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Efficacy and tolerability of two single-day regimens of triclabendazole for fascioliasis in Peruvian children

Abstract:

INTRODUCTION:

The therapeutic scheme of triclabendazole (TCBZ), the recommended anthelmintic against Fasciola hepatica , involves 10mg/kg of body weight administered in a single dose; however, clinical trials in children are scarce. We evaluated the efficacy and tolerability of 2 schemes of TCBZ.

METHODS

: Eighty-four Peruvian children with F. hepatica eggs in their stools were allocated into 2 groups: 44 received 2 dosages of 7.5mg/kg each with a 12-h interval (Group I), and 40 received a single 10-mg/kg dose (Group II). Evaluation of efficacy was based on the presence of eggs in stools, and tolerability was based on the presence of symptoms and signs post-treatment.

RESULTS

: A parasitological cure was obtained in 100% of individuals from Group I and 95% of individuals from Group II. The most common adverse event was biliary colic.

CONCLUSIONS

: The tested scheme was efficacious and tolerable, and it might be an optimal scheme in the region. To the best of our knowledge, this represents the largest series of children treated with TCBZ in a non-hospital setting.

Keywords:
Fascioliasis; Treatment; Children; Highlands; Peru

INTRODUCTION

Fascioliasis is a zoonotic disease caused by Fasciola hepatica ( F. hepatica ) or Fasciola gigantica ( F. gigantica ) that disproportionally affects poor people living in cattle-raising areas and has a diverse distribution in all continents 1Mas-Coma MS, Esteban JG, Bargues MD. Epidemiology of human fascioliasis: a review and proposed new classification. Bull World Health Organ 1999; 77: 340-346. 2Mas-Coma S. Epidemiology of fascioliasis in human endemic areas. J Helminthology 2005; 79: 207-216. . Humans acquire the disease through the consumption of aquatic, semi-aquatic, or waterside undercooked or raw vegetables; consumption of drinking water; or use of fomites infected with the larval stage metacercariae 3Mas-Coma S, Bargues MD, Valero MA. Fascioliasis and other plant-borne trematode zoonoses. Int J Parasitol 2005; 35: 1255-1278. . Human fascioliasis is an important public health problem that affects several regions in Peru 4Marcos LA, Terashima A, Leguia G, Canales M, Espinoza JR, Gotuzzo E. Fasciola hepatica infection in Peru: an emergent disease. Rev Gastroenterol Peru 2007; 27:389-396.including the Mantaro Valley in Junín 5Stork MG, Venables GS, Jennings SM, Beesley JR, Bendezu P, Capron A. An investigation of endemic fascioliasis in Peruvian village children. J Trop Med Hyg 1973; 76: 231-235. 6Marcos LA, Maco V, Terashima A, Samalvides F, Miranda E, Tantalean M et al Hyperendemicity of human fasciolosis in the Mantaro Valley, Peru: factors for infection with Fasciole hepatica . Rev Gastroenterol Peru2004; 24:158-164. the Altiplano in Puno 7Sánchez C. Distomatosis hepática en la población humana de la irrigación Asillo-Azángaro-Puno. Libro de Resúmenes del XI Congreso Latinoamericano de Parasitología y I Congreso Peruano de Parasitología; 1993: p. 50. , the Cajamarca Valley 8Ortiz P, Cabrera M, Jave J, Williams D. Human fascioliasis: prevalence and treatment in a rural area of Peru. Infect Dis Rev 2000; 2:42-46. , Arequipa 9Espinoza JR, Terashima A, Herrera-Velit P, Marcos LA. Human and animal fascioliasis in Peru: impact in the economy of endemic zones. Rev Peru Med Exp Salud Publica 2010; 27:604-612. , and Huarochirí in Lima 1010 Marcos L, Romani L, Florencio LE, Terashima A, Canales M, Nestares J et al Zonas Hiperendémicas y Mesoendémicas de la Infección por Fasciola hepática aledañas a la Ciudad de Lima: una Enfermedad Emergente. Rev Gastroenterol Peru2007; 27: 31-36. .

