Bulevirtide (BLV) is an entry inhibitor approved in Europe and Australia as a therapy for patients with chronic hepatitis delta (CHD); noninvasive tests (NITs) have demonstrated improvements in hepatic function and burden of liver disease with BLV treatment. Here we describe changes in NITs through up to 3 years of treatment.A longitudinal analysis was conducted using the Phase 3 MYR301 (NCT03852719) study data to determine the effect of BLV on results of alanine aminotransferase (ALT) level measurements and 3 NITs: fibrosis index based on 4 factors (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and liver stiffness measurement (LSM). In total, 150 patients with CHD were randomised to either no treatment for 48 weeks (W) followed by BLV 10 mg/d for 96W, or to BLV 2 or 10 mg/d for 144W. Change from baseline (BL) in NITs was assessed through 96W and 144W of treatment. This analysis was repeated for the pooled immediate treatment groups stratified by hepatitis delta virus (HDV) RNA response at W144: virologic responders (VR; undetectable HDV RNA or ≥ 2 log10 IU/mL decline in HDV RNA from BL), partial responders (PR; ≥ 1 log10 IU/mL but < 2 log10 IU/mL decline in HDV RNA from BL), and nonresponders (NR; < 1 log10 IU/mL decline in HDV RNA from BL). Patients with HDV RNA values missing at W144 were excluded. Results are reported as median (quartile [Q]1, Q3) unless otherwise stated.Overall, 149 patients with CHD were treated with BLV monotherapy (BLV 2 mg [n = 49]; BLV 10 mg [n = 100]); 99 were randomised to immediate BLV treatment for 144W, and 50 in the BLV 10 mg group received treatment for 96W. NITs showed improvements in all cohorts after 48W of therapy, which were maintained through 144W of therapy. Changes from BL at W144 were: BLV 2 mg group, FIB-4, −0.52 (−1.19, −0.03); LSM, −4.00 (−6.00, −1.00) kPa; immediate BLV 10 mg treatment group, FIB-4, −0.43 (−0.94, −0.14); LSM, −3.80 (−6.70, −1.20) kPa; and BLV delayed treatment group at W144 after 96W of treatment, FIB-4, −0.27 (−0.62, 0.02); LSM, −3.15 (−7.00, −0.40) kPa. Improvements at W144 in NITs were also seen across all viral response groups in the pooled immediate treatment cohort, including VR (n = 74), PR (n = 7), and NR (n = 8) at W144. Among VR, changes from BL were FIB-4, −0.43 (−1.05, −0.11); and LSM, −3.85 (−6.50, −1.20) kPa. Among PR, changes from BL were FIB-4, −0.39 (−0.48, −0.09); and LSM, −1.30 (−3.80, 0.20) kPa. Among NR, changes from BL were FIB-4, −1.02 (−1.60, −0.78); and LSM, −4.00 (−15.70, −1.10) kPa. Changes from BL in ALT levels and APRI scores were consistent with the trends observed in FIB-4 across all treatment cohorts. Treatment with BLV 2 or 10 mg monotherapy for up to 3 years resulted in longitudinal improvements in NITs in patients with CHD and were numerically greater with longer treatment duration. These improvements were seen even among the few patients without viral response.

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.

