Many trials have explored the efficacy of individual drugs and drug combinations to treat bancroftian filariasis. This narrative review summarizes the current evidence for drug management of bancroftian filariasis. Diethylcarbamazine (DEC) remains the prime antifilarial agent with a well-established microfilaricidal and some macrofilaricidal effects. Ivermectin (IVM) is highly microfilaricidal but minimally macrofilaricidal. The role of albendazole (ALB) in treatment regimens is not well established though the drug has a microfilaricidal effect. The combination of DEC+ALB has a better long-term impact than IVM+ALB. Recent trials have shown that doxycycline therapy against Wolbachia, an endosymbiotic bacterium of the parasite, is capable of reducing microfilaria rates and adult worm activity. Followup studies on mass drug administration (MDA) are yet to show a complete interruption of transmission, though the infection rates are reduced to a very low level. 1. Introduction There are nine filarial nematodes causing disease in humans. According to the location of the parasite and the pathogenesis, the disease can be classified as lymphatic, subcutaneous, and serous cavity filariasis. Two filarial worms, namely, Wuchereria bancrofti and Brugia malayi cause lymphatic filariasis. The World Health Organization (WHO) considers lymphatic filariasis to be a global health problem affecting approximately 120 million people in over 80 countries [1]. One-third of affected individuals are from South Asia and another one third is from Africa [1]. One sixth of the world population is at risk of infection [1]. The adult W. bancrofti worms live within the human lymphatic system. They have a long life span of 4–6 years. Females are viviparous and release thousands of microfilaria into the blood stream of the host after mating. These are taken up by vector mosquitoes during feeding, and the parasite undergoes several moults within the intermediate host to become the L3 larva which is the infective stage. During a feed, this larva enters the human blood stream and migrates to the lymphatics where it moults to become an adult worm [2]. There is a range of clinical manifestations in bancroftian filariasis with asymptomatic microfilaremics being at one end of the spectrum. Symptomatic patients may have acute (lymphangitis, lymphadenitis), chronic (elephantiasis, lymphoedema, hydrocoele, chyluria), or atypical (funiculitis, mastitis) manifestations [3]. Some may suffer from tropical pulmonary eosinophilia (TPE) due to the immunological hyperresponsiveness to the parasite [4].
V. K. Vijayan, “Tropical pulmonary eosinophilia: pathogenesis, diagnosis and management,” Current Opinion in Pulmonary Medicine, vol. 13, no. 5, pp. 428–433, 2007.
K. D. Ramaiah, H. Guyatt, K. Ramu, P. Vanamail, S. P. Pani, and P. K. Das, “Treatment costs and loss of work time to individuals with chronic lymphatic filariasis in rural communities in south India,” Tropical Medicine and International Health, vol. 4, no. 1, pp. 19–25, 1999.
K. D. Ramaiah, K. Ramu, H. Guyatt, K. N. Vijar Kumar, and S. P. Pani, “Direct and indirect costs of the acute form of lymphatic filariasis to households in rural areas of tamil nadu, south india,” Tropical Medicine and International Health, vol. 3, no. 2, pp. 108–115, 1998.
P. Johnson, C. D. Mackenzie, D. A. Denham, and R. R. Suswillo, “The effect of diethylcarbamazine on the in vitro serum-mediated adherence of feline granulocytes to microfilariae of Brugia pahangi,” Tropical Medicine and Parasitology, vol. 39, no. 4, pp. 291–294, 1988.
N. Kanesa-thasan, J. G. Douglas, and J. W. Kazura, “Diethylcarbamazine inhibits endothelial and microfilarial prostanoid metabolism in vitro,” Molecular and Biochemical Parasitology, vol. 49, no. 1, pp. 11–20, 1991.
C. A. Peixoto, A. C. O. Santos, and C. F. J. Ayres, “Molecular evidence for apoptosis in microfilariae of Wuchereria bancrofti induced by diethylcarbamazine,” Parasitology Research, vol. 103, no. 3, pp. 717–721, 2008.
E. A. Ottesen, “Efficacy of diethylcarbamazine in eradicating infection with lymphatic-dwelling filariae in humans,” Reviews of Infectious Diseases, vol. 7, no. 3, pp. 341–356, 1985.
M. Abramowicz, M. A. Rizack, D. Goodstein, A. Faucard, P. D. Hansten, and N. H. Steigbigel, “Drugs for parasitic infections,” Medical Letter on Drugs and Therapeutics, vol. 40, no. 1017, pp. 1–12, 1998.