Since the first cases reported in Peru by Edmundo Escomel in 1924 1111 Zegarra N. Distomatosis hepatica. Primer Congreso Peruano de Gastroenterologia. Lima, Peru; 1964. 1212 .Naquira C. Edmundo Escomel: 1880-1959. Acta Med Per 2006; 23:193-195. , the chemotherapeutic armamentarium to treat human fascioliasis has been limited for decades, and most treatments had to be discontinued due to adverse events. Emetine hydrochloride (30-60mg/day intramuscularly for 8-18 days) was effective but also highly toxic; it can cause cardiac arrhythmias including atrial ectopic beats, bradycardia, hypotension, and vomiting 1111 Zegarra N. Distomatosis hepatica. Primer Congreso Peruano de Gastroenterologia. Lima, Peru; 1964. 1313 Hadden JW, Pascarelli EF. Diagnosis and treatment of human fascioliasis. JAMA 1967; 202:149-151. 1414 Ashton WL, Boardman PL, D'Sa CJ, Everall PH, Houghton AW. Human fascioliasis in Shropshire. Br Med J 1970; 3:500-502. 1515 Hardman EW, Jones RL, Davies AH. Fascioliasis--a large outbreak. Br Med J1970; 3:502-505. 1616 Diaz J, Pina B, Lastre M, Rivera L, Perez O. Epidemic human fascioliasis. Cuba 1983. VI. Clinical study of 40 children in the Hospital Provincial of Sagua la Grande. G e N 1990; 44:385-388. , had to sometimes be co-administered with steroids 1111 Zegarra N. Distomatosis hepatica. Primer Congreso Peruano de Gastroenterologia. Lima, Peru; 1964. , and required hospitalization for monitoring. Chloroquine was also used, with limited efficacy 1515 Hardman EW, Jones RL, Davies AH. Fascioliasis--a large outbreak. Br Med J1970; 3:502-505. . Bithionol also caused abnormalities in cardiac rhythm such as extrasystoles, first-degree heart block, and hypertension as well as gastrointestinal disturbances such as diarrhea, abdominal pain, nausea, vomiting, anorexia, and urticaria 1414 Ashton WL, Boardman PL, D'Sa CJ, Everall PH, Houghton AW. Human fascioliasis in Shropshire. Br Med J 1970; 3:500-502. 1717 Farag HF, Salem A, el-Hifni SA, Kandil M. Bithionol (Bitin) treatment in established fascioliasis in Egyptians. J Trop Med Hyg1988; 91:240-244. 1818 Gorgolas M, Torres R, Verdejo C, Garay J, Robledo A, Ponte MC et al. Fasciola hepatica infestation. Biopathology and new diagnostic and therapeutic aspects. Enferm Infecc Microbiol Clin 1992; 10:514-519. 1919 Price TA, Tuazon CU, Simon GL. Fascioliasis: case reports and review. Clin Infect Dis 1993; 17:426-430. 2020 García ML, Marugan de Miguelsanz JM, Ordóñez MJ, Costilla S, Díez N. Fascioliasis hepática: Un nuevo caso en la infancia. An Esp Pediatr 1999; 50: 65-67. . Other drugs such as praziquantel 1818 Gorgolas M, Torres R, Verdejo C, Garay J, Robledo A, Ponte MC et al. Fasciola hepatica infestation. Biopathology and new diagnostic and therapeutic aspects. Enferm Infecc Microbiol Clin 1992; 10:514-519. 1919 Price TA, Tuazon CU, Simon GL. Fascioliasis: case reports and review. Clin Infect Dis 1993; 17:426-430. 2121 Knobloch J, Delgado E, Alvarez A, Reymann U, Bialek R. Human fascioliasis in Cajamarca/Peru. I. Diagnostic methods and treatment with praziquantel. Trop Med Parasitol 1985; 36:88-90. 2222 Schiappacasse RH, Mohammadi D, Christie AJ. Successful treatment of severe infection with Fasciola hepatica with praziquantel. J Infect Dis 1985; 152:1339-1340. 2323 Farid Z, Trabolsi B, Boctor F, Hafez A. Unsuccessful use of praziquantel to treat acute fascioliasis in children. J Infect Dis1986; 154:920-921. 2424 Ishii Y, Nakamura-Uchiyama F, Nawa Y. A praziquantel-ineffective fascioliasis case successfully treated with triclabendazole. Parasitol Int 2002; 51:205-209. 2525 Ripert CL. Praziquantel and Fasciola hepatica infection. Trans R Soc Trop Med Hyg 1990; 84:610. , metronidazole 2626 Nik-Akhtar B, Tabibi V. Metronidazole in fascioliasis: report of four cases. J Trop Med Hyg1977; 80:179-180. , and niclofolan 2727 Eckhardt T, Heckers H. Treatment of human fascioliasis with niclofolan. Gastroenterology 1981; 81:795-798. had discouraging or discrepant results, and albendazole 2828 Yilmaz H, Oner AF, Akdeniz H, Arslan S. The effect of triclabendazole (Fasinex) in children with fasciolosis. J Egypt Soc Parasitol 1998; 28:497-502. , mebendazole 2929 Laird PP, Boray JC. Human fascioliasis successfully treated with triclabendazole. Aust N Z J Med 1992; 22:45-47. , and phanquinone 1818 Gorgolas M, Torres R, Verdejo C, Garay J, Robledo A, Ponte MC et al. Fasciola hepatica infestation. Biopathology and new diagnostic and therapeutic aspects. Enferm Infecc Microbiol Clin 1992; 10:514-519. were not effective. Nitazoxanide had an efficacy of 94% after a 7-day course in a Mexican study and could be considered as a second line option 3030 Zumaquero-Rios JL, Sarracent-Perez J, Rojas-Garcia R, Rojas-Rivero L, Martinez-Tovilla Y, Valero MA et al. Fascioliasis and intestinal parasitoses affecting schoolchildren in atlixco, puebla state, Mexico: epidemiology and treatment with nitazoxanide. PLoS Negl Trop Dis 2013; 7:e2553. ; however, it has lower cure rates in Peruvian children (40% as compared with placebo) 3131 Favennec L, Jave Ortiz J, Gargala G, Lopez Chegne N, Ayoub A, Rossignol JF. Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru. Alimentary Pharmacol Ther 2003; 17: 265-270. and requires a longer therapeutic time than a single dose of triclabendazole (TCBZ), resulting in greater expense for the rural communities of Peru.

