HCC and liver-related events in HDV infection

Hepatocellular carcinoma (HCC) and liver-related events (such as decompensation and cirrhosis progression) are significant complications in individuals with hepatitis D virus (HDV) infection. HDV infection is known to cause the most severe form of viral hepatitis, with a high risk of early-onset cirrhosis and HCC. The study summarized in the context provides valuable insights into the predictors, risk factors, and clinical tools for managing these outcomes in anti-HDV–positive individuals.

### Key Findings on HCC and Liver-Related Events in HDV Infection:

#### **Incidence of HCC and Liver-Related Events:**

• The 5-year cumulative incidence of HCC in anti-HDV–positive individuals was **3.8%**, while the incidence of liver-related events was **15.6%**.
• Patients with **cirrhosis** had a markedly higher risk:
• 5-year HCC incidence: **12%**.
• 5-year liver-related event rate: **41.3%**.
• Non-cirrhotic patients had negligible risks:
• 5-year HCC incidence: **0%**.
• 5-year liver-related event rate: **0.9%**.

#### **Risk Stratification Using PAGE-B and FIB-4 Scores:**

• **PAGE-B** and **FIB-4** scores were validated as effective tools for predicting both HCC and liver-related outcomes in HDV-infected individuals.
• **Low-risk groups** (PAGE-B <10 or FIB-4 <1.45):
• HCC incidence: **0%**.
• Liver-related event rate: **0.9%–2.1%**.
• **High-risk groups** (PAGE-B >17 or FIB-4 >3.25):
• 5-year HCC incidence: **25%** and **21%**, respectively.
• Liver-related event rate: **~45%–63%**.

#### **Independent Predictors of HCC and Liver-Related Events:**

• **Age** and **platelet count** were independently associated with both HCC and liver-related outcomes in multivariate analyses.
• Detectable **HDV RNA** doubled the risk of liver-related events (adjusted hazard ratio [aHR]: **2.6**; 95% confidence interval [CI]: 1.3–5.0).

#### **Diagnostic and Predictive Tools:**

• **Liver stiffness measurement (LSM):**
• LSM ≥10 kPa: 100% sensitivity for detecting cirrhosis.
• LSM ≥12 kPa: 100% specificity for confirming cirrhosis.
• **FIB-4:**
• FIB-4 >3.25 had a high positive predictive value (PPV) of **91.7%** for advanced fibrosis but poor sensitivity (**36.7%**).

#### **Comparative Risk:**

• Anti-HDV–positive patients had:
• **4.2-fold higher HCC risk** compared to HBV mono-infected controls.
• **7.8-fold higher risk** of liver-related events compared to HBV mono-infected controls.

#### **Antiviral Therapy and Novel Treatments:**

• Only **15.2%** of patients received pegylated interferon, reflecting its limited efficacy and tolerability in clinical practice.
• **Bulevirtide**, an HBV entry inhibitor, represents a promising new therapy for HDV but is costly and requires parenteral administration.

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### Clinical Implications for Management:

1. **Risk Stratification:**

• **PAGE-B and FIB-4 scoring systems** allow simple, noninvasive, and cost-effective assessment of HCC and liver-related event risk in HDV-infected individuals.
• These tools can guide personalized care and surveillance strategies.

2. **Surveillance Recommendations:**

• **Low-risk patients** (e.g., PAGE-B <10 or FIB-4 <1.45): May require less frequent imaging follow-up due to negligible HCC and minimal liver-related event risk.
• **High-risk patients** (e.g., PAGE-B >17 or FIB-4 >3.25): Require intensified surveillance, including frequent imaging, strict HCC monitoring, and prioritization for novel antiviral treatments.

3. **Therapeutic Considerations:**

• The limited use of pegylated interferon highlights the need for more effective and tolerable therapies.
• Bulevirtide offers a new treatment option, but its cost and administration challenges must be considered.

4. **Validation Needs:**

• The study authors recommend external validation of PAGE-B and FIB-4 scores in **bulevirtide-treated** and **ethnically diverse HDV populations** to confirm their utility in broader clinical settings.

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### Conclusion:

HCC and liver-related events are significant risks in HDV-infected individuals, particularly in those with cirrhosis or high-risk scores (PAGE-B >17, FIB-4 >3.25). The use of noninvasive scoring tools like PAGE-B and FIB-4 enables early identification of at-risk patients, guiding surveillance intensity and treatment prioritization. While novel therapies like bulevirtide offer hope, addressing their accessibility and efficacy in diverse populations remains a key challenge.