Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

A Phase 3, Randomized Trial of Bulevirtide in Chronic Hepatitis D.

BACKGROUND: Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes. METHODS: In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group. RESULTS: A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups. CONCLUSIONS: After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).

Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase 3 randomized trial.

BACKGROUND & AIMS: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. METHODS: In this ongoing, open-label, randomized phase 3 study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/mL from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. RESULTS: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independent of virologic response. Adverse events (AEs) were mostly mild, with no serious AEs related to BLV. CONCLUSIONS: Virologic and biochemical responses were maintained and/or increased with longer-term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. IMPACT AND IMPLICATIONS: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2-mg and 10-mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96. GOV IDENTIFIER: NCT03852719.

Clinical trials in hepatitis D virus: Measuring success.

Chronic hepatitis D infection results in the most severe form of chronic viral hepatitis but currently lacks effective treatment options. Therapy with pegylated interferon alpha is recommended for finite treatment duration by major liver societies. Still, it is plagued by low rates of sustained virologic response (SVR) and frequent relapses even if SVR is achieved. Recently, a wave of investigational therapies has come under evaluation, including bulevirtide, lonafarnib, pegylated interferon lambda, and REP-2139 creating excitement with this viral infection. However, there has been significant variability in the endpoints used to evaluate these therapeutics. One of the recently introduced endpoints is characterized by a decline in HDV RNA by 2 logs, with or without achieving an undetectable serum hepatitis D virus (HDV) RNA, as a marker of virologic response. Furthermore, this measure has been combined with alanine aminotransferase normalization, also known as a biochemical response, to formulate the primary endpoint of several late-stage studies. Per recent guidance by the US Food and Drug Administration, these should be surrogate endpoints that will ultimately portend long-term clinical benefits. These clinical benefits may include reducing the risk of progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, and mortality. However, the optimal way to measure success in HDV clinical trials remains unknown and will continue to evolve.

Impact of COVID-19 Pandemic on Liver Transplantation and Alcohol-Associated Liver Disease in the USA.

BACKGROUND AND AIMS: The surge in unhealthy alcohol use during the COVID-19 pandemic may have detrimental effects on the rising burden of alcohol-associated liver disease (ALD) on liver transplantation (LT) in the USA. We evaluated the effect of the pandemic on temporal trends for LT including ALD. APPROACH AND RESULTS: Using data from United Network for Organ Sharing, we analyzed wait-list outcomes in the USA through March 1, 2021. In a short-period analysis, patients listed or transplanted between June 1, 2019, and February 29, 2020, were defined as the "pre-COVID" era, and after April 1, 2020, were defined as the "COVID" era. Interrupted time-series analyses using monthly count data from 2016-2020 were constructed to evaluate the rate change for listing and LT before and during the COVID-19 pandemic. Rates for listings (P = 0.19) and LT (P = 0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (-21.69%, P < 0.001) and NASH (-13.18%; P < 0.001). There was a significant increase in ALD listing (+7.26%; P < 0.001) and LT (10.67%; P < 0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcohol-associated hepatitis (+50%). Patients with ALD presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a Model for End-Stage Liver Disease-Sodium score ≥30. CONCLUSIONS: Since the start of COVID-19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on health care resources.

Risk Factors for Delta Hepatitis in a North American Cohort: Who Should Be Screened?

INTRODUCTION: The American Association for the Study of Liver Diseases recommends hepatitis D virus (HDV) screening in certain high-risk groups; however, the effectiveness is unknown. METHODS: A study of North American patients with hepatitis B (HBV) referred to the NIH was performed to identify risk factors associated with HDV infection. Active HDV was "confirmed" by serum HDV RNA or histologic HDV antigen staining. RESULTS: Six hundred fifty-two were studied, of which 91 were HDV "confirmed." Independent risk factors for HDV included: intravenous drug users, HBV-DNA <2,000 IU/mL, alanine aminotransferase >40 U/L, and HDV endemic country of origin. DISUSSION: North American patients with HBV and significant risk factors should be screened for HDV.

Coronavirus Disease 2019 Hangover: A Rising Tide of Alcohol Use Disorder and Alcohol-Associated Liver Disease.

