An RCT to Evaluate Treatment Modalities to Halt the Progression of Schistosomiasis Related Hepatic Fibrosis

Project Summary Currently, preventative chemotherapy strategies with Praziquantel (PZQ) are the mainstay of treatment for schistosomiasis, with “mass drug administration” (MDA) delivered annually in schools or communities. The primary cause of severe morbidity and death due to intestinal schistosomiasis is portal fibrosis secondary to intra-hepatic egg deposition with consequent portal hypertension and esophageal varices with high risk of hemorrhage. Importantly, there are no current recommendations globally to identify individuals with earlier stages of hepatic fibrosis while it is still reversible. No trials have examined whether treating more than annually, which leaves a significant proportion of individuals without a change in severity of fibrosis, can reduce the grade of fibrosis and its consequences. Our control group will receive annual treatment with PZQ which represents current WHO recommendations and exceeds current Uganda guidelines. The overarching goals of this proposal are to conduct a randomized controlled trial (RCT) among N=600 subjects ages 15-40 in Lake Albert, Uganda, that will examine varying frequencies of treatment with Praziquantel (every 4 months or annually for three years) to identify approaches that best reverse or halt fibrosis as captured by ultrasound (US) annually. We will also identify novel biomarkers with a multiplexed assay which captures 40 analytes involved in fibro -degradation and -proliferation, which best predict progression of fibrosis. After excluding other causes of hepatic fibrosis, we will recruit N = 600 subjects for the RCT (N = 150 individuals in each age (15-24, 25-40 years) and sex strata (4 sub-groups) who have compensated schistosomal fibrosis of any grade based on the WHO “Niamey” US protocol for S. mansoni developed by co- investigator Dr. Richter. Using stratified randomization by subgroup, subjects will be allocated to either intensive treatment with PZQ (40 mg/kg every 4 months) OR standard, annual treatment with 40 mg/kg (matched placebo at the intervening 4 month timepoints). The primary endpoint will be any improvement in US derived grade of fibrosis. Secondary endpoints will be improvement in grade of portal hypertension after three years and improvement or stability of fibrosis and portal hypertension grades after one and two years. We will also identify key fibrosis biomarkers associated longitudinally with risk of progression which could ultimately be employed in point of care tests. The lack of approaches to reverse higher grade fibrosis once established, and sub-optimal interventions for addressing portal hypertension and its high mortality rate, motivate the need to evaluate biomarkers that can identify individuals with mild to moderate fibrosis while it still may improve and examine whether more frequent treatment can accomplish this.