Hou XY, Ellis M, McManus DP. A double-blind field trial on the effects of artemether on Schistosoma japonicum infection in a highly endemic focus in southern China. Acta Trop. 2005. Nov-Dec;96(2–3):184–90. doi: 10.1016/j.actatropica.2005.07.013
    1. Elmorshedy H, Tanner M, Bergquist RN, Sharaf S, Barakat R. Prophylactic effect of artemether on human schistosomiasis mansoni among Egyptian children: A randomized controlled trial. Acta Trop. 2016. Jun;158:52–58. doi: 10.1016/j.actatropica.2016.02.015
    1. Basra A, Mombo-Ngoma G, Melser MC, Diop DA, Würbel H, Mackanga JR, et al.. Efficacy of mefloquine intermittent preventive treatment in pregnancy against Schistosoma haematobium infection in Gabon: a nested randomized controlled assessor-blinded clinical trial. Clin Infect Dis. 2013. Mar;56(6):e68–75. doi: 10.1093/cid/cis976
    1. Borrmann S, Szlezák N, Faucher JF, Matsiegui PB, Neubauer R, Binder RK, et al.. Artesunate and praziquantel for the treatment of Schistosoma haematobium infections: a double-blind, randomized, placebo-controlled study. J Infect Dis. 2001. Nov 15;184(10):1363–6. doi: 10.1086/324004
    1. Ramharter M, Agnandji ST, Adegnika AA, Lell B, Mombo-Ngoma G, Grobusch MP, et al.. Development of sustainable research excellence with a global perspective on infectious diseases: Centre de Recherches Médicales de Lambaréné (CERMEL), Gabon. Wien Klin Wochenschr. 2021;133(9–10):500–508. doi: 10.1007/s00508-020-01794-8
    1. Mombo-Ngoma G, Mackanga JR, González R, Ouedraogo S, Kakolwa MA, Manego RZ, et al.. Young adolescent girls are at high risk for adverse pregnancy outcomes in sub-Saharan Africa: an observational multicountry study. BMJ Open. 2016. Jun 29;6(6):e011783. doi: 10.1136/bmjopen-2016-011783
    1. Ramharter M, Adegnika AA, Agnandji ST, Matsiegui PB, Grobusch MP, Winkler S, et al.. History and perspectives of medical research at the Albert Schweitzer Hospital in Lambaréné, Gabon. Wien Klin Wochenschr. 2007;119(19–20 Suppl 3):8–12. doi: 10.1007/s00508-007-0857-5
    1. Ateba Ngoa U, Zinsou JF, Kassa RF, Kassa RF, Kassa Kassa RF, Ngoune Feugap E, Honkpehedji YJ, et al.. Assessment of the effect of Schistosoma haematobium co infection on malaria parasites and immune responses in rural populations in Gabon: study protocol. Springerplus. 2014;3:388. Published 2014 Jul 29. doi: 10.1186/2193-1801-3-388
    1. Peters PA, Mahmoud AAF, Warren KS, Ouma JH, Siongok TKA. Field studies of a rapid, accurate means of quantifying Schistosoma haematobium eggs in urine samples. Bull World Health Organ. 1976;54(2):159–62.
    1. Peters PA, Warren KS, Mahmoud AA. Rapid, accurate quantification of schistosome eggs via nuclepore filters. J Parasitol. 1976. Feb;62(1):154–5.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009. Apr;42(2):377–81. doi: 10.1016/j.jbi.2008.08.010
    1. Self-diagnosis as a possible basis for treating urinary schistosomiasis: a study of schoolchildren in a rural area of the United Republic of Tanzania. Partnership for Child Development. Bull World Health Organ. 1999;77(6):477–83.
    1. Dejon-Agobé JC, Zinsou JF, Honkpehedji YJ, Ateba-Ngoa U, Edoa JR, Adegbite BR, et al.. Schistosoma haematobium effects on Plasmodium falciparum infection modified by soil-transmitted helminths in school-age children living in rural areas of Gabon. PLoS Negl Trop Dis. 2018. Aug 6;12(8):e0006663. doi: 10.1371/journal.pntd.0006663
    1. Anchang-Kimbi JK, Elad DM, Sotoing GT, Achidi EA. Coinfection with Schistosoma haematobium and Plasmodium falciparum and Anaemia Severity among Pregnant Women in Munyenge, Mount Cameroon Area: A Cross-Sectional Study. J Parasitol Res. 2017;2017:6173465. doi: 10.1155/2017/6173465
    1. Li HJ, Wang W, Li YZ, Qu GL, Xing YT, Tao YH, et al.. Effects of artemether, artesunate and dihydroartemisinin administered orally at multiple doses or combination in treatment of mice infected with Schistosoma japonicum. Parasitol Res. 2011. Aug;109(2):515–9. doi: 10.1007/s00436-011-2474-5
    1. Keiser J, N’Guessan NA, Adoubryn KD, Silué KD, Vounatsou P, Hatz C, et al.. Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against Schistosoma haematobium: randomized, exploratory open-label trial. Clin Infect Dis. 2010. May 1;50(9):1205–13. doi: 10.1086/651682
    1. Koehne E, Zander N, Rodi M, Held J, Hoffmann W, Zoleko-Manego R, et al.. Evidence for in vitro and in vivo activity of the antimalarial pyronaridine against Schistosoma. PLoS Negl Trop Dis. 2021. Jun 24;15(6):e0009511. doi: 10.1371/journal.pntd.0009511

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