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.     

Liver cirrhosis stages and the incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving antiviral therapy

Objectives: Long-term antiviral therapy decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB), however, it cannot eliminate the risk. We investigated the incidence of HCC at different stages of liver cirrhosis (LC) and identified clinical predictors for HCC development during antiviral therapy.

Methods: The data from 356 treatment-naïve patients aged 40 to 69 years without a history of HCC who had received entecavir for ≥6 months were collected retrospectively. The incidence of HCC was evaluated in patients with CHB only, with LC without varices (stage 1), with varices (stage 2), and with ascites (stage 3).

Results: The median follow-up period was 3.6 years. In total, 45 patients (12.6%) developed HCC. The annual incidence rates of HCC in patients with CHB only or LC in stages 1, 2, and 3 were 0.4%, 2.6%, 9.8%, and 6.7%, respectively. In multivariate analyzes, LC at stage 2 (hazard ratio [HR] 17.16, 95% confidence interval [C.I.] 3.93–75.01, p?<?.001), alcohol consumption (HR 3.84, 95% C.I. 1.99–7.39, p?<?.001), and older age (HR 1.06, 95% C.I. 1.01–1.11, p?=?.010) were significantly associated with HCC development. The risk decreased in those who stopped drinking after 2 years of abstinence (p?=?.0314).

Conclusions: LC with significant portal hypertension (varices or ascites), alcohol consumption, and older age at the time of starting antiviral therapy are independent predictors for future HCC development.     

Increasing hepatitis B viral load is associated with risk of significant liver fibrosis in HBeAg‐negative but not HBeAg‐positive chronic hepatitis B

Background/aims: To evaluate the association between demographical features, serum ALT and HBV DNA and the prevalence of significant fibrosis and inflammation on liver biopsy in patients with chronic hepatitis B. Methods: In this cross‐sectional study of patients on St Vincent's Hospital HBV database, patients were classified into three groups on the basis of HBeAg status and HBV DNA level and the prevalence of significant (F2/3/4) fibrosis and (A2/3) inflammation in each group was established. Patients were also divided into HBeAg‐positive and ‐negative groups and examined for the prevalence of significant fibrosis/inflammation in the strata of HBV DNA and ALT. Predictors of significant fibrosis and inflammation in HBeAg‐positive and ‐negative patients were examined by logistic regression. Results: Three hundred and ninety four patients (HBeAg positive=198; HBeAg negative=196) with liver biopsy were identified. Fifty‐eight percent of HBeAg‐negative patients with HBV DNA >25 000 IU/ml had F2/3/4 fibrosis. HBV DNA and F2/3/4 were positively correlated in HBeAg‐negative patients [odds ratio (OR) 1.42, P=0.001] but inversely correlated in HBeAg‐positive patients (OR 0.71, P=0.03). HBV DNA was an independent predictor of significant fibrosis in HBeAg negative (P=0.03) but not HBeAg‐positive patients. In HBeAg‐positive patients, age was the only predictor of significant fibrosis (P=0.001) and ALT the only predictor of significant inflammation (P=0.003). In the whole cohort there was a close positive association between inflammation and fibrosis. Conclusion: Increasing levels of HBV DNA are associated with increasing prevalence of significant fibrosis only in patients with HBeAg‐negative CHB.     

Immunological biomarkers as indicators for outcome after discontinuation of nucleos(t)ide analogue therapy in patients with HBeAg‐negative chronic hepatitis B

The optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg‐negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off‐treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off‐treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed ‘inactive carriers’) served as controls. Results were validated using qRT‐PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long‐term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off‐treatment remission segregated as a distinct out‐group. Twenty‐one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off‐treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78‐0.92. IFNγ, IL‐8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long‐term NA therapy had expression levels of all these four genes below cut‐off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg‐negative CHB who remain in off‐treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL‐8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy.     

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.     

慢性乙型肝炎抗病毒治疗的几点思考

HBV持续高水平复制是慢性乙型肝炎进展的最关键因素,抗病毒治疗是最重要的措施。本文就抗病毒治疗的原因、适应证和治疗终点进行了讨论。病毒载量、患者年龄和感染时间的长短是决定治疗的主要因素。高病毒载量、ALT≥2×正常值上限（upper limit of normal,ULN）的患者应接受抗病毒治疗;ALT＜2×ULN的患者,如肝组织学有明显炎症坏死或纤维化,也是抗病毒治疗的适应证。治疗的主要目标是减少肝硬化、肝细胞癌的发生及改善生存质量。病毒学、生化学、组织学应答是实现这一目标的必要条件,其中,病毒学应答是关键。治疗的理想终点是HBsAg消失,但难以达到;HBeAg血清转换是HBeAg阳性患者的满意治疗终点;对所有患者,保持HBVDNA在不可检测水平是最基本的治疗终点。     

