Novel combination chemotherapy for treatment and control of schistosomiasis among school children

Despite reported success in reducing severe disease-associated morbidities in endemic countries, praziquantel (PZQ) alone has failed to control and eliminate schistosomiasis, partly due to its poor efficacy against immature/juvenile worms. Artemisinin derivatives are efficacious against juvenile schistosomes. Therefore, combining PZQ with Dihydroartemisinin-piperaquine (DHP) would complement and potentially add to the killing effect of both mature and immature (juvenile) stages of the parasite to improve cure rates and hence hasten control and elimination of the disease (multi-factorial) and delay development of resistance against PZQ. This PhD thesis aimed to assess the efficacy and safety of PZQ and DHP combination therapy for the treatment and control of intestinal schistosomiasis among school children in Busega district, North-western Tanzania.

First, a baseline survey was conducted to assess the prevalence and correlates of intestinal schistosomiasis infection among 830 school-aged children in North-western Tanzania (paper I). A high (90.6%) prevalence of intestinal schistosomiasis infection was observed among school children despite several rounds of mass PZQ treatments in the study area. The prevalence of malaria was found to be very low (<2%). Anaemia (24.6%) and undernutrition such as stunting 29.0% and wasting 11.3% continued to be a major burden among this age group. Being male, having loose stool, and being stunted were the factors found to be significantly associated with high egg counts among those infected. Only lower age (≤ 12 years) was significantly associated with intestinal schistosomiasis infection and not malaria, anaemia or undernutrition status.

In paper II, a prospective surveillance study was conducted among 341 infected school children to assess the efficacy and safety of single-dose PZQ for treatment of Schistosoma mansoni infection. Follow-up was done at three weeks post-treatment according to WHO guidelines. We observed that PZQ given as a single-dose at 40 mg/kg body weight is still efficacious and safe for the treatment of Schistosoma mansoni infection. The overall cure and egg reduction rates were 81.2% and 95.0%, respectively. The incidence of adverse events was 28.5%, with abdominal pain being the most common. Post-treatment abdominal pain and vomiting were significantly associated with pre-treatment infection intensity and anaemia, respectively.

In paper III, a randomized, open-label, non-inferiority clinical trial was conducted to assess the efficacy and safety of PZQ and DHP combination (n = 298) versus PZQ alone (n = 341). This study has found that PZQ and DHP combination therapy is equally safe and more efficacious than PZQ alone for the treatment of intestinal schistosomiasis. At three weeks post-treatment, cure rates were significantly higher in combination therapy (88.3%) than PZQ alone (81.2%) (p = 0.01). At eight weeks post-treatment, there was a significant drop in the cure rates in PZQ alone to 63.9% compared to 81.9% in the PZQ and DHP combination therapy (p < 0.0001). Egg reduction rates at eight weeks post-treatment were significantly higher in the PZQ and DHP combination therapy (93.6%) than 87.9% in the PZQ alone group (p = 0.01). Overall, 30.8% of the study participants experienced mild and transient adverse events, abdominal pain being the most common adverse event. There was no significant difference in the overall incidence of adverse events between treatment groups.

In paper IV, a two-arm pharmacokinetic study was conducted among 64 treated children to assess drug-drug interaction and its clinical significance between PZQ and DHP. This study has found that the systemic exposure of PZQ and its enantiomers is increased following coadministration with DHP. The geometric means of AUCs and Cmax of both total PZQ, R-PZQ and S-PZQ were significantly higher among those children treated with PZQ and DHP combination (n = 32) than those who were treated by PZQ alone (n = 32). The 90% confidence interval of the geometric mean ratios of both total PZQ, R-PZQ and S-PZQ were outside the acceptable bioequivalent interval of 0.80, 1.25, indicating higher systemic exposure among those who were treated with PZQ and DHP combination therapy. The increased PZQ bioavailability in the PZQ and DHP combination is an additional mechanism to enhance the cure rates apart from the killing of both mature and immature stages of the parasite.

In paper V, a pharmacogenetics study was conducted among 340 children to assess the effect of genetic variations in CYP450 on plasma drug concentrations, treatment efficacy and adverse events.. We observed a significant association between CYP2C19 genotype and PZQ concentration, and its metabolic ratio (trans-4-OH-PZQ/PZQ). PZQ concentration was significantly higher among children carrying CYP2C19 (*2, *3) defective alleles than the wild type (CYP2C19 *1/*1) and CYP2C19 *17 carriers (ultra-rapid metabolizers) (p = 0.04). The metabolic ratio was significantly higher among CYP2C19 *17 carriers than CYP2C19 (*2, *3) carriers (p = 0.01). There was no significant effect of CYP3A4, CYP2C19 and CYP2C9 genotypes on schistosomiasis treatment efficacy and adverse events (p > 0.05). However, a border line association between CYP3A5 genotype and adverse events was observed (p = 0.048). On multivariate logistic regression analysis, baseline infection intensity was found to be the only significant predictor of adverse events following PZQ treatment.

In conclusion, PZQ and DHP combination therapy is equally safe and more efficacious than PZQ alone for treatment of schistosomiasis. The increased systemic PZQ exposure following a co-administration of DHP, yet without affecting overall safety, is an additional mechanism to the observed higher cure rate among children treated with PZQ and DHP combination therapy. These findings call for policy makers and other stakeholders to consider the use of PZQ and DHP combination therapy for the treatment and control of schistosomiasis in endemic countries.

List of scientific papers

I. Mnkugwe RH, Minzi OS, Kinung'hi SM, Kamuhabwa AA, Aklillu E. Prevalence and correlates of intestinal schistosomiasis infection among school-aged children in North-Western Tanzania. PloS one. 2020;15(2):e0228770.
https://doi.org/10.1371/journal.pone.0228770

II. Mnkugwe RH, Minzi OS, Kinung'hi SM, Kamuhabwa AA, Aklillu E. Efficacy and Safety of Praziquantel for Treatment of Schistosoma mansoni Infection among School Children in Tanzania. Pathogens. 2019;9(1).
https://doi.org/10.3390/pathogens9010028

III. Mnkugwe RH, Minzi O, Kinung’hi S, Kamuhabwa A, Aklillu E (2020). Efficacy and safety of praziquantel and dihydroartemisinin piperaquine combination for treatment and control of intestinal schistosomiasis: A randomized, non-inferiority clinical trial. PLoS Negl Trop Dis. 14(9): e0008619.
https://doi.org/10.1371/journal.pntd.0008619

IV. Minzi, O.M.; Mnkugwe, R.H.; Ngaimisi, E.; Kinung’hi, S.; Hansson, A.; Pohanka, A.; Kamuhabwa, A.; Aklillu, E. Effect of Dihydroartemisinin-Piperaquine on the Pharmacokinetics of Praziquantel for Treatment of Schistosoma mansoni Infection. Pharmaceuticals. 2021, 14, 400.
https://doi.org/10.3390/ph14050400

V. Mnkugwe RH, Minzi OS, Kinung'hi SM, Kamuhabwa AA, Aklillu E. Effect of pharmacogenetics variations on praziquantel plasma concentration and intestinal schistosomiasis treatment outcomes among infected school-aged children in Tanzania. [Manuscript]