BACKGROUND & AIMS:Direct-acting antiviral agents (DAA)-mediated HCV cure correlates with better outcomes, but there are insufficient data on detailed mortality-related risk factors after cure. This study sought to clarify mortality and associated risk factors post-HCV cure. METHODS:The study included HCV patients with sustained virological response following DAA (DAA-SVR) from 39 REAL-C centres in North America, Europe and Asia-Pacific. The primary outcome was all-cause mortality in DAA-SVR patients. Mortality rate per 1000 patient-years (PY) was calculated as the number of deaths divided by total PY multiplied by 1000. RESULTS:A total of 10 034 DAA-SVR patients (stratified by cirrhosis status: 5611 non-cirrhosis, 4153 compensated, 270 decompensated) were included. With a median follow-up of 4.76 PY, 4.9% (491) died. The all-cause mortality rates were 6.2, 13.1, 60.0 and 10.4 per 1000 PY for patients without cirrhosis, compensated and decompensated cirrhosis, and overall patients, respectively. The 5-year cumulative survival was 95.1% (94.5%-95.6%) overall, with the lowest rate of 73.9% (67.0%-79.5%) in decompensated cirrhosis. Non-liver-related death was the main cause in non-cirrhosis (non-liver-related vs. liver: 5.2 vs. 0.8 per 1000 PY)/compensated cirrhosis (8.2 vs. 4.8 per 1000 PY), while liver-related death was dominant in decompensated cirrhosis (24.7 vs. 33.8 per 1000 PY). Risk factors for higher mortality included age > 65 (3.2-fold), male (1.5-fold), cirrhosis (decompensated 7.6-fold) and baseline DM (1.5-fold). CONCLUSION:This study showed significant age, sex, fibrosis stage and DM differences in mortality and causes among DAA-SVR patients. It provided granular subgroup data for precision medicine to support individualised care, future modelling studies and public health planning.

BACKGROUND:ALG-000184 (pevifoscorvir sodium) is a prodrug of the class-E (empty) capsid assembly modulator (CAM), ALG-001075. CAM-Es prevent hepatitis B virus (HBV) replication by inhibiting capsid assembly and pregenomic RNA encapsidation and preventing covalently closed circular DNA (cccDNA) establishment. This part of the study aimed to assess the safety, tolerability, pharmacokinetics and short-term antiviral activity of ALG-000184 in participants with HBeAg-negative and HBeAg-positive chronic HBV infection to determine the subsequent development pathway for this novel therapeutic. METHODS:ALG-000184-201 was a phase 1, multicentre, randomised, dose escalation trial designed to evaluate the safety and pharmacokinetics of ALG-000184 in healthy participants (parts 1-2, reported separately) and antiviral activity in treatment-naive or currently not treated participants with chronic HBV infection (part 3, presented here). Eligible participants were 18-65 years old with BMI 18·0-35·0 kg/m2, and HBeAg-negative or HBeAg-positive chronic HBV infection with serum HBV DNA concentration more than 2000 IU/mL and serum ALT concentrations less than 5 times the upper limit of normal. Eligible patients were randomly assigned (4:1) to receive 28 days of oral ALG-000184 (10 mg, 50 mg, 100 mg, or 300 mg) or matching placebo once per day. Randomisation was managed via an interactive web response system and other than knowing the dose being evaluated in each cohort, all investigational site personnel and study participants were unaware of treatment assignments. The primary objective of this study was to evaluate the safety and tolerability of ALG-000184 in all randomly assigned participants (intention to treat population) using safety data including all treatment emergence adverse events, physical exam and vital signs findings, 12-lead electrocardiogram, and clinical laboratory findings. This study was registered at ClinicalTrials.gov, NCT04536337, and is complete. FINDINGS:Between March 16, 2021, and Oct 13, 2022, 135 participants were screened for inclusion from seven clinical investigational sites in Hong Kong, China, Moldova, New Zealand, and the UK. 76 participants did not meet one or more of the inclusion criteria or met one or more exclusion criteria and 59 participants were enrolled and randomly assigned to receive ALG-000184 10 mg (n=14), 50 mg (n=8), 100 mg (n=16), or 300 mg (n=10) or placebo (n=11). Participants had a median age of 37·0 years (IQR 31·0-45·5). 