AGA issues updated guidance on HDV management
An AGA panel recommended universal HDV screening for all patients with chronic HBV infection.
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11/06/2025
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by Amy Pfeiffer
American Gastroenterological Association (AGA) has released a Clinical Practice Update on the management of hepatitis delta virus (HDV) infection, providing current guidance on epidemiology, screening, diagnosis, and treatment.
Hepatitis delta virus occurs in patients with hepatitis B virus (HBV) infection and substantially increases the risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality compared with HBV monoinfection. Recent analyses estimate that approximately 30,000 to 60,000 people in the United States have active HDV infection.
Among those with chronic hepatitis B, prevalence varies across groups, with 4.2% among non–US-born patients, 6.7% among people with HIV coinfection, 43.8% among persons who inject drugs, and 5.1% among men who have sex with men. A recent meta-analysis found that concurrent HDV infection nearly doubles the risk of compensated cirrhosis and increases the risk of decompensated cirrhosis, hepatocellular carcinoma, and liver-related death by up to fourfold.
Testing for HDV remains limited in the United States. Among more than 40,000 veterans with positive hepatitis B surface antigen, only about 11% were tested for HDV, and few received confirmatory RNA testing. Even in populations with high-risk features, HDV screening rates have not improved significantly over the past decade, noted Tatyana Kushner, MD, (Division of Gastroenterology and Hepatology, Weill Cornell School of Medicine, New York, NY) and colleagues, in the published article in Gastroenterology.
In line with the World Health Organization’s 2024 guidance, the AGA panel recommended universal HDV screening for all patients with chronic HBV infection. Screening should begin with anti-HDV antibody testing, followed by confirmatory HDV RNA polymerase chain reaction testing to identify active infection.
Patients with HDV infection should be evaluated for cirrhosis using noninvasive methods such as vibration-controlled transient elastography or FIB-4, both of which show high diagnostic accuracy. Given the elevated risk of hepatocellular carcinoma, all patients with HDV should be enrolled in liver cancer surveillance programs.
Pegylated interferon-alpha remains the only approved treatment for chronic HDV in the United States. Sustained virologic response rates range from 23% to 57%, and relapse occurs in about half of patients after discontinuation. Despite these limitations, responders show improved survival and reduced liver-related complications. Several new therapeutic agents are in late-stage clinical trials.
Bulevirtide, a viral entry inhibitor, has been approved in Europe since 2020 and achieved response rates of 45% to 48% at 48 weeks in phase 3 trials; an expanded access program is available in the US. Brelovitug, a monoclonal antibody targeting hepatitis B surface antigen, showed a 67% HDV RNA decline at 24 weeks in phase 2 data. A combination therapy of tobevibart and elebsiran achieved approximately 50% alanine aminotransferase normalization and a 2-log or greater HDV RNA decline in all treated participants at 24 weeks. Lonafarnib, an oral farnesyltransferase inhibitor, produced response rates of 10% to 19% at 48 weeks, and nucleic acid polymers such as REP2139 demonstrated a 73% HDV RNA decline in early trials.
"The concurrent development of novel therapeutics with increased efficacy and safety will hopefully improve disease outcomes in patients living with HDV," wrote Dr. Kushner and colleagues. "As promising HDV treatments enter phase 3 trials and in particular drugs that also target functional cure of HBV are developed, the future will hopefully bring curative treatments for HDV that can decrease disease burden and optimize outcomes for patients living with HDV."
Summary content
7 Key Takeaways
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Developed a paper-based colorimetric sensor array for chemical threat detection.
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Can detect 12 chemical agents, including industrial toxins.
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Production cost is under 20 cents per chip.
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Utilizes dye-loaded silica particles on self-adhesive paper.
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Provides rapid, simultaneous identification through image analysis.
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Inspired by the mammalian olfactory system for pattern recognition.
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Future developments include a machine learning-enabled reader device.
The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.