Direct-acting antiviral therapies can cure most people with hepatitis C virus (HCV) infection with little need for testing or monitoring. A major challenge to eliminating HCV is ensuring patients complete all steps of care, including confirmation of cure. We assessed the concordance of sustained virologic response (SVR) at 4 weeks (SVR4) and 12 weeks (SVR12) post-treatment to evaluate the viability of SVR4 as a predictor of cure in patients treated with sofosbuvir (SOF)/velpatasvir (VEL). We conducted a retrospective analysis of patients from the Phase 3 ASTRAL-1, -2, and -3 programs and a historical cohort from the Louisiana Department of Health Sexually Transmitted Infection (STI)/HIV/Hepatitis Program claims database. Concordance analyses were performed for patients with both SVR4 and SVR12 data. The concordance analysis in the ASTRAL studies included 1015 patients; 1005 and 1002 achieved SVR4 and SVR12, respectively. Among SVR4 achievers, 3 failed to maintain SVR12, while all (10/10) patients who did not achieve SVR4 also failed SVR12. In the real-world cohort, 479/509 (94%) patients achieved SVR4 and 485/509 (95%) achieved SVR12. Of those with SVR4, 7 failed SVR12; 17 of 30 patients who did not achieve SVR4 also failed SVR12. High concordance between SVR4 and SVR12 was observed in both ASTRAL and the real-world dataset, supporting the use of SVR4 as a predictor of long-term SVR in patients with HCV infection treated with SOF/VEL. Streamlining cure confirmation by shifting SVR determination from week 12 to week 4 post-treatment may reduce patient loss to follow-up.

BACKGROUND:Peg-interferon (peg-IFN) plays an increasingly important role in HBV cure strategies, either in combination with novel antivirals, as a lead-in or as consolidation treatment. OBJECTIVE:We aimed to provide estimates of hepatitis B surface antigen (HBsAg) decline and clearance that can be achieved with peg-IFN addition to nucleos(t)ide analogue (NA) therapy. DESIGN:This is a post hoc meta-analysis of individual participant data from eight clinical trials involving chronic hepatitis B patients on NA therapy who received peg-IFN add-on. The primary endpoint was HBsAg loss at end of follow-up (EOF, 6-12 months after end of peg-IFN). Secondary analyses focused on HBsAg decline. RESULTS:581 patients were included. At the start of peg-IFN therapy (SOT), 44% were hepatitis B envelope antigen (HBeAg) positive, mean HBsAg level was 3.03 log10 IU/mL (HBsAg<100: 12%; 100-1000: 28%; ≥1000: 60%), and planned duration of peg-IFN was 48 weeks in 496 patients (85%).At EOF, 50 (8.6%) patients achieved HBsAg loss (HBsAg<100/100-1000/≥1000: 37.7/9.8/2.3%, p<0.001) Findings were consistent across ethnicities (Caucasian: 30.0/8.7/3.6%; Asian: 39.3/9.2/2.2%). In patients with SOT HBsAg≥1000 IU/mL, levels <1000 and <100 were achieved in 29.7% and 8.9% at 24 weeks and in 47.5% and 16.3% at 48 weeks of peg-IFN therapy, respectively. CONCLUSION:Peg-IFN add-on results in HBsAg loss in 18% of patients with SOT HBsAg<1000 IU/mL, and in 38% if SOT HBsAg<100 IU/mL. Among patients with higher HBsAg levels, peg-IFN could be used to reduce HBsAg to below thresholds associated with response to novel compounds.