30 (51%) of 59 patients were male and 29 (49%) were female. 40 (68%) of patients were Asian. 28 (58%) of 48 participants assigned to receive ALG-000184 and seven (64%) of 11 in the placebo group experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs were increased alanine aminotransferase (ALT; 15 [31%] of 48 participants assigned to ALG-000184 and two [18%] of 11 participants assigned to placebo), increased aspartate aminotransferase (AST) concentrations (12 participants [25%] vs one [9%]), hyperuricemia (five [10%] vs two [18%]), headache (four [8%] vs one [9%]), elevated amylase (three [6%] vs none) and upper respiratory tract infection (three [6%] vs none). There were two serious adverse events unrelated to ALG-000184 (mild spinal pain and spontaneous pneumothorax). There were no deaths in the study. Doses of 10 mg to 300 mg ALG-000184 for 28 days resulted in multi-log reduction of HBV DNA (about 3-4 log10 IU/mL) and HBV RNA (about 0·5-3·0 log10 copies per mL). 19 (83%) of 23 HBeAg-negative participants achieved HBV DNA levels less than the lower limit of quantification (10 IU/mL) and 23 (100%) achieved HBV RNA levels less than the lower limit of quantification (10 copies per mL). Due to higher baseline levels, no HBeAg-positive participant achieved HBV DNA or HBV RNA less than the lower limit of quantification by 28 days. A decrease in HBsAg of 0·5 log10 IU/mL was observed in one HBeAg-positive participant who received 100 mg ALG-000184 and four of eight HBeAg-positive participants who received 300 mg ALG-000184 for 28 days had decreases of 0·2-0·8 log10 IU/mL. ALG-000184 had a dose-dependent linear pharmacokinetic profile. INTERPRETATION:ALG-000184 was safe and well tolerated, demonstrated predictable pharmacokinetic properties, and reduced HBV DNA and HBV RNA at all doses regardless of HBeAg status. These results support the evaluation of 300 mg ALG-000184 over longer periods in larger studies to determine its potential role in chronic suppressive therapy, with or without a nucleos(t)ide analogue, or as part of a finite curative regimen. FUNDING:Aligos Therapeutics.

Low-level residual viremia can be present in chronic hepatitis B (CHB) patients on nucleos(t)ide analogues (NUCs). Due to the detection limits of current HBV DNA assays, the association between residual viremia and HBV-related HCC has not been well studied. This study included NUC-treated HBV-related HCC patients with unquantifiable serum HBV DNA by the conventional Cobas-Taqman assay (< 20 IU/mL) at HCC diagnosis. The HCC patients were matched in a 1:1 ratio with NUC-treated non-HCC controls. Serum samples at the time of HCC diagnosis, 1 year before, and 2 years before diagnosis were retrospectively retrieved and tested for residual viremia by a validated high-sensitivity droplet digital polymerase chain reaction assay (lower limit of detection 1.6 IU/mL). Among 208 patients (104 HCC vs. 104 controls; mean age 63.1, 80.8% male, 54.3% cirrhosis), residual viremia within 2 years was observed in 82.7% of HCC patients and 49.0% of controls (p < 0.001), and was independently associated with HCC occurrence (OR 7.243, 95% CI 1.862-28.170, p = 0.004). In HCC patients, residual viremia was associated with histological microvascular invasion (44.4% vs. 9.1% in patients without residual viremia, p = 0.033) and lower probability of presenting with Barcelona Clinic Liver Cancer stage 0 HCC (OR 0.281, 95% CI 0.094-0.838, p = 0.023). After median follow-up for 7.2 years, residual viremia within 2 years before HCC diagnosis was independently associated with liver-related mortality (HR 4.472, 95% CI 1.212-16.504, p = 0.025). Residual viremia in NUC-treated CHB patients is associated with a higher risk of HCC development, more advanced tumour staging and poorer outcomes. High-sensitivity HBV DNA assays may be utilized for monitoring in NUC treatment.