Re-purposing anti-Helicobacter therapy to prevent development of liver fluke induced-cholangiocarcinoma

Tens of millions of people in countries surrounding the Lower Mekong Basin are infected with a liver fluke, that can cause serious liver disease and develop into bile duct cancer. In spite of education/screening/treatment programmes, cases of bile duct cancer (cholangiocarcinoma) remain very high in this region, with >25,000 cases reported in Thailand alone in 2022, impacting some of the poorest communities. The disease is often diagnosed at a late stage and there are few effective treatment options. The high morbidity and mortality from liver disease following liver fluke infection thus hampers economic development in these regions and has severe social impacts on these communities. New approaches to prevent the development of bile duct cancer are urgently needed. Our recent research has shown that liver disease can persist or even worsen after effective clearance of the liver fluke by use of anti-helminth drugs. Importantly, these individuals test positive for a bacterium (Helicobacter pylori) that is recognised to induce gastric (stomach) inflammation that can develop into stomach cancers. Our research also shows that the liver fluke itself is infected with this bacterium, and hence it is carried to the liver (by the liver fluke), where it promotes inflammation to trigger liver disease, that if unchecked can progress to bile duct cancer. When people are treated with anti-helminth drugs to eliminate the liver fluke, the cancer-inducing bacterium remains in the liver causing persistent inflammation and worsening liver disease. We propose that prevention of bile duct cancer following liver fluke infection requires treatment with both an anti-helminth drug and antibiotics to eliminate the cancer-inducing bacterium. Importantly, there are well-established, cheap and effective ways to treat people for infections with this bacterium. The aim of this project is to demonstrate that we can break this cycle of persistent liver inflammation and liver disease, and we will use standard antibiotics, that are currently used to treat stomach infections with this bacterium, re-purposed to eliminate it from the liver. As part of our follow up studies, we have already identified a cohort of individuals who were originally infected with liver fluke (but now are liver fluke-free after anti-helminth treatment) but who have persistent liver disease and test positive for the cancer-inducing bacterium. We will measure their liver disease, markers of inflammation, and levels of the cancer-inducing bacterium and liver fluke at baseline and 18-months after antibiotic treatment. We have assembled a team of world experts of scientists and clinicians who have the interdisciplinary skills and experience to deliver this project to successful outcomes. This project has great potential to provide a step change in lowering the incidence of this devasting disease that has had serious socio-economic impacts in this region of the world for many years. Throughout this project we will engage policy makers (Ministries of Public Health) and other stakeholders (clinicians, affected communities and community leaders) to maximise engagement, and to enable a rapid roll out of a large-scale, international clinical trial of this dual treatment for those who test positive for the liver form of this bacterium after liver fluke infection. We have developed new tools that can distinguish between the stomach and liver forms of this bacterium to aid this large scale roll out of dual therapy.