Comparison of overall survival between antiviral‐induced viral suppression and inactive phase chronic hepatitis B patients

Nucleot(s)ide analogues (NAs) reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. However, the risk of HCC is reportedly higher for NA‐treated patients than for patients in the inactive CHB phase. This study aimed to compare the long‐term outcomes of CHB patients with NA‐induced viral suppression and those of patients with inactive CHB. This retrospective study involved 1118 consecutive CHB patients whose HBV DNA level was continuously <2000 IU/mL during follow‐up with/without antiviral agents. The patients were classified into inactive CHB (n = 373) or NA groups (n = 745). The primary endpoint was overall survival. Secondary endpoints included development of HCC and other liver‐related events. The median duration of follow‐up was 41.0 (interquartile range = 26.5‐55.0) months. The difference in overall survival between the NA group vs. the inactive CHB group was not significant (hazard ratio [HR] = 0.78; 95% confidence interval [CI] = 0.33‐1.85; P = .57). The NA group showed a significantly higher risk of HCC (HR = 3.44; 95% CI = 1.82‐6.52; P < .01), but comparable risk for non‐HCC liver‐related events (HR = 1.02; 95% CI = 0.66‐1.59; P = .93), compared with the inactive CHB group. Among patients with cirrhosis, the NA group showed a significantly lower risk of death (HR = 0.31; 95% CI = 0.097‐0.998; P = .05) and non‐HCC liver‐related events (HR = 0.51; 95% CI = 0.31‐0.83; P < .01), but a slightly higher risk of HCC (HR = 2.39; 95% CI = 0.85‐6.75; P = .09), compared to the inactive CHB group. The overall survival of untreated patients with inactive CHB and of CHB patients achieving viral suppression with NA was comparable. However, NA treatment of cirrhotic patients was significantly associated with longer overall survival and lower risk of liver‐related events.     

Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct‐acting antiviral therapy

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon‐free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co‐infected patients and 765 patients with resolved HBV infection during and after treatment with direct‐acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti‐HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)‐positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti‐HBs titres at baseline with those at post‐DAA therapy in 123 patients without HBsAg. There was no significant difference in anti‐HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg‐negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV‐reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy.     

Entecavir and tenofovir reduce hepatitis B virus‐related hepatocellular carcinoma recurrence more effectively than other antivirals

Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high‐potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low‐potency NAs after curative treatment of hepatitis B virus (HBV)‐related HCC. This study included 607 consecutive HBV‐related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low‐potency NA; n = 90) and group C (high‐potency NA; n = 256). The primary end‐point was recurrence‐free survival (RFS). During the duration of follow‐up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log‐rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time‐dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.     

HBcrAg is a predictor of post‐treatment recurrence of hepatocellular carcinoma during antiviral therapy

Background/Aims: The recurrence rate of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV‐related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence. Methods: We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC. Results: Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2–7.4) years. In multivariate analysis, serum HBcrAg levels ≥4.8log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94–41.4) and portal vein invasion (3.94, 1.25–12.4) were independent factors for HCC recurrence. The recurrence‐free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC. Conclusion: HBcrAg is a predictor of the post‐treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence.     

Intrahepatic cholangiocarcinoma: report of 272 patients compared with 5,829 patients with hepatocellular carcinoma

Purpose  To clarify clinicopathologic differences between patients with intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), and identify potential factors influencing survival after hepatectomy for ICC. Methods  Comparison of clinicopathologic data was made between patients who underwent hepatectomy for ICC (n = 272) and HCC (n = 5,829) during the same period. Twenty-five clinicopathologic variables were selected for univariate and multivariate analyses to evaluate their influence on prognosis of ICC. Results  Compared with patients with HCC, ICC patients were more common in females and more elderly, had a lower proportion of asymptomatic tumors, lower serum alpha-fetoprotein, higher serum carcinoembryonic antigen, carbohydrate antigen 19–9 and alkaline phosphatase levels; lower incidence of hepatitis history, associated cirrhosis and serum hepatitis B surface antigen; lower proportion of small tumors, well-encapsulated tumors and tumor emboli in the portal vein; higher proportion of single tumor, perihila lymph node involvement and poor differentiation; and less frequency of limited resection (all, P < 0.0001). Distant metastasis was less frequent in patients with ICC (P = 0.027). A total of 5-years overall and disease-free survival (in brackets) after resection was 26.4% (13.1%) and 44.5% (33.1%) (P < 0.0001, P < 0.0001) for patients with ICC and HCC, respectively. Factors influencing survival after resection of ICC can be divided mainly into two categories: early detection of asymptomatic ICC (P < 0.0001) and curative resection (P = 0.002). Conclusion  ICC Patients have distinct clinicopathologic features as compared with HCC patients. Surgery remains the only effective treatment for ICC. Early detection of asymptomatic ICC and curative resection were the key to achieve optimal survival.     

