The influence of hepatitis?B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma

Background

Prediction and prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) recurrence is an important clinical issue. We investigated whether HBV DNA level and antiviral therapy are associated with HCC recurrence.

Methods

This retrospective study involved 103 patients who underwent hepatic resection or radiofrequency ablation for initial HCC. Patients were divided into four groups. Thirty had high serum HBV DNA levels (>4 log₁₀ copies/mL) and had not received antiviral therapy (high virus group; HVG). Thirty-four had low HBV DNA levels (≤4 log₁₀ copies/mL) and had not received antiviral therapy (low virus group; LVG). Twenty received antiviral therapy after HCC developed (therapeutic group A, TG-A). Nineteen received antiviral therapy before HCC developed (therapeutic group B, TG-B).

Results

Cumulative HCC recurrence rates at 3 years in the HVG, LVG, TG-B, and TG-A were 71.1%, 42.2%, 42.3%, and 52.0%, respectively. Recurrence rates differed significantly between the HVG and LVG (P = 0.016) and between the HVG and TG-B (P = 0.008). Recurrence rate in the TG-A was marginally lower than in the HVG (P = 0.10). On multivariate analysis, high serum hepatitis B virus DNA levels (hazard ratio: HR 2.67; 95% CI 1.31–5.47; P = 0.007) and absence of antiviral therapy (HR 2.57; 95% CI 1.34–4.94; P = 0.005) were independent risk factors for hepatocellular carcinoma recurrence.

Conclusion

HBV DNA level and antiviral therapy are associated with HCC recurrence. For patients with high HBV DNA levels, antiviral therapy before the development of HCC is important for prevention of recurrence.     

Tolerance of radiofrequency ablation by patients of hepatocellular carcinoma

Background

Radiofrequency ablation (RFA) is currently an effective method for ablation of hepatocellular carcinoma (HCC). Early reports have indicated that RFA is safe and virtually free from major complications. Unlike partial hepatectomy for HCC on patients with cirrhosis, there are no data on the safety limit of RFA. However, information is vital for selection of appropriate patients for the procedure. In this study, we analyzed results from use of RFA on HCC patients and determined the lower limit of liver function with which HCC patients can tolerate RFA.

Method

Preoperative variables of 310 patients who underwent RFA for HCC were analyzed to identify the risk factors in RFA intolerance in terms of morbidity associated with stress-induced complications.

Results

Thirty-nine (12.6%) patients developed intolerance of RFA. Postoperative morbidity was mainly because of intractable ascites (n = 13), hyperbilirubinemia (n = 10), massive pleural effusion (n = 7), and other complications (n = 14). Multivariate analysis revealed that serum albumin level (P = 0.001), serum bilirubin level (P = 0.000), tumor number (P = 0.002), and RFA duration (P = 0.017) all played a role in this issue.

Conclusions

Simple data such as serum bilirubin, serum albumin level, and tumor number can be used to predict HCC patients’ tolerance of RFA. Avoidance of excessive RFA time and careful monitoring of patients at risk are important means of reducing the postoperative morbidity rate.     

Fibrosis and AST to platelet ratio index predict post-operative prognosis for solitary small hepatitis B-related hepatocellular carcinoma

Purpose

Although advanced liver fibrosis is crucial in the development of hepatocellular carcinoma (HCC) for patients with chronic hepatitis B, whether it is associated with the recurrence of HCC after resection remains obscure. This study was aimed to compare the outcomes for patients with minimal or advanced fibrosis in solitary small hepatitis B virus (HBV)-related HCC.

Methods

This study enrolled 76 patients with small (<5 cm) solitary HBV-related HCC who underwent resection. The outcomes of patients with minimal and advanced fibrosis in non-tumor areas were compared. Serum markers were tested to assess the stage of hepatic fibrosis and to predict prognosis.

