144 Weeks of bulevirtide monotherapy for chronic hepatitis D: Final and posttreatment results from a Phase 3 randomized trial

Background & aims: Bulevirtide 2 mg/day is approved in Europe, Australia, Russia, and Canada for treatment of compensated chronic hepatitis D (CHD). However, long-term outcomes after treatment discontinuation are 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 48W of delayed treatment (DT; n=51) followed by bulevirtide 10 mg/day for 96W (DT/10 mg; n=50), and 96W of posttreatment follow-up (FU96) in the MYR301 study. Efficacy endpoints included virologic response (VR; undetectable hepatitis D virus [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%; 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. Posttreatment 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. (Funded by Gilead Sciences; MYR301 ClinicalTrials.gov number, NCT03852719). Impact and implications: Although bulevirtide is approved for treatment of chronic hepatitis D (CHD) in 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 who were undetectable at EOT maintained HDV RNA undetectability posttreatment, with duration of continuous HDV RNA undetectability at EOT 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.