D. Addiss and G. Dreyer, “Treatment of lymphatic filariasis,” in Lymphatic Filariasis, T. B. Nutman, Ed., pp. 103–125, Imperial College Press, London, UK, 2000.
A. P. Oomen, “Fatalities after treatment of onchocerciasis with diethylcarbamazine,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 63, no. 4, p. 548, 1969.
A. C. Bird, H. El-Sheikh, J. Anderson, and H. Fuglsang, “Visual loss during oral diethylcarbamazine treatment for onchocerciasis,” Lancet, vol. 2, no. 8132, p. 46, 1979.
L. D. Andrade, Z. Medeiros, M. L. Pires et al., “Comparative efficacy of three different diethylcarbamazine regimens in lymphatic filariasis,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 89, no. 3, pp. 319–321, 1995.
R. M. R. Ramzy, M. El Setouhy, H. Helmy et al., “The impact of single-dose diethylcarbamazine treatment of bancroftian filariasis in a low-endemicity setting in Egypt,” American Journal of Tropical Medicine and Hygiene, vol. 67, no. 2, pp. 196–200, 2002.
M. V. Weerasooriya, E. Kimura, D. A. Dayaratna, T. R. Weerasooriya, and W. A. Samarawickrema, “Efficacy of a single dose treatment of Wuchereria bancrofti microfilaria carriers with diethylcarbamazine in Matara, Sri Lanka,” The Ceylon Medical Journal, vol. 43, no. 3, pp. 151–155, 1998.
M. K. Beuria, M. S. Bal, N. N. Mandal, and M. K. Das, “Antigenemia at 10 years after diethylcarbamazine treatment of asymptomatic microfilaraemic individuals: marginal conversion to infection-free state,” Parasite Immunology, vol. 24, no. 2, pp. 109–111, 2002.
D. O. Freedman, D. Adam Plier, A. B. De Almeida, A. L. De Oliveira, J. Miranda, and C. Braga, “Effect of aggressive prolonged diethylcarbamazine therapy on circulating antigen levels in bancroftian filariasis,” Tropical Medicine and International Health, vol. 6, no. 1, pp. 37–41, 2001.
S. P. Pani, G. Subramanyam Reddy, L. K. Das et al., “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 Journal, vol. 1, no. 1, article 1, 2002.
W. A. Stolk, G. J. Van Oortmarssen, S. P. Pani et al., “Effects of ivermectin and diethylcarbamazine on microfilariae and overall microfilaria production in bancroftian filariasis,” American Journal of Tropical Medicine and Hygiene, vol. 73, no. 5, pp. 881–887, 2005.
G. S. Reddy, N. Vengatesvarlou, P. K. Das et al., “Tolerability and efficacy of single-dose diethyl carbamazine (DEC) or ivermectin in the clearance of Wuchereria bancrofti microfilaraemia in Pondicherry, South India,” Tropical Medicine and International Health, vol. 5, no. 11, pp. 779–785, 2000.
M. Ducorps, N. Gardon-Wendel, S. Ranque et al., “Secondary effects of the treatment of hypermicrofilaremic loiasis using ivermectinEffets secondaires du traitement de la loase hypermicrofilarémique par l'ivermectine,” Bulletin de la Société de Pathologie Exotique, vol. 88, no. 3, pp. 105–112, 1995.
B. Carme, B. Ebikli, A. Mbitsi, and N. Copin, “Therapeutic trial with ivermectin against loiasis with medium and high microfilaremia,” Annales de la Societe Belge de Medecine Tropicale, vol. 71, no. 1, pp. 47–50, 1991.
G. Dreyer, D. Addiss, J. Williamson, and J. Nor？es, “Efficacy of co-administered diethylcarbamazine and albendazole against adult Wuchereria bancrofti,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 100, no. 12, pp. 1118–1125, 2006.
M. J. Bockarie, L. Tavul, I. Ibam et al., “Efficacy of single-dose diethylcarbamazine compared with diethylcarbamazine combined with albendazole against Wuchereria bancrofti infection in Papua New Guinea,” American Journal of Tropical Medicine and Hygiene, vol. 76, no. 1, pp. 62–67, 2007.
L. M. Fox, B. W. Furness, J. K. Haser et al., “Tolerance and efficacy of combined diethylcarbamazine and albendazole for treatment of Wuchereria bancrofti and intestinal helminth infections in Haitian children,” American Journal of Tropical Medicine and Hygiene, vol. 73, no. 1, pp. 115–121, 2005.
O. Hussein, M. El Setouhy, E. S. Ahmed et al., “Duplex doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult filarial worms and adjacent host tissues in bancroftian filariasis,” American Journal of Tropical Medicine and Hygiene, vol. 71, no. 4, pp. 471–477, 2004.
