Pegylated interferon alfa (PEG-IFNa) has been used (off-label) to treat HDV infection for almost two decades. However, PEG-IFNa treatment is associated with frequent and sometimes severe side effects and can lead to severe hepatitis flares in patients with HDV-associated autoimmune hepatitis, a particular common and sometimes serious feature of HDV infection. Moreover, reliable factors predicting response to PEG-IFNa treatment are not defined. Thus, there is an urgent need for personalized risk stratification which patients have realistic chance to benefit from PEG-IFNa therapy. In summer 2020, EMA granted a conditional approval for the treatment of hepatitis D to bulevirtide, a novel HBV/HDV entry inhibitor targeting the bile acid transporter NTCP, based on promising results from pivotal phase 2 studies. Bulevirtide, a peptide that requires daily s.c. injections, leads to a decline in HDV RNA levels and improvement of biochemical disease activity in the majority of patients without causing major systemic side effects. However, and importantly, several key questions how to use bulevirtide are completely unclear. E.g., once the entry inhibitor has been started, the optimal duration of treatment is undefined. While some patients may require life-long maintenance treatment, there is evidence that many patients may achieve immune control once the drug is stopped. There is concern, however, that severe relapses can lead to potentially life-threatening hepatitis flares if treatment is stopped too early. Therefore, biomarkers are needed to determine factors predicting long-term control of HDV after discontinuation of bulevirtide.