Background/Objectives: Systemic treatment of advanced hepatocellular carcinoma (HCC) is based on combinations of immunotherapies (ITs) and lacks predictive markers of efficacy. Objectives: To define the prognostic value of the CRAFITY and RECA biological scores for overall survival (OS) before and during IT, and to evaluate the value of these two models for predicting the therapeutic response. Patients and methods: This was a multicenter retrospective analysis of 229 patients. OS was analyzed using Kaplan-Meier curves, log-rank tests, and Cox models, through which second-line therapy was modeled as a time-dependent covariate to avoid immortal time bias. The predictive capacity was assessed using univariate logistic regression. Validation was performed within two external Chinese cohorts. Results: Sixty-six percent of patients had Barcelona Clinic Liver Cancer (BCLC) stage C HCC (vascular invasion: 36.3%, metastases: 32.6%). After a mean follow-up of 14.9 (12.8) months, the median OS was 17.4 (6.9-38.0) months. The CRAFITY score distinguished only two different prognostic subgroups before treatment, but its prognostic value was confirmed with three different prognostic groups after 3 and 5 cycles and 6 months of treatment. The RECA score was strongly associated with OS before treatment and after 3 and 5 cycles and after 6 months of IT. Conversely, neither score had a discriminatory ability to predict early therapeutic response. The prognostic value of both models for OS was confirmed in the external cohorts. Conclusions: The RECA and CRAFITY scores have strong prognostic value for OS during IT. Beyond the models, the dynamic effects of systemic inflammation on IT reveal distinct clinical outcomes. Neither score has the ability to predict early therapeutic response, further supporting their use during treatment.

Hepatitis delta (HDV) infection affects 5% of hepatitis B (HBV)-positive patients and is associated with an increased risk of cirrhosis and hepatocellular carcinoma; however, it remains underdiagnosed. The first part of our Delta Describe study highlights the insufficient level of HDV screening among patients in metropolitan France. In this study, we report on their real-world management. Patients with at least one positive HDV RNA test performed in 2019 were identified through the major public and private laboratories in France. From January 2024 to July 2025, informed patients were interviewed, and physicians supplemented the collected data. A total of 547 patients were included, with a median age of 44 years; most originated from Africa or Eastern Europe. HIV and hepatitis C coinfections were reported in 15.2% and 4.6% of patients, respectively. Liver fibrosis was primarily assessed using FibroScan®. Most patients knew the year of their delta diagnosis, and 69.1% knew their fibrosis stage. Liver-related events occurred in 14.3% (67/468) of patients, mainly comprising portal hypertension (61.6%), liver failure (12.3%), and hepatocellular carcinoma (26%), and 45 patients (45/468) underwent liver transplantation. At the time of the survey, 47.1% of the patients reported undetectable HDV RNA; 40.6% (222/547) had currently or previously undergone BLV treatment. Among patients receiving ongoing treatment for HDV at the time of the survey, 84.8% were receiving nucleos(t)ide analogs (NUCs). In metropolitan France, HDV patients had access to specialized follow-up care and innovative therapies (bulevirtide), were mostly on NUCs, and demonstrated good disease awareness.

Background and Aim: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with chronic hepatitis B virus (HBV) infection being a major risk factor. To date, existing predictive scores of HCC are mainly based on traditional Cox proportional hazard (CPH) models. This study aimed to compare the variable selection process and performance of CPH models with those of machine learning (ML) and deep learning (DL) algorithms in predicting HCC among patients with chronic HBV infection. Methods: We used data from 4,370 individuals with chronic HBV infection enrolled in the French prospective multicentre ANRS CO22 HEPATHER cohort, of which 56 (1.3%) developed an HCC. Two published CPH-based scores (ADAPTT and SADAPTT) were compared to Random Survival Forest (RSF), Survival Support Vector Machine (SVM), Survival XGBoost, and DeepSurv algorithms. Models were evaluated using Harrell's C-index, Inverse-Probability-of-Censoring Weighting win ratio statistic, and time-dependent area under the ROC curve at 3, 5, and 8 years. The same set of covariables was used to build all the models. Results: CPH models demonstrated similar or higher performances (C-index [95% confidence interval]: 0.84 [0.82 -0.85]) for HCC prediction compared to ML and DL models, with less overfitting. Survival SVM and RSF performed similarly (0.81 [0.79-0.83] and 0.81 [0.79-0.82], respectively) without outperforming CPH models. Variable selection was consistent across top-performing models, though CPH models more effectively captured the predictive value of certain behavioural factors, such as soft drink intake. Conclusions: In this dataset with a limited sample size and strongly imbalanced outcome, traditional CPH models provided robust, interpretable, and computationally efficient predictions for HCC risk. ML and DL methods did not outperform traditional models, reinforcing the validity of traditional statistical approaches in small to medium datasets.