Triclabendazole, or 5-chloro-6-(2,3-dichlorophenoxy)-2[methylthio] benzimidazole, acts against the microtube-dependent secretory processes in F. hepatica , was first used in animals in 1983 and humans in 1986 3232 Wessely K, Reischig HL, Heinerman M, Stempka R. Human fascioliasis treated with triclabendazole (Fasinex) for the first time. Trans R Soc Trop Med Hyg1988; 82:743-744. 3333 Markwalder K, Koller M, Goebel N, Wolff K. Fasciola hepatica infection. Successful therapy using triclabendazole. Schweiz Med Wochenschr 1988; 118:1048-1052. , and has a well-established therapeutic use in human fascioliasis and paragonimiasis 3434 Keiser J, Engels D, Buscher G, Utzinger J. Triclabendazole for the treatment of fascioliasis and paragonimiasis. Expert Opin Investig Drugs 2005; 14:1513-1526. . The compound represents the first-line treatment against fascioliasis in different regions of the world 2323 Farid Z, Trabolsi B, Boctor F, Hafez A. Unsuccessful use of praziquantel to treat acute fascioliasis in children. J Infect Dis1986; 154:920-921. 2424 Ishii Y, Nakamura-Uchiyama F, Nawa Y. A praziquantel-ineffective fascioliasis case successfully treated with triclabendazole. Parasitol Int 2002; 51:205-209. 2525 Ripert CL. Praziquantel and Fasciola hepatica infection. Trans R Soc Trop Med Hyg 1990; 84:610. 2626 Nik-Akhtar B, Tabibi V. Metronidazole in fascioliasis: report of four cases. J Trop Med Hyg1977; 80:179-180. 2727 Eckhardt T, Heckers H. Treatment of human fascioliasis with niclofolan. Gastroenterology 1981; 81:795-798. 2828 Yilmaz H, Oner AF, Akdeniz H, Arslan S. The effect of triclabendazole (Fasinex) in children with fasciolosis. J Egypt Soc Parasitol 1998; 28:497-502. 2929 Laird PP, Boray JC. Human fascioliasis successfully treated with triclabendazole. Aust N Z J Med 1992; 22:45-47. 3232 Wessely K, Reischig HL, Heinerman M, Stempka R. Human fascioliasis treated with triclabendazole (Fasinex) for the first time. Trans R Soc Trop Med Hyg1988; 82:743-744. 3333 Markwalder K, Koller M, Goebel N, Wolff K. Fasciola hepatica infection. Successful therapy using triclabendazole. Schweiz Med Wochenschr 1988; 118:1048-1052. , and is recommended by the World Health Organization (WHO) as the first-line drug in all cases of fascioliasis 3535 World Health Organization. (WHO). Report of the WHO expert consultation on foodborne trematode infections and taeniasis/cysticercosis. Vientiane, Lao People's Democratic Republic. Geneva, Switzerland: WHO; 2011. . However, most of these studies have been performed in adults, and few data are available for children 3131 Favennec L, Jave Ortiz J, Gargala G, Lopez Chegne N, Ayoub A, Rossignol JF. Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis in adults and children from northern Peru. Alimentary Pharmacol Ther 2003; 17: 265-270. 3636 Villegas F, Angles R, Barrientos R, Barrios G, Valero MA, Hamed K et al. Administration of triclabendazole is safe and effective in controlling fascioliasis in an endemic community of the Bolivian Altiplano. PLoS Negl Trop Dis2012; 6:e1720. , who are generally the most affected in Peru, Bolivia, and Egypt 2Mas-Coma S. Epidemiology of fascioliasis in human endemic areas. J Helminthology 2005; 79: 207-216. . The veterinary TCBZ formulation (Fasinex(r)), successfully used for the first time in 1986, has proven to be effective and tolerable in humans 3232 Wessely K, Reischig HL, Heinerman M, Stempka R. Human fascioliasis treated with triclabendazole (Fasinex) for the first time. Trans R Soc Trop Med Hyg1988; 82:743-744. 3333 Markwalder K, Koller M, Goebel N, Wolff K. Fasciola hepatica infection. Successful therapy using triclabendazole. Schweiz Med Wochenschr 1988; 118:1048-1052. .

We aimed to evaluate the efficacy and tolerability of two therapeutic schemes of TCBZ among children using both a TCBZ suspension (Fasinex(r)) and TCBZ tablets (Egaten(r)) in an open-label, randomized study in different endemic areas in Peru under field conditions.

METHODS

Study sites and design

This open-label, phase II, multicentric clinical trial was conducted between 2001 and 2006 in 5 rural areas of several endemic areas ( Figure 1 ): 1 in the district of Asillo (3,895m/12,778 f) in the province of Azángaro, Puno (recruited between March and August 2001); 1 in the district of Lachaqui (2,819m/9,248 f) in the province of Canta, Lima (recruited between March and August 2005); 1 each in the districts of Anta (3,345m/10,974 f) and Sicuani (3,552 m/11,653 f) in the provinces of Anta and Canchis, Cusco, respectively (recruited between March and August 2005); and 1 in the district of Jauja (3,353m/11,000 f) in the province of the same name, Junín (recruited between July and August 2005). Participants were recruited from a field validation study using a serological test against F . hepatica 3737 Espinoza JR, Maco V, Marcos L, Saez S, Neyra V, Terashima A et al. Evaluation of Fas2-ELISA for the serological detection of Fasciola hepatica infection in humans. Am J Trop Med Hyg2007; 76:977-982. and a series of coprological-based, longitudinal epidemiological studies 1010 Marcos L, Romani L, Florencio LE, Terashima A, Canales M, Nestares J et al Zonas Hiperendémicas y Mesoendémicas de la Infección por Fasciola hepática aledañas a la Ciudad de Lima: una Enfermedad Emergente. Rev Gastroenterol Peru2007; 27: 31-36. 3838 Marcos L, Maco V, Samalvides F, Terashima A, Espinoza JR, Gotuzzo E. Risk factors for Fasciola hepatica infection in children: a case-control study. Trans R Soc Trop Med Hyg2006; 100:158-166. .

Figure 1:
Study sites along the Highlands of Peru, which are hyperendemic areas for human fascioliasis. The Asillo irrigation canals are located in the district of the same name in Azángaro, Puno, at an altitude of 3,895m.

Case definition

A case was defined as an individual aged 2-16 years residing in a study site at the time of recruitment with confirmed fascioliasis (presence of characteristic eggs of the fluke F . hepatica [130-150µm × 80-85µm operculate eggs] in at least 1 single stool sample using the rapid sedimentation technique (RST) 3939 Lumbreras H, Cantella R, Burga R. Acerca de un procedimiento de sedimentación rápida para investigar huevos de Fasciola hepatica en las heces, su evaluación y uso en el campo. Rev Medica Peruana 1962; 31:167-174. , and/or the Kato-Katz (KK) method 4040 Katz N, Chaves A, Pellegrino J. A simple device for quantitative stool thick-smear technique in Schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo 1972; 14:397-400. . Exclusion criteria were any acute or severe illness during the study period or a known chronic liver disease; known pregnancy, lactation, or a positive urine test for β-human chorionic gonadotrophin (β-hCG) hormone; drug therapy for F . hepatica or other parasitic infection administered 30 days before enrollment; history of allergy to benzimidazoles; and/or concurrent use of drugs with known TCBZ interactions.

Anthelmintic and therapeutic schemes

Given the unavailability of the human TCBZ formulation in Peru in 2001 (the compound was approved by the Ministry of Health of Peru in 2005 owing to the high prevalence of human fascioliasis), we had to use the veterinary TCBZ formulation (Fasinex(r)) for all participants in the district of Asillo, under strict surveillance, monitoring of side effects, and local ethical approval. The human TCBZ formulation (Egaten(r), 250-mg tablets, donated by Novartis Pharma AG, Basel, Switzerland) was used in the remaining study sites.

Eligible volunteers were sequentially assigned to 1 of 2 therapeutic schemes based on a block randomization schedule: Group I received 15mg/kg TCBZ orally in two 7.5-mg/kg doses after a meal (breakfast and dinner), separated by a 12h-interval; Group II received a single 10mg/kg dose of TCBZ after breakfast or dinner. The meals were consumed a maximum of 30 min before drug administration to improve systemic bioavailability 4141 De Ronde T, Melange M, Van Beers B, Trigaux JP, Dive C, Lecaillon JB et al. Distomatosis of the bile ducts. Value of retrograde cholangiography. Efficacy of triclabendazole. Acta Clin Belg 1992; 47:209-214. 4242 Lecaillon JB, Godbillon J, Campestrini J, Naquira C, Miranda L, Pacheco R et al. Effect of food on the bioavailability of triclabendazole in patients with fascioliasis. Br J Clin Pharmacol 1998; 45:601-604. .

We hypothesized a dose-response cure rate (efficacy), with limited side effects and using oral antispasmodic therapy as needed (tolerability). The spasmolytic agent was anticholinergic hyoscine butylbromide, based on body weight (kg).

Efficacy evaluation

The primary outcome of efficacy was evaluated at 60 days post-treatment according to the presence (parasitological failure) or absence (parasitological cure) of eggs compatible with F . hepatica using either RST or KK of a stool sample.

One pre-treatment KK thick smear was performed on all stool samples. A total of 6 post-treatment stool samples were also examined for each individual. Stool samples were collected on post-treatment days 1, 3, 5, 10, 30, and 60 in Asillo and on post-treatment days 30, 60, 90, 120, 150, and 180 in Lachaqui, Anta, Sicuani, and Jauja. All of the stool samples were transported to the Laboratory of Parasitology of the Institute of Tropical Medicine Alexander von Humboldt (ITM AvH), Cayetano Heredia University (UPCH) in Lima and examined by an experienced technician using RST for qualitative diagnosis.

Tolerability

Secondary outcomes for the TCBZ tolerability were documented by evaluating the symptoms and signs at each site (Peripheral Primary Health Care Centers) daily during the first 7 days post-treatment for close surveillance and directed intervention of any adverse events. A local, trained physician at each site recorded demographic data and daily signs, symptoms, and adverse events (biliary colic, abdominal and epigastric pain; nausea or vomiting; diarrhea; anorexia; jaundice; pruritus; skin rash; headaches; dizziness; dyspnea; cough; cervical, thoracic, lumbar or muscular pain; and use of antispasmodics). Because pain intensity is inherently subjective, we stratified pain as severe (symptoms required observation and treatment by the physician at the health care center), moderate (symptoms were managed at home and did not require physician intervention), or mild (symptoms did not require any intervention but were only reported to the physician during follow up). Routine physical examinations were performed on a periodic schedule until day 90.

Quantitative assessment of infection intensity

To quantify the infection intensity (egg output), we collected and conducted KK thick smears with post-treatment stool samples from all participants only in the district of Asillo on a more frequent basis: every other day during the first week (days 1, 3, and 5) and then on days 10, 30, and 60. Serology and eosinophilia were assessed to evaluate the subgroup homogeneity prior to treatment allocation. An enzyme-linked immunosorbent assay (ELISA) assessment was also offered to detect immunoglobulin G (IgG) against the 25KDa excretory/secretory antigen Fas 2. A cut-off value of >0.20 units of optical density (OD) measured at 450nm was considered positive 4343 Maco V, Marcos L, Terashima A, Samalvides F, Miranda E, Espinoza J et al. Fas2-ELISA y la técnica de sedimentación rápida modificada por Lumbreras en el diagnóstico de la infección por Fasciola hepatica . Rev Med Hered 2002; 13:49-57. . A complete blood count to measure baseline eosinophilia (eosinophils >500/cc) was also performed.

Statistical analysis

Data were double entered and analyzed using Statistical Package for the Social Sciences (SPSS)(r), v21 (IBM(r) Corp, Armonk, NY) and STATA 12.1 (StataCorp, College Station, TX). A sample size calculation was not performed because the study was designed to estimate the dose-response and safety of TCBZ.

First, univariate analyses were performed to calculate frequencies and percentages (and 95% confidence intervals [CIs]) for discrete variables and mean and standard deviation for continuous variables. Bivariate analyses using Chi-square tests ( X 2) or Student's t -tests were performed for discrete or continuous variables, respectively. A p value <0.05 was considered statistically significant for all tests. The adverse events were reported and tabulated for each regimen.

Geographical data and coordinates for the map with the study sites ( Figure 1 ) were obtained from the National Geographic Institute of Peru and manually entered into the visual processor Smart Draw(r) v2012 (San Diego, CA).

Ethical considerations

Written informed consent was obtained from the participants' parents or guardians before recruitment. Because this clinical trial involved a vulnerable population, and, most importantly, given that the human TCBZ formulation was not available in Peru at the time of the study, we verbally emphasized the use of the veterinary compound to the parents and community leaders as well as in the consent form (see supplemental file). Confidentiality was maintained at all points of the study. Treatment was provided free-of-charge. Efficacy and tolerability results were reviewed by an independent medical monitor.

The study protocol was approved by the Institutional Ethics Committee of the UPCH in September 04, 2001 (Project No. 01086) and then renewed and registered by the same committee under the Research Project No. 0000050647 on July 01, 2005 (http://www.upch.edu.pe/vrinve/duict; see supplemental files).

RESULTS

Total population

The mean age of the 84 individuals (Asillo: n = 59; Canta: n = 4; Anta and Sicuani: n = 3; and Jauja: n = 18) was 9.27 (2.48) years. No statistically significant differences in age, sex, or infection intensity were found between the groups (Group I, n = 44, 52.4%; Group II, n = 40, 47.6%) (p-value > 0.05). None of the children had a high-intensity infection [>400 eggs per gram (EPG) of stool].

Efficacy results

All cases were cured in Group I (100%); persistent F . hepatica infection was present in 2 individuals (2/40; 5%) in Group II (1 each from Asillo and Lachaqui), resulting in a cure rate of 95% (38/40). These 2 individuals in Group II were retreated with a similar TCBZ dose and cured, reaching an efficacy of 100% after the second dose. One from Asillo had positive results on day 60 and 1 from Lachaqui had positive results on days 14 and 30. The latter received a further single 10-mg/kg TCBZ dose on day 30 (on day 60, no eggs were detected in his stool). On day 60, all of the participants showed negative results for the stool samples.