Hepatitis delta virus (HDV) causes the most severe form of viral hepatitis. Although nucleos(t)ide analogues (NAs) are the first-line treatment for chronic hepatitis B virus (HBV) infection, NAs have not been effective in reducing HDV RNA levels in patients with chronic hepatitis delta (CHD). Recent HBV/HDV treatment guidelines recommend NAs for patients with CHD with or without cirrhosis but with HBV DNA levels ≥2000 IU/mL. We evaluated the virologic outcomes of bulevirtide (BLV) treatment over a 96-week period, comparing its effects when administered with and without NAs.Table.Treatment Outcomes at Week 48 for All Groups and Week 96 (BLV 2 and 10 mg) by Concomitant NA Treatment (Pooled Analysis of Studies MYR204 and MYR301)aThe DT group included 51 patients who did not receive BLV for 48 weeks; 50 of these patients received BLV 10 mg from week 48 to 144 and are included in the 10mg/d group. Change from baseline for these 50 patients was reset at week 48 in the BLV 10 mg/d group. bDefined as ALT, alanine aminotransferase; BL, baseline; BLV, bulevirtide; d, day; DT, delayed treatment; HBV, hepatitis B virus; HDV, hepatitis delta virus; NA, nucleos(t)ide analogue. Data from 2 randomized studies (MYR204 [NCT03852433]; MYR301 [NCT03852719]) were pooled for patients receiving BLV monotherapy 2 or 10 mg/day (d) for 96 weeks, including a delayed treatment (DT) arm with no BLV treatment for 48 weeks as a control. NA treatment was allowed per treatment guidelines. Treatment outcomes included undetectable HDV RNA < the lower limit of quantitation (50 IU/mL, target not detected), virologic response (VR; undetectable HDV RNA or ≥2 log10 IU/mL decline from baseline [BL]), alanine aminotransferase (ALT) normalization, change from BL in ALT, combined response (VR and ALT normalization), and change from BL in HBV DNA and liver stiffness, all assessed over 96 weeks with vs without NAs. We included patients in 3 groups: BLV 2 mg/d (n = 49), BLV 10 mg/d (n = 150), and the DT arm (n = 51). Overall, NAs were used in 32/49 (65%), 83/150 (55%), and 32/51 (63%) patients in the BLV 2 mg, 10 mg, and DT groups, respectively. BL characteristics were comparable, except the proportions of patients with cirrhosis, prior interferon use, and mean liver stiffness were higher in those with NAs (54%; 61%; 14.8 kPa) vs without NAs (30%; 41%; 13.4 kPa). The most common therapy was tenofovir based (97/114 [85%]). Treatment outcomes with vs without NAs at week 48 for the DT group and week 96 for the BLV 2 and 10 mg groups are shown in the table. BLV given for 96 weeks is effective in achieving HDV virologic outcomes and ALT normalization in patients with CHD regardless of NA use. While the addition of NA therapy did not substantially improve HDV outcomes, it did contribute to a greater reduction in HBV DNA levels. Pietro Lampertico, MD, AbbVie: Speaking/teaching fees/advisory committee/review panel|Aligos Therapeutics: Speaking/teaching fees/advisory committee/review panel|Alnylam Pharmaceuticals: Speaking/teaching fees/advisory committee/review panel|Antios Therapeutics: Speaking/teaching fees/advisory committee/review panel|Arrowhead Pharmaceuticals: Speaking/teaching fees/advisory committee/review panel|Bristol Myers Squibb: Speaking/teaching fees/advisory committee/review panel|Eiger Biopharmaceuticals: Speaking/teaching fees/advisory committee/review panel|Gilead Sciences, Inc.: Speaking/teaching fees/advisory committee/review panel|GSK: Speaking/teaching fees/advisory committee/review panel|Janssen: Speaking/teaching fees/advisory committee/review panel|Merck Sharp & Dohme: Speaking/teaching fees/advisory committee/review panel|MYR GmbH: Speaking/teaching fees/advisory committee/review panel|Roche: Speaking/teaching fees/advisory committee/review panel|Spring Bank Pharmaceuticals: Speaking/teaching fees/advisory committee/review panel Maurizia Brunetto, MD, AbbVie: Consulting/speaker bureaus|Eisai–Merck Sharp & Dohme: Consulting/speaker bureaus|Gilead Sciences, Inc.: Consulting/speaker bureaus|Janssen: Consulting/speaker bureaus|Roche: Consulting/speaker bureaus Maria Buti, MD, PhD, AbbVie: Speaker fees/research support/consulting fees|Gilead Sciences, Inc.: Speaker fees/research support/consulting fees|Janssen: Speaker fees/research support/consulting fees Soo Aleman, MD, PhD, AbbVie: Grant/Research Support|AbbVie: Honoraria|Biogen: Honoraria|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Merck Sharp & Dohme: Honoraria Vladimir Chulanov, MD, PhD, AbbVie: Consultant/sponsored lectures|AstraZeneca: Consultant/sponsored lectures|Bristol Myers Squibb: Consultant/sponsored lectures|Gilead