What is the recommended treatment approach for a patient diagnosed with hepatitis D?

Hepatitis D: Comprehensive Lecture

Overview and Clinical Significance

Hepatitis D virus (HDV) represents the most severe form of viral hepatitis, requiring the presence of hepatitis B virus (HBV) for infection and replication. 1 HDV coinfection leads to more rapid progression to cirrhosis, increased risk of hepatocellular carcinoma, and higher mortality compared to HBV monoinfection. 2

• The primary treatment endpoint is suppression of HDV replication, typically accompanied by normalization of ALT levels and reduced necroinflammatory activity on liver biopsy. 1
• Approximately 10% of patients may have mild chronic hepatitis D with an uneventful course during short-term follow-up, though advanced liver disease can develop subtly with long-lasting mild necro-inflammation. 1

Current Treatment Landscape

Pegylated Interferon-Alpha: The Standard of Care

All patients with chronic hepatitis D and compensated liver disease, regardless of cirrhosis status, should be considered for treatment with pegylated interferon-alpha (PegIFNα) for 48 weeks. 1 This recommendation is based on guideline evidence showing that high-dose interferon therapy (9 MU three times weekly for 1 year) provides long-term beneficial effects. 1

Efficacy Data

• Standard-dose IFN-α (3-5 MU/m² three times weekly for 12 months) showed no difference in sustained virologic response compared to placebo in a 61-patient trial, with only 1 patient achieving sustained biochemical response. 1
• High-dose IFN-α (9 MU three times weekly) demonstrated significantly higher rates of virologic, biochemical, and histologic response. 1
• Although most patients experience virologic relapse, improvement in liver histology was maintained 10 years post-treatment in patients who received high-dose IFN-α. 1
• Approximately one-quarter to one-third of patients benefit from interferon treatment with persistent suppression of HDV replication. 3
• Meta-analysis of five trials showed that interferon alpha led to failure of sustained virological response in 82.6% of treated patients versus 94.8% of controls (RR 0.89,95% CI 0.80 to 0.98, P = 0.02). 4

Treatment Duration Considerations

• Pegylated interferon-alpha for 48 weeks should be the preferred treatment schedule. 1
• Personalized treatment durations may be considered based on HDV RNA and HBsAg kinetics and treatment tolerability. 1
• Prolongation of pegylated IFN treatment to 2 years does not appear to increase virologic response rates, but liver histology improved in most patients treated for 96 weeks. 1
• Some patients may benefit from prolonged or repeated treatments, with higher rates of HDV RNA undetectability associated with higher rates of HBsAg loss in long-term follow-up. 1

Long-Term Outcomes

• Patients with undetectable HDV RNA at 6 months after treatment completion, or at any time during post-treatment follow-up, had better outcomes with fewer liver-related events than non-responders. 1
• Successful interferon treatment is associated with improved clinical long-term outcomes. 3

Contraindications and Special Populations

Pegylated interferon-alpha is absolutely contraindicated in patients with decompensated cirrhosis due to risk of liver failure. 5, 6 These patients should be referred to specialized transplant centers. 1

• Because of the rarity of hepatitis D, patients should be referred to specialized centers for treatment. 1
• Cirrhosis status did not show impact on response in the HIDIT-1 and HIDIT-2 trials, though one retrospective study suggested higher platelet counts (indicating less advanced disease) predicted better off-treatment viral response. 1

Ineffective Therapies

Nucleoside Analogues

Lamivudine has been evaluated in small numbers of patients and found to be completely ineffective in inhibiting HDV replication. 1 This is because nucleoside analogues target HBV polymerase, which HDV does not possess. 7

• Combination therapy with lamivudine or ribavirin has not shown significant advantages over monotherapy with either standard or pegylated interferon. 7
• The combination of pegylated interferon-alpha with HBV-specific nucleos(t)ide analogues does not appear to improve virologic response. 1

Adverse Events and Monitoring

Common Side Effects

Adverse events related to interferon-alpha are common and sometimes severe, requiring continuous monitoring. 1

• Flu-like symptoms, asthenia, weight loss, alopecia, thrombocytopenia, and leukopenia were reported in all trials. 4
• One patient in a treatment group died by suicide toward the end of the study period. 4
• Treatment should be continued as long as possible until loss of hepatitis B surface antigen, adjusting the dose to patient tolerance. 7

Emerging Therapies

Bulevirtide

In 2023, bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D. 8 This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide (NTCP) receptor on liver cells, which is the primary entry point for the virus. 8

Other Investigational Agents

• Viral entry inhibitors: HH003 and tobevibart 8
• Nucleic acid polymers: REP 2139-Mg 8
• Prenylation inhibitors: lonafarnib 8
• RNA interference-based therapies: elebsiran 8

Combination Therapy Trials

• The SOLSTICE Phase 2 clinical trial is evaluating tobevibart alone or combined with elebsiran, with monthly combination dosing achieving >50% virologic and biochemical response at 24 weeks of therapy. 8
• Efficacy and safety will be further evaluated in ECLIPSE 1,2, and 3 trials. 8

Management of HBV Coinfection

Treatment Principles

The ultimate goal of treatment is eradication of both HDV and HBV. 7 Treatment is associated with decline of both HBV and HDV markers, suggesting that combined action on both viral infections is essential to achieve full control of HDV infection. 1

HBV-Specific Considerations

• For patients with HBV/HDV coinfection requiring HBV suppression, entecavir or tenofovir should be used as first-line therapy due to high potency and high barrier to resistance. 5, 6
• All HBsAg-positive patients with cirrhosis require ultrasound every 6 months for hepatocellular carcinoma surveillance. 6
• Continue lifelong HCC screening even after HBsAg loss if significant fibrosis or cirrhosis was present at baseline. 6

Clinical Pitfalls and Practical Considerations

Key Pitfalls to Avoid

• Do not assume that standard-dose interferon will be effective; high-dose regimens are necessary for optimal outcomes. 1
• Do not use lamivudine or other nucleoside analogues as monotherapy for HDV, as they are completely ineffective against HDV replication. 1
• Do not treat patients with decompensated cirrhosis with pegylated interferon-alpha; refer immediately to transplant centers. 5, 6
• Do not discontinue treatment prematurely in patients showing slow virologic response, as some patients demonstrate more pronounced viral load decline after the first 24 weeks of treatment. 1

Monitoring Strategy

• Monitor HDV RNA levels, ALT levels, and clinical status regularly during treatment. 1
• Assess for adverse events continuously, adjusting dose as needed for patient tolerance. 7
• Evaluate liver histology or use non-invasive fibrosis assessment to guide treatment decisions and monitor response. 1

Future Directions

With new treatments including bulevirtide and combination therapies on the horizon, the prospects for improved HDV patient outcomes are promising. 8 However, pegylated interferon-alpha will likely continue to have an important role in hepatitis D management, either alone or in combination with novel agents. 3

• Better biomarkers are needed to select patients with high likelihood to benefit from interferon-based treatments. 3
• More randomized trials with large sample sizes and less risk of bias are needed before definitive treatment recommendations can be established. 4