Signs, symptoms, and adverse events

The signs, symptoms, and adverse events from post-treatment days 1 to 7 are shown in Table 1 . The most common adverse event was biliary colic, which occurred in 25% of Group II (95% CI: 11.9-38.9) on day 2 post-treatment and subsequently decreased on days 3 (12.5%, 95% CI: 4.8-24.3), 4 (15%, 95% CI: 3.1-22.4), 5 (5%, 95% CI: 0.0-11.7), and 7 (2.5%, 95% CI: 0.0-8.9). While the intensity varied from mild to severe during days 1 to 7, only severe intensity was experienced on days 2 and 4 in 2.5% of Group II (95% CI: 0.0-6.8). Severe biliary colic occurred in 4.5% of Group I (95% CI: 0.0-15.2) on day 2. All of the cases (n = 4) with severe biliary colic responded to antispasmodic medication within 2 hours and did not require any further medical or surgical intervention.

TABLE 1:
Percentages of adverse events from days 1 to 7 post-treatment with triclabendazole in children in Peru.

Mild to moderate abdominal pain was reported on days 1 to 5, affecting 20% of Group I (95% CI: 11.8-33.1) and 15% of Group II (95% CI: 3.1-29.2) on day 2. Mild to severe epigastric pain was reported on days 1 to 6, affecting 18.2% of Group I (95% CI: 8.2-32.1) and 17.5% of Group II (95% CI: 6.1-30.7) on day 2. Only 2.5% of Group II (95% CI: 0.0-6.8) experienced severe abdominal pain on day 2.

The frequency of mild to moderate headaches varied from 4.5% on days 1 and 3 to 11.4% on day 2 in Group I. The occurrence of nausea and vomiting in Group I varied from 2.3% (95% CI: 0.0-8.4) on days 2 and 3 to 6.8% (95% CI: 0.0-14.4) on day 5. The occurrence of anorexia in Group I ranged from 2.3% (95% CI: 0.0-6.6) on day 2 to 9.1% (95% CI: 2.5-18.2) on day 4.

A sharp decrease in the occurrence of clinical signs and symptoms was observed in all groups at 7 days post-treatment. Patients remained without signs and symptoms 60 days post-treatment, and no cases of diarrhea, jaundice, pruritus, skin rash, dizziness, dyspnea, cough, or cervical, thoracic, lumbar, or muscular pain were reported. None of the participants were withdrawn from the study due to adverse events during the follow-up period. All of the participants completed the study period (60 days in Asillo, 180 days in the remaining sites).

Population subset of Asillo

All 59 participants in Asillo (Group I, n = 31; Group II, n = 28) provided stools samples on days 1, 3, 5, 10, 30, and 60; 81.3% (48/59) and 62.7% (37/59) provided sera for Fas 2 ELISA and baseline eosinophilia, respectively. At the time of recruitment (2001), they all received the veterinary TCBZ formulation (Fasinex(r)). Table 2 summarizes the age, sex, infection intensity, serology studies, and baseline eosinophilia in the Asillo population subset.

Table 2:
Baseline characteristics of children from Asillo, Peru (n = 59) treated with the veterinary triclabendazole formulation.

The entire subset had a mean OD of 0.35 (0.13) with the Fas 2 ELISA: 0.33 (0.15) in Group I (25/48) and 0.38 (0.12) in Group II (23/48) (p - value = 0.65). The entire subset had a mean eosinophil count of 876.46 (1,403 cells/cc) (range, 0-7,150): 745 (1,121) cells/cc (range, 0-5,124) in Group I (21/37) and 1,049 (1,729) cells/cc (range, 0-7,150) in Group II (16/37) (p -value 0.61).

Assessment of post-treatment infection intensity

The post-treatment infection intensity in the subset of Asillo (n = 59) is summarized in Table 3 . The mean EPG was higher in Group II than in Group I on post-treatment days 1 (56.00 vs. 50.52; p-value = 0.05) and 10 (6.00 vs. 1.87; p-value = 0.05). The mean EPG in Group I steadily decreased from 50.82 on post-treatment day 1 to 1.87 on day 5 and became undetectable on days 30 and 60. In contrast, the mean EPG in Group II decreased from 56.0 on post-treatment day 1 to 6.0 on day 5 and remained unchanged until day 60. There were no statistically significant differences between the two groups on days 1 (p-value = 0.85), 3 (p-value = 0.92) 5 (p- value = 0.57), or 10 (p-value = 0.46).

TABLE 3:
Mean egg count per gram of stool during the 60-day triclabendazole treatment in Asillo, Peru, calculated using a 1 Kato-Katz thick smear.

DISCUSSION

The overall cure rate with TCBZ was ˃95% using either the veterinary (Fasinex(r)) or human formulation (Egaten(r)) in 84 children aged 2-16 years, which represents the largest pediatric series under field conditions (non-hospital settings). Furthermore, the tolerability was high with both treatment schemes, contributing to the safety data of this anthelmintic.