Sciences, Inc.: Consultant/sponsored lectures|GSK: Consultant/sponsored lectures|Hepatera: Consultant/sponsored lectures|Merck Sharp & Dohme: Consultant/sponsored lectures|Roche: Consultant/sponsored lectures|R-Pharm: Consultant/sponsored lectures Renee-Claude Mercier, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Mingyang Li, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Amos Lichtman, MPH, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Dmitry Manuilov, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Heiner Wedemeyer, MD, Abbott: Advisor/Consultant|Abbott: Honoraria|AbbVie: Advisor/Consultant|AbbVie: Honoraria|Aligos Therapeutics: Advisor/Consultant|Arbutus Biopharma: Advisor/Consultant|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Bristol Myers Squibb: Advisor/Consultant|Bristol Myers Squibb: Honoraria|Dicerna Pharmaceuticals: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|Johnson & Johnson/Janssen-Cilag: Advisor/Consultant|Johnson & Johnson/Janssen-Cilag: Honoraria|Merck/Schering-Plough: Advisor/Consultant|Merck/Schering-Plough: Honoraria|MYR GmbH: Advisor/Consultant|MYR GmbH: Honoraria|Novartis: Advisor/Consultant|Novartis: Honoraria|Roche: Advisor/Consultant|Roche: Honoraria|Siemens: Advisor/Consultant|Siemens: Honoraria|Transgene: Advisor/Consultant|Transgene: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria|Vir Biotechnology: Advisor/Consultant Tarik Asselah, MD PhD, AbbVie: Speaker/investigator|Eiger Biopharmaceutical: Speaker/investigator|Gilead Sciences, Inc.: Speaker/investigator|Janssen: Speaker/investigator|Merck: Speaker/investigator|Myr Pharmaceutical: Speaker/investigator|Roche: Speaker/investigator Fabien Zoulim, MD, PhD, Aligos Therapeutics: Advisor/Consultant|Aligos Therapeutics: Grant/Research Support|Assembly Biosciences: Advisor/Consultant|Assembly Biosciences: Grant/Research Support|Gilead Sciences, Inc.: Advisor/Consultant|GSK: Advisor/Consultant|Vir Biotechnology: Advisor/Consultant

Background & Aims: Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antiger (HBsAg) and HBV DNA to below the lower limit of quantification (

Abstract Background Chronic Hepatitis Delta (CHD) is the most severe form of viral hepatitis. Bulevirtide (BLV) is a first-in-class entry inhibitor approved in the EU for the treatment of compensated CHD. In MYR204, a Phase 2b study evaluating finite treatment with BLV with or without pegylated interferon alfa-2a (Peg-IFNa), combination treatment with 10mg BLV resulted in higher undetectable HDV RNA rates 24 weeks (W) post end of treatment (EOT) compared with either monotherapy regimen. Here, we present predictors of undetectable HDV RNA at 48W (FU-48) post-EOT.Table 1.Comparison of Key Efficacy Endpoints at EOT vs FU-48 Methods 174 patients with CHD were randomized (1:2:2:2) with stratification of cirrhosis status and received (A) Peg-IFNa for 48W; or (B) BLV 2mg + Peg-IFNa, or (C) BLV 10mg + Peg-IFNa for 48W followed by 48W of monotherapy with BLV 2mg or 10mg, respectively; or (D) BLV 10mg for 96W. All patients were followed up to FU-48. Efficacy endpoints were compared by Fisher’s exact test. The logistic regression model examined if any baseline (BL) characteristics predicted responses at FU-48 with arms B and C. Characteristics with p< 0.05 were considered potential predictors. The MMRM was used to evaluate treatment effect on HDV RNA during initial 48W on-treatment.Figure 1.Selected Characteristics as Potential Predictors of undetectable HDV RNA at FU-48 in patients treated with BLV +Peg-IFNa. Logistic regression analysis was performed on a merged data set of patients that were treated with combination therapy of BLV (either 2 or 10mg) +Peg-IFNa to evaluate predictors of HDV RNA undetectability. P values <0.05 are represented in bold. Results BL characteristics were similar between all arms. Key endpoints such as, HDV RNA undetectability, ALT normalization, and composite response (HDV RNA undetectable and ALT normalization) at EOT and FU-48 are shown in Table 1. Selected potential BL predictors of undetectable HDV RNA at FU-48 included BL HDV RNA < median of 5.54 log10 IU/mL (Odds Ratio (OR): 5.6, p=0.0003), and BL liver stiffness < 11.1kPa (OR: 2.9, p< 0.02) (Fig.1). Time to onset of HDV RNA undetectability (OR: 0.99, p=0.0015), and undetectable by on-treatment 24W (OR:13.5, p< 0.0001) predicted HDV RNA undetectability at FU-48. BLV (2 or 10mg) + Peg-IFNa had a higher weekly decline of HDV RNA compared to Peg-IFNa (LS-means difference: -0.0414 log10IU/mL or -0.0542 log10IU/mL (p< 0.0001), respectively) within the first 48W on-treatment. Conclusion In patients with