The coronavirus disease 2019 (COVID-19) pandemic has had a tremendous global impact since it began in November of 2019. However, there are concerns that the COVID-19 pandemic will not affect all equally and that some populations will be particularly vulnerable. Relevant to liver disease, patients with alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) may be among the populations that are the most severely impacted. The reasons for this include being at a higher risk of severe COVID-19 infection due to a depressed immune system and high-risk underlying comorbidities, the injurious effect of COVID-19 on the liver, the inability to attend regular visits with providers, diversion of hospital resources, and social isolation leading to psychological decompensation and increased drinking or relapse. As a result, we fear that there will be a dramatic rising tide of alcohol relapse, admissions for decompensated ALD, and an increase in newly diagnosed patients with AUD/ALD post-COVID-19 pandemic. Providers and their institutions should implement preemptive strategies such as telehealth and aggressive patient outreach programs now to curb this anticipated problem. Liver transplantation (LT) centers should adapt to the pandemic by considering leniency to some LT candidates with ALD who cannot access appropriate alcohol treatment due to the current situation. In conclusion, the COVID-19 pandemic will likely be especially detrimental to patients with AUD/ALD, and actions need to be taken now to limit the scope of this anticipated problem.

Vibration-controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection.

Noninvasive detection of cirrhosis via vibration-controlled transient elastography (VCTE) has revolutionized the management of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, VCTE has not been studied in chronic hepatitis D virus (HDV) infection and accuracy remains in question due to the significant hepatic inflammation associated with this infection. Consecutive HBV, HCV and HDV patients who underwent VCTE (2006-2019) were evaluated. Diagnosis of cirrhosis was made via liver biopsy or clinical findings. VCTE was compared with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compared. We evaluated 319 patients (HBV-112; HCV-132; HDV-75), 278(87%) patients had histology for evaluation. HDV patients had evidence of higher hepatic inflammation as evidence by aspartate aminotransferase, alanine aminotransferase and histology activity index. Cirrhotic HDV patients had higher mean liver stiffness measurements compared with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE demonstrated excellent diagnostic accuracy for the detection of cirrhosis with an AUROC of 0.90 compared with APRI (0.83), FIB-4 (0.88), AAR (0.73) and RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) and HCV (0.94). At the optimized cut-off value of ≥14.0 kPa for determining cirrhosis in HDV, VCTE had a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 and PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for determining cirrhosis despite the presence of significant hepatic inflammation.

High-risk symptoms do not predict gastric cancer precursors.

BACKGROUND & STUDY AIMS: Gastric intestinal metaplasia (GIM) is the most common precursor of gastric cancer. Our aim is to determine if presenting symptoms predict gastric cancer precursor lesions in a high-risk population. PATIENT AND METHODS: Consecutive unique patients evaluated by endoscopy for upper gastrointestinal symptoms at the Los Angeles County Hospital between 2010 and 2014 were evaluated. Presenting symptoms were classified as low- or high-risk depending on the procedure indication as coded using the Clinical Outcomes Research Initiative (CORI) system. Endoscopy and histology results were used to classify findings as benign, GIM, high-risk GIM, or malignant. The primary outcome was the proportion of patients with premalignant or malignant gastric findings who had high-risk clinical indications for endoscopy relative to those with benign results. RESULTS: A total of 3699 patients underwent endoscopy to evaluate upper gastrointestinal symptoms. There were 373 (10.1%) patients with GIM of which 278 had high-risk GIM. One hundred and sixty (4.3%) patients were diagnosed with gastric cancer. High-risk indications for upper endoscopy predicted gastric cancer (OR 1.8 [95% CI 1.3-2.6]) but not GIM (OR 1.0 [0.8-1.3]) or high-risk GIM (OR 0.9 [0.7-1.2]). Hispanic or Asian patients and patients >50 years old were more likely to have GIM, high-risk GIM, and cancer. CONCLUSIONS: Performance of upper endoscopy for high-risk indications is inadequate to detect GIM and marginal for malignancy. At risk patients should undergo upper endoscopy for both low- and high-risk symptoms. Screening certain populations deserve additional study and may, in fact, be cost-effective.

The Pancreatitis Activity Scoring System predicts clinical outcomes in acute pancreatitis: findings from a prospective cohort study.

