Pharmacovigilance of preventive chemotherapy for the control of schistosomiasis and soil-transmitted helminths in Ethiopia

Sammanfattning: The World Health Organization (WHO) recommends preventive chemotherapy (PC) as a core public health intervention for the control and elimination of schistosomiasis and soil transmitted helminths (STHs) in endemic countries. Despite being amenable to available treatments and ongoing PC, schistosomiasis and STHs remain causes of significant morbidity and associated complications in endemic areas. Therefore, assessing the efficacy and safety of medicines used in PC for the control and elimination of schistosomiasis and STHs will provide an evidence for decision making. The aim of this thesis was therefore, to assess the efficacy and safety of praziquantel and albendazole coadministration used for the control and elimination of schistosomiasis and STHs among school children in Ethiopia. Additionally, we have also investigated the influence of pharmacogenetic variations on praziquantel pharmacokinetics. In paper I, a baseline survey assessing the prevalence, intensity and correlates of S.mansoni and STHs (Ascaris lumbricoides, hookworm and Trichuris trichiura) was conducted among 3162 school children aged 5-15 years in four primary schools using Kato-Katz thick smear technique. An overall prevalence of 64.2% infection with at least one parasite was observed. The prevalence of S.mansoni infection was 25.8% and that of STHs was 54.7% (Ascaris lumbricoides (45%), Trichuris trichiura (25.3%) and hookworm (6.1%)). About 61.6% of S.mansoni infected children had STHs co-infection. Locations of schools and being coinfected with STHs were significantly associated with S.mansoni infection (p<0.05). For STHs infection, location of the schools and being young less than ≤ 9 years were factors significantly associated with infection (p<0.05). In paper II, a prospective large scale safety surveillance was conducted among 5848 school children (infected, uninfected and unscreened) who received single dose praziquantel and albendazole through school-based mass drug administration (MDA). The assessment of adverse events was done through active (day 1 and day 7) and passive (days 2-6) monitoring post MDA. The cumulative incidence of experiencing at least one adverse events was 13.3%. The majority of the observed adverse events were mild and moderate in intensity (85.5% and 12.4% respectively) with few severe adverse events observed (1.8%). The most frequently observed adverse events were headache, abdominal pain, vomiting, dizziness and nausea. Females, older age groups and children infected with either S.mansoni and/or STHs were at increased risk of developing adverse events. In paper III, a prospective observational study assessing the efficacy of praziquantel and its safety when co-administered with albendazole was conducted among 512 S.mansoni infected school children. Efficacy was assessed at weeks 4 and 8 post-MDA using the thick smear Kato-Katz technique. The safety assessment was similar with paper II. The findings show that single dose praziquantel provided through PC is efficacious and safe with 89.1 % cure rate and 93.5% egg reduction rate at week 4 follow-up. Only 17.0% of the children experienced at least one adverse events following praziquantel and albendazole co administration. Abdominal pain followed by headache and vomiting were the commonest adverse events observed. The cure rate were significantly higher among children with light intensity infection and older age group (p=0.03 and p=0.01, respectively). In paper IV, a prospective observational efficacy study of a single dose albendazole against STHs and re-infection was conducted among 984 school children aged 5-15 years infected with at least one STH in southern part of Ethiopia. The follow-up assessment was done at week 4 (for efficacy) and week 8 (for re-infection) post-MDA using similar technique with that used in paper III. A satisfactory efficacy of albendazole against hookworm with 97.2% cure rate and 98.8% egg reduction rate was observed. Single dose albendazole showed reduced efficacy against Ascaris lumbricoides (71.5% cure rate and 84.5% egg reduction rate) and not efficacious against Trichuris trichiura (49.5% cure rate and 68.3% egg reduction rate). Younger age groups had significantly lower cure rate against Ascaris lumbricoides. About 18.3% and 52.4% re-infection after cure was observed at week eight follow-up for Ascaris lumbricoides and Trichuris trichiura, respectively. In paper V, pharmacogenetic-pharmacokinetic study investigating the effect of genetic variations on praziquantel plasma concentration was conducted among 446 school children aged 7-15 years who received single dose praziquantel through school based MDA. We observed a significant association between sex of the participant, CYP2C19 and CYP2J2 genotypes and praziquantel plasma concentration and the metabolic ratios (trans- and cis-4OH-praziquantel/praziquantel). Praziquantel plasma concentration was significantly higher among carrier of defective allele (CYP2C19'2,'3) (p=0.005). Carrier of CYP2C19'1/'1 and '17 had significantly higher metabolic ratios (p<0.001). Likewise, CYP2J2'7 carriers had lower praziquantel plasma concentration (p=0.05) and significantly high metabolic ratio of cis-4-OH-praziquantel/praziquantel (p=0.04). Male children also had significantly higher praziquantel plasma concentration and lower metabolic ratios compared to females (p=0.006 and p=0.001, respectively). In conclusion, PC with single dose praziquantel is still efficacious and safe among school children for the control and elimination of schistosomiasis. However, PC with single dose albendazole had reduced efficacy against Ascaris lumbricoides and not efficacious against Trichuris trichiura and this could explain the high prevalence of these infections observed in paper I. The majority of adverse events observed after co-administration of single dose praziquantel and albendazole were mild and moderate in intensity and transient by nature with few severe adverse events, indicating the safety and tolerability of praziquantel and albendazole co-administration.CYP2C19 and CYP2J2 genotypes and sex were significantly associated with praziquantel plasma concentration and the metabolic ratios. The association of CYP2J2 genotype with praziquantel plasma concentration and the metabolic ratios highlights a possible important pathway for praziquantel metabolism. Generally, these findings emphasize on the need to integrate efficacy and safety surveillance in PC programs, exploring for possible treatment options against STHs especially Ascaris lumbricoides and Trichuris trichiura and implementation of water and sanitation as well as hygiene practice for achieving the elimination target by 2030.