Hepatits Delta Virus

Description

Hepatitis D virus (HDV) infection is a rare but severe liver disease caused by a defective RNA virus that requires the presence of Hepatitis B virus (HBV) to replicate. Globally, an estimated 12–20 million people are infected with HDV, with the highest prevalence in regions such as Central Asia, Eastern Europe, the Amazon Basin, parts of the Middle East, and sub-Saharan Africa.

HDV infection often leads to more aggressive liver disease than HBV alone. Co-infection (simultaneous infection with HBV and HDV) may cause acute hepatitis, which can be severe but is often self-limiting. Superinfection (HDV infection in someone already chronically infected with HBV) typically results in chronic hepatitis D, which increases the risk of developing cirrhosis. 

Without treatment, chronic HDV infection has a high likelihood of progressing to cirrhosis, decompensation or liver cancer. It carries the highest mortality of all chronic viral hepatitis infections. Early diagnosis and intervention are critical, but therapeutic options have historically been limited (Peg-interferon monotherapy in some countries, but not licensed for this indication). Recently, bulevirtide, the first approved HDV-specific therapy, offers new hope for improved outcomes.

Clinical presentation

Hepatitis D virus (HDV) infection presents with a wide clinical spectrum. In acute co-infection with HBV and HDV, patients may experience symptoms similar to acute hepatitis B: fatigue, nausea, jaundice, abdominal discomfort, anorexia, and elevated liver enzymes. In most cases, this acute phase resolves spontaneously, although a small percentage may develop fulminant hepatitis which can progress to liver failure and need for liver transplantation.

In contrast, superinfection—HDV infection in a person with chronic HBV—is more likely to progress to chronic hepatitis D, often with subtle or non-specific early symptoms such as fatigue, right upper quadrant pain, and mild hepatomegaly. Over time, persistent inflammation accelerates liver fibrosis, leading to early-onset cirrhosis.

As the disease progresses, patients may develop signs of advanced liver disease, including ascites, variceal bleeding, hepatic encephalopathy, and other signs of portal hypertension. Extrahepatic manifestations are rare but can include vasculitis and glomerulonephritis.

Risk factors

Hepatitis D infection requires Hepatitis B virus (HBV) co-infection; therefore, chronic HBV is the primary risk factor. Individuals with high-risk HBV exposure—such as people from countries with high HBV prevalence, people who inject drugs,men who have sex with men, and those with multiple sexual partners—are at increased risk. Blood transfusions, hemodialysis, and unsterile medical or tattoo equipment in endemic regions also contribute. There is no known genetic predisposition. Migrants from HDV-endemic areasand those with co-existing liver disease are particularly vulnerable.

Diagnosis

Diagnosis of Hepatitis D begins with identifying HBsAg-positive individuals, as HDV can only infect those with Hepatitis B. Testing for anti-HDV antibodies is recommended in all HBsAg positive people. If anti-HDV is positive, reflex HDV RNA testing confirms active infection. Quantitative HDV RNA is crucial for assessing viral replication and monitoring response to therapy. Some patients may be anti-HDV positive but HDV RNA negative, indicating prior exposure with spontaneous of treatment related viral clearance.

Liver function tests, imaging studies and transient elastography or liver biopsy may be considered as all are useful tools to stage liver disease severity.

Management

Management of Hepatitis D (HDV) focuses on preventing disease progression, and improving long-term outcomes. Bulevirtide is the first approved antiviral for HDV. It blocks viral entry into hepatocytes by inhibiting the NTCP receptor and is recommended for adults with compensated liver disease and detectable HDV RNA. Combination therapy with pegylated interferon-alpha may enhance response but carries more side effects. 

Patients should be monitored every 6–12 months (and more often when initiating or discontinuing antiviral therapy), with HDV RNA, liver function tests, and fibrosis assessments to track disease activity and treatment response. 

Supportive care includes abstaining from alcohol, maintaining a healthy diet and weight and avoiding hepatotoxic drugs. Management of co-infections (e.g., HBV, HIV, HCV) and other comorbidities (i.e diabetes mellitus) is also essential. Patients with cirrhosis due to hepatitis D should be monitored in a specialized center with access to a liver transplant program, given the high risk of disease progression and potential need for transplantation. 

Complications

HDV co-infection is associated with more rapid disease progression when compared to otherforms of chronic viral hepatitis . Major complications include rapid progression to cirrhosis, hepatic decompensation, portal hypertension, and hepatocellular carcinoma (HCC). In some cases, acute liver failure can occur, particularly in co-infection scenarios.

Preventive strategies focus on early detection and treatment of HDV in individuals with chronic hepatitis B. Routine screening of HBsAg-positive patients for anti-HDV, followed by HDV RNA testing, enables timely diagnosis and intervention. Initiating antiviral therapy in eligible patients can significantly reduce viral activity and disease progression. Additionally, effective management of metabolic risk factors such as obesity and diabetes, along with strategies to prevent alcohol use, is essential. Regular monitoring for fibrosis and HCC allows for early detection of complications and prompt management, including referral to transplant centers when necessary.

CPMS

The Clinical Patient Management System (CPMS) is a secure, web-based platform developed by the European Commission to support European Reference Networks (ERNs) in diagnosing and treating rare and complex diseases, such as Hepatitis Delta. Within the ERN RARE-LIVER network, CPMS enables healthcare professionals to collaborate across borders by enrolling patient cases, sharing clinical data, and convening virtual expert panels for multidisciplinary consultations.