OBJECTIVES: The Pancreatitis Activity Scoring System (PASS) has been derived by an international group of experts via a modified Delphi process. Our aim was to perform an external validation study to assess for concordance of the PASS score with high face validity clinical outcomes and determine specific meaningful thresholds to assist in application of this scoring system in a large prospectively ascertained cohort. METHODS: We analyzed data from a prospective cohort study of consecutive patients admitted to the Los Angeles County Hospital between March 2015 and March 2017. Patients were identified using an emergency department paging system and electronic alert system. Comprehensive characterization included substance use history, pancreatitis etiology, biochemical profile, and detailed clinical course. We calculated the PASS score at admission, discharge, and at 12 h increments during the hospitalization. We performed several analyses to assess the relationship between the PASS score and outcomes at various points during hospitalization as well as following discharge. Using multivariable logistic regression analysis, we assessed the relationship between admission PASS score and risk of severe pancreatitis. PASS score performance was compared to established systems used to predict severe pancreatitis. Additional inpatient outcomes assessed included local complications, length of stay, development of systemic inflammatory response syndrome (SIRS), and intensive care unit (ICU) admission. We also assessed whether the PASS score at discharge was associated with early readmission (re-hospitalization for pancreatitis symptoms and complications within 30 days of discharge). RESULTS: A total of 439 patients were enrolled, their mean age was 42 (±15) years, and 53% were male. Admission PASS score >140 was associated with moderately severe and severe pancreatitis (OR 3.5 [95% CI 2.0, 6.3]), ICU admission (OR 4.9 [2.5, 9.4]), local complications (3.0 [1.6, 5.7]), and development of SIRS (OR 2.9 [1.8, 4.5]) as well as prolongation of hospitalization by a mean of 1.5 (1.3-1.7) days. For the prediction of moderately severe/severe pancreatitis, the PASS score (AUC = 0.71) was comparable to the more established Ranson's (AUC = 0.63), Glasgow (AUC = 0.72), Panc3 (AUC = 0.57), and HAPS (AUC = 0.54) scoring systems. Discharge PASS score >60 was associated with early readmission (OR 5.0 [2.4, 10.7]). CONCLUSIONS: The PASS score is associated with important clinical outcomes in acute pancreatitis. The ability of the score to forecast important clinical events at different points in the disease course suggests that it is a valid measure of activity in patients with acute pancreatitis.

Noncirrhotic portal hypertension.

PURPOSE OF REVIEW: Noncirrhotic portal hypertension represents a heterogeneous group of liver disorders that is characterized by portal hypertension in the absence of cirrhosis. The purpose of this review is to serve as a guide on how to approach a patient with noncirrhotic portal hypertension with a focus on recent developments. RECENT FINDINGS: Recent studies pertaining to noncirrhotic portal hypertension have investigated aetiological causes, mechanisms of disease, noninvasive diagnostic modalities, clinical characteristics in the paediatric population and novel treatment targets. SUMMARY: Noncirrhotic portal hypertension is an underappreciated clinical entity that can be difficult to diagnosis without a healthy suspicion. Diagnosis then relies on a comprehensive understanding of the causes and clinical manifestations of this disease, as well as a careful interpretation of the liver biopsy. Noninvasive approaches to diagnosis may play a significant role moving forward in this disease. Treatment in NCPH remains largely targeted at the individual sequalae of portal hypertension.

Early Aggressive Hydration Hastens Clinical Improvement in Mild Acute Pancreatitis.

OBJECTIVES: Early aggressive intravenous hydration is recommended for acute pancreatitis treatment although randomized trials have not documented benefit. We performed a randomized trial of aggressive vs. standard hydration in the initial management of mild acute pancreatitis. METHODS: Sixty patients with acute pancreatitis without systemic inflammatory response syndrome (SIRS) or organ failure were randomized within 4 h of diagnosis to aggressive (20 ml/kg bolus followed by 3 ml/kg/h) vs. standard (10 ml/kg bolus followed by 1.5 mg/kg/h) hydration with Lactated Ringer's solution. Patients were assessed at 12-h intervals. At each interval, in both groups, if hematocrit, blood urea nitrogen (BUN), or creatinine was increased, a bolus of 20 ml/kg followed by 3 ml/kg/h was given; if labs were decreased and epigastric pain was decreased (measured on 0-10 visual analog scale), hydration was then given at 1.5 ml/kg/h and clear liquid diet was started. The primary endpoint, clinical improvement within 36 h, was defined as the combination of decreased hematocrit, BUN, and creatinine; improved pain; and tolerance of oral diet. RESULTS: The mean age of the patients was 45 years and only 14 (23%) had comorbidities. A higher proportion of patients treated with aggressive vs. standard hydration showed clinical improvement at 36 h: 70 vs. 42% (P=0.03). The rate of clinical improvement was greater with aggressive vs. standard hydration by Cox regression analysis: adjusted hazard ratio=2.32, 95% confidence interval 1.21-4.45. Persistent SIRS occurred less commonly with aggressive hydration (7.4 vs. 21.1%; adjusted odds ratio (OR)=0.12, 0.02-0.94) as did hemoconcentration (11.1 vs. 36.4%, adjusted OR=0.08, 0.01-0.49). No patients developed signs of volume overload. CONCLUSIONS: Early aggressive intravenous hydration with Lactated Ringer's solution hastens clinical improvement in patients with mild acute pancreatitis.

Liver stiffness measurement as a noninvasive method for the diagnosis of liver cirrhosis in patients with chronic hepatitis D virus infection.

BACKGROUND: Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited. AIMS: To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients. METHODS: We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies. RESULTS: Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB-4], and 0.69 [AAR]). The optimal cut-off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut-off for diagnosing non-advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients. CONCLUSIONS: LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut-offs of <10.2 and < 15.2 kPa reliably diagnose non-advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients.