The Influence of Hepatitis B Viral Load and Pre-S Deletion Mutations on Post-Operative Recurrence of Hepatocellular Carcinoma and the Tertiary Preventive Effects by Anti-Viral Therapy

<div><p>Background</p><p>Whether or not hepatitis B virus (HBV) genotypes, mutations, and viral loads determine outcomes for patients with HBV-induced hepatocellular carcinoma (HCC) remains controversial.</p><p>Aims</p><p>To study the influence of HBV viral factors on prognoses for patients with HBV-induced HCC after resection surgery and investigate if antiviral therapy could counteract the adverse effects of viral factors.</p><p>Methods</p><p>A total of 333 HBV-related HCC patients who underwent tumor resection were enrolled retrospectively. Serum HBV DNA levels, mutations, anti-viral therapy, and other clinical variables were analyzed for their association with post-operative recurrence.</p><p>Results</p><p>After a median follow-up of 45.9 months, 208 patients had HCC recurrence after resection. The 5-year overall survival and recurrence-free survival rates were 55.4% and 35.3%, respectively. Multivariate analysis showed indocyanine green retention rate at 15 minutes >10%, gamma-glutamyltransferase (GGT) level >60 U/L, macroscopic and microscopic venous invasion, and the absence of anti-viral therapy were significant risk factors for recurrence. Anti-viral therapy could decrease recurrence in patients with early stage HCC, but the effect was less apparent in those with the Barcelona-Clinic Liver Cancer stage C HCC. For patients without antiviral therapy after resection, serum HBV DNA levels >10⁶ copies/mL, GGT >60 U/L, and macroscopic and microscopic venous invasion were significant risk factors predicting recurrence. Among the 216 patients without anti-viral therapy but with complete HBV surface gene mapping data, 73 were with pre-S deletion mutants. Among patients with higher serum HBV DNA levels, those with pre-S deletion had significantly higher rates of recurrence. Moreover, multivariate analysis showed multi-nodularity, macroscopic venous invasion, cirrhosis, advanced tumor cell differentiation, and pre-S deletion were significant risk factors predictive of recurrence.</p><p>Conclusions</p><p>Ongoing HBV viral replication and pre-S deletion are crucial for determining post-operative tumor recurrence. Anti-viral therapy can help reduce recurrence and improve prognosis, especially for those with early stage HCC.</p></div

The effect of anti-viral therapy on post-operative prognosis stratified by tumor stage.

<p>Among patients with early stage HCC, those who received anti-viral therapy after resection had higher overall survival rate (<b>A</b>, BCLC stage A, <i>p</i> = 0.001; <b>B</b>, BCLC stage B, <i>p</i><0.001) and lower recurrence rate (<b>C</b>, BCLC stage A, <i>p</i> = 0.045; <b>D</b>, BCLC stage B, <i>p</i> = 0.009) than their counterpart. For patients with BCLC stage C HCC, the overall survival rate were comparable between those with and without antiviral therapy (<b>E</b>, p = 0.158); but patients receiving anti-viral therapy after resection had a trend of lower recurrence rate than those who did not receive anti-viral therapy (<b>F</b>, p = 0.065).</p

The impact of anti-viral therapy and tumor stage on post-operative prognosis.

<p>Patients who received anti-viral therapy after resection had (<b>A</b>) higher overall survival rate (<i>p</i><0.001) and (<b>B</b>) lower recurrence rate (<i>p</i><0.001) than those who did not receive anti-viral therapy. Moreover, patients in BCLC stage C HCC had lower overall survival rate (<b>C</b>) and higher recurrence rate (<b>D</b>) than those in BCLC stage A or B.</p

Comparison of HCC patients with and without the pre-S deletion mutants of HBV.

*<p>missing data at the time of resection surgery for this parameter.</p><p>Continuous variables are expressed as median; 25 and 75 percentiles.</p><p>Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Alk-P, alkaline phosphatase; GGT, gamma-glutamyltransferase; ICG-15R, indocyanine green retention rate at 15 minutes; PT, prothrombin time; INR, international normalized ratio; HBsAg, hepatitis B surface antigen; BCP, basal core promoter; BCLC, the Barcelona-Clinic Liver Cancer.</p

The impact of anti-viral therapy on post-operative recurrence stratified by viral factors.

<p>Patients who received anti-viral therapy after resection had significantly lower recurrence rate both in the setting of serum HBV DNA levels >10⁵ copies/mL (<b>A</b>, <i>p</i><0.001) and ≤10⁵ copies/mL (<b>B</b>, <i>p</i> = 0.038). (<b>C</b>) Among patients with serum HBsAg >500 IU/mL, anti-viral therapy was associated with lower recurrence rate (<i>p</i> = 0.001). (<b>D</b>) In patients with serum HBsAg ≤500 IU/mL, the recurrence rates were also lower in patients receiving antiviral therapy after resection surgery (<i>p</i> = 0.037).</p