The relationship between HBcrAg and HBV reinfection in HBV related post-liver transplantation patients

Background

Post-transplant hepatitis B virus (HBV) reinfection is one of the major problems facing patients who undergo HBV-related liver transplantation (LT). We analyzed the clinical impact of serum hepatitis B core-related antigen (HBcrAg) on HBV reinfection in post-LT patients with HBV-related liver diseases.

Methods

Serum hepatitis B surface antigen (HBsAg), HBV DNA, and HBcrAg were measured over time in 32 post-LT patients. Twenty-one out of 32 patients had HCC at LT. The effects of HBcrAg, hepatocellular carcinoma (HCC) recurrence, and HBs gene mutation on HBV reinfection and withdrawal from hepatitis B immune globulin (HBIG) were analyzed.

Results

Sixteen out of 32 patients (50 %) were positive for HBcrAg even though only six patients were thought to have experienced HBV reinfection based on reappearance of either HBV DNA or HBsAg during a median follow-up time of 75 months. Three of these six patients who became re-infected with HBV experienced HCC recurrence after LT. The HBV DNA reappearance rate was significantly higher in patients with HCC recurrence after LT (p < 0.001). Two HBV re-infected patients without HCC recurrence had HBs gene mutations G145R and G145A, respectively. Anti-HBs antibody development rate by HB vaccination was similar between HBcrAg-positive and negative patients (p = 0.325).

Conclusions

HBV reinfection is more common than is usually considered based on conventional measurement of HBsAg and HBV DNA. HCC recurrence and mutations in the HBV S gene were associated with HBV reinfection after LT.

     

Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co‐infected patients from Western Africa

The nucleotide substitution G1896A on the precore (pc) region has been implicated in virological and serological responses during treatment in hepatitis B virus (HBV)‐infected patients. Whether this mutation affects the therapeutic course of HIV‐HBV co‐infected patients, especially from Western Africa, is unknown. In this prospective cohort study, 86 antiretroviral (ARV)‐naïve HIV‐HBV co‐infected patients from Côte d'Ivoire, initiating ARV‐treatment containing lamivudine (n = 53) or tenofovir (n = 33), had available baseline pc sequences. Association of the pcG1896A mutation with time to undetectable HBV‐DNA, hepatitis B “e” antigen (HBeAg) seroclearance (in HBeAg‐positive patients), and hepatitis B surface antigen (HBsAg) seroclearance was evaluated using Cox proportional hazards regression. At ARV‐initiation, median HBV‐DNA was 6.04 log₁₀ copies/mL (IQR = 3.70‐7.93) with 97.7% harbouring HBV genotype E. Baseline pcG1896A mutation was identified in 51 (59.3%) patients, who were more commonly HBeAg‐negative (P < .001) and had basal core promotor A1762T/G1764A mutations (P < .001). Patients were followed for a median 36 months (IQR = 24‐36). Cumulative proportion of undetectable HBV‐DNA was significantly higher in patients with baseline mutation (pcG1896A = 86.6% vs no pcG1896A = 66.9%, P = .04), but not after adjusting for baseline HBV‐DNA levels and anti‐HBV agent (P = .2). No difference in cumulative proportion of HBeAg seroclearance was observed between mutation groups (pcG1896A = 57.1% vs no pcG1896A = 54.3%, P = .7). Significantly higher cumulative proportion of HBsAg seroclearance was observed in patients without this mutation (pcG1896A = 0% vs no pcG1896A = 36.9%, P < .001), even after adjusting for baseline HBsAg quantification and anti‐HBV agent (P < .001). In conclusion, lacking the pcG1896A mutation before ARV initiation appeared to increase HBsAg seroclearance rates during treatment. The therapeutic implications of this mutation need further exploration in this setting.     

