Abstract
DEC or ivermectin (IVM) in combination with albendazole (ALB) has been the recommended strategy of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) since 2000. Despite effective population coverage (> 65%) with several rounds of MDA with DEC or combination of DEC plus ALB, microfilariae persist in few individuals and they continue to be the source of infection for transmitting LF. We report an individual’s variability in response to DEC by defining the response as complete absence of microfilaria (mf) (post-treatment mf count = 0) and non-response as presence of mf (post-treatment mf count ≥ 1). We analyzed follow-up data on individual’s response to treatment from two randomized clinical trials in which 46 microfilaremic individuals were treated with single-dose DEC (6 mg/kg body weight). They were classified into low, medium, and high mf density categories based on their pre-treatment mf counts. Of the 46 individuals, 65.2% have not responded throughout the 12-month post-treatment period. Application of a logistic regression model with fixed (age, gender, mf density, post-treatment time, and their interactions) and random (individual’s response over time) effects indicated that treatment response is independent of age, gender, and time. The overall treatment response increases in low and decreases in high mf density categories. Furthermore, the estimates for the random coefficients model showed that there is a greater variability in response between individuals over post-treatment time. The results substantiate that individual variation in response to DEC exists which indicate the importance of studying the parasite as well as host genetic factors associated with DEC action.
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References
Awadzi K, Boakye DA, Edwards G, Opoku NO, Attah SK, Osei-Atweneboana MY, Lazdins-Helds JK, Ardrey AE, Addy ET, Quartey BT, Ahmed K, Boatin BA, Soumbey-Alley EW (2004) An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Ann Trop Med Parasitol 98:231–249. https://doi.org/10.1179/000349804225003253
Bockarie MJ, Tavul L, Ibam I, Kastens W, Hazlett F, Tisch DJ, Alpers MP, Kazura JW (2007) Efficacy of single-dose diethylcarbamazine compared with diethylcarbamazine combined with albendazole against Wuchereria bancrofti infection in Papua New Guinea. Am J Trop Med Hyg 76:62–66
Bourguinat C, Pion SD, Kamgno J, Gardon J, Duke BO, Boussinesq M, Prichard RK (2007) Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment. PLoS Negl Trop Dis 1:e72. https://doi.org/10.1371/journal.pntd.0000072
Cazajous T, Prevot F, Kerbiriou A, Milhes M, Grisez C, Tropee A, Godart C, Aragon A, Jacquiet P (2018) Multiple-resistance to ivermectin and benzimidazole of a Haemonchus contortus population in a sheep flock from mainland France, first report. Vet Parasitol Reg Stud Reports 14:103–105. https://doi.org/10.1016/j.vprsr.2018.09.005
Chen LY, Mehta JL (1996) Further evidence of the presence of constitutive and inducible nitric oxide synthase isoforms in human platelets. J Cardiovasc Pharmacol 27:154–158. https://doi.org/10.1097/00005344-199601000-00024
de Souza LP, Lelis RT, Granja IR, DaMatta RA, Santos Cde P (2012) Efficacy of albendazole and moxidectin and resistance to ivermectin against Libyostrongylus douglassii and Libyostrongylus dentatus in ostriches. Vet Parasitol 189:387–389. https://doi.org/10.1016/j.vetpar.2012.04.030
Dickson BFR, Graves PM, Aye NN, Nwe TW, Wai T, Win SS, Shwe M, Douglass J, Bradbury RS, McBride WJ (2018) The prevalence of lymphatic filariasis infection and disease following six rounds of mass drug administration in Mandalay Region, Myanmar. PLoS Negl Trop Dis 12:e0006944. https://doi.org/10.1371/journal.pntd.0006944
Eberhard ML, Lowrie RC Jr, Lammie PJ (1988) Persistence of microfilaremia in bancroftian filariasis after diethylcarbamazine citrate therapy. Trop Med Parasitol 39:128–130
Eberhard ML, Lammie PJ, Dickinson CM, Roberts JM (1991) Evidence of nonsusceptibility to diethylcarbamazine in Wuchereria bancrofti. J Infect Dis 163:1157–1160. https://doi.org/10.1093/infdis/163.5.1157
