Long-term bulevirtide use safe, efficacious in patients with chronic HDV

Longer treatment with bulevirtide (BLV) monotherapy in patients with chronic hepatitis delta (CHD) for 96 weeks results in sustained or continued improvements in virologic, biochemical, and combined responses, a study has shown.

Continuous therapy is also beneficial to patients with early virologic responses to BLV at week 24, with many achieving virologic response or biochemical improvement by week 96.

“These findings argue against a stopping rule in patients not showing a marked early virologic response to BLV monotherapy and support continuous treatment with BLV monotherapy regardless of whether early (week 24) virologic response is achieved,” the investigators said.

This open-label, randomized phase III study included 150 patients with CHD, who were randomly assigned to treatment with BLV 2 mg/day (n=49) or 10 mg/day (n=15), each for 144 weeks, or to delayed treatment for 48 weeks, followed by BLV 10 mg/day for 96 weeks (n=51).

Combined response referred to undetectable hepatitis delta virus (HDV) RNA or a reduction in HDV RNA by ≥2 log₁₀ IU/ml from baseline and alanine aminotransferase (ALT) normalization. The investigators also examined other endpoints, namely virologic response, ALT normalization, and change in HDV RNA.

Efficacy response

Of the trial participants, 143 (95 percent) completed the study. Patients with CHD showed improved or sustained efficacy responses between weeks 48 and 96, with comparable rates of combined, virologic, and biochemical responses between the 2- and 10-mg doses. [J Hepatol 2024;81:621-629]

Among patients with a suboptimal early virologic response at week 24, nearly half of nonresponders (43 percent) and most partial responders (82 percent) achieved virologic response at week 96. Those who achieved biochemical improvement usually did so independently of virologic response.

In addition, most of the adverse events (AEs) that occurred were mild in severity, and no serious AEs were considered associated with BLV therapy.

“Most patients achieved virologic response after 96 weeks of BLV 2 or 10 mg (76 percent to 82 percent),” the investigators said. “Even among those with minimal virologic improvement with BLV at week 96, potential clinical benefit in the form of ALT improvement or ALT normalization was still observed.”

This finding was consistent with that in real-world studies, which reported improvements in ALT occurring independently of virologic response with BLV. [JHEP Rep 2023;5:100686]

“This occurrence may be related to BLV preventing de novo infections and not directly inhibiting viral replication or to the potential hepatoprotective effects of sodium taurocholate cotransporting polypeptide (NTCP) inhibition, which prevents the intrahepatic accumulation of bile salts that can lead to liver injury,” the investigators said. [Hepatology 2017;65:1393-1404]

Safety

Treatment with BLV through week 96 was well tolerated with no new safety concerns in comparison with week 48. [N Engl J Med 2023;389:22-32]

Moreover, no serious AEs related to BLV were reported, and no treatment cessation occurred due to AEs associated with BLV therapy.

“Although dose-dependent asymptomatic elevations in serum total bile acid levels continued to be observed with BLV treatment, this was expected to be due to inhibition of NTCP, a bile acid transporter,” the investigators said. [N Engl J Med 2023;389:22-32; Clin Pharmacol Ther 2018;103:341-348]