Hepatitis B virus DNA in patients with hepatitis B‐related liver cirrhosis with or without hepatocellular carcinomas: a matched case‐control study

OBJECTIVE: The relationship between serum viremia and the development of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)‐related cirrhosis remains unclear. We aimed at calculating odds ratios (OR) for the presence of HCC over a range of HBV DNA levels in these patients. METHODS: Patients were identified retrospectively and 155 pairs of matched, treatment‐naive HBV‐related cirrhotic patients with and without HCC were recruited. Their serum HBV DNA levels were measured at HCC diagnosis, or at the equivalent age in non‐HCC patients, and correlations between the presence of HCC and different DNA levels were calculated using conditional logistic regression. RESULTS: The median HBV DNA level was significantly higher in HCC patients than in non‐HCC patients (5.15 vs 4.83 log₁₀ copies/mL, P = 0.024). The overall OR for HCC in patients with HBV DNA ≥ 3 log₁₀ copies/mL was 2.13, compared with patients with levels <3 log₁₀ copies/mL. Compared with patients with <3 log₁₀ copies/mL, the OR for HCC were 2.39 and 2.61 for patients with 4 to <5 and 5 to <6 log₁₀ copies/mL, respectively, while the OR for DNA levels of ≥6 log₁₀ copies/mL were not significantly different. CONCLUSION: In HBV‐related cirrhosis, a detectable serum HBV DNA was associated with the presence of HCC, but the likelihood of having HCC did not successively increase with increasing serum HBV DNA levels: patients with serum HBV DNA levels between 4 and <6 log₁₀ copies/mL were most likely to present with HCC.     

Hepatitis B core‐related antigen levels after HBeAg seroconversion is associated with the development of hepatocellular carcinoma

Hepatitis B core‐related antigen (HBcrAg) is a novel serological marker for hepatitis B virus infection. Its clinical significance after HBeAg seroconversion has not been defined. We aimed to determine the relationship between HBcrAg levels after spontaneous HBeAg seroconversion and hepatocellular carcinoma (HCC). A total of 207 chronic hepatitis B patients with documented time of HBeAg seroconversion were enrolled. HBcrAg and HBsAg were checked within 3 years (as baseline), at 5 and 10 years after HBeAg seroconversion. HBV DNA was measured at the baseline. Multivariate Cox regression model was used to investigate the predictors for HCC development. The median follow‐up time was 13.1 (11.8‐15.5) years. Fourteen patients developed HCC (15‐year cumulative incidence: 7%). The median level of HBcrAg at baseline was significantly higher in patients who developed HCC when compared with patients without HCC (5.68 vs 4.78 log U/ml, respectively; P = .003). Cox proportional hazards model indicated that age of HBeAg seroconversion older than 40 years (hazard ratio (HR): 4.60; P = .049), presence of baseline cirrhosis (HR: 6.23; P = .003) and a higher baseline HBcrAg (HR: 1.75; P = .032) were independently associated with HCC development. A cut‐off value of baseline HBcrAg level ≥5.21 log U/mL yielded an AUROC of 0.74 with a negative predictive value of 97.7%. High HBcrAg levels within 3 years after HBeAg seroconversion were independently associated with the development of HCC in chronic hepatitis B patients.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus‐positive or non‐B non‐C patients who underwent curative resection

Aim

The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)‐positive or non‐B non‐C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV‐positive and NBNC HCC patients.

Methods

This study investigated 145 HBV‐positive or NBNC patients who underwent hepatectomy for HCC between January 2001 and May 2009. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to lymphocyte infiltration in tumor.

Results

In patients with low lymphocyte infiltration, the 5‐year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P < 0.0001), high α‐fetoprotein (AFP) value (HR 2.06, P = 0.005), and low lymphocyte infiltration (HR 2.50, P = 0.0001). The independent risk factors for OS were low albumin value (HR 3.69, P = 0.003), high AJCC T stage (HR 2.10, P = 0.049), high AFP value (HR 3.98, P < 0.001), and low lymphocyte infiltration (HR 3.47, P = 0.001).

Conclusions

Lymphocyte infiltrate in tumor is significantly associated high recurrence rate and poor overall survival. Evaluation of the infiltrating lymphocyte could improve the prediction of prognosis in HCC patients after curative resection.     