Although the therapeutic scheme involving 15mg/kg oral TCBZ administered as two post-prandial doses of 7.5mg/kg each with a 12-h interval had a higher cure rate (100%) than the single postprandial 10mg/kg TCBZ dose, the difference was not statistically significant. Similar results (cure in at least ~80%) have been reported previously; however, these studies also included adults 4444 Hammouda NA, el-Mansoury ST, el-Azzouni MZ, el-Gohari Y. Therapeutic effect of triclabendazole in patients with fascioliasis in Egypt. A preliminary study. J Egypt Soc Parasitol1995; 25:137-143. 4545 Yadegari D, Talaie H, Massoud J. Clinical trial of triclabendazole on human fascioliasis: Long term follow up. Med J Islamic Rep Iran 1999; 13:89-91. 4646 Millan JC, Mull R, Freise S, Richter J. The efficacy and tolerability of triclabendazole in Cuban patients with latent and chronic Fasciola hepatica infection. Am J Trop Med Hyg2000; 63:264-269. 4747 Talaie H, Emami H, Yadegarinia D, Nava-Ocampo AA, Massoud J, Azmoudeh M et al. Randomized trial of a single, double and triple dose of 10 mg/kg of a human formulation of triclabendazole in patients with fascioliasis. Clin Exp Pharmacol Physiol 2004; 31:777-782. 4848 Ulger BV, Kapan M, Boyuk A, Uslukaya O, Oguz A, Bozdag Z et al. Fasciola hepatica infection at a University Clinic in Turkey. J Infect Dev Ctries 2014; 8:1451-1455. , administered different doses of TCBZ 4545 Yadegari D, Talaie H, Massoud J. Clinical trial of triclabendazole on human fascioliasis: Long term follow up. Med J Islamic Rep Iran 1999; 13:89-91. , included fewer subjects (n ≤10) 2828 Yilmaz H, Oner AF, Akdeniz H, Arslan S. The effect of triclabendazole (Fasinex) in children with fasciolosis. J Egypt Soc Parasitol 1998; 28:497-502. 4444 Hammouda NA, el-Mansoury ST, el-Azzouni MZ, el-Gohari Y. Therapeutic effect of triclabendazole in patients with fascioliasis in Egypt. A preliminary study. J Egypt Soc Parasitol1995; 25:137-143. 4949 Kabaalioglu A, Ceken K, Saba R, Artan R, Cevikol C, Yilmaz S. Pediatric fascioliasis: report of three cases. Turk J Pediatr 2003; 45:51-54. , or administered a fasting or post-prandial dose 5050 Jave JA, Alban M, Sagastegui C, Soriano S. Tratamiento de la Fasciolasis Hepática Humana con Triclabendazole. Rev Gastroenterol Peru1999; 19:216-220. .

Case reports and series evaluating the efficacy of flukicidal drugs in children are scant or limited. Before the advent of TCBZ, praziquantel was administered to 34 individuals in Peru (n = 19, 8-15 years old), with an overall cure rate of 21% 2121 Knobloch J, Delgado E, Alvarez A, Reymann U, Bialek R. Human fascioliasis in Cajamarca/Peru. I. Diagnostic methods and treatment with praziquantel. Trop Med Parasitol 1985; 36:88-90. . In Egypt, a small series of 7 children (aged 4-10 years) were unsuccessfully treated with praziquantel 2323 Farid Z, Trabolsi B, Boctor F, Hafez A. Unsuccessful use of praziquantel to treat acute fascioliasis in children. J Infect Dis1986; 154:920-921. , whereas another series of 8 children (aged 4-16 years) were treated with bithionol but required long-term therapy 1717 Farag HF, Salem A, el-Hifni SA, Kandil M. Bithionol (Bitin) treatment in established fascioliasis in Egyptians. J Trop Med Hyg1988; 91:240-244. . In Cuba, 40 children (aged 1-14 years) were treated with emetine hydrochloride, but efficacy was not evaluated 1616 Diaz J, Pina B, Lastre M, Rivera L, Perez O. Epidemic human fascioliasis. Cuba 1983. VI. Clinical study of 40 children in the Hospital Provincial of Sagua la Grande. G e N 1990; 44:385-388. . Case reports 5151 Iglesias Escalera G, Elvira Pardilla AI, Rodrigo Palacios J, Merino Arribas JM, Marrero Calvo M, García Bravo M et al. Tratamiento con triclabendazol en la fasciolasis hepática infantil. An Esp Pediatr2002; 57:171-172. , small series 2828 Yilmaz H, Oner AF, Akdeniz H, Arslan S. The effect of triclabendazole (Fasinex) in children with fasciolosis. J Egypt Soc Parasitol 1998; 28:497-502. 4444 Hammouda NA, el-Mansoury ST, el-Azzouni MZ, el-Gohari Y. Therapeutic effect of triclabendazole in patients with fascioliasis in Egypt. A preliminary study. J Egypt Soc Parasitol1995; 25:137-143. 4949 Kabaalioglu A, Ceken K, Saba R, Artan R, Cevikol C, Yilmaz S. Pediatric fascioliasis: report of three cases. Turk J Pediatr 2003; 45:51-54. 5252 Karadag-Oncel E, Ozsurekci Y, Ozkaya-Parlakay A, Celik M, Cengiz AB, Haliloglu M et al. Fasciola hepatica infection: clinical and radiological findings in pediatric patients. Turk J Pediatr2012; 54:362-367. , and larger trials of TCBZ treatment in pediatric populations have been described. A cure rate of 79.2% was obtained in 24 individuals (14 children, 11-16 years old) in Chile with a single 10-mg/kg TCBZ dose (Fasinex(r)) administered after an overnight fast, which might have altered the absorption of the drug 5353 Apt W, Aguilera X, Vega F, Miranda C, Zulantay I, Perez C et al. Treatment of human chronic fascioliasis with triclabendazole: drug efficacy and serologic response. Am J Trop Med Hyg1995; 52:532-535. ; similarly, a cure rate of 77.5% was obtained after a single 10-mg/kg post-prandial dose in 40 children (4-15 years old) 5454 El-Karaksy H, Hassanein B, Okasha S, Behairy B, Gadallah I. Human fascioliasis in Egyptian children: successful treatment with triclabendazole. J Trop Pediatrics 1999; 45:135. . One of the largest series to assess the efficacy of TCBZ included 38 children (aged 0-15 years) in Peru, with an overall cure rate of 83% 5050 Jave JA, Alban M, Sagastegui C, Soriano S. Tratamiento de la Fasciolasis Hepática Humana con Triclabendazole. Rev Gastroenterol Peru1999; 19:216-220. . More recently, a cure rate of 77.8% in 80 pediatric outpatients and 10 pediatric inpatients (aged 5-14 years) was achieved in Bolivia with a single 10-mg/kg dose 3636 Villegas F, Angles R, Barrientos R, Barrios G, Valero MA, Hamed K et al. Administration of triclabendazole is safe and effective in controlling fascioliasis in an endemic community of the Bolivian Altiplano. PLoS Negl Trop Dis2012; 6:e1720. .