El Setouhy M, Ramzy RM, Ahmed ES, Kandil AM, Hussain O, Farid HA, Helmy H, Weil GJ (2004) A randomized clinical trial comparing single- and multi-dose combination therapy with diethylcarbamazine and albendazole for treatment of bancroftian filariasis. Am J Trop Med Hyg 70:191–196
Farid HA, Hammad RE, Hassan MM, Ramzy RM, El Setouhy M, Weil GJ (2005) Effects of combined diethylcarbamazine and albendazole treatment of bancroftian filariasis on parasite uptake and development in Culex pipiens L. Am J Trop Med Hyg 73:108–114
Florencio MS, Peixoto CA (2003) The effects of diethylcarbamazine on the ultrastructure of microfilariae of Wuchereria bancrofti. Parasitology 126:551–554
Hoti SL, Subramaniyan K, Das PK (2003) Detection of codon for amino acid 200 in isotype 1 beta-tubulin gene of Wuchereria bancrofti isolates, implicated in resistance to benzimidazoles in other nematodes. Acta Trop 88:77–81. https://doi.org/10.1016/s0001-706x(03)00159-1
King CL, Suamani J, Sanuku N, Cheng YC, Satofan S, Mancuso B, Goss CW, Robinson LJ, Siba PM, Weil GJ, Kazura JW (2018) A trial of a triple-drug treatment for lymphatic filariasis. N Engl J Med 379:1801–1810. https://doi.org/10.1056/NEJMoa1706854
Lau CL, Sheridan S, Ryan S, Roineau M, Andreosso A, Fuimaono S, Tufa J, Graves PM (2017) Detecting and confirming residual hotspots of lymphatic filariasis transmission in American Samoa 8 years after stopping mass drug administration. PLoS Negl Trop Dis 11:e0005914. https://doi.org/10.1371/journal.pntd.0005914
Mackenzie CD, Kron MA (1985) Diethylcarbamazine: a review of its action in onchocerciasis, lymphatic filariasis and inflammation. Trop Dis Bull 82:R1–R37
Maizels RM, Denham DA (1992) Diethylcarbamazine (DEC): immunopharmacological interactions of an anti-filarial drug. Parasitology 105(Suppl):S49–S60. https://doi.org/10.1017/s0031182000075351
McGarry HF, Plant LD, Taylor MJ (2005) Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria J 4:4. https://doi.org/10.1186/1475-2883-4-4
Nana-Djeunga H, Bourguinat C, Pion SD, Kamgno J, Gardon J, Njiokou F, Boussinesq M, Prichard RK (2012) Single nucleotide polymorphisms in beta-tubulin selected in Onchocerca volvulus following repeated ivermectin treatment: possible indication of resistance selection. Mol Biochem Parasitol 185:10–18. https://doi.org/10.1016/j.molbiopara.2012.05.005
Noroes J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D (1997) Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo. Trans R Soc Trop Med Hyg 91:78–81. https://doi.org/10.1016/s0035-9203(97)90405-3
Ottesen EA (2000) The Global Programme to Eliminate Lymphatic Filariasis. Trop Med Int Health 5:591–594. https://doi.org/10.1046/j.1365-3156.2000.00620.x
Pani SP, Srividya A, Rajagopalan PK (1991) Clearance of microfilaraemia following diethylcarbamazine (DEC) therapy in periodic Wuchereria bancrofti infection: relation with age, sex, microfilaria count and clinical status. Trop Biomedicine 8:59–65
Pani S, Subramanyam Reddy G, Das L, Vanamail P, Hoti S, Ramesh J, Das P (2002) Tolerability and efficacy of single dose albendazole, diethylcarbamazine citrate (DEC) or co-administration of albendazole with DEC in the clearance of Wuchereria bancrofti in asymptomatic microfilaraemic volunteers in Pondicherry, South India: a hospital-based study. Filaria J 1:1. https://doi.org/10.1186/1475-2883-1-1
Peixoto CA, Alves LC, Brayner FA, Florencio MS (2003) Diethylcarbamazine induces loss of microfilarial sheath of Wuchereria bancrofti. Micron 34:381–385. https://doi.org/10.1016/S0968-4328(03)00099-4
Prichard RK (2007) Markers for benzimidazole resistance in human parasitic nematodes? Parasitology 134:1087–1092. https://doi.org/10.1017/S003118200700008X
Ramaiah KD, Vanamail P, Yuvaraj J, Das PK (2011) Effect of annual mass administration of diethylcarbamazine and albendazole on bancroftian filariasis in five villages in south India. Trans R Soc Trop Med Hyg 105:431–437. https://doi.org/10.1016/j.trstmh.2011.04.006
