Efficacy and safety of praziquantel and dihydroartemisinin piperaquine combination for treatment and control of intestinal schistosomiasis: A randomized, non-inferiority clinical trial

Background Despite the reported success in reducing morbidity, praziquantel alone is insufficient for the control and elimination of schistosomiasis, partly due to its poor efficacy against the juvenile worms. Artemisinin derivatives are effective against juvenile worms but are less effective against adult worms. We compared the safety and efficacy of praziquantel and Dihydroartemisinin-piperaquine combination against the standard praziquantel alone for treatment of intestinal schistosomiasis. Methods In this randomized, open-label, non-inferiority trial, 639Schistosoma mansoniinfected children were enrolled and randomized to receive either praziquantel alone or praziquantel plus Dihydroartemisinin-piperaquine combination. Two stool samples were collected on consecutive days at baseline, 3 and 8 weeks post-treatment and analyzed using thick smear Kato Katz method. Efficacy was assessed by cure and egg reduction rates at 3 and 8 weeks post-treatment. Adverse events were assessed within four hours of drugs intake. The primary outcome was cure rates at 8 weeks of post-treatment. Secondary outcomes were egg reduction rates at 8 weeks of post-treatment and treatment-associated adverse events. Results At 3 weeks of post-treatment, cure rates were 88.3% (263/298, 95% CI = 84.1%- 91.4%) and 81.2% (277/341, 95% CI = 76.7%- 85.0%) for the combination therapy and praziquantel alone, respectively (p< 0.01, odds ratio (OR) = 1.74, 95% CI of OR = 1.11 to 2.69). At 8 weeks, there was a significant drop in the cure rates in praziquantel alone group to 63.9% (218/341, 95% CI = 58.7%- 68.8%) compared to 81.9% (244/298, 95% CI = 77.1%- 85.8%) in the combination therapy group (p< 0.0001, OR = 2.55, 95%CI of OR = 1.75 to 3.69). Egg reduction rates at 8 weeks post-treatment were significantly higher in the combination therapy group 93.6% (95% CI = 90.8%- 96.4%) compared to 87.9% (95% CI = 84.4%- 91.4%) in the praziquantel only group (p= 0.01). On both Univariate and Multivariate regression analysis, type of treatment received was a significant predictor of cure at week 8 post-treatment. Overall, 30.8% (95% CI = 27.2%- 34.4%) of the study participants experienced mild and transient treatment-associated adverse events, post-treatment abdominal pain (27.1%) being the most common adverse event observed. There was no significant difference in the overall occurrence of adverse events between the two treatment groups. Conclusion Praziquantel and Dihydroartemisinin piperaquine combination therapy is safe, and more efficacious compared to praziquantel alone for the treatment of intestinal schistosomiasis. Further studies are needed to explore if the combination therapy can be considered as an option for mass drug administration to control and eventually eliminate schistosomiasis. Author summary Schistosomiasis is a Neglected Tropical Disease, which is caused by a parasite called Schistosoma. The disease is mainly manifested by bloody urine (urinary schistosomiasis) and bloody diarrhea (intestinal schistosomiasis). Schistosomiasis is usually asymptomatic during early infection but, if not treated, may cause devastating long-term complications, including poor growth and cognitive development in children, portal hypertension, and cancers. For several years, children in Sub Saharan Africa have been receiving targeted mass praziquantel treatments for the control and elimination of schistosomiasis. Despite the reported success in reducing morbidity, single dose praziquantel alone treatment is apparently insufficient for elimination of schistosomiasis in endemic countries. This is partly due to its poor activity against the immature/juvenile stage of the parasite. Previous studies reported that artemisinin derivatives are effective against juvenile worms. In this study, we explored if combination therapy of praziquantel and Dihydroartemisinin-piperaquine would increase the efficacy by targeting to kill both developmental stages (matured and juvenile worms) of the parasite. In a randomized clinical trial, we compared the efficacy and safety of combination therapy of praziquantel and Dihydroartemisinin-piperaquine against the standard praziquantel alone for the treatment of intestinal schistosomiasis in a rural endemic setting in North-Western Tanzania. Our findings indicate that praziquantel and Dihydroartemisinin piperaquine combination therapy is safe and more effective than praziquantel alone for the treatment of intestinal schistosomiasis.