Although the cure rates with a single 10-mg/kg dose of TCBZ range from 69 to 79.4%, the cure rates with a double dose are reportedly higher (76.9 vs. 69% 4545 Yadegari D, Talaie H, Massoud J. Clinical trial of triclabendazole on human fascioliasis: Long term follow up. Med J Islamic Rep Iran 1999; 13:89-91. and 75 vs. 69.8% 4747 Talaie H, Emami H, Yadegarinia D, Nava-Ocampo AA, Massoud J, Azmoudeh M et al. Randomized trial of a single, double and triple dose of 10 mg/kg of a human formulation of triclabendazole in patients with fascioliasis. Clin Exp Pharmacol Physiol 2004; 31:777-782. in adults. A higher cure rate was obtained with two 10-mg/kg doses (mean age, 16.10 years) than with 1 dose (mean age, 14.20 years) (93.9 vs. 79.4%) 5555 el-Morshedy H, Farghaly A, Sharaf S, Abou-Basha L, Barakat R. Triclabendazole in the treatment of human fascioliasis: a community-based study. East Mediterr Health J 1999; 5:888-894. . In Peru, cure rates of 83% 5050 Jave JA, Alban M, Sagastegui C, Soriano S. Tratamiento de la Fasciolasis Hepática Humana con Triclabendazole. Rev Gastroenterol Peru1999; 19:216-220. , and 100% (13 children aged 3-17 years) 8Ortiz P, Cabrera M, Jave J, Williams D. Human fascioliasis: prevalence and treatment in a rural area of Peru. Infect Dis Rev 2000; 2:42-46. were reported after administering two 12-mg/kg TCBZ doses in a fasting state. Therefore, a dose-response relationship might exist with TCBZ treatment of fascioliasis. While 1 dose might increase compliance among patients, a higher dose divided in 2 could reduce the side effects and be more effective and tolerable than the standard single 10-mg/kg dose. Further studies comparing 2 doses in children with similar infection intensities are needed to prove this hypothesis.

The tolerability of TCBZ was high in both arms of the study. Most of the adverse events were mild in severity and more frequently reported from individuals in Group I than from individuals in Group II, likely because of the higher total dose in the former group. The most common adverse event was biliary colic, which occurred in 25% of individuals in Group II; this value subsequently declined to 4.5% on day 6 and was not reported by day 7.

Overall, the majority of the mild adverse events were recorded in Group I, while the majority of moderate events were reported in Group II, including biliary colic (mild and moderate severity), which explains the more frequent use of antispasmodics in this group. On day 1, complaints were more frequent in Group I. On day 2, mild abdominal pain was more frequent in Group I (p = 0.028); however, epigastric pain and biliary colic were more frequent in Group II. Mild biliary colic was of longer duration in Group I, whereas moderate biliary colic lasted longer in Group II; biliary colic was better tolerated in Group I except for one individual with severe biliary colic who responded well (within 2h) to the antispasmodic therapy. Between days 3 and 6, the frequency of abdominal pain was similar in both groups.

Only 2 participants from Group I reported severe adverse events (biliary colic), which rapidly subsided after administration of antispasmodics. However, these adverse events might not have been related to the toxicity of the drug itself, but rather to the expulsion of damaged or dead parasites induced by TCBZ. Some clinical observations support this hypothesis. First, the biliary colic presented from days 2 to 6 post-treatment, peak serum TCBZ concentration occurred at 4-10h post-administration, and elimination of the foreign bodies (dead parasites) occurred 48h post-administration. Second, other studies have shown that liver enzymes significantly increase on post-treatment day 7 but not day 3 during fascioliasis, indicating that these hepatic markers increase after the onset of biliary colic 5555 el-Morshedy H, Farghaly A, Sharaf S, Abou-Basha L, Barakat R. Triclabendazole in the treatment of human fascioliasis: a community-based study. East Mediterr Health J 1999; 5:888-894. 5656 El-Tantawy WH, Salem HF, Nirmeen ASMS. Effect of Fascioliasis on the pharmacokinetic parameters of triclabendazole in human subjects. Pharm World Sci 2007; 29:190-198. 5757 Hien TT, Truong NT, Minh NH, Dat HD, Dung NT, Hue NT et al. A randomized controlled pilot study of artesunate versus triclabendazole for human fascioliasis in central Vietnam. Am J Trop Med Hyg2008; 78:388-392. . Third, biliary colic and increased liver enzymes do not occur in individuals treated with TCBZ for other indications such as paragonimiasis 5858 Calvopina M, Guderian RH, Paredes W, Chico M, Cooper PJ. Treatment of human pulmonary paragonimiasis with triclabendazole: clinical tolerance and drug efficacy. Trans R Soc Trop Med Hyg1998; 92:566-569. . Last, ultrasonographic studies of the liver fluke have shown that the parasites stop moving on post-treatment day 3, and the whole parasite or its fragments are eliminated through the biliary tract, with a transitory increase in the diameter of the biliary duct 5959 Richter J, Freise S, Mull R, Millan JC. Fascioliasis: sonographic abnormalities of the biliary tract and evolution after treatment with triclabendazole. Trop Med Int Health 1999; 4:774-781. 6060 Mansour Ghanaei F, Alizadeh A, Pourrasouli Z, Vahidi H, Naghipour MR. Sonographic Findings of Human Fascioliasis. Iran J Radiol 2006; 4:11-15. .

Biliary colic usually occurs 2-5 days after therapy and might be related to dead parasites passing the common bile duct, with antispasmodics serving as an appropriate therapeutic option to minimize abdominal pain. Therefore, biliary colic during TCBZ treatment for fascioliasis might represent an early indicator of treatment efficacy (Lumbreras; unpublished data). We conclude that treatment and follow up can be performed in the outpatient clinic (Terashima: unpublished data). No patients required in-hospital interventions or presented with biliary obstruction.

