Background and aim: Bulevirtide (BLV) monotherapy yields high rates of virological and biochemical response in patients with cirrhosis due hepatitis Delta virus (HDV), however clinical benefits on hard outcomes remain unknown. Aim of the study was to evaluate liver-related outcomes in BLV-treated vs. untreated patients with cirrhosis. Methods: Consecutive patients with HDV-related cirrhosis treated with BLV monotherapy for 3 years in a retrospective multicenter European study (SAVE-D) were compared with two BLV-untreated cohorts (cohort #1 from Italy and cohort #2 from France). Liver-related events (LRE: hepatocellular carcinoma [HCC], decompensation) occurring within the first 3 years were compared by inverse probability treatment weighting (IPTW) analysis. BLV start (BLV-treated cohort) or diagnosis of cirrhosis (untreated controls) were considered the baseline for the analysis. Results: 344 patients were included in the BLV-treated cohort and 298 in the untreated control group. Treated patients were older (median age 50 vs. 40 years, p<0.0001), more likely to be females (males 62% vs. 78%, p=0.001), Caucasian (84% vs. 62%, p<0.0001), under long-term NUC (91% vs. 40%, p<0.0001) and had higher HDV RNA levels (5.4 vs. 4.9 Log10IU/mL, p=0.002). By contrast, the proportion of patients with previous decompensation or HCC or CSPH was similar. The 3-year cumulative incidence of liver-related events was lower in BLV-treated compared to untreated patients: 8.9% (95% CI 4-12%) vs. 16.2% (95% CI 11-22%), respectively (p=0.03). The corresponding figures for decompensation and HCC were 2.7% (95% CI 1-4%) vs. 11.3% (95% CI 7-16%) (p=0.001) and 6.1% (95% CI 3-8%) vs. 6.6% (95% CI 3-11%) (p=0.49), respectively. By IPTW-Adjusted Cox Regression Analysis, the risk of developing liver-related events or decompensation were statistically significantly lower in BLV-treated than in the untreated controls (HR 0.44, 95% CI 0.27-0.72, p=0.001; HR 0.16, 95% CI 0.07-0.36, p<0.0001). These results were confirmed by IPTW-Adjusted Competing Risks Regression Model not only in the combined untreated cohorts (SHR 0.16, 95% CI 0.06-0.40, p<0.0001) but also in each individual cohort (cohort#1: SHR 0.16, 95% CI 0.05-0.47, p<0.001; cohort #2: SHR 0.19, 95% CI 0.06-0.62, p<0.005). Conversely, the HCC risk was similar between treated and untreated cohorts. Baseline lower albumin values were the strongest independent predictor of LREs, both in the BLV-treated cohort (HR 0.22, 95% CI 0.08-0.64, p=0.006) and in the untreated control group (HR 0.38, 95% CI 0.20-0.72, p=0.002), together with higher bilirubin values in the untreated cohort, only (HR 1.20, 95% CI 1.06-1.38, p=0.005). Conclusions: In patients with HDV-related cirrhosis, a 3-year course of BLV monotherapy reduced the risk of liver-related events and of liver decompensation, but not of HCC, compared to untreated IPTW-matched population.

BACKGROUND & AIMS:Bulevirtide (BLV) 2 mg/day is EMA approved for the treatment of compensated chronic HDV infection; however, real-world data in large cohorts of patients with cirrhosis are lacking. METHODS:Consecutive HDV-infected patients with cirrhosis starting BLV 2 mg/day from September 2019 were included in a European retrospective multicenter real-world study (SAVE-D). Patient characteristics before and during BLV treatment were collected. Virological, biochemical, combined responses, adverse events and liver-related events (hepatocellular carcinoma [HCC], decompensation, liver transplant) were assessed. RESULTS:A total of 244 patients with HDV-related cirrhosis receiving BLV monotherapy for a median of 92 (IQR 71-96) weeks were included: at BLV start, median (IQR) age was 49 (40-58) years and 61% were men; median ALT, LSM and platelet count were 80 (55-130) U/L, 18.3 (13.0-26.3) kPa, and 94 (67-145) x103/mm3, respectively; 54% had esophageal varices, 95% Child-Pugh A cirrhosis, and 10% HIV coinfection; 92% were on nucleos(t)ide analogues; median HDV RNA and HBsAg were 5.4 (4.1-6.5) log10 IU/ml and 3.8 (3.4-4.1) log10 IU/ml, respectively. At weeks 48 and 96, virological, biochemical and combined responses were observed in 65% and 79%, 61% and 64%, 44% and 54% of patients, respectively. AST, GGT, albumin, IgG and LSM values significantly improved throughout treatment. Serum bile acid levels increased in most patients, but only 10% reported mild and transient pruritus, which was independent of bile acid levels. The week 96 cumulative risks of de novo HCC and decompensation were 3.0% (95% CI 2-6%) and 2.8% (95% CI 1-5%), respectively. Thirteen (5%) patients underwent liver transplantation (n = 11 for HCC, n = 2 for decompensation). CONCLUSION:BLV 2 mg/day monotherapy for up to 96 weeks was safe and effective in patients with HDV-related cirrhosis. Virological and clinical responses increased over time, while the incidence of liver-related complications was low. IMPACT AND IMPLICATIONS:Bulevirtide 2 mg/day is EMA approved for the treatment of compensated chronic hepatitis delta; however, real-world data in large cohorts of patients with cirrhosis are lacking. Bulevirtide 2 mg/day monotherapy for up to 96 weeks was safe and effective (week 96: 79% virological, 64% biochemical and 54% combined response) in a large real-world cohort of patients with HDV-related cirrhosis, including patients with clinically significant portal hypertension. Liver function tests and liver stiffness improved, suggesting a potential clinical benefit in patients with advanced liver disease, while the incidence of de novo liver-related events (hepatocellular carcinoma and decompensation) was low during the 96-week study period.