M. El Setouhy, R. M. R. Ramzy, E. S. Ahmed et al., “A randomized clinical trial comparing single- and multi-dose combination therapy with diethylcarbamazine and albendazole for treatment of bancroftian filariasis,” American Journal of Tropical Medicine and Hygiene, vol. 70, no. 2, pp. 191–196, 2004.
M. J. Beach, T. G. Streit, D. G. Addiss, R. Prospere, J. M. Roberts, and P. J. Lammie, “Assessment of combined ivermectin and albendazole for treatment of intestinal helminth and Wuchereria bancrofti infections in Haitian schoolchildren,” American Journal of Tropical Medicine and Hygiene, vol. 60, no. 3, pp. 479–486, 1999.
F. O. Richards, D. D. Pam, A. Kal et al., “Significant decrease in the prevalence of Wuchereria bancrofti infection in anopheline mosquitoes following the addition of albendazole to annual, ivermectin-based, mass treatments in Nigeria,” Annals of Tropical Medicine and Parasitology, vol. 99, no. 2, pp. 155–164, 2005.
W. A. Stolk, S. J. De Vlas, and J. D. F. Habbema, “Anti-Wolbachia treatment for lymphatic filariasis,” Lancet, vol. 365, no. 9477, pp. 2067–2068, 2005.
M. M. Ismail, R. L. Jayakody, G. J. Weil et al., “Long-term efficacy of single-dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of bancroftian filariasis,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 95, no. 3, pp. 332–335, 2001.
M. M. Ismail, R. L. Jayakody, G. J. Weil et al., “Efficacy of single dose combinations of albendazole, ivermectin and diethylcarbamazine for the treatment of bancroftian filariasis,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 92, no. 1, pp. 94–97, 1998.
S. K. Dunyo, F. K. Nkrumah, and P. E. Simonsen, “Single-dose treatment of Wuchereria bancrofti infections with ivermectin and albendazole alone or in combination: evaluation of the potential for control at 12 months after treatment,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 94, no. 4, pp. 437–443, 2000.
S. K. Dunyo, F. K. Nkrumah, and P. E. Simonsen, “A randomized double-blind placebo-controlled field trial of ivermectin and albendazole alone and in combination for the treatment of lymphatic filariasis in Ghana,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 94, no. 2, pp. 205–211, 2000.
W. H. Makunde, L. M. Kamugisha, J. J. Massaga et al., “Treatment of co-infection with bancroftian filariasis and onchocerciasis: a safety and efficacy study of albendazole with ivermectin compared to treatment of single infection with bancroftian filariasis,” Filaria Journal, vol. 2, no. 1, article 15, 2003.
M. E. A. De Kraker, W. A. Stolk, G. J. Van Oortmarssen, and J. D. F. Habbema, “Model-based analysis of trial data: microfilaria and worm-productivity loss after diethylcarbamazine-albendazole or ivermectin-albendazole combination therapy against Wuchereria bancrofti,” Tropical Medicine and International Health, vol. 11, no. 5, pp. 718–728, 2006.
M. J. Bockarie, D. J. Tisch, W. Kastens et al., “Mass treatment to eliminate filariasis in Papua New Guinea,” New England Journal of Medicine, vol. 347, no. 23, pp. 1841–1848, 2002.
M. J. Bockarie, E. Ibam, N. D. E. Alexander et al., “Towards eliminating lymphatic filariasis in Papua New Guinea: impact of annual single-dose mass treatmnet on transmission of Wuchereria bancrofti in East Sepik Province,” Papua and New Guinea Medical Journal, vol. 43, no. 3-4, pp. 172–182, 2000.
D. J. Tisch, M. J. Bockarie, Z. Dimber et al., “Mass drug administration trial to eliminate lymphatic filariasis in Papua New Guinea: changes in microfilaremia, filarial antigen, and Bm14 antibody after cessation,” American Journal of Tropical Medicine and Hygiene, vol. 78, no. 2, pp. 289–293, 2008.
M. M. Ismail, G. J. Weil, K. S. A. Jayasinghe et al., “Prolonged clearance of microfilaraemia in patients with bancroftian filariasis after multiple high doses of ivermectin or diethylcarbamazine,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 90, no. 6, pp. 684–688, 1996.
D. Kyelem, S. Sanou, B. Boatin, J. Medlock, S. Coulibaly, and D. H. Molyneux, “Impact of long-term ivermectin (Mectizan) on Wuchereria bancrofti and Mansonella perstans infections in Burkina Faso: strategic and policy implications,” Annals of Tropical Medicine and Parasitology, vol. 97, no. 8, pp. 827–838, 2003.