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乙型肝炎病毒(HBV)持续高水平复制是促进慢性乙型肝炎进展的最关键因素,抗病毒是治疗慢性乙型肝炎最重要的措施。文章就抗病毒治疗的适应证、药物选择和治疗终点进行了讨论。从"需要"和"可能"两个方面考虑,处于免疫清除期和再活动期的患者是治疗的对象。如果条件允许,应选择高效、低耐药的药物。治疗的目标是通过长期抑制病毒,减少肝硬化、原发性肝细胞癌的发生并改善生存质量。病毒学、生化学、组织学应答是实现这一目标的必要条件。治疗的理想终点是HBsAg消失,但不易达到;HBeAg血清转换是HBeAg阳性患者的满意治疗终点,也较为现实。对所有患者,保持HBV DNA在不可检测水平是最基本的治疗终点。     

Prognostic significance of liver stiffness for hepatocellular carcinoma and mortality in HBeAg‐negative chronic hepatitis B

Summary. The prognostic value of liver stiffness measurements for chronic hepatitis B (CHB) is not known. The present study aimed to investigate the use of transient elastography in predicting hepatocellular carcinoma (HCC) development and mortality in patients with CHB. Five hundred and twenty‐eight patients with HBeAg‐negative CHB underwent liver stiffness measurements and were prospectively followed up every 3–6 months for a median length of 35 months. The patients were divided into those with liver stiffness <10 kPa (group 1) and ≥10 kPa (group 2). Of the 528 patients, 324 (61%) were men. The median age was 42 years. Compared with group 1, group 2 had a higher percentage of men, with higher median levels of age, liver biochemistry, and viral load. At the third year of follow‐up, the cumulative incidence of HCC was higher in group 2 compared with group 1 (9%vs 0%, respectively, P < 0.001). The cumulative liver‐related mortality was also higher in group 2 compared to group 1 (4%vs 0%, respectively, P < 0.001). After multivariate analysis, only liver stiffness measurement (LSM) was significantly associated with HCC development and mortality. There was also a higher cumulative incidence of hepatitis flares in group 2 compared to group 1 (46%vs 14%, respectively, P = 0.001) in patients with normal ALT, with higher LSM and AST being significantly associated with subsequent flares. In HBeAg‐negative CHB patients, a liver stiffness measurement of ≥10 kPa was associated with a significantly increased risk of subsequent HCC development and mortality.     

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.     

High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection

BACKGROUND AND AIMS: Hepatitis B virus (HBV) is considered a major risk factor for the progression to liver cirrhosis and hepatocellular carcinoma (HCC). The serum level of HBV-DNA is correlated with progression of the disease. The aim of the present study was to determine the relationship between the level of HBV-DNA and hepatocarcinogenesis in patients with chronic HBV infection. METHODS: The authors studied 73 patients who were diagnosed with chronic HBV infection at Nagasaki University Hospital (Nagasaki, Japan) between January 1980 and December 1999. The significance of age, sex, habitual drinking, serum alanine aminotransferase level, HBV viral load, interferon treatment, hepatic fibrosis and hepatic inflammation on the development of HCC were examined using univariate and multivariate analyses. RESULTS: The cumulative incidence rates of HCC were 14%, 29% and 48% at 5, 10 and 15 years after liver biopsy, respectively. Multivariate analysis identified high viral load, together with age and severe fibrosis, as independent and significant risk factors (P = 0.045, 0.047 and 0.013, respectively) for HCC. CONCLUSIONS: The present findings indicate that high viral load is a risk factor for HCC in patients with chronic HBV infection. Patients with a high HBV viral load should be carefully monitored for HCC.     

乙型肝炎特殊人群抗病毒治疗的新认识

在慢性乙型肝炎人群中,合并HIV/HCV/HDV感染、儿童和青少年、妊娠妇女、慢性肾损害、应用化疗和免疫抑制剂等特殊人群的抗病毒治疗问题日益受到重视。关于乙型肝炎特殊人群的抗病毒治疗指征、药物选择及调整、抗病毒疗程等是目前临床研究的热点。近几年各大乙型肝炎防治指南均提出要规范乙型肝炎特殊人群的管理,但对该人群抗病毒治疗的推荐证据级别不高。临床工作中应结合现有的研究成果,规范管理流程,力求建立高质量的队列研究,以获得强有力的循证医学证据,更好的指导临床治疗。