Abstract Background Prospective data after switch from intravenous infliximab (IV-IFX) to subcutaneous (SC-IFX) in Inflammatory Bowel Disease (IBD) is needed. The aim of this prospective multicenter cohort was to describe SC-IFX persistence, efficacy and tolerance after switch from IV-IFX. Methods IBD patients in steroid-free clinical remission (defined by a Harvey Bradshaw index (HBI) ≤ 4 for Crohn’s disease (CD), and partial Mayo Score (PMS) ≤ 2 with no subscore >1 for ulcerative colitis UC)) for at least 6 months on IV-IFX, were enrolled in this prospective cohort if they switched to SC-IFX. Clinical (HBI, PMS), biological (CRP, fecal calprotectin (FC)) and pharmacokinetic evaluations were performed at 3, 6, 12 and 24 months from switch. In case of clinical or biological relapse, as per physicians’ judgement, SC-IFX dose could be increased, or drug changed. Primary endpoint was SC-IFX persistence at week 48 (W48). Secondary endpoints comprised steroid-free clinical remission at W48, proportion of patients who switched back to IV-IFX, HBI and PMS changes and FC, CRP and infliximab serum level changes. Statistical comparisons were performed using Fisher’s exact test. Survival without treatment discontinuation was analysed using a Kaplan-Meyer curve. Results 426 patients were included (72.4% CD, 45.1% female, median age 37 years), with a median time from diagnosis of 143 months in CD, 154 months in UC. At baseline, 74% were on IV-IFX standard dose (5mg/kg every 8-week) and 68 (16%) received combination therapy with an immunosuppressant. Among patients with complete data until W48, SC-IFX persistence was 95.3% (CI, 93.2-97.5). 319/367 (89.9%) were on steroid-free clinical remission. From baseline to W48, median HBI and PMS scores were 0, CRP did not change significantly, median FC rate decreased significantly from 52µg/g to 36 µg/g (p=0.015). Mean Infliximab trough level at inclusion was 7.97µg/mL, while it reached 17.96µg/mL at W48 (p<0.0001). 23 (5.4%) patients had an increase of SC-IFX dose and 22 (5.2%) stopped SC-IFX, of which 6 patients switched back to IV-IFX. SC-IFX persistence was significantly higher among patients treated with SC-IFX monotherapy (98.8%) as compared to those on combination therapy (90.0%) (HR=0.14 [0.04-0.53]). Adverse events were reported in 181/426 patients (42.4%), 12 led to treatment discontinuation. Nine severe adverse events (2%) were reported. Three patients (0.7%) had IBD-related surgery and 8 (1.9%) IBD-related hospitalization. Conclusion In this large multicenter prospective cohort of IBD patients in remission, one-year persistence of SC-IFX after switch from IV-IFX was 95.3%, supporting excellent efficacy and tolerance of SC-IFX.

Background Data on the management of Hepatitis B-Delta (HB-D) by hepatogastroenterologists (HGs) practicing in nonacademic hospitals or private practices are unknown in France. Objective We aimed to evaluate the knowledge and practices of HGs practicing in nonacademic settings regarding HB-D. Methods A Google form document was sent to those HGs from May to September 2021. Results A total of 130 HGs (mean age, 45 years) have participated in this survey. Among HBsAg-positive patients, Delta infection was sought in only 89% of cases. Liver fibrosis was assessed using FibroScan in 77% of the cases and by liver biopsy in 81% of the cases. A treatment was proposed for patients with >F2 liver fibrosis in 49% of the cases regardless of transaminase levels and for all the patients by 39% of HGs. Responding HGs proposed a treatment using pegylated interferon in 50% of cases, bulevirtide in 45% of cases and a combination of pegylated interferon and bulevirtide in 40.5% of cases. Among the criteria to evaluate the treatment efficacy, a decrease or a normalization of transaminases was retained by 89% of responding HGs, a reduction of liver fibrosis score for 70% of them, an undetectable delta RNA and HBsAg for 55% of them and a 2 log 10 decline in delta viremia for 62% of the cases. Conclusion Hepatitis Delta screening was not systematically performed in HBsAg-positive patients despite the probable awareness and knowledge of the few responders who were able to prescribe treatments of hepatitis delta.