Results

Fourteen patients with an Ishak fibrosis score of 0 or 1 were defined as having minimal fibrosis; the remaining 62 patients were defined as having advanced fibrosis. During a follow-up period of 77.0 ± 50.7 months, 41 patients died. The overall survival rate was significantly higher (P = 0.018) and recurrence rate was lower (P = 0.018) for patients in the minimal fibrosis group. Aspartate aminotransferase–platelet ratio index (APRI) exhibited the most reliable discriminative ability for predicting advanced fibrosis. The overall survival rate was significantly higher (P = 0.003) and recurrence rate was lower (P = 0.005) for patients with an APRI of 0.47 or less.

Conclusions

For patients with solitary small HBV-related HCC who underwent resection, minimal fibrosis is associated with a lower incidence of recurrence and with better survival. APRI could serve as a reliable marker for assessing hepatic fibrosis and predicting survival.     

Effects of antiviral therapy on long-term outcome after liver resection for hepatitis B virus-related hepatocellular carcinoma

Background/purpose

We investigated the effects of nucleos(t)ide analogues (NAs) on long-term outcome in patients following curative treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).

Methods

This study involved 70 of the 76 patients who had undergone liver resection for HBV-related HCC in our department; 6 patients were excluded due to non-curative resection or advanced cancer. The 70 patients were divided into three groups, as follows: 13 patients with high serum concentration of HBV DNA (≥4?log₁₀?copies/mL) and no antiviral therapy (high viral group); 46 patients who received antiviral therapy during the serial follow up (antiviral therapy group) because of high viral concentration (≥4?log₁₀?copies/mL); and 11 patients with low serum concentration of HBV DNA (<4?log₁₀?copies/mL) and no antiviral therapy (low viral group).

Results

Tumor-free survival rate was significantly higher in the low viral group than in the high viral group (P?=?0.0058). Multivariate analysis revealed that a high serum concentration of HBV DNA (≥4?log₁₀?copies/mL) (risk ratio 6.717, 95% confidence interval 1.435–31.434, P?=?0.0156) was an independent risk factor for a short tumor-free survival time. Tumor-free survival rate was significantly higher in the antiviral therapy group than in the high viral group (P?=?0.0478). Multivariate analysis revealed that presence of multiple tumors (risk ratio 2.857, 95% confidence interval 1.403–5.816, P?=?0.0038) was an independent risk factor for a short tumor-free survival time. The cumulative survival rate was significantly higher in the antiviral therapy group than in the high viral group (P?=?0.0025). Multivariate analysis revealed that not undergoing antiviral therapy (risk ratio 0.121, 95% confidence interval 0.024–0.608, P?=?0.0104) was an independent risk factor for a short survival time.

Conclusions

A high serum concentration of HBV DNA (≥4?log₁₀?copies/mL) was a strong risk factor for HCC recurrence after resection of HBV-related HCC. Antiviral therapy with NAs improved the long-term outcome after resection of HBV-related HCC in patients with high serum concentrations of HBV DNA.     

Radiofrequency ablation for hepatocellular carcinoma: the relationship between a new grading system for the ablative margin and clinical outcomes

Background

In our previous study, we classified the radicality (R grading) of percutaneous radiofrequency ablation (RFA) therapy for single hepatocellular carcinoma (HCC) according to the extent of the ablated margin, and demonstrated that this grading system was useful for predicting local tumor progression (LTP) after RFA. The aim of this study was to measure the overall survival (OS), the recurrence free survival (RFS), and the distant recurrence (DR) rate for each R grade (A–D), and to examine the relationship between clinical outcome and R grading.

Methods

This study involved 368 patients with solitary HCC who had undergone RFA. The mean tumor diameter was 2.0 ± 0.7 cm. We calculated the post-RFA cumulative OS, RFS, and DR rate for each R grade and analyzed the factors contributing to clinical outcomes.

Results

In the multivariate analysis, significant factors were as follows: tumor size >2 cm, serum albumin >3.5 g/dL, prothrombin time >70 %, HCC recurrence within 1 year, and R grading (grade A) in OS; cause of liver disease (hepatitis B), gamma glutamyl transpeptidase (GGT) >80 IU/L, platelet count >10 × 10⁴/mm³, and R grading (grade A or B) in RFS; GGT >80 IU/L, platelet count >10 × 10⁴/mm³, and R grading (grade A or B) in DR. In patients with sufficient Lipiodol accumulation (n = 219), very similar results were obtained. However, in patients with grade A and B (n = 232), R grade was not a significant independent factor linked to OS, although grade A patients had lower LTP rate.

