Dynamics of Virological and Clinical Response Parameters of Bulevirtide Treatment for Hepatitis D: Real-World Data

Abstract

Background and aims: The entry inhibitor bulevirtide represents the first specific treatment for hepatitis-D virus (HDV)-infected patients. In clinical trials, around 80% of patients achieve normalization of alanine aminotransferase (ALT) with about 60% virological response after 1 year, but little is known about the dynamics of responses and clinical predictors of treatment outcomes. We report our single-center data from 15 patients and describe response dynamics, clinical outcomes, and predictive factors for treatment response.

Methods: Retrospective data from 15 patients have been analyzed at our department who started treatment with bulevirtide between 10/2020 and 08/2022. According to our standard procedures, laboratory parameters were controlled monthly; transient elastography was performed every 3 months, and the treatment duration was 12 months.

Results: Treatment response rates after 1 year of treatment were similar to published data from clinical trials. ALT normalization usually occurs between months 2-6 of treatment, followed by a virological response after ≥6 months. Patients with more severe hepatitis at the start of treatment were less likely to respond in the first year of treatment. Loss of HDV-RNA was observed in one-third of patients after ≥1 year of treatment. Low body mass index and high alpha-fetoprotein at baseline were possible predictors of a delayed treatment response.

Conclusion: Bulevirtide is a safe treatment option for HDV, leading to a fast hepatological response. Of note, decrease in transaminases precedes virological response. Patients with high viral load and ALT levels respond slower, but nonresponders (as classified by Food and Drug Administration criteria) still show a reduction in viremia. Longer observation periods are required to determine the optimal duration of bulevirtide monotherapy.

Keywords: Antiviral-Treatment; Delta; Entry-Inhibitor; Treatment Kinetics.

Figure 1

Dynamics of treatment response: (A) First treatment responses occurred after 1 month for ALT normalization and (B) after 3 months for HDV-decrease of ≥2 log. In general, ALT response is seen more frequently and earlier than virological response. (C) HDV-RNA became undetectable after the first year of treatment in 3/5 patients. Bar: median time to undetectable HDV-RNA levels.

Figure 2

Individual treatment responses for (A) HDV-RNA and (B) ALT. Nonresponders for both parameters have higher baseline values in HDV-viremia and ALT elevation but still show somewhat reduced HDV and ALT levels. ALT decline occurs earlier during treatment than HDV-RNA decline. (C) HDV-viremia is reduced to 60% on average, but initial treatment response is faster with slower to no response from months 6–8 and then again accelerated as of month 9. (D) Liver stiffness, presented as relative changes of median values, decreases during the first 6 months to 73% of baseline values and then stabilizes, which may reflect a predominant effect on hepatic inflammation during the first months of treatment. (E) Relative changes of HBsAg.

Figure 3

Change of mean values over first year of bulevirtide treatment. Analysis with ANOVA showed significant changes for (A) ALT, (B) AST, (C) bile acids, and (D) HDV RNA. (E) Changes in FIB-4 in patients with hepatological response and liver cirrhosis were not significant, but with a slight trend toward a reduction in FIB4. (F) Platelet count stayed at similar over treatment.

Figure 4

Data from this report (=UKD) compared with available data from phase 3 studies MYR 202 and MYR 301^, and various real-world data., , Outcomes are similar, with the highest treatment response rates reported for the Milan liver cirrhosis cohort.

Figure 5

Comparison of baseline values of virological nonresponders to responders: We found higher BMI, lower levels of AFP, lower baseline bile acid, and lower ALT levels to be associated with treatment response. Box plot graphs show mean values and minimum-maximum. BMI, body mass index.