Background: In the nucleos(t)ide analog (NA)-control arm of the REEF-2 study (NCT04129554), virologic relapse (confirmed increase in HBV DNA >2000 IU/mL) and biochemical flare (ALT increases >= 3x upper limit of normal) were frequently observed after stopping NA treatment. We characterized the posttreatment virologic relapses and biochemical flares and assessed their association with end-of-treatment (EOT) HBV serum markers. Methods: In REEF-2, a randomized-controlled study, virologically suppressed HBeAg-negative patients stopped treatment at week 48, followed by 48 weeks of follow-up. EOT HBV RNA, hepatitis B core-related antigen, and quantitative anti-hepatitis B core (HBc) IgG levels were assessed in 41/45 NA-control arm patients; their association with off-treatment response was evaluated. Results: A similar proportion of patients with EOT HBV RNA or hepatitis B core-related antigen detectable and target not detectable had virologic relapse or ALT flares (p>0.05). A higher frequency of severe virologic relapse (peak HBV DNA >100,000 IU/mL) and/or severe biochemical flares (peak ALT >= 10x upper limit of normal) was observed in patients with EOT detectable hepatitis B core-related antigen levels, HBsAg <1000 IU/mL, and/or anti-HBc IgG titers <300 IU/mL, respectively (p<0.05). None of the 11 patients with EOT anti-HBc titers >= 300 IU/mL had severe virologic or biochemical flare off treatment (100% positive predictive value and 48% negative predictive value). Conclusions: In this prospective study of patients who stopped NA, anti-HBc levels >= 300 IU/mL were associated with a low risk of developing virologic relapse and severe biochemical flares. Future research should confirm a potential protective effect of high anti-HBc IgG levels.

Migrants in Europe are disproportionately affected by hepatitis B virus (HBV) infection, especially those coming from endemic countries. We aimed to determine whether migrant status was associated with all-cause mortality risk in people living with chronic HBV infection integrated into a hospital-based care pathway in France. We analysed clinical and socio-behavioural data collected over 8 years of follow-up among patients with chronic HBV infection enrolled in the French prospective multicentre cohort ANRS CO22 HEPATHER. Migrant status was tested as a binary variable (non-migrants versus migrants) and according to three categories (low, moderate, and high) of HBV endemicity in the migrants’ region of birth. The association between migrant status and all-cause mortality risk was assessed using a multivariable Cox proportional hazards model. A competing risks analysis was conducted for liver-related and non-liver-related mortality. Of the 5597 study participants, accounting for 33,222.8 person-years (PY), 68.1

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

BACKGROUND:How selective internal radiation therapy (SIRT) with personalized dosimetry fits with intermediate and advanced hepatocellular carcinoma (HCC) treatment remains unclear. The aims of our study were to investigate the efficacy and safety of SIRT in real-life settings within a nonsurgical HCC population and to identify prognostic factors for survival. METHODS:From January 2019 to December 2023, 73 consecutive HCC patients who underwent SIRT with personalized dosimetry at three French centers were retrospectively analyzed. A post-matched comparison with a large single-center cohort of HCC patients (n=1,049) enrolled from January 2007 to December 2023 and treated with other therapeutic modalities was performed. Overall survival (OS) was compared between the two patient groups. RESULTS:Patients treated with SIRT had mostly Child-Pugh (CP) grade A cirrhosis and multifocal and unilobar HCCs, which were classified as Barcelona Clinic Liver Cancer (BCLC) stage B or C with vascular invasion (49%) or metastases (5%). SIRT was a first-line therapy in half of the patients and was used in combination for nearly one-quarter of the patients. In total, 94% of the patients received a tumor dose of 205 Gy or higher. After a median follow-up of 11.9 (6.2-21.1) months, 53% of patients treated with SIRT died. Stage B and C HCC patients had median OS times of 35.2 (6.5-infinite) and 12.8 (6.8-infinite) months, respectively. A comparative analysis of the two cohorts revealed the superiority of SIRT in terms of OS for advanced-stage HCCs with unilateral intrahepatic portal vein tumor thrombosis and the similarity of SIRT for intermediate-stage HCCs compared with other modalities. No significant difference in OS was observed after matching BCLC B/C HCC patients who received SIRT with those who did not after a median follow-up of approximately 12 months. The independent prognostic variables for survival following SIRT therapy were CP grade, largest tumor size and hemoglobin level. No deaths occurred in the SIRT group. CONCLUSIONS:This study revealed that SIRT following personalized dosimetry is used in current practice as a therapeutic solution for advanced and intermediate HCC, typically in combination therapies and beyond first-line treatment. Our results support SIRT as an alternative therapeutic option for intermediate-stage HCC and as an effective therapeutic solution for advanced HCC with intrahepatic vascular invasion, with a good safety profile.