Conclusions

Our proposed R grading system appears to be useful for predicting clinical outcomes after RFA.     

Post-transplantation sequential entecavir monotherapy following 1-year combination therapy with hepatitis B immunoglobulin

Background

Combination therapy of intravenous hepatitis B immunoglobulin (ivHBIG) and nucleos(t)ide (NA) analogues is the best post-liver transplantation (LT) prophylactic measure for hepatitis B virus (HBV). However, to reduce the long-term drawbacks of ivHBIG, we evaluated the efficacy of sequential entecavir (ETV) monotherapy.

Methods

Twenty-nine candidates with HBV-related liver disease were prospectively enrolled. The patients were selected if the patient was suitable for one of the following inclusion criteria: (1) NA-naïve patients except for ETV, and (2) negative HB e antigen (HBeAg) and undetectable HBV DNA at the time of LT. Post-LT HBV prophylaxis consisted of 1-year combination therapy with ETV (0.5 mg daily) plus ivHBIG per 5 weeks, followed by ETV monotherapy. The primary endpoint was the 2-year recurrence rate of HB. The median follow-up period was 31 months.

Results

At the time of transplantation, HBeAg was positive in 21 % and HBV DNA was detectable in 52 % of the study participants. No HBV recurrence was reported during the first year. During the second year, HBV recurrence was noted in one who suffered from HCC recurrence without viral mutation. Recurrence free survival rates were 96.6 and 96.4 % at 1- and 2-year post-transplant by intention-to-treat analysis. One patient died of fungal infection.

Conclusion

Sequential ETV monotherapy after 1-year combination therapy might be safe in NA-naïve replicators as well as non-replicators.     

Clinical features and natural history of portal vein thrombosis after radiofrequency ablation for hepatocellular carcinoma in Japan

Purpose

Little is known about portal vein thrombosis (PVT) after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). We aimed to determine the incidence, background, and natural history of RFA-related PVT.

Methods

This is a retrospective study of 317 patients (219 males and 98 females) with HCC treated by RFA. Clinical data were compared between patients with and without PVT detected by ultrasound/CT. The median follow-up period after RFA was 15.8 months.

Results

PVT was detected in 6 (1.9 %) of 317 patients, 6 (0.8 %) of 802 treatments for HCC, and 6 (0.6 %) of 964 sessions of RFA. Body mass index was significantly higher in patients with PVT (26.9 ± 3.1 kg/m²) than in those without (22.9 ± 3.5 kg/m², p = 0.0075). PVT was significantly more frequent in RFA for the left lobe of the liver (2.7 %) than for the other sites (0 %, p < 0.0001). Five of the six patients received no treatment for PVT, with natural outcomes of disappearance in one patient, improvement in one patient, and unchanged appearance in three patients. Anticoagulation was applied in the one remaining patient and resulted in a successful recanalization. In the six patients, there was no significant difference in hepatic functional reserve between baseline and time of detection of PVT.

Conclusions

These results indicated that a high body mass index and RFA for HCC in the left lobe might be significant risk factors for PVT and that RFA-related PVT was rarely progressive with little influence on liver function.     

Combination of Radiofrequency Ablation with Transarterial Chemoembolization for Hepatocellular Carcinoma: A Meta-Analysis

Background

Recent studies suggest that the combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have a synergistic effect for hepatocellular carcinoma (HCC).

Aims

The aim of this meta-analysis was to compare the effectiveness of combination of RFA and TACE with that of RFA alone in patients with HCC.

Methods

Randomized controlled trials and retrospective cohort studies comparing RFA plus TACE with RFA alone for HCC were included into this meta-analysis. Study quality was rated with a standardized scale and the strength of evidence was also rated by using the grading of recommendations assessment, development, and evaluation system (GRADE system).