Antiviral therapy decreases viral reactivation in patients with hepatitis B virus–related hepatocellular carcinoma undergoing hepatectomy: a randomized controlled trial

This prospective randomized controlled trial investigated whether antiviral therapy decreases the risk of perioperative viral reactivation in patients with hepatitis B virus–induced hepatocellular carcinoma. Patients with hepatitis B virus–related hepatocellular carcinoma undergoing liver resection were screened. Eighty‐four patients with low viral load were randomly assigned to receive either antiviral treatment with telbivudine or no therapy. The primary outcome was reactivation of viral replication. Secondary outcomes included liver function recovery and postoperative liver insufficiency. A total of 15 patients developed HBV reactivation during the perioperative period, of which 8 (57.1%) were within the first week after hepatectomy. The incidence of viral reactivation during the perioperative period was 2.5% (1/40) in the antiviral‐treated group, compared with 31.8% (14/44) in the control group [HR 0.07 (95%CI 0.01–0.65); P = 0.001]. Liver function recovery was achieved in 82.5% (33/40) patients in the antiviral group on day 30 after hepatectomy, compared with 91.0% (40/44) in the nonantiviral group [HR 1.23 (95%CI 0.98–2.55); P = 0.109]. A total of 7 patients (8.9%) had postoperative liver insufficiency in both groups, but there was no relevant difference between the two groups. Antiviral therapy with telbivudine can significantly decrease the perioperative reactivation of viral replication in patients with hepatitis B virus–related hepatocellular carcinoma undergoing liver resection. Antiviral therapy is an appropriate option for all patients with viral replication undergoing liver resection. (Chinese Clinical Trial Registry, number ChiCTR‐TRC‐0900615).     

Direct-acting antivirals reduce the risk of tumour progression of hepatocellular carcinoma after curative treatment

Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on HCC progression remains uninvestigated. We conducted a retrospective cohort study of patients with hepatitis C virus-related HCC with BCLC stage 0/A diagnosed for the first time and treated by curative resection or ablation. Using a time-varying method, we estimated the risk of tumour progression (defined as progression to BCLC stage B-D) and liver-related death and the characteristics of repeated recurrence. Overall, 165 patients were enrolled. Following curative HCC treatment, 72 patients received DAA therapy (DAA-treated group), whereas 93 did not (untreated group). Approximately 75% of the recurrences were at an early stage and expected to be disease-free by retreatment. We recorded 56 tumour progressions, of which 60.7% were observed after second recurrence. Multivariate adjusted time-varying Cox regression analysis showed that the DAA-induced SVR significantly reduced the risk of tumour progression (hazard ratio [HR] 0.28; p = .001) and liver-related death (HR 0.12; p < .001). The annual incidence of HCC treatment until tumour progression was 82.8% and 23.9% in the untreated and DAA-treated groups, respectively (HR 0.30; p < .001). DAA-induced SVR significantly reduced the risk for tumour progression and liver-related death and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A.     

A systematic review and meta‐analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis‐related hepatocellular carcinoma

The efficacy of adjuvant interferon treatment for the management of patients with viral hepatitis‐related hepatocellular carcinoma (HCC) following curative treatment is controversial. We have conducted a systematic review with meta‐analysis to assess the effects of adjuvant interferon therapy on survival outcomes. Randomized and nonrandomized studies (NRSs) comparing adjuvant interferon treatment with the standard of care for viral hepatitis‐related HCC after curative treatment were included. CENTRAL, Medline, EMBASE and the Science Citation Index were searched with complementary manual searches. The primary outcomes were recurrence‐free survival (RFS) and overall survival (OS). Nine randomized trials and 13 NRSs were included in the meta‐analysis. These nine randomized trials included 942 participants, of whom, 490 were randomized to the adjuvant interferon treatment group and 452 to the control group. The results of meta‐analysis showed unexplained heterogeneity for both RFS and OS. The 13 NRSs included 2214 participants, of whom, 493 were assigned to the adjuvant interferon treatment group and 1721 to the control group. The results of meta‐analysis showed that, compared with controls, adjuvant interferon treatment significantly improved the RFS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.52–0.84, I² = 29%] and OS (HR 0.43, 95% CI 0.34–0.56, I² = 0%) of patients with hepatitis C virus‐related HCC following curative treatment. There was little evidence for beneficial effects on patients with hepatitis B virus‐related HCC. Future research should be aimed at clarifying whether the effects of adjuvant interferon therapy are more prominent in hepatitis C patients with sustained virological responses.     

An integrated analysis of SOCS1 down‐regulation in HBV infection‐related hepatocellular carcinoma

Persistent inflammation together with genetic/epigenetic aberrations is strongly associated with chronic Hepatitis B virus (HBV) infection‐related hepatocarcinogenesis. Here, we investigated the alterations of the suppressor of cytokine signalling (SOCS) family genes in HBV‐related hepatocellular carcinoma (HCC). A total of 116 patients with HCC were enrolled in this study. The methylation statuses of SOCS1‐7 and CISH genes were quantitatively measured and clinicopathological significance of SOCS1 methylation was statistically analysed. The gene copy number variation was assayed by aCGH. Luciferase reporter assay and Western blot were used to detect the involvement of SOCS1 in p53 signalling. We found high frequencies of SOCS1 gene hypermethylation in both tumour (56.03%) and adjacent nontumour tissues (54.31%), but tumour tissues exhibited increased methylation intensity (24.01% vs 13.11%, P < 0.0001), particularly in patients with larger tumour size or cirrhosis background (P < 0.0001). In addition, the frequency and intensity of SOCS1 hypermethylation in tumour tissues were both significantly higher than those in nontumour tissues in male gender patients and in patients ≥45 years old (P = 0.0214 and P < 0.0001, P = 0.0232 and P < 0.0001, respectively). SOCS1 gene deletion was found in 8 of 25 aCGH assayed tumour specimens, which was associated with lower SOCS1 mRNA expression (P = 0.0448). Furthermore, ectopic SOCS1 overexpression could activate the p53 signalling pathway in HCC cell lines. Hypermethylation of SOCS2‐7 and CISH genes was seldom found in HCC. Our results suggested that the gene loss and epigenetic silencing of SOCS1 were strongly associated with HBV‐related HCC.     

Sustained low hepatitis B viral load predicts good outcome after curative resection in patients with hepatocellular carcinoma

Background and Aim: Little is known about the role of hepatitis B virus (HBV) factors in the long‐term prognosis of hepatocellular carcinoma (HCC) after resection. The objective of the present study was to identify the changing patterns of HBV levels and its effect on outcome after resection. Methods: This study recruited 188 patients with HBV‐related HCC who underwent curative resection. Among the 188 patients, 115 were alive without recurrence at 12 months, and had serial measurements of viral levels. Results: The mean age was 53 years and the mean follow‐up period was 48.5 months. With multivariate analysis, tumor size > 5 cm (P = 0.047), Child‐Pugh class B (P = 0.017), vascular invasion (P = 0.028), and HBV DNA > 10⁴ copies/mL at the time of resection (P = 0.003) were independently predictive of HCC recurrence for the entire population. For the 115 patients with serial measurements of viral levels, tumor size > 5 cm, HBV DNA > 10⁴ copies/mL at resection, and the absence of sustained HBV DNA level < 10⁴ copies/mL, the presence of cirrhosis, and elevated aminotransferase levels (> 40 IU/L) were marginally or significantly associated with HCC recurrence and overall survival. However, on multivariate analysis, sustained HBV DNA level < 10⁴ copies/mL was the only factor for both low recurrence (P = 0.002; odds ratio [OR] 3.13; 95% confidence interval [CI] 1.55–6.35) and longer survival (P = 0.002; OR 3.76; 95% CI 1.61–8.78). Conclusions: A high HBV replication state is among the most important predictors of adverse outcome after resection of HBV‐related HCC. The sustained suppression of HBV below 10⁴ copies/mL is a strong protective factor for long‐term recurrence‐free and overall survival.     

PD‐1 expression on CTL may be related to more severe liver damage in CHB patients with HBV genotype C than in those with genotype B infection