People infected with both hepatitis B virus (HBV) and hepatitis Delta virus (HDV) face a higher mortality risk than those mono-infected with HBV. As unhealthy behaviours can influence liver disease progression, we compared the effects of various behavioural factors on all-cause mortality among people with chronic hepatitis B (CHB), with or without chronic hepatitis Delta (CHD). We used 5-year follow-up data from people with CHB participating in the French ANRS CO22 HEPATHER cohort. A Cox proportional hazards model helped determine whether the pattern of risk factors for all-cause mortality differed according to CHD status. Of the 3884 people included, 183 had CHD and 154 died during follow-up. After multivariable adjustment, daily soft drink consumption significantly increased mortality risk in people with CHD and almost reached significance in those without CHD (adjusted hazard ratio (aHR) [95% CI]: 6.09 [2.40-15.48], p < 0.001, and 1.58 [0.97-2.56], p = 0.066 respectively). Moreover, past or current unhealthy alcohol use and tobacco smoking were both associated with a higher risk of mortality in all people with CHB (1.74 [1.09-2.79], p = 0.020, and 1.61 [1.13-2.31], p = 0.009 respectively). Daily soft drink consumption significantly increased all-cause mortality in people with CHD. Unhealthy alcohol use and tobacco smoking were associated with a higher mortality risk in all people with CHB. Education about healthy eating and support for smoking cessation and alcohol reduction could greatly improve health and survival of people with CHB, with and without CHD.

BACKGROUND AND AIMS:Early assessment of hepatocellular carcinoma (HCC) risk could improve long-term outcomes in people with chronic hepatitis B virus (HBV) infection. Some existing HCC predictive scores are not easily implementable. We developed easy-to-use HCC predictive scores based on behavioural and routine bio-clinical data in people with chronic HBV infection. METHODS:Eight-year follow-up data was analysed from people with chronic HBV infection enrolled in the French ANRS CO22 HEPATHER cohort. Patients were randomly split into two samples (training/testing). A multivariable Cox model for time to HCC was estimated on the training sample. The HCC predictive score was computed by summing the points assigned to model predictors, normalising their coefficients over a 10-year age increment, and rounding to the nearest integer. The Youden index identified the score's optimal risk threshold. Comparisons with existing predictive scores were performed on the testing sample. RESULTS:In the study population (N = 4370; 63% of men; 65% of < 50 years old), 56 HCC cases occurred during 25,900 follow-up person-years. Two HCC predictive scores were defined: SADAPTT (daily soft drink consumption, age, hepatitis Delta infection, unhealthy alcohol use, platelet count, heavy tobacco smoking, and HBV treatment) and ADAPTT (the same predictors except for daily soft drink consumption), with ranges 0-13 and 0-14, respectively, and values ≥ 3 indicating a high HCC risk. Their performances were similar to existing scores. CONCLUSIONS:We developed two effective behaviour-based HCC predictive scores, implementable in many settings, including primary care and decentralised areas. Further studies are needed to validate these scores in other datasets.

