144 Weeks of bulevirtide monotherapy for chronic hepatitis D: Final and post-treatment results from a phase III randomized trial.

BACKGROUND & AIMS: Bulevirtide is approved in several countries and regions for the treatment of compensated chronic hepatitis D (CHD). However, long-term outcomes after treatment discontinuation remain unknown.

METHODS

Patients with CHD (n = 150) were randomized to immediate treatment with bulevirtide 2 mg/day (n = 49) or 10 mg/day (n = 50) for 144 weeks (W), or a 48W delay before starting treatment (DT; n = 51) followed by bulevirtide 10 mg/day for 96W (DT/10 mg; n = 50), and 96W of post-treatment follow-up (FU96) in the MYR301 study. Efficacy endpoints included virologic response (VR; undetectable HDV RNA or ≥2 log10 IU/ml decline from baseline), combined response (CR; VR and alanine aminotransferase [ALT] normalization), ALT normalization, and undetectable HDV RNA.

RESULTS

At the end of treatment (EOT), response rates in the 2, 10, and DT/10 mg groups were: VR, 73%, 76%, and 92%; ALT normalization, 59%, 60%, and 58%; CR, 57%, 54%, and 56%; and HDV RNA undetectability, 29%, 50%, and 52%. At FU96, VR rates declined to 33%, 30%, and 32%, respectively; CR rates were 24% across all groups. HDV RNA undetectability rates were 20%, 22%, and 20% at FU96. Sustained undetectability through follow-up was observed in 23/64 (36%) patients with undetectable HDV RNA at EOT, with weeks continuously undetectable at EOT being the most important predictor of sustained undetectability. Post-treatment hepatic serious adverse events occurred in 20/142 (14%) patients and resolved in 17/20 (85%).

CONCLUSIONS

Bulevirtide treatment for CHD for up to 144W was safe and effective. Response rates decreased after treatment discontinuation; however, some patients had sustained undetectable HDV RNA throughout 2 years of follow-up.

IMPACT AND IMPLICATIONS: Although bulevirtide is approved for treatment of chronic hepatitis D (CHD) in several countries and regions including the United States, the European Economic Area, the United Kingdom, Switzerland, the Russian Federation, Australia, and Canada, treatment outcomes beyond 2 years and after bulevirtide discontinuation remain unknown. In this analysis, we demonstrate that efficacy was maintained with bulevirtide monotherapy for up to 144 weeks compared with that at 96 weeks, while rates of HDV RNA undetectability continued to improve with extended treatment duration. Virologic and biochemical responses decreased after treatment discontinuation, but some patients with undetectable HDV at the end of treatment maintained HDV RNA undetectability post-treatment, with duration of continuous HDV RNA undetectability at the end of treatment being the strongest predictor of non-relapse. While most patients benefit from continued bulevirtide therapy, a subset of those who achieve undetectable HDV RNA may be able to discontinue treatment without loss of response even in the absence of HBsAg loss.

CLINICAL TRIAL NUMBER: NCT03852719.