Ramasamy D, Laxmanappa HS, Sharma R, Das MK (2011) Influence of anti-filarial chemotherapy strategies on the genetic structure of Wuchereria bancrofti populations. Mem Inst Oswaldo Cruz 106:240–247. https://doi.org/10.1590/s0074-02762011000200020
Rao RU, Samarasekera SD, Nagodavithana KC, Goss CW, Punchihewa MW, Dassanayaka TDM, Ranasinghe USB, Mendis D, Weil GJ (2018) Comprehensive assessment of a hotspot with persistent bancroftian filariasis in coastal Sri Lanka. Am J Trop Med Hyg 99:735–742. https://doi.org/10.4269/ajtmh.18-0169
Sankari T, Hoti SL, Das LK, Govindaraj V, Das PK (2013) Effect of diethylcarbamazine (DEC) on prostaglandin levels in Wuchereria bancrofti infected microfilaraemics. Parasitol Res 112:2353–2359. https://doi.org/10.1007/s00436-013-3399-y
Schwab AE, Boakye DA, Kyelem D, Prichard RK (2005) Detection of benzimidazole resistance-associated mutations in the filarial nematode Wuchereria bancrofti and evidence for selection by albendazole and ivermectin combination treatment. Am J Trop Med Hyg 73:234–238
Schwab AE, Churcher TS, Schwab AJ, Basanez MG, Prichard RK (2006) Population genetics of concurrent selection with albendazole and ivermectin or diethylcarbamazine on the possible spread of albendazole resistance in Wuchereria bancrofti. Parasitology 133:589–601. https://doi.org/10.1017/S003118200600076X
Shriram AN, Krishnamoorthy K, Sivan A, Saha BP, Kumaraswami V, Vijayachari P (2014) Impact of MDA and the prospects of elimination of the lone focus of diurnally sub periodic lymphatic filariasis in Nicobar Islands, India. Acta Trop 133:93–97. https://doi.org/10.1016/j.actatropica.2014.02.004
Shriram AN, Premkumar A, Krishnamoorthy K, De A, Paul SK, Subramanian S, Vijayachari P, Jambulingam P (2020) Elimination of diurnally sub-periodic Wuchereria bancrofti in Andaman and Nicobar Islands, India, using mass DEC-fortified salt as a supplementary intervention to MDA. Parasitol Res 119:1467–1483. https://doi.org/10.1007/s00436-020-06659-7
Stolk WA, Vano GJ, Pani SP, Dev SJ, Subramanian S, Das PK, Habbema JD (2005) Effects of ivermectin and diethylcarbamazine on microfilariae and overall microfilaria production in bancroftian filariasis. Am J Trop Med Hyg 73:881–887
Subramanyam Reddy G, Vengatesvarlou N, Das PK, Vanamail P, Vijayan AP, Kala S, Pani SP (2000) Tolerability and efficacy of single-dose diethyl carbamazine (DEC) or ivermectin in the clearance of Wuchereria bancrofti microfilaraemia in Pondicherry, south India. Trop Med Int Health 5:779–785. https://doi.org/10.1046/j.1365-3156.2000.00644.x
Sunish IP, Rajendran R, Mani TR, Munirathinam A, Dash AP, Tyagi BK (2007) Vector control complements mass drug administration against bancroftian filariasis in Tirukoilur. India, Bulletin of the World Health Organization 85:138–145
Swaminathan S, Perumal V, Adinarayanan S, Kaliannagounder K, Rengachari R, Purushothaman J (2012) Epidemiological assessment of eight rounds of mass drug administration for lymphatic filariasis in India: implications for monitoring and evaluation. PLoS Negl Trop Dis 6:e1926. https://doi.org/10.1371/journal.pntd.0001926
Thangadurai R, Hoti SL, Kumar NP, Das PK (2006) Phylogeography of human lymphatic filarial parasite, Wuchereria bancrofti in India. Acta Trop 98:297–304. https://doi.org/10.1016/j.actatropica.2006.06.004
WHO (2020) Lymphatic filariasis, Key facts. https://www.who.int/news-room/fact-sheets/detail/lymphatic-filariasis. Accessed 15 June 2020.
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TS and SS carried out statistical analysis and drafted the manuscript. SLH and SPP intellectually contributed to drafting the manuscript. PJ critically reviewed the manuscript and PKD contributed to the design and coordination of the study.
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Sankari, T., Subramanian, S., Hoti, S.L. et al. Heterogeneous response of Wuchereria bancrofti–infected persons to diethylcarbamazine (DEC) and its implications for the Global Programme to Eliminate Lymphatic Filariasis (GPELF). Parasitol Res 120, 311–319 (2021). https://doi.org/10.1007/s00436-020-06950-7
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DOI: https://doi.org/10.1007/s00436-020-06950-7