F. O. Richards, A. Eigege, D. Pam et al., “Mass ivermectin treatment for onchocerciasis: lack of evidence for collateral impact on transmission of Wuchereria bancrofti in areas of co-endemicity,” Filaria Journal, vol. 4, article 6, 2005.
K. D. Ramaiah, P. K. Das, P. Vanamail, and S. P. Pani, “Impact of 10 years of diethylcarbamazine and ivermectin mass administration on infection and transmission of lymphatic filariasis,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 101, no. 6, pp. 555–563, 2007.
J. L. Liang, J. D. King, K. Ichimori, T. Handzel, M. Pa'au, and P. J. Lammie, “Impact of five annual rounds of mass drug administration with diethylcarbamazine and albendazole on Wuchereria bancrofti infection in American Samoa,” American Journal of Tropical Medicine and Hygiene, vol. 78, no. 6, pp. 924–928, 2008.
J. U. Mataika, E. Kimura, J. Koroivueta, and M. Shimada, “Efficacy of five annual single doses of diethylcarbamazine for treatment of lymphatic filariasis in Fiji,” Bulletin of the World Health Organization, vol. 76, no. 6, pp. 575–579, 1998.
P. C. Fan, “Eradication of bancroftian filariasis by diethylcarbamazine-medicated common salt on Little Kinmen (Liehyu District), Kinmen (Quemoy) Islands, Republic of China,” Annals of Tropical Medicine and Parasitology, vol. 84, no. 1, pp. 25–33, 1990.
P. C. Fan, H. W. Peng, and C. C. Chen, “Follow-up investigations on clinical manifestations after filariasis eradication by diethylcarbamazine medicated common salt on Kinmen (Quemoy) Islands, Republic of China,” Journal of Tropical Medicine and Hygiene, vol. 98, no. 6, pp. 461–464, 1995.
D. W. Meyrowitsch, P. E. Simonsen, and W. H. Makunde, “Mass diethylcarbamazine chemotherapy for control of bancroftian filariasis through community participation: comparative efficacy of a low monthly dose and medicated salt,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 90, no. 1, pp. 74–79, 1996.
P. Krishnarao, R. Kaur, and T. K. Ghosh, “Long term effect of diethylcarbamazine medicated common salt on bancroftian filariasis,” Journal of Communicable Diseases, vol. 23, no. 2, pp. 128–130, 1991.
S. Adinarayanan, J. Critchley, P. K. Das, and H. Gelband, “Diethylcarbamazine (DEC)-medicated salt for community-based control of lymphatic filariasis,” Cochrane Database of Systematic Reviews, vol. 24, no. 1, Article ID CD003758, 2007.
D. W. Meyrowitsch, P. E. Simonsen, and W. H. Makunde, “Mass DEC chemotherapy for control of bancroftian filariasis: comparative efficacy of four strategies two years after start of treatment,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 90, no. 4, pp. 423–428, 1996.
L. Jingyuan, C. Zi, H. Xiaohang, and T. Zhaoping, “Mass treatment of filariasis using DEC-medicated salt,” Journal of Tropical Medicine and Hygiene, vol. 95, no. 2, pp. 132–135, 1992.
M. V. Narasimham, S. P. Sharma, R. M. Sundaram et al., “Control of bancroftian filariasis by diethylcarbamazine medicated common salt in Karaikal, Pondicherry, India,” Journal of Communicable Diseases, vol. 21, no. 3, pp. 157–170, 1989.
A. R. Freeman, P. J. Lammie, R. Houston et al., “A community-based trial for the control of lymphatic filariasis and iodine deficiency using salt fortified with diethylcarbamazine and iodine,” American Journal of Tropical Medicine and Hygiene, vol. 65, no. 6, pp. 865–871, 2001.
D. W. Meyrowitsch, P. E. Simonsen, and S. M. Magesa, “Long-term effect of three different strategies for mass diethylcarbamazine administration in bancroftian filariasis: follow-up at 10 years after treatment,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 98, no. 11, pp. 627–634, 2004.
I. P. Sunish, R. Rajendran, T. R. Mani, A. Munirathinam, A. P. Dashb, and B. K. Tyagi, “Vector control complements mass drug administration against bancroftian filariasis in Tirukoilur, India,” Bulletin of the World Health Organization, vol. 85, no. 2, pp. 138–145, 2007.