Results

Meta-analyses showed that the combination of RFA and TACE was obviously associated with higher survival rates (odds ratio [OR]_1-year = 2.14, 95 % confidence interval [95 % CI] 1.57–2.91, P < 0.001; OR_3-year = 1.98, 95 % CI 1.28–3.07, P = 0.001; OR_5-year = 2.70, 95 % CI 1.42–5.14, P = 0.003). The overall quality of evidence was judged to be low by using the GRADE system.

Conclusions

The combination of TACE with RFA can improve the overall survival rate and provides better prognosis for patients with HCC, but more randomized controlled trials using large sample size are needed to provide sufficient evidence.     

Combination of Radiofrequency Ablation with Transarterial Chemoembolization for Hepatocellular Carcinoma: A Meta-Analysis

Background

Recent studies suggest that the combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have a synergistic effect for hepatocellular carcinoma (HCC).

Aims

The aim of this meta-analysis was to compare the effectiveness of combination of RFA and TACE with that of RFA alone in patients with HCC.

Methods

Randomized controlled trials and retrospective cohort studies comparing RFA plus TACE with RFA alone for HCC were included into this meta-analysis. Study quality was rated with a standardized scale and the strength of evidence was also rated by using the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE system).

Results

Meta-analyses showed that the combination of RFA and TACE was obviously associated with higher survival rates (OR_1-year = 2.06, 95 % CI 1.46–2.91, P < 0.001; OR_3-year = 1.93, 95 % CI 1.18–3.15, P = 0.009; OR_5-year = 1.87, 95 % CI 1.23–2.83, P = 0.003). The overall quality of the evidence was judged to be low by using the GRADE system.

Conclusions

The combination of TACE with RFA can improve the overall survival rate and provides better prognosis for patients with HCC, but more randomized controlled trials using large sample sizes are needed to provide sufficient evidence.     

Value of Highly Sensitive Fucosylated Fraction of Alpha-Fetoprotein for Prediction of Hepatocellular Carcinoma Recurrence After Curative Treatment

Background

The fucosylated fraction of alpha-fetoprotein (AFP-L3) has been used as a diagnostic marker for hepatocellular carcinoma (HCC). Recently, a highly sensitive immunoassay using an on-chip electrokinetic reaction and separation by affinity electrophoresis (micro-total analysis system; μTAS) has been developed.

Aim

The aim of this study was to investigate the relationship between changes in the serum AFP-L3 level measured by μTAS assay and recurrence of HCC after curative treatment.

Methods

A total of 414 HCC patients who met the Milan criteria and underwent hepatectomy or radiofrequency ablation were investigated prospectively for the relationship between HCC recurrence and values of tumor markers.

Results

There were significant differences in recurrence-free survival between groups with and without AFP-L3 elevation measured before and after treatment (p = 0.024 and p = 0.001 for before and after treatment, respectively). Multivariate analysis revealed that AFP-L3 status (p = 0.002) measured 1 month after treatment was a significant independent predictor of HCC recurrence after curative treatment.

Conclusions

Elevation of the serum AFP-L3 level before treatment is a predictor of HCC recurrence, and sustained elevation of the AFP-L3 level after treatment is an indicator of HCC recurrence. Repeated measurement of μTAS AFP-L3 should be performed for surveillance of HCC recurrence after curative treatment.     

Long-term interferon therapy after radiofrequency ablation is effective in treating patients with HCV-associated hepatocellular carcinoma

Purpose

This study investigates the usefulness of long-term interferon (IFN) therapy following radiofrequency ablation (RFA) for HCV-associated hepatocellular carcinoma (HCC).

Methods

This is a retrospective observational study. Patients underwent pegylated IFN-α/ribavirin combination therapy for 48 weeks and then were maintained on IFN-α administration on average for 68 weeks (mean total duration 116 weeks). Patients who underwent IFN monotherapy were maintained on IFN administration on average for 78 weeks.

