Bulevirtide for chronic hepatitis delta: from clinical trials to real life data: an expert opinion report

Hepatitis D virus (HDV) is a small RNA virus that requires Hepatitis B Surface Antigen (HBsAg) for its envelope. Eight genotypes with more than 80 % sequence homology and many subgenotypes have been described. Worldwide prevalence of chronic hepatitis delta (CHD) is estimated at about 5 % of chronic hepatitis B cases, translating to 15-20 million individuals. The diagnosis of HDV infection involves presence of antibodies to hepatitis D antigen (anti-HDV antibodies). Anti-HDV total antibody indicates HDV exposure (not infection). To document infection; the patient needs to undergo PCR testing and only if PCR is positive should the diagnosis of HDV ongoing infection done. Testing for the antibodies should be performed in all HBsAg-positive persons. CHD is more severe and progressive than HBV mono-infection, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC), transplantation and death. Pegylated interferon-alpha (pegIFN-a) has been used for treating CHD with only limited durable responses. A 48-week course of weekly subcutaneous injections of pegIFN-a suppresses HDV replication in approximately 20-30 % of patients 24 weeks off therapy, with significant side effects. Bulevirtide (BLV) was approved by the European Medicines Agency (EMA) in 2020 for CHD and compensated liver disease. Since its approval, real-life data on the use of BLV have been accumulating, with most treated patients in Europe having advanced fibrosis or cirrhosis. Real life data efficacy is concordant to that seen in clinical trials, with many patients achieving significant reductions in HDV RNA levels and ALT normalization after several months of treatment, and favorable safety. However, HBsAg loss is relatively rare. Finite therapy of BLV, in combination with pegIFN-a, leads to significant durable response, with more than 30 % of patients achieving HDV RNA undetectability off therapy. We need new finite therapies. Further real-world data and newer therapies are required for this severe disease.