BACKGROUND AND AIMS:Atezolizumab-Bevacizumab (AtezoBev) was the first immunotherapy approved for hepatocellular carcinoma (HCC) in France, with initial trials primarily involving patients with viral-related liver disease. This prospective study aimed to evaluate the efficacy of AtezoBev in a French HCC population predominantly affected by non-viral liver disease. METHODS:Data from 545 HCC patients treated with AtezoBev as first-line systemic therapy were collected from 32 French centres in the CHIEF cohort between July 2020 and January 2023. Kaplan-Meier analysis evaluated overall survival (OS) and progression-free survival (PFS), while log-rank tests assessed the impact of baseline characteristics. RESULTS:Median age was 69, with 81% Child-Pugh A and 19% Child-Pugh B. Liver disease was primarily alcohol-related (30%) or viral (16%), with mixed aetiology with at least alcohol consumption in 58%. At AtezoBev initiation, 72% of cases were treatment-naive, 31% were BCLC-B and 64% were BCLC-C. Median OS was 23.1 months, with a 12-month survival rate of 66%. OS was higher in BCLC-B patients (27.8 months) compared to BCLC-C (17.2 months, p = 0.0043) and in Child-Pugh A (26.4 months) compared to Child-Pugh B (10.6 months, p < 0.001). Median PFS was 5.2 months, with BCLC-B patients showing significantly longer PFS (6.7 months vs. 3.7 months for BCLC-C, p = 0.05). CONCLUSION:Real-world data from the CHIEF cohort demonstrate AtezoBev's effectiveness in a large French HCC population, showing survival and response rates comparable to the IMbrave150 study. These findings validate AtezoBev as effective in routine practice across diverse clinical profiles.

BACKGROUND & AIMS:Whether the dynamics of non-invasive tests (NITs) correlate with hepatocellular carcinoma (HCC) risk in patients with cirrhosis following sustained virological response (SVR) remains unknown. Thus, we aimed to describe NIT dynamics and assess their correlation with HCC risk. METHODS:The dynamics of NITs (fibrosis-4 index [FIB-4], aspartate aminotransferase-to-platelet ratio index [APRI] and liver stiffness measurement) were described in patients with cirrhosis after SVR included in two prospective French multicenter cohorts (ANRS CO22 Hepather and CO12 CirVir) between 2006 and 2015. To assess their relationship with the risk of HCC, a joint modeling approach was employed using both standard and flexible models adjusted for age and sex. The impacts of NIT current value and slope during follow-up on HCC risk were assessed, considering competing risks of death. RESULTS:A total of 3,067 patients with cirrhosis who achieved SVR were analyzed, among whom 228 (7.4%) developed HCC and 210 (6.9%) died during a 26-month follow-up. All NITs were increased at baseline in patients who ultimately developed HCC, whereas platelet counts were lower. All NITs improved in patients who did not develop HCC. More varied changes were observed during the follow-up of patients who ultimately developed HCC. Joint model analyses showed that current values of FIB-4, APRI and platelet count at any time impacted HCC risk. Only FIB-4 and APRI slopes influenced the same outcome. When considering NIT current value and slope simultaneously, only the current value of NITs impacted HCC risk while the slopes were not informative. CONCLUSIONS:The dynamics of NITs following SVR do not identify patients with cirrhosis who could be safely excluded from surveillance programs. NIT current value is more informative than slope, which will necessitate regularly re-assessment of HCC risk to design individualized surveillance strategies. IMPACT AND IMPLICATIONS:It has been postulated that monitoring non-invasive test (NIT) dynamics following HCV cure may provide information on the residual risk of hepatocellular carcinoma (HCC) in patients with cirrhosis and may allow for the discontinuation of surveillance in certain patient subsets. We analyzed data from over 3,000 patients and found that while all NITs improved in patients with cirrhosis who did not develop HCC, those who eventually developed liver cancer showed more varied changes in these tests. Specifically, the current values of tests like FIB-4 (fibrosis-4 index) and APRI (aspartate aminotransferase-to-platelet ratio index) were linked to an increased risk of HCC, while their slopes did not provide additional useful information, suggesting that dedicated prospective studies are warranted to define how repeated measurement of NITs could be combined with other variables into HCC risk stratification algorithms. Until then, HCC surveillance should be maintained in all patients with cirrhosis following HCV eradication, even in case of decreased NIT values.