Results

There were biases in the background factors between the IFN and non-IFN groups. Therefore, a covariate adjustment was performed using the propensity score. An analysis of 20-matched patients from each group showed the 5-year cumulative survival rate was higher in the IFN group than in the non-IFN group (100 and 76%, respectively), and the 3-year cumulative recurrence rate was significantly lower in the IFN group than in the non-IFN group (38.0 and 64.2%, respectively). In 14 patients (i.e., IFN responders), the serum alanine aminotransferase (ALT) level remained normalized at 30 IU/mL or lower, regardless of disappearance of serum HCV RNA. In these patients, the cumulative recurrence rate was low, the hazard ratio was 0.158 (95% confidence interval = 0.045–0.561, P = 0.004), and the serum albumin level was retained.

Conclusion

These results show the importance of maintaining the liver function and suggest that long-term IFN administration after RFA inhibits recurrence and contributes to an improved outcome in patients (in particular, IFN responders) who initially develop HCC.     

Diffusion-weighted imaging of hepatocellular carcinoma for predicting early recurrence and survival after hepatectomy

Purpose

The effectiveness of imaging (including apparent diffusion coefficient [ADC] of diffusion-weighted magnetic resonance imaging [DWI]) and laboratory variables for predicting early tumor recurrence and overall survival after surgery in hepatocellular carcinoma (HCC) patients are analyzed.

Methods

The present study included 116 consecutive patients with HCC who underwent partial hepatectomy. Patients were classified into two groups: patients with and without early recurrence (<1 year). Preoperative imaging variables (tumor number, size, shape, capsule, ADC, and venous invasion) and laboratory variables were evaluated to predict early recurrence using univariate and multivariate analyses. Overall survival was calculated using the Kaplan–Meier method.

Results

Twenty patients (17 %) developed early recurrence after surgery. Multivariate logistic regression analysis showed that tumor ADC (p = 0.0002), aspartate aminotransferase (p = 0.0121), and serum prothrombin time activity percentage (p = 0.0082) were statistically significant for predicting early recurrence. The optimal ADC cutoff value for predicting early recurrence obtained from receiver operating characteristic analysis was ≤0.898 × 10^?3 mm²/s. In patients with ADC ≤0.898 × 10^?3 mm²/s, the 3- and 5-year survival rates (77 and 56 %, respectively) were significantly decreased compared with those in patients with ADC >0.898 × 10^?3 mm²/s (97 and 97 %, respectively; p = 0.0015).

Conclusions

Low tumor ADC value by DWI was a risk factor for early postoperative HCC recurrence and was associated with lower patient survival rates.     

Up-regulation of dbpA mRNA in hepatocellular carcinoma associated with metabolic syndrome

Purpose

Metabolic syndrome (MS) is a group of recognized risk factors for the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. The aim of this study was to analyze the clinicopathological characteristics of HCC patients with MS and the risk factors for recurrence. Also, the aim was to investigate the cold shock protein: DNA-binding protein A (dbpA) expression in HCC patients with MS.

Methods

A total of 243 patients who underwent curative resections for HCC were classified into two groups. dbpA expression was investigated in 66 HCC patients with MS and in 30 patients without MS by using real-time RT-PCR. Promoter methylation status was examined by using MS-PCR.

Results

The incidence of metabolic factors affect the HCC significantly higher in non-B non-C patients than in hepatitis B virus (HBV) or hepatitis C virus (HCV) patients (P < 0.001). Univariate analysis of HCC patients with MS recurrence revealed aspartate amino transferase (AST), multiple tumors, liver damage, hepatic vein invasion, advanced cancer stages (P < 0.01), alpha-fetoprotein (AFP) and diabetes mellitus type II (P < 0.05) as risk factors. Multivariate analysis, AST, multiple tumors, and hepatic vein invasion (P < 0.01) were identified as independent factors for the recurrence. dbpA mRNA was higher in patients with MS than in those without MS (P = 0.016), and it was mostly upregulated in non-B non-C HCC patients with MS than in non-B non-C HCC patients without HBV or HCV. Especially, in HCC patients with diabetes mellitus type II, the mRNA and protein levels were highly upregulated. The dbpA expression was regulated by promoter methylation status (P < 0.05).

