Response-Guided Long-Term Treatment of Chronic Hepatitis D Patients With Bulevirtide

Results of a 'Real World' Study

Mathias Jachs; Caroline Schwarz; Marlene Panzer; Teresa Binter; Stephan W. Aberle; Lukas Hartl; Kristina Dax; Elmar Aigner; Albert F. Stättermayer; Petra Munda; Ivo Graziadei; Heidemarie Holzmann; Michael Trauner; Heinz Zoller; Michael Gschwantler; Mattias Mandorfer; Thomas Reiberger; Peter Ferenci

Disclosures

Aliment Pharmacol Ther. 2022;56(1):144-154. 

In This Article

Abstract and Introduction

Abstract

Background and Aim: Bulevirtide (BLV) blocks the uptake of the hepatitis D virus (HDV) into hepatocytes via the sodium/bile acid cotransporter NTCP. BLV was conditionally approved by the EMA but real-life data on BLV efficacy are limited.

Methods: Patients were treated with BLV monotherapy. Patients who did not achieve further decreases in HDV-RNA after 24 weeks were offered PEG-IFN as an add-on therapy in a response-guided manner.

Results: Twenty-three patients (m: 10, f: 13; mean age: 47.9 years, cirrhosis: 16; median ALT: 71 IU/ml; median HDV-RNA: 2.1 × 105 copies/ml) started BLV monotherapy (2 mg/day: 22; 10 mg/day: 1). Twenty-two completed ≥24 weeks of treatment (24–137 weeks): Ten (45%) were classified as BLV responders at week 24. BLV was stopped in two patients with >6 months HDV-RNA undetectability, but both became HDV-RNA positive again. One patient was transplanted at week 25. One patient terminated treatment because of side effects at week 60. Ten patients are still on BLV monotherapy. Adding PEG-IFN in eight patients induced an HDV-RNA decrease in all (1.29 ± 0.19 SD log within 12 weeks). HDV-RNA decreased by >2log or became undetectable in 45%(10/22), 55%(11/20), 65% (13/20) and 69% (9/13); and ALT levels normalised in 64% (14/22), 85% (17/20), 90% (18/20) and in 92% (12/13) patients at weeks 24, 36, 48 and 60, respectively. Portal pressure decreased in 40% (2/5) of patients undergoing repeated measurement under BLV therapy.

Conclusion: Long-term BLV monotherapy is safe and effectively decreases HDV-RNA and ALT—even in patients with cirrhosis. The optimal duration of BLV treatment alone or in combination with PEG-IFN remains to be established. An algorithm for a response-guided BLV treatment approach is proposed.

Introduction

Infection with hepatitis D virus (HDV) frequently causes progression to cirrhosis and hepatocellular carcinoma.[1,2] HDV relies on hepatitis B virus (HBV), specifically on HBV surface antigen (HBsAg) to form infectious HDV particles. Worldwide, about 0.16% (0.11–0.25) of the general population, totaling 12.0 (8.7–18.7) million people are estimated to be anti-HDV positive.[3] Pegylated interferon alpha (PEG-IFN) achieves sustained suppression of HDV replication only in 25% of patients.[4] Nucleos(t)ide analogs (NUCs) are ineffective against HDV.[5] Therefore, there is an urgent need for novel HDV therapies. The HBV entry inhibitor Bulevirtide (BLV) is a synthetic N-acylated preS1 lipopeptide that blocks the sodium/bile acid cotransporter (NTCP/SLC10A1),[6] serving as receptor for the entry of HBV and HDV into hepatocytes.[7,8] The results of recent clinical studies on BLV monotherapy have only been published as abstracts[9,10] or as a preliminary report in six patients[11] and demonstrated a ≥2 log decline or undetectable HDV-RNA levels in up to 50% of patients after 24 weeks when used as monotherapy and undetectable HDV-RNA levels after 48 weeks of treatment in 60% of patients when used in combination with PEG-IFN (two out of three, i.e. 40% of overall patients maintained undetectability after another 24 weeks). BLV was well tolerated—including in patients with compensated cirrhosis—with the only documented laboratory side effect being an increase in serum bile acids levels. The European Medical Agency (EMA) approved BLV for treatment of HDV[12] given the urgent medical need in an orphan disease. Unfortunately, the phase 2 study[10] with 90 patients assigned to six different treatment arms and the interim data of two ongoing phase 3 studies[13,14] do not provide sufficient guidance for the use of BLV treatment for HDV in clinical practice. Thus, important information on the most effective dose of BLV, the duration of treatment, the need for combination with PEG-IFN or NUCs is lacking.

Here, we report the real-life efficacy and safety of BLV monotherapy using doses of 2 to 10 mg per day in 23 HDV patients mostly with cirrhosis.

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