Pharmacovigilance of mass drug administration for the control of schistosomiasis and soil transmitted helminths in Rwanda

Sammanfattning: Preventive chemotherapy (PC) is a WHO recommended core interventional measure or a strategy to prevent, control and eliminate STH and schistosomiasis as public health burden by 2030. Though preventable and treatable, they are still endemic in Rwanda and continue to cause significant mortality and morbidity. This prompted us to conduct a cross-sectional study to assess the prevalence, intensity, and correlates of STH after a decade of PC. In addition, an active safety surveillance study to identify the incidence, type, severity, and risk factors for AEs following MDA of praziquantel (PZQ) and albendazole co-administration was conducted. We further assessed the effectiveness of both 400 mg single-dose albendazole against STH infections and single-dose PZQ 40 mg/kg body weight against schistosomiasis, administered to SAC during MDA campaign respectively. Lastly, the effect of pharmacogenetic variations on PZQ plasma concentrations and safety outcomes was equally investigated. Firstly, in paper I, we screened and assessed for STH prevalence amongst 4998 SAC between 5 to 15 years old from four selected districts alongside Lake Kivu in the western province of Rwanda. An overall 77.7% prevalence of STH irrespective of several rounds of mass albendazole PC was reported. T. trichiura was found to be the most common STH species with 66.8%, followed by A. lumbricoides with 49.9%, and lastly hookworms with 1.9%. The prevalence of single, double, and triple parasite co-infection was 48.6%, 50.3%, and 1.1%, respectively. The study findings revealed that male sex, district, stunting, and schistosomiasis co-infection were significant predictors of STH infections. Subsequently, in paper II, an active safety surveillance study was conducted and enrolled a total of 8037 SAC (5-15 years old). AEs were actively monitored on days 1, 2 and 7-post- MDA to identify and categorize AEs following mass administration of PZQ and albendazole. During the study, a total of 3196 AEs were reported by 1658 SAC and respectively, 91.3%, 8.4%, and 0.3% of the AEs were mild, moderate, and severe. The reported AEs mostly resolved within 3 days after drug administration and during the active safety monitoring, headache (21%), dizziness (15.2 %), nausea (12.8%) and stomach pain (12.2%) were the most reported AEs. 20.6% of SAC experienced at least one type of AE and this was significantly higher in SAC with pre-MDA clinical Events (27.5%) compared to those without (18.7%) clinical events. In this paper, it was further observed that being a female, older age, having pre-MDA events, types of food taken before MDA and taking two or more PZQ tablets were significantly associated with AEs. In paper III, a total of 1526 SAC were enrolled in a cross-sectional efficacy surveillance study to assess the effectiveness of single-dose albendazole (400 mg) against STH infections. Drug efficacy follow-up was performed 21 days post-MDA treatment in accordance with the WHO guidelines. Thereafter, we observed that cure rate (CR) and egg reduction rate (ERR) for hookworms (CR = 96.7%, ERR = 97.4%) was above the recommended WHO threshold and for A. lumbricoides (CR = 95.1%, ERR = 94.6%) at borderline compared with the WHO efficacy threshold (CR and ERR ≥ 95%). We further observed a low efficacy rate for T. trichiura with CR (17.6%) and ERR (40.3%) respectively as opposed to the recommended WHO threshold of ≥ 50%. Exhibiting moderate -heavy infection intensity and STH parasite co-infections were found to be risk factors of CR and ERR against T. trichiura. 400 mg single-dose albendazole used in mass deworming campaigns was found to be effective for the treatment of hookworms and A. lumbricoides but not effective for T. trichiura infections. In paper IV, efficacy surveillance of PZQ 40 mg/kg body weight following MDA was conducted and 265 SAC infected with intestinal schistosomiasis were enrolled in the study. our findings indicated that PZQ used in MDA is effective in treating light and moderate infection intensities of S. mansoni infection. CR and ERR were revealed to be 97.9% and 97.0% respectively way higher compared with the WHO recommended efficacy threshold. Among 173 cases of light infection intensity for intestinal schistosomiasis, 98. 3% (170) of SAC got healed or cured whereas 1.7% (3) were not cured post-MDA. 93.3% of the 15(8%) SAC who had moderate infection intensities were cured and 6.7% were not post-MDA. The findings indicated no significant association between CR, Pre-MDA treatment and post-MDA infection intensities. In this paper therefore, PZQ exhibited high efficacy potential and reduced morbidities correlated to light and moderate infection intensities. It is evident to say that single dose PZQ 40 mg/kg is still efficacious against intestinal schistosomiasis infections. Finally in paper V, the effect of pharmacogenetics variations on PZQ plasma concentrations and safety outcomes amongst 462 Rwandan SAC who were given the single dose PZQ co-administered with albendazole during MDA was investigated. Genotyping for common functional variant alleles CYP3A4'1B, CYP3A5 ('3, '6, '7), CYP2C19 ('2, '3, '17), CYP2C9 ('2, '3) and CYP2J2'7 were performed from the collected whole blood samples. Our findings showed that, CYP2C19 and CYP2C9 were associated with plasma PZQ concentrations and cis- and trans-4-OH-PZQ metabolic rations (MRs) respectively. It was equally observed that, CYP2C9 genotype was associated with a decreased trans-4-OH-PZQ MR and a closer association with PZQ and cis-4-OHPZQ/PZQ MR. CYP3A4 genotype was reported to be in association with Cis-4-OHPZQ/PZQ MR, but not with the parent drug and Trans-4-OH-PZQ/PZQ metabolites. our findings further demonstrated relevance of plasma PZQ exposure and its MRs for MDAassociated AEs. We observed no meaningful relationship between the CYP3A4, CYP3A5, CYP2C9, CYP2C19 and CYP2J2 genotypes and MDA-associated AEs. On the other hand, SAC who experienced AEs had a significantly lower mean cis-4-OH-PZQ MR in comparison with those who did not experienced AEs. In conclusion, irrespective of several rounds of mass albendazole, the prevalence of STH remains high with T. trichiura being reported to be the most common specie. Evidently, T. trichiura indicated no response to the preventive chemotherapeutic interventions. Active safety surveillance of mass PZQ co-administered with albendazole revealed that one in five SAC who participated in the study experienced transient- mild to moderate AEs and some reported fewer severe AEs cases post- MDA. Similarly, single-dose PZQ is reported to still be effective against intestinal schistosomiasis. Both preventive chemotherapeutic drugs used in MDA were reported to be safe. CYP2C19 and CYP2C9 were associated with plasma PZQ concentrations and cis- and trans-4-OH-PZQ MR. CYP2C9 genotype was reported to associate with a decreased trans-4-OH-PZQ MR and a closer association with PZQ and cis-4-OH- PZQ/PZQ MR. Equally, CYP3A4 genotype was found to be in association with Cis-4-OH-PZQ/PZQ MR and no significant correlation between CYP3A4, CYP3A5, CYP2C9, CYP2C19 and CYP2J2 genotypes and MDA-associated AEs.