I. P. Sunish, R. Rajendran, T. R. Mani et al., “Resurgence in filarial transmission after withdrawal of mass drug administration and the relationship between antigenaemia and microfilaraemia—a longitudinal study,” Tropical Medicine and International Health, vol. 7, no. 1, pp. 59–69, 2002.
P. E. Simonsen, D. W. Meyrowitsch, D. A. Mukoko et al., “The effect of repeated half-yearly diethylcarbamazine mass treatment on Wuchereria bancrofti infection and transmission in two East African communities with different levels of endemicity,” American Journal of Tropical Medicine and Hygiene, vol. 70, no. 1, pp. 63–71, 2004.
P. Esterre, C. Plichart, Y. Sechan, and N. L. Nguyen, “The impact of 34 years of massive DEC chemotherapy on Wuchereria bancrofti infection and transmission: the Maupiti cohort,” Tropical Medicine and International Health, vol. 6, no. 3, pp. 190–195, 2001.
E. Michael, M. N. Malecela, M. Zervos, and J. W. Kazura, “Global eradication of lymphatic filariasis: the value of chronic disease control in parasite elimination programmes,” PLoS ONE, vol. 3, no. 8, Article ID e2936, 2008.
E. Michael, M. N. Malecela-Lazaro, and J. W. Kazura, “Epidemiological modelling for monitoring and evaluation of lymphatic filariasis control,” Advances in Parasitology, vol. 65, pp. 191–237, 2007.
K. Awadzi, D. A. Boakye, G. Edwards et al., “An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana,” Annals of Tropical Medicine and Parasitology, vol. 98, no. 3, pp. 231–249, 2004.
A. E. Schwab, D. A. Boakye, D. Kyelem, and R. K. Prichard, “Detection of benzimidazole resistance-associated mutations in the filarial nematode Wuchereria bancrofti and evidence for selection by albendazole and ivermectin combination treatment,” American Journal of Tropical Medicine and Hygiene, vol. 73, no. 2, pp. 234–238, 2005.
A. E. Schwab, T. S. Churcher, A. J. Schwab, M. G. Basá？ez, and R. K. Prichard, “An analysis of the population genetics of potential multi-drug resistance in Wuchereria bancrofti due to combination chemotherapy,” Parasitology, vol. 134, no. 7, pp. 1025–1040, 2007.
J. Mccarthy, “Is anthelmintic resistance a threat to the program to eliminate lymphatic filariasis?” American Journal of Tropical Medicine and Hygiene, vol. 73, no. 2, pp. 232–233, 2005.
A. Hoerauf, “Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis,” Current Opinion in Infectious Diseases, vol. 21, no. 6, pp. 673–681, 2008.
A. Hoerauf, S. Mand, K. Fischer et al., “Doxycycline as a novel strategy against bancroftian filariasis - Depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production,” Medical Microbiology and Immunology, vol. 192, no. 4, pp. 211–216, 2003.
M. J. Taylor, W. H. Makunde, H. F. McGarry, J. D. Turner, S. Mand, and A. Hoerauf, “Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomised placebo-controlled trial,” Lancet, vol. 365, no. 9477, pp. 2116–2121, 2005.
A. Y. Debrah, S. Mand, Y. Marfo-Debrekyei et al., “Macrofilaricidal effect of 4 weeks of treatment with doxycycline on Wuchereria bancrofti,” Tropical Medicine and International Health, vol. 12, no. 12, pp. 1433–1441, 2007.
A. Y. Debrah, S. Mand, Y. Marfo-Debrekyei et al., “Reduction in levels of plasma vascular endothelial growth factor-A and improvement in hydrocele patients by targeting endosymbiotic Wolbachia sp. in Wuchereria bancrofti with doxycycline,” American Journal of Tropical Medicine and Hygiene, vol. 80, no. 6, pp. 956–963, 2009.
J. D. Turner, S. Mand, A. Y. Debrah et al., “A randomized, double-blind clinical trial of a 3-week course of doxycycline plus albendazole and ivermectin for the treatment of Wuchereria bancrofti infection,” Clinical Infectious Diseases, vol. 42, no. 8, pp. 1081–1089, 2006.
A. Y. Debrah, S. Mand, S. Specht et al., “Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis.,” PLoS Pathogens, vol. 2, no. 9, article e92, 2006.
M. V. Weerasooriya, N. K. Gunawardena, M. Itoh, X. G. Qiu, and E. Kimura, “Prevalence and intensity of Wuchereria bancrofti antigenaemia in Sri Lanka by Og4C3 ELISA using filter paper-absorbed whole blood,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 96, no. 1, pp. 41–45, 2002.
