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144 Weeks of bulevirtide monotherapy for chronic hepatitis D: Final and post-treatment results from a phase III randomized trial
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Highlights
• Bulevirtide is well tolerated and effective through 144 weeks of treatment.
• Virologic and biochemical response rates decreased post-treatment.
• Some patients had sustained undetectable HDV RNA through up to 2 years of follow-up.
• These patients maintained improvements in biochemical response post-treatment.
• Duration of continuous HDV RNA undetectability at the end of treatment predicts sustained post-treatment undetectability.
Abstract
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%).
In the univariate analysis, baseline predictors of undetectable HDV RNA at EOT included lower baseline HDV RNA (log10 IU/ml) and bulevirtide 10 mg vs. 2 mg (Fig. S6).
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.
In summary, treatment with bulevirtide monotherapy for up to 144 weeks in patients with CHD was safe, well tolerated, and effective, with improvements observed in combined, virologic, and biochemical response rates, and continued increases in HDV RNA undetectability from 96 to 144 weeks of treatment. Higher rates of HDV RNA undetectability with bulevirtide 10 mg daily compared with bulevirtide 2 mg continued through EOT, although rates were similar at FU96. Of patients who achieved HDV RNA undetectability at EOT, a subset did not relapse through 2 years of follow-up, predicted by a longer duration of continuous on-treatment undetectability. In patients who discontinue bulevirtide therapy, hepatic function should be monitored for at least 6 months due to the risk of hepatitis flares. Overall, virologic and biochemical response rates decreased after stopping bulevirtide, suggesting a clinical benefit of continued treatment in most patients.
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