CHD treated with a finite regimen of BLV + Peg-IFNa early rapid on-treatment viral decline and achievement of HDV RNA undetectability are associated with undetectable HDV RNA at FU-48. Disclosures Tarik Asselah, PhD, Abbvie: Expert Testimony|Abbvie: Investigator|Eiger Pharmaceuticals: Expert Testimony|Eiger Pharmaceuticals: Investigator|Gilead Sciences, Inc.: Expert Testimony|Gilead Sciences, Inc.: Investigator|Janssen: Expert Testimony|Janssen: Investigator|Merck: Expert Testimony|Merck: Investigator|Myr pharmaceutical: Expert Testimony|Myr pharmaceutical: Investigator|Roche: Expert Testimony|Roche: Investigator Fabien Zoulim, MD, PhD, Aligos Therapeutics: consulting fees|Antios Therapeutics: consulting fees|Assembly Biosciences: Grant/Research Support|Assembly Biosciences: consulting fees|Beam Therapeutics: Grant/Research Support|Gilead Sciences, Inc.: consulting fees|Janssen: Grant/Research Support Dana Tedesco, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Renee-Claude Mercier, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Dmitry Manuilov, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Audrey Lau, MD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Marc Bourliere, MD, PhD, AbbVie: Board Member|AbbVie: Expert Testimony|Gilead Sciences, Inc.: Board Member|Gilead Sciences, Inc.: Expert Testimony|Intercept: Board Member|Intercept: Expert Testimony|Roche: Board Member|Roche: Expert Testimony Vladimir Chulanov, MD, PhD, AbbVie: Advisor/Consultant|AbbVie: Expert Testimony|AstraZeneca: Advisor/Consultant|AstraZeneca: Expert Testimony|Bristol Myers Squibb: Advisor/Consultant|Bristol Myers Squibb: Expert Testimony|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Expert Testimony|GSK: Advisor/Consultant|GSK: Expert Testimony|Hepatera: Advisor/Consultant|Hepatera: Expert Testimony|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: Expert Testimony|Roche: Advisor/Consultant|Roche: Expert Testimony|R-Pharm: Advisor/Consultant|R-Pharm: Expert Testimony

Abstract Background Bulevirtide (BLV) is a first-in-class entry inhibitor for chronic hepatitis D (CHD) approved in Europe. Interim results from MYR301 (NCT03852719), a phase 3 randomized study, showed monotherapy with BLV 2 mg/d or 10 mg/d given subcutaneously was effective and safe over 144 weeks (W). With a greater risk of developing cirrhosis with HDV than HBV alone, we explore the impact of cirrhosis status on efficacy and safety of BLV monotherapy through 144W.Table 1.Efficacy results at Week 144 based on cirrhosis status Methods 150 patients with CHD were randomized and stratified based on the presence/absence of compensated cirrhosis (investigator-determined) as follows: Arm A: no anti-HDV treatment for 48W followed by BLV 10mg/d for 96W (n=51), Arm B: immediate treatment with BLV at 2 mg/d (n=49) or Arm C: immediate treatment with BLV at 10 mg/d (n=50) each for 144W. Combined response (CR) was defined as undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline (virologic response (VR)) and ALT normalization. Other endpoints included VR, ALT normalization and undetectable HDV RNA. HDV RNA was quantified using RoboGene 2.0 (lower limit of quantification, 50 IU/mL; limit of detection, 6 IU/mL).Table 2:Safety results for BLV at Week 144 based on cirrhosis status Results A total of 71/150 (47%) participants had compensated cirrhosis; 73% and 27% were Child-Pugh score 5 and 6 respectively. Baseline (BL) characteristics were similar between those with and without cirrhosis with a few expected differences; higher liver stiffness measurement (LSM) and lower platelet count in those with cirrhosis. Differences in efficacy response rates by cirrhosis status were not consistently observed (Table 1). In a univariate logistic regression in W144 completers in Arm B and C, with BL HDV RNA > 250 IU/mL, cirrhosis status was not a predictor of efficacy. Declines in both HDV RNA and ALT over time were consistent across subgroups regardless of cirrhosis status. There was no progression to liver-related outcomes over 144W except for 1 case of mild ascites in a patient with cirrhosis in Arm A. BLV was safe and well tolerated in both patients with and without cirrhosis (Table 2). Conclusion BLV monotherapy through Week 144 maintains efficacy and safety in patients regardless of cirrhosis status at baseline. Disclosures Soo Aleman, MD, PhD, AbbVie: Grant/Research Support|AbbVie: Honoraria|Biogen: Honoraria|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|MSD: Honoraria Heiner Wedemeyer, MD, PhD, Abbott: Advisor/Consultant|Abbott: Honoraria|AbbVie: Advisor/Consultant|AbbVie: Honoraria|Arbutus: