Pharmacotherapy of hepatitis D: the current and the future

Hepatitis D virus (HDV), a satellite virus requiring hepatitis B surface antigen (HBsAg) for propagation, is a hepatotropic virus implicated in acute and chronic viral hepatitis, with an accentuated risk of cirrhosis and hepatocellular carcinoma. The epidemiology of HDV infection is underestimated owing to underdiagnosis and low screening rates. Being inherently defective, HDV depends on HBsAg, the envelope protein of the hepatitis B virus (HBV), for hepatocyte entry and exit. However, viral replication is then HBV-independent but dependent on the host cell RNA polymerases. Infection can either be a coinfection with HBV or superinfection in individuals with pre-existing HBV, with the latter exhibiting a higher propensity for progression to chronicity. Clinical manifestations could range from acute hepatitis to acute flares in chronic hepatitis to rapidly progressive chronic liver disease. For decades, the treatment of HDV infection relied heavily on conventional and pegylated interferons (PEG-IFNs), which, despite limited efficacy and high relapse rates, continue to be a therapeutic option in patients with compensated liver disease. The past decade witnessed an advanced understanding of HDV virology and pathogenesis, which led to the development of multiple specific and targeted therapeutic agents, most notably the HDV viral entry inhibitor, bulevirtide, and the prenylation inhibitor, lonafarnib. In 2020, bulevirtide became the first drug approved in the European Union to treat chronic HDV with compensated liver disease. The emergence of lambda interferons, nucleic acid polymers, RNA silencers, and immune modulators further expands the therapeutic landscape. Combination regimens leveraging complementary mechanisms are promising but require further validation to optimize dosing and treatment durations. While novel therapies provide hope, significant unmet needs remain, especially for patients with decompensated cirrhosis. Future research must prioritize comprehensive strategies to enhance treatment efficacy and accessibility, offering a brighter prognosis for those affected by this devastating virus.