Conclusions

This study identifies that dbpA may accelerate the hepatocarcinogenesis in HCC patients with MS via inflammation-induced and oxidative stress pathways. The demethylation-related epigenetic activation may be one of the regulating factors for HCC patients with MS.     

Hepatocellular carcinoma patients with increased oxidative stress levels are prone to recurrence after curative treatment: a prospective case series study using the d-ROM test

Purpose

Oxidative stress plays an important role in liver carcinogenesis. To determine the impact of oxidative stress on the recurrence of stage I/II hepatocellular carcinoma (HCC) after curative treatment, we conducted a prospective case series analysis.

Methods

This study included 45 consecutive patients with stage I/II HCC, who underwent curative treatment by surgical resection or radiofrequency ablation at Gifu Municipal Hospital from 2006 to 2007. In these 45 cases, recurrence-free survival was estimated using the Kaplan–Meier method. The factors contributing to HCC recurrence, including the serum levels of derivatives of reactive oxygen metabolites (d-ROM) as an index of oxidative stress, were subjected to univariate and multivariate analyses using the Cox proportional hazards model.

Results

The serum levels of d-ROM (P = 0.0231), α-fetoprotein (AFP, P = 0.0274), and fasting plasma glucose (P = 0.0400) were significantly associated with HCC recurrence in the univariate analysis. Multivariate analysis showed that the serum levels of d-ROM (hazard ratio [HR] 1.0038, 95 % confidence interval [CI] 1.0002–1.0071, P = 0.0392) and AFP (HR 1.0002, 95 % CI 1.0000–1.0003, P = 0.0316) were independent predictors of HCC recurrence. Kaplan–Meier analysis showed that recurrence-free survival was low in patients with high serum d-ROM (≥570 Carr U, P = 0.0036) and serum AFP (≥40 ng/dL, P = 0.0185) levels.

Conclusions

The serum levels of d-ROM and AFP can be used for screening patients with a high risk for HCC recurrence. Patients who show increased levels of these factors require careful surveillance.     

The prognostic significance of preoperative plasma levels of osteopontin in patients with TNM stage-I of hepatocellular carcinoma

Purpose

To evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in patients with early stage of hepatocellular carcinoma (HCC).

Methods

Preoperative plasma levels of OPN were detected by ELISA in 68 patients with tumor-node-metastasis system stage-I of HBV-related HCC, and their association with tumor recurrence or patients’ survival was analyzed.

Results

The median plasma OPN level of patients was 82.51 ng/ml (25–75% interquartile range, 63.15–110.45 ng/ml). Plasma OPN levels in patients with tumor size ≥5 cm in diameter were significantly higher than that of patients with tumor size <5 cm in diameter (104.76 vs. 75.16 ng/ml, P = 0.003). When the 100 ng/ml was used as a cut-off value to divide the patients into two groups: the higher plasma OPN group and the lower plasma OPN group, the tumor recurrence rate of the higher plasma OPN group was significantly higher than that of the lower plasma OPN group (52.17 vs. 24.44%, P = 0.022). Meanwhile, the recurrence rate of the patients with positive alpha fetoprotein (AFP) (45.5%) was significantly higher than that of those negative AFP patients (12.5%, P = 0.006). A higher plasma OPN level was one leading independent prognostic factor for both overall survival (OS) and relapse-free survival in multivariate Cox models.

Conclusion

The preoperative plasma OPN level and serum AFP level in patients with early stage of HCC can be used as a prognostic marker for early stage of HCC.     

Clinicopathologic study on complications of orthotopic liver transplantation in 54 patients with chronic hepatitis B viral infection

Objective

To study the complication incidence of 54 patients with chronic HBV infection following orthotopic liver transplantation (OLT) and risk factors associated with HBV recurrence and hepatocellular carcinoma (HCC) recurrence or metastasis post-OLT.

Methods

The light-microscopic appearance of hepatic allograft biopsies in 54 patients with chronic HBV infection following OLT was examined. The related clinical data were analyzed. The incidence and occurrence time of post-OLT complications were studied. Furthermore, the relationship between hepatitis B virus recurrence and acute rejection and the relationship among HCC recurrence/metastasis, acute rejection, tumor diameter, and portal vein invasion were particularly studied.