Compared with Chronic hepatitis B (CHB) patients infected with genotype B, those infected with genotype C have higher hepatic histopathological activity and higher level of alanine aminotransferase (ALT). Our previous studies suggest that this phenomenon is related to lower level of HBV specific cytotoxic T lymphocyte (CTL) of patients infected with genotype C than those infected with genotype B, but its mechanism was not clear. The aim of present study was to explain the possible mechanism of lower level of HBV specific CTL and more serious liver function damage of patients infected with genotype C than those infected with genotype B through study on relationship between expression of HBV specific CTL surface programmed death receptor‐1 (PD‐1) and viral genotypes of CHB patients. A total of 100 CHB patients were studied, human leukocyte antigen (HLA)‐A2 positive, hepatitis B virus (HBV) DNA>10³ copies/ml, of which 48 cases were genotype C (48%) positive, and 52 cases were genotype B positive (52%). Expression of Peripheral blood HBV specific CTL surface PD‐1, levels of HBV specific CTL, HBV DNA, ALT and total bilirubin (TBil) of patients infected with genotype C and B were compared. Expression of HBV specific CTL surface PD‐1 of CHB patients infected with genotype C was significantly higher than that of patients infected with genotype B, t = 17.57, P < 0.001, level of HBV specific CTL was significantly lower than that of patients infected with genotype B, t = 23.64, P < 0.001, level of HBV DNA was significantly higher than that of patients infected with genotype B, t = 9.43, P < 0.001, level of ALT was significantly higher than that of patients infected with genotype B, t = 13.42, P < 0.001. Expression of peripheral blood HBV specific CTL surface PD‐1 of CHB patients infected with genotype C was significantly higher than that of patients infected with genotype B, resulting in lower level of HBV specific CTL and higher level of HBV DNA of patients infected with genotype C than those of patients infected with genotype B. So liver function damage of CHB patients infected with genotype C was more serious than those infected with genotype B.     

Negative hepatitis B envelope antigen predicts intrahepatic recurrence in hepatitis B virus-related hepatocellular carcinoma after ablation therapy

Background and Aim: Patients with persistently active hepatitis B virus (HBV) replication are at high risk for progression to liver cirrhosis and hepatocellular carcinoma (HCC). The influence of the viral load of HBV on intrahepatic recurrence after local ablation therapy in patients with HBV‐related HCC has not been elucidated. We aimed to evaluate predictors of intrahepatic recurrence and clarify the correlation between viral load and intrahepatic recurrence after percutaneous ablation. Methods: Patients with HBV‐related, solitary HCC undergoing radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), between October 2004 and December 2008 were prospectively enrolled. Statistical analyses were performed using the Kaplan–Meier method and Cox regression model to identify risk factors for intrahepatic recurrence. Results: A total of 145 patients (male, 81.4%; mean age, 55.3 years) were included. Ninety patients (62.1%) had serum HBV DNA ≥ 2000 IU/mL. The median follow‐up duration was 28.9 months (range, 12.0–57.0) and 63 patients (43.4%) experienced intrahepatic tumor recurrence. Multivariate analysis indicated that seropositivity for hepatitis B envelope antigen (HBeAg) was an independent negative predictor of intrahepatic recurrence (hazard ratio, 0.473; P = 0.026) and late (≥ 1 year) recurrence (HR, 0.288; P = 0.012). The serum alpha fetoprotein (AFP) level also significantly predicted late recurrence (HR, 1.001; P = 0.005). However, neither the ablation method nor serum HBV DNA titers were correlated with intrahepatic recurrence. Conclusions: These findings show that HBeAg‐negativity and serum AFP levels were associated with late intrahepatic recurrence of HCC, implicating HBeAg‐negativity as a risk factor for de novo recurrence after percutaneous ablation in HBV‐related HCC.     

Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection

Background: Elevated serum hepatitis B virus (HBV) DNA increases the development of hepatocellular carcinoma (HCC). Rather than instantaneous DNA level, the duration of persistent HBV replication is more important in carcinogenesis. Nevertheless, most investigators evaluated the DNA level at study entry. We assessed the effects of persistently detectable serum HBV DNA on HCC recurrence. Patients and methods: We included 230 consecutive patients undergoing curative resection between 2000 and 2006. Patients who had antiviral therapy (at diagnosis or during follow‐up), fluctuating DNA (cut‐off value: 100 000 copies/ml) or recurrence within 12 months of resection were excluded. Ultimately, 157 were enrolled: 89 (non‐viraemia group) had consistently negative DNA (<100 000 copies/ml), while 68 (viraemia group) had consistently positive DNA (>100 000copies/ml). Serum DNA level, biochemical tests, α‐foetoprotein (AFP) and liver dynamic computed tomography were obtained every 3 months after surgery. Results: There were no significant differences in age, gender, liver function, histology, AFP, tumour stages or follow‐up duration between the two groups. During follow‐up (median: 35 months), patients in the non‐viraemia group had a lower 5‐year cumulative recurrence rate (54.7%) than those in the viraemia group (72.9%; P=0.043). In multivariate analysis, sustained viraemia (P=0.041) increased recurrence independently. Conclusions: Persistent viraemia increased recurrence independently after surgery. To prevent long‐term recurrences, antiviral therapy should be initiated in those with detectable serum HBV DNA.