Finding biomarkers for stopping bulevirtide treatment of patients with hepatitis delta

This is a multicenter, prospective, single-arm, discontinuation study in which patients who have been treated with BLV for at least 48 weeks, are intentionally discontinued from the treatment.

Currently, the treatment duration has not yet been defined and BLV can be given as long as a clinical benefit; is evident. In patients with advanced liver disease, maintenance treatment is recommended by most experts.

In pivotal phase II studies in which patients were treated with BLV for 24-48 weeks, some patients (10-20%) maintained a reduced HDV viral load with normal liver enzymes after the end of treatment (Wedemeyer et al., 2018, 2019, 2020). However, it is completely unclear which patients are able to control HDV infection without antiviral therapies. Biomarkers would be needed to identify patients in whom treatment can stopped safely. This is even more important because HDV flares can be life-threatening in the event of a relapse after stopping BLV. Thus, the main aim of this study is to explore biomarkers in blood and liver associated with maintained virological control after at least 24 weeks of HDV-RNA levels below 100 IU/ml, with at least 2 tests plus one test at screening, on BLV treatment. The investigators hypothesize that biomarker-based criteria should be able to identify patients with a sustained immune control. This information would be highly relevant to personalize treatment duration (or stopping) of BLV treatment, could reduce long-term disease burden, would enable safer treatments and also reduce treatment costs. Within the proposed systematic, unbiased study the investigators follow a broad screening for biomarkers that may be suitable to discriminate in a first step between patients that will experience a virological relapse (HDV RNA above 1000 IU/ml) after discontinuation of treatment and those without.

The investigators plan to include 20 patients in this study. These patients have to have received BLV treatment for at least 48 weeks and have to show HDV-RNA levels below 100 IU/ml in two repeated tests plus one test at screening, for at least 24 weeks while still being on treatment. Treatment will be stopped with the beginning of the study and patients will be followed for 48 weeks. It is expected that up to 14 patients will maintain HDV-RNA control (HDV-RNA below 1000 IU/ml). The other patients are expected to experience a virological relapse. Treating physicians should consider to re-initiate BLV at HDV-RNA levels of above 1000 IU/ml.

The aim of the study is to identify biomarkers that are associated with maintained virological response and could therefore be further investigated as predictive markers for treatment response.

Inclusion Criteria:

1. Men, women, inter/diverse* aged ≥ 18 years
2. Signed written informed consent from subject
3. Chronic hepatitis delta
4. Stable and continued NUC treatment of the underlying HBV infection
5. Previous interferon treatment must have stopped at least 6 months before the start of BLV monotherapy
6. Previous immunosuppressant therapy must have stopped at least 6 months before the start of BLV therapy
7. BLV treatment for at least 48 weeks
8. HDV-RNA below 100 IU/ml under BLV treatment for at least 24 weeks. Patients should have had at least 2 tests with HDV-RNA below 100 IU/ml plus one test with HDV-RNA below 100 IU/ml+ at screening.
9. ALT level below 1.5 fold ULN

Exclusion Criteria:

1. Patients with decompensated liver cirrhosis (transient mild deviations in liver function parameters are acceptable at the discretion of the investigator) or history of decompensated liver cirrhosis (patients with minimal perihepatic ascites could be included at the discretion of the investigator)
2. Hepatocellular carcinoma (HCC)
3. Thrombocytopenia (platelet count below 90.000/µl)
4. Participation in another interventional clinical trial (other investigational drugs or devices at the time of enrolment or within 30 days prior to enrolment)
5. Any additional medical reason not to stop BLV