The veterinary formulation has been shown safe and tolerable in different countries worldwide since 1986, when it was first used in humans 3232 Wessely K, Reischig HL, Heinerman M, Stempka R. Human fascioliasis treated with triclabendazole (Fasinex) for the first time. Trans R Soc Trop Med Hyg1988; 82:743-744. 3333 Markwalder K, Koller M, Goebel N, Wolff K. Fasciola hepatica infection. Successful therapy using triclabendazole. Schweiz Med Wochenschr 1988; 118:1048-1052. as an alternative therapy in view of the inefficacy and low tolerability of other drugs. An exhaustive literature review with no language restriction produced a total of 554 (441 adults and 113 children) documented cases between 1986 and 2002 from Germany 3232 Wessely K, Reischig HL, Heinerman M, Stempka R. Human fascioliasis treated with triclabendazole (Fasinex) for the first time. Trans R Soc Trop Med Hyg1988; 82:743-744. 3333 Markwalder K, Koller M, Goebel N, Wolff K. Fasciola hepatica infection. Successful therapy using triclabendazole. Schweiz Med Wochenschr 1988; 118:1048-1052. 6161 Bechtel U, Feucht HE, Held E, Vogl T, Nothdurft HD. Fasciola hepatic infection in a family: diagnosis and therapy. Dtsch Med Wochenschr 1992; 117:978-982. , Switzerland 6262 Loutan L, Bouvier M, Rojanawisut B, Stalder H, Rouan MC, Buescher G et al. Single treatment of invasive fascioliasis with triclabendazole. Lancet 1989; 2:383. , France 6363 Picot S, Querrec M, Ghez JL, Goullier-Fleuret A, Grillot R, Ambroise-Thomas P. A new report of triclabendazole efficacy during invading phase fasciolasis. Eur J Clin Microbiol Infect Dis 1992; 11:269-270. 6464 Le Bras M, Beylot J, Biessy H, Tribouley J, Sicard C, Couprie B et al. Traitement de la Fasciolose humaine par le Triclabendazole. Med Chir Dig 1989; 18:477-479. , Belgium 4141 De Ronde T, Melange M, Van Beers B, Trigaux JP, Dive C, Lecaillon JB et al. Distomatosis of the bile ducts. Value of retrograde cholangiography. Efficacy of triclabendazole. Acta Clin Belg 1992; 47:209-214. , Australia 2929 Laird PP, Boray JC. Human fascioliasis successfully treated with triclabendazole. Aust N Z J Med 1992; 22:45-47. , Venezuela 6565 Abdul-Hadi S, Contreras R, Tombazzi C, Alvarez M, Melendez M. Hepatic fascioliasis: case report and review. Rev Inst Med Trop Sao Paulo1996; 38:69-73. , Spain 6666 Merino J, Amerigo MJ, Alvarez L, Erdozain I. Fasciolasis humana con presentacion atipica y grave. Tratamiento con triclabendazol. Enferm Infecc Microbiol Clin1998; 16:28-30. 6767 López-Vélez R, Domínguez-Castellano A, Garrón C. Successful Treatment of Human Fascioliasis with Triclabendazole. Eur J Clin Microbiol Infect Dis1999; 18:525-526. 6868 Caminal Montero L, Fernandez Fernandez C, de Quiros JF, Parra F. The treatment of human fascioliasis with triclabendazole. Rev Clin Esp 1999; 199:333-335. , the US 6969 Graham CS, Brodie SB, Weller PF. Imported Fasciola hepaticainfection in the United States and treatment with triclabendazole. Clin Infect Dis2001; 33:1-5., Japan 2424 Ishii Y, Nakamura-Uchiyama F, Nawa Y. A praziquantel-ineffective fascioliasis case successfully treated with triclabendazole. Parasitol Int 2002; 51:205-209. , Iran 4545 Yadegari D, Talaie H, Massoud J. Clinical trial of triclabendazole on human fascioliasis: Long term follow up. Med J Islamic Rep Iran 1999; 13:89-91. 7070 Massoud J. Fascioliasis outbrake of man and drug test (triclabendazole) in Caspian littoral, Northern part of Iran, 1989. VII Int Congr Parasit Paris. Paris: Bull Soc Franc Parasit 1990; p. 438. , Chile, 5353 Apt W, Aguilera X, Vega F, Miranda C, Zulantay I, Perez C et al. Treatment of human chronic fascioliasis with triclabendazole: drug efficacy and serologic response. Am J Trop Med Hyg1995; 52:532-535.and Egypt 2828 Yilmaz H, Oner AF, Akdeniz H, Arslan S. The effect of triclabendazole (Fasinex) in children with fasciolosis. J Egypt Soc Parasitol 1998; 28:497-502. 4444 Hammouda NA, el-Mansoury ST, el-Azzouni MZ, el-Gohari Y. Therapeutic effect of triclabendazole in patients with fascioliasis in Egypt. A preliminary study. J Egypt Soc Parasitol1995; 25:137-143. 5454 El-Karaksy H, Hassanein B, Okasha S, Behairy B, Gadallah I. Human fascioliasis in Egyptian children: successful treatment with triclabendazole. J Trop Pediatrics 1999; 45:135. 5555 el-Morshedy H, Farghaly A, Sharaf S, Abou-Basha L, Barakat R. Triclabendazole in the treatment of human fascioliasis: a community-based study. East Mediterr Health J 1999; 5:888-894. , that received the veterinary formulation with no or minimal adverse events. In Peru, it has been administered since 1996 8Ortiz P, Cabrera M, Jave J, Williams D. Human fascioliasis: prevalence and treatment in a rural area of Peru. Infect Dis Rev 2000; 2:42-46. 4242 Lecaillon JB, Godbillon J, Campestrini J, Naquira C, Miranda L, Pacheco R et al. Effect of food on the bioavailability of triclabendazole in patients with fascioliasis. Br J Clin Pharmacol 1998; 45:601-604. . In the present subgroup of participants from Asillo (n = 59) that received the veterinary TCBZ formulation, the adverse events were minimal; only 1 individual reported severe biliary colic that subsided upon treatment with antispasmodics, as documented in the safety documentation.

In conclusion, TCBZ is an effective and tolerable anthelmintic for the treatment of chronic fascioliasis among children in rural areas of the Peruvian Highlands. Adverse events might be related to the high efficacy in inducing parasite expulsion through the biliary tract. The therapeutic scheme involving an oral, post-prandial, double dose of 7.5mg/kg TCBZ, administered with a 12-h interval, had greater efficacy (100% vs. 95.83%) and a similar tolerability profile than a single 10-mg/kg dose, making it a reasonable therapeutic alternative. Because the 15-mg/kg dose divided into two administrations was well tolerated, we recommend that this dose be tested in future treatment studies.

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Publication Dates

  • Publication in this collection
    Aug 2015

History

  • Received
    05 May 2015
  • Accepted
    13 July 2015
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