Results

Frequent complications of patients with chronic HBV infection following OLT were acute rejection [38 (70.4 %); occurrence time: 5–365 days], chronic rejection [1 (1.9 %); occurrence time: 10.7 months], bile duct complications [24 (44.4 %);occurrence time: 7–940 days], HBV recurrence [7 (13.0 %); occurrence time: 1–540 days], HCV infection [3 (5.6 %); occurrence time: 60 days, 60 days, 33 months], CMV infection [8 (14.8 %); occurrence time: 67–90 days], and HCC recurrence or metastasis [17 (31.5 %); occurrence time: 2–41 months]. At the end of 1 year post-OLT, 95 % of patients with post-hepatitis B cirrhosis were alive. At the end of 3 years post-OLT, 85 % of patients with post-hepatitis B cirrhosis were alive. However, at the end of 1 year post-OLT, 67.6 % of patients with post-hepatitis B HCC were alive. At the end of 3 years post-OLT, 50 % of patients with post-hepatitis B HCC were alive. The number of acute rejection episodes in patients with recurrent HBV infection and in those without recurrent HBV infection was 0.86 ± 1.46 times/patient and 1.07 ± 0.90 times/patient, respectively (p > 0.05); the number of moderate acute rejection episodes (RAI score ≥4) in patients with recurrent HBV infection and in those without recurrent HBV infection was 0.29 ± 0.49 times/patient and 0.50 ± 0.63 times/patient (p > 0.05). Incidence of patients with ≥3 episodes of acute rejection in patient with recurrent HBV infection and in those without recurrent HBV infection was 14.3 and 10.6 % (p > 0.05). Furthermore, the number of acute rejection episodes in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 1.12 ± 0.93 times/patient and 1.06 ± 1.39 times/patient, respectively (p > 0.05). The number of moderate acute rejection episodes (RAI score ≥4) in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 0.65 ± 0.79 times/patient and 0.65 ± 1.06 times/patient, respectively (p > 0.05). Incidence of patients with ≥3 episodes of acute rejection in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 5.9 and 17.6 %, respectively (p > 0.05). The tumor diameter in patients with HCC recurrence or metastasis was 6.72 ± 3.40 cm; however, that in patients without HCC recurrence or metastasis was 3.55 ± 2.17 cm (p = 0.0047). The incidence of portal vein invasion in patients with HCC recurrence or metastasis and in those without HCC recurrence or metastasis was 68.75 and 33.3 %, respectively (p = 0.006).

Conclusion

There was no significant difference between HBV recurrence and acute rejection post-liver transplantation in patients with chronic HBV infection. There was no significant difference between HCC recurrence and acute rejection. The tumor diameter in patients with HCC recurrence or metastasis was significantly greater than that in patients with no HCC recurrence or metastasis. Portal vein invasion was significantly more frequent in patients with HCC recurrence or metastasis than in those with no HCC recurrence or metastasis.     

Combining the HBsAg decline and HBV DNA levels predicts clinical outcomes in patients with spontaneous HBeAg seroconversion

Purpose

The aim was to investigate whether the quantitation of the hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels can predict HBV reactivation and advanced liver disease after spontaneous hepatitis B e antigen (HBeAg) seroconversion.

Methods

A total of 121 patients who experienced spontaneous HBeAg seroconversion were included in this longitudinal study. Serial HBsAg and HBV DNA levels were measured before and after HBeAg seroconversion.

Results

Of the 121 patients, 32 experienced HBV reactivation and six achieved an HBsAg loss after HBeAg seroconversion during the follow-up period. The decline in the HBsAg level was considerably more pronounced in patients without HBV reactivation when compared to those with HBV reactivation (p = 0.016). Multivariate analysis revealed that the age of >40 years at HBeAg seroconversion, male sex, and HBsAg decline, and HBV DNA levels at month 12 after HBeAg seroconversion were independent factors for the development of HBeAg-negative hepatitis. All the six patients who achieved HBsAg loss had HBsAg level of <1,000 IU/mL at month 12 after HBeAg seroconversion (p < 0.001). The risk of HBeAg-negative hepatitis, cirrhosis, and HCC was substantially increased in patients who had a combination of both, i.e., no decline in the HBsAg level and HBV DNA level of >10⁴ copies/mL at month 12 after HBeAg seroconversion.