Background and aimBulevirtide (BLV) monotherapy yields high rates of virological and biochemical response in hepatitis Delta (HDV) cirrhotic patients, however clinical benefits on hard outcomes remain unknown.MethodsPatients with HDV-related cirrhosis treated with BLV monotherapy in a retrospective multicenter European study (SAVE-D) were compared with untreated HDV cirrhotic patients enrolled in a previous cohort study (Romeo, Gastroenterology 2009). Liver-related events (LRE: HCC, decompensation) and overall mortality were compared by inverse probability treatment weighting (IPTW) analysis.ResultsThe BLV-treated cohort included 176 patients (median follow-up: 15 [2-46] months): at BLV start, median age was 50 (19-82) years, 59% men, ALT 77 (23-1,074) U/L, albumin 3.9 (2.8-4.9) g/dL, 100% CPT score A, 55% with varices. The untreated cohort included 140 patients (median follow-up: 91 [3-359] months): at study entry, median age was 40 (18-66) years, 78% men, ALT 102 (11-3,054) U/L, albumin 4.0 (2.0-5.2) g/dL, 94% CPT score A, 46% with varices. Overall, the 2-year cumulative probabilities of LRE were 6.9% (95% CI 3-11%) in the BLV-treated cohort vs. 15.7% (95% CI 9-22%) in untreated patients (p=0.02): 4.9% vs. 6.7% for de-novo HCC (p=0.45) and 2.0% vs. 9.1% for decompensation (p=0.01), respectively. The 2-year probability of overall mortality was 1.2% (95% CI 0.3-3%) vs. 3% (95% CI 0.5-6%) in BLV-treated vs. untreated patients (p=0.13). By IPTW analysis adjusted for confounding baseline factors and competing mortality risks, the BLV-treated cohort had a significantly decreased risk of all-type liver-related events (HR 0.38; 95% CI 0.24-0.60, p<0.0001), decompensation (HR 0.15; 95% CI 0.06-0.36, p<0.0001) and mortality (HR 0.27; 95% CI 0.08-0.93, p=0.04) compared to untreated patients. Conversely, the HCC risk was similar (HR 0.76; 95% CI 0.42-1.40, p=0.38).ConclusionsIn HDV cirrhotic patients, a 2-year course of BLV monotherapy resulted in lower risks of decompensation and mortality, but did not impact HCC risk.

BACKGROUND:The systematic use of susceptibility testing and tailored first-line treatment for Helicobacter pylori eradication has yet to be established. AIM:To compare 14-day tailored PCR-guided triple therapy to 14-day non-Bismuth concomitant quadruple therapy for first-line Helicobacter pylori eradication. PATIENTS AND METHODS:We performed a multicenter, parallel-group, randomized noninferiority controlled trial. Naive adult patients with Helicobacter pylori infection were treated with 14-day tailored PCR-guided triple therapy (esomeprazole 40 mg and amoxicillin 1000 mg b.d. plus clarithromycin 500 mg or levofloxacin 500 mg b.d. according to clarithromycin susceptibility) or 14-day non-Bismuth concomitant quadruple therapy (esomeprazole 40 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and metronidazole 500 mg b.d.). The primary endpoint was H. pylori eradication. RESULTS:We screened 991 patients for eligibility and randomized 241 patients. The first-line eradication rate was 99.2% in the tailored PCR-guided group and 95.9% in the control group (ITT population; absolute difference of +3.30%, with a lower bound of CI at -0.68%). Both first-line therapies were well tolerated, with a formally significant difference in favor of the tailored PCR-guided group (61.4% vs. 41.2%, p = 0.003). Economic analyses revealed a lower cost of the tailored PCR-guided arm, with a 92% chance of being jointly more effective and less expensive than the control arm in the ITT population. CONCLUSION:In a country with a high level of clarithromycin resistance, the results of our study demonstrated the noninferiority of 14-day tailored PCR-guided triple therapy as a first-line H. pylori eradication therapy compared to 14-day non-Bismuth quadruple therapy (ClinicalTrials.gov NCT02576236).