Estimating the controlled direct effect (CDE) from observational data is challenging when the DAG is unknown. Causal discovery methods can infer a partially oriented DAG, enabling the identification of potential adjustment sets. We use a local causal discovery algorithm that focuses on the relevant portion of the graph, reducing assumptions and complexity compared to global methods. This approach is applied to a viral hepatitis cohort to estimate the CDE of diabetes on severe liver fibrosis. The CDE of diabetes on liver fibrosis in patients with HBV or HCV was assessed using baseline data from the French ANRS CO22 HEPATHER cohort initiated in 2012. A local causal discovery algorithm, LocalPC-CDE, with bootstrap augmentation identified a robust adjustment set, retaining only variables minimally affected by sampling variability. The CDE was quantified as a causal odds ratio using logistic regression. Causal discovery included 20858 patients, with estimation performed on 8802 completecase observations. The algorithm identified an adjustment set of seven variables: geographical origin, age, hepatitis type, total cholesterol, HDL cholesterol, past alcohol consumption, blood glucose, and sex. The CDE of diabetes on severe fibrosis in viral hepatitis patients was significantly positive, with an estimated odds ratio of 2.03 (95% CI [1.78, 2.31]). After causal adjustment using a targeted, data-driven approach, diabetes retained a direct and statistically significant effect on liver fibrosis in patients with chronic viral hepatitis. This paper more generally introduces a methodological pipeline for local causal discovery when the underlying DAG is uncertain.

BACKGROUND & AIMS:REP 2139-Mg (REP), a nucleic acid polymer, blocks HBV subviral particle assembly and HDV replication. We report the outcomes of REP treatment in patients with HDV enrolled in a compassionate access program (NCT05683548). METHODS:Thirty-three patients with HDV and advanced chronic liver disease received weekly subcutaneous REP 250 mg plus a nucleotide analogue for a planned 48-week treatment course. Pegylated interferon-α (PegIFN) 45-180 μg weekly was added in 20 patients without contraindications. Safety and efficacy were assessed regularly, and intrahepatic markers were evaluated in one liver explant. RESULTS:Among the 33 patients (age 21-69 years; 21 males), 85% (28/33) had prior treatment failure, and six had decompensated cirrhosis (ascites in five). Suboptimal responses to REP were managed with dose modifications (250 mg intravenously or 500 mg subcutaneously or intravenously) and/or treatment extension in 21 patients. At end of therapy, HDV RNA declined by >2 log10 in 70% (23/33) and became undetectable in 58% (19/33). HBsAg loss occurred in 27% (9/33). Among the 28 patients with available follow-up, HDV RNA and HBsAg remained undetectable in 46% (13/28) and 18% (5/28), respectively. ALT normalized in 50% (14/28). Responses were similar with or without PegIFN. Ascites improved in two of five affected patients. Three patients underwent liver transplantation while receiving REP without complications. In one liver explant, HDV RNA and HDAg were undetectable, and intrahepatic covalently closed circular DNA activity and HBsAg levels were very low. No REP-related serious adverse events were observed. CONCLUSIONS:REP treatment was safe and effective in patients with HDV and advanced chronic liver disease. REP may induce sustained virological response of HDV and functional cure of HBV, independent of PegIFN co-administration. Clinical improvement may also occur in patients with decompensated cirrhosis. IMPACT AND IMPLICATIONS:No approved antiviral therapy exists for patients with chronic hepatitis D (CHD) and decompensated cirrhosis, or for those who have failed bulevirtide and/or pegylated interferon. In the Replicor Compassionate Access Program, 33 patients with CHD and advanced chronic liver disease received REP 2139-Mg (REP) plus a nucleotide analogue, with or without pegylated interferon. HBsAg loss occurred in 27% at end of treatment and remained undetectable in 18% after 1 year, indicating sustained HDV virological response and HBV functional cure. Among six patients with decompensated cirrhosis, five achieved a virological response and two showed clinical improvement with reduced ascites. No REP-related serious adverse events were observed. Overall, REP demonstrated promising efficacy and acceptable tolerability in this difficult-to-treat population and warrants evaluation in a response-guided clinical trial.