Advisor/Consultant|Boeringer Ingelheim: Advisor/Consultant|Boeringer Ingelheim: Honoraria|Bristol Myers Squibb: Advisor/Consultant|Bristol Myers Squibb: Honoraria|Dicerna: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|Johnson & Johnson/Janssen-Cilag: Advisor/Consultant|Johnson & Johnson/Janssen-Cilag: Honoraria|Merck/Schering-Plough: Advisor/Consultant|Merck/Schering-Plough: Honoraria|MYR GmbH: Advisor/Consultant|MYR GmbH: Honoraria|Novartis: Advisor/Consultant|Novartis: Honoraria|Roche: Advisor/Consultant|Roche: Honoraria|Siemens: Advisor/Consultant|Siemens: Honoraria|Transgene: Advisor/Consultant|Transgene: Honoraria|Viiv Healthcare: Advisor/Consultant|Viiv Healthcare: Honoraria|Vir Biotechnology: Advisor/Consultant Maurizia Brunetto, MD, AbbVie: Advisor/Consultant|AbbVie: speaker bureau|EISAI-MSD: Advisor/Consultant|EISAI-MSD: speaker bureau|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: speaker bureau|Janssen: Advisor/Consultant|Janssen: speaker bureau|Roche: Advisor/Consultant|Roche: speaker bureau Antje Blank, MD, Myr GMBH: Grant/Research Support Vladimir Chulanov, MD, PhD, AbbVie: Advisor/Consultant|AbbVie: Expert Testimony|AstraZeneca: Advisor/Consultant|AstraZeneca: Expert Testimony|Bristol Myers Squibb: Advisor/Consultant|Bristol Myers Squibb: Expert Testimony|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Expert Testimony|GSK: Advisor/Consultant|GSK: Expert Testimony|Hepatera: Advisor/Consultant|Hepatera: Expert Testimony|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: Expert Testimony|Roche: Advisor/Consultant|Roche: Expert Testimony|R-Pharm: Advisor/Consultant|R-Pharm: Expert Testimony Grace Chee, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Dmitry Manuilov, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Mingyang Li, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Audrey Lau, MD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Anu Osinusi, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Steve Tseng, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Private Company) Julian Schulze Zur Wiesch, MD, PhD, Gilead Sciences, Inc.: Consultation and lecture fees Markus Cornberg, MD, PhD, AbbVie: Honoraria|Falk: Honoraria|Gilead Sciences, Inc.: Honoraria|GSK: Honoraria|Janssen-Cilag: Honoraria|Merck Sharp & Dohme: Honoraria|Novartis: Honoraria|Roche: Honoraria|Spring Bank Pharmaceuticals: Honoraria|Swedish Orphan Biovitrum: Honoraria Stefan Zeuzem, MD, PhD, AbbVie: Advisor/Consultant|AbbVie: speaker bureau|Allergan: Advisor/Consultant|Allergan: speaker bureau|BioMarin: Advisor/Consultant|BioMarin: speaker bureau|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: speaker bureau|Intercept: Advisor/Consultant|Intercept: speaker bureau|Janssen: Advisor/Consultant|Janssen: speaker bureau|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: speaker bureau|Novo Nordisk: Advisor/Consultant|Novo Nordisk: speaker bureau|Swedish Orphan Biovitrum: Advisor/Consultant|Swedish Orphan Biovitrum: speaker bureau|Theratechnologies: Advisor/Consultant|Theratechnologies: speaker bureau Pietro Lampertico, MD, AbbVie: speaking and teaching fees/ advisory committees and review panels|Aligos: speaking and teaching fees/ advisory committees and review panels|Alnylam: speaking and teaching fees/ advisory committees and review panels|Antios: speaking and teaching fees/ advisory committees and review panels|Arrowhead: speaking and teaching fees/ advisory committees and review panels|Bristol Myers Squibb: speaking and teaching fees/ advisory committees and review panels|Eiger Pharmaceuticals: speaking and teaching fees/ advisory committees and review panels|Gilead Sciences, Inc.: speaking and teaching fees/ advisory committees and review panels|GSK: speaking and teaching fees/ advisory committees and review panels|Janssen: speaking and teaching fees/ advisory committees and review panels|Merck Sharp & Dohme: speaking and teaching fees/ advisory committees and review panels|MYR GmbH: speaking and teaching fees/ advisory committees and review panels|Roche: speaking and teaching fees/ advisory committees and review panels|Spring Bank Pharmaceuticals: speaking and teaching fees/ advisory committees and review panels

Background & Aims Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD. Methods In an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS). Results Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale. Conclusion PROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD. Impact and implications Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group). Clinical trial registration ClinicalTrials.gov Identifier, NCT03852719