Conclusions

Combining HBsAg reduction and HBV DNA levels at month 12 after HBeAg seroconversion was a useful marker to predict clinical outcomes in spontaneous HBeAg seroconverters. HBsAg level of <1,000 IU/mL at month 12 after HBeAg seroconversion could predict the HBsAg loss after HBeAg seroconversion.     

Anti-HBs response to hepatitis B immunoglobulin prophylaxis in liver transplant recipients

Background

Hepatitis B virus (HBV) recurrence after a liver transplant (LT) is a global issue. Several strategies have been adopted to prevent this recurrence. Most strategies recommend a combination of hepatitis B immunoglobulin (HBIG) and or nucleos(t)ide analogue.

Aim of the Study

The aim of the study is to determine the anti-HBs response to HBIG among Indian patients who had undetectable pre-transplant HBV DNA.

Methods

Seven adult HBV-related LT recipients of Indian origin with low pre-transplant HBV titres who had a liver transplant between August 2009 and June 2012 were included in the study. The protocol followed for post-liver transplant HBIG dose was titrated to achieve an anti-HBs titre of at least 100 IU/L. All recipients were on entecavir. Anti-HBs titre, and HBsAg status was checked at regular intervals. A retrospective analysis of the anti-HBs response to a loading and maintenance dose of HBIG was done.

Results

Seven adult HBV-related LT recipients on post-transplant prophylaxis with HBIG and nucleoside analogue (entecavir) fulfilled the criteria for the study. The median anti-HBs response to the anhepatic and loading dose of HBIG was high at 555 IU/L. In two, the response was less than 100 IU/L. The median dose of HBIG reduced at end of 1 month to 800 IU, and the median titre was 223 IU/L. For the next 11 months, the median requirement of HBIG was 3,000 and 4,000 IU, and the titre was low at 53.8 and 60.9 IU/L at end of 6 and 12 months, respectively.

Conclusions

The anti-HBs response to HBIG was variable, and titres even below 100 IU/L did not result in HBV recurrence when HBIG was given in combination with entecavir.     

Methylation profiling of serum DNA from hepatocellular carcinoma patients using an Infinium Human Methylation 450 BeadChip

Background

Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). The methylation status of circulating DNA might serve as a potential biomarker for cancers.

Methods

Six early stage HCC patients with chronic hepatitis B virus (HBV) infection and six age-matched healthy controls were selected for genome-scale DNA methylation screening of serum by Illumina Infinium Human Methylation 450 BeadChip. The chosen methylation sites were reassessed by bisulfite sequencing in four healthy controls and four early stage HCC patients with chronic HBV infection and were used for bead array screening. Another 27 healthy controls and 31 early stage HCC patients with chronic HBV infection were also chosen for further bisulfite sequencing validation.

Results

Whole-genome methylation was significantly lower in serum from HCC patients than in that from healthy controls. After bioinformatics analysis, methylation at DBX2 and Thy-1 membrane glycoprotein (THY1) was reassessed by bisulfite sequencing. The correlation coefficients of DBX2 and THY1 between the Illumina 450 BeadChip and bisulfite sequencing were respectively 0.9145 and 0.8232. Twenty-seven healthy controls and 31 early stage HCC patients with chronic HBV infection were chosen for further validation. The diagnostic sensitivity and specificity of DBX2 for differentiating healthy controls and early stage HCC were 88.89 and 87.10 % and of THY1 were 85.19 and 80.65 %.

Conclusions

The results demonstrated that the 450K BeadChip is a useful tool for whole-genome serum DNA methylation screening of HCC, and some HCC-related DNA methylation sites were screened.