Interferon-based treatment of chronic hepatitis D

Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon-alfa for more than three decades. First studies to treat HDV-infected patients with type 1 interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one-quarter to one-third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long-term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon-alfa will still have an important role in the management of hepatitis D – either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon-based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development.     

Securing wider EU commitment to the elimination of hepatitis C virus

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes—from the municipality level to the EU level—were launched, resulting in an overall decrease in viremic HCV infections and liver-related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID-19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct-acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost-saving than treating and caring for patients with liver-related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale-up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the ‘Call-to-Action’ statement supported by all the major relevant European associations in the field.     

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+-taurocholate co-transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p = .0029) and evidence of portal hypertension (p = .0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = −0.577; p = .0078; rho = −0.635, p = .0026; rho = −0.577, p = .0077; rho = −0.519, p = .0191; rho = −0.564, p = .0119 and rho = −0.393, p = .087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV-induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed.