Hepatitis B virus‐related hepatocellular carcinoma in the era of antiviral therapy: The emerging role of non‐viral risk factors

Hepatocellular carcinoma (HCC), one of the major malignant lethal tumours, is most prevalent in Asian patients with chronic hepatitis B virus (HBV) infection. Both viral and non‐viral factors contribute to the development of HCC. It is established that viral factors associated with HBV DNA level, HBV genotype, designated gene mutation, HBV DNA integration, HBx protein, hepatitis B surface antigen (HBsAg), hepatitis B core‐related antigen (HBcrAg) and HBV RNA are correlated with hepatocarcinogenesis. Before the introduction of antiviral therapy, viral factors once attracted more attention during the development of HCC. With the widespread use of antiviral therapy, predominantly nucleos(t)ide analogues (NAs), most patients with chronic hepatitis B (CHB) have achieved sustained viral control. The role of non‐viral factors, especially modifiable factors, is anticipated to be reinforced in the future. Herein, we reviewed the modifiable non‐viral risk factors of HBV‐related HCC, in the hope of providing substantial evidence for further development of novel precautionary measures for HCC. In addition, the therapeutic interventions for reducing the risk of HCC, like potential conventional pharmaceutical interventions and lifestyle modification are also discussed in this review. Future studies that would explore the specific mechanism of HBV‐related HCC development in patients with satisfactory viral control and related precision treatment are warranted.     

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.     

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.     

Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma

Chronic hepatitis B virus(HBV) infection is a critical risk factor for the carcinogenesis and progression of hepatocellular carcinoma(HCC). It promotes HCC development by inducing liver fibrogenesis, genetic and epigenetic alterations, and the expression of active viral-coded proteins. Effective antiviral treatments inhibit the replication of HBV, reduce serum viral load and accelerate hepatitis B e antigen serum conversion. Timely initiation of antiviral treatment is not only essential for preventing the incidence of HCC in chronic hepatitis B patients, but also important for reducing HBV reactivation, improving liver function, reducing or delaying HCC recurrence, and prolonging overall survival of HBV-related HCC patients after curative and palliative therapies. The selection of antiviral drugs, monitoring of indicators such as HBV DNA and hepatitis B surface antigen, and timely rescue treatment when necessary, are essential in antiviral therapies for HBVrelated HCC.     

血清HBV DNA与肝动脉化疗栓塞术后肝癌复发的相关性研究

目的观察肝癌患者血清HBV DNA载量与肝动脉化疗栓塞术(TACE)后肿瘤复发的关系。方法检测193例乙型肝炎病毒标记物阳性的肝癌患者在TACE治疗前血清HBV DNA载量,分析患者血清HBV DNA载量与栓塞术后肿瘤复发的关系。结果在193例患者中,介入治疗术后2年内共有169例(87.6%)患者肿瘤复发;血清HBV DNA阳性(≥5×102copies/ml)138例,平均血清病毒载量为6.20±1.12lg copies/ml;单因素及多因素分析显示,肝功能Child-Pugh B级或C级、多发肿瘤、肿瘤最长径大于3cm、血清HBV DNA≥5×102copies/ml患者肿瘤复发的相对危险性较高,无肿瘤复发生存期较短。结论肝癌患者血清HBV DNA≥5×102copies/ml是TACE治疗后肿瘤复发的危险因素之一。     

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??Abstract??Hepatitis B and C viruses play important roles in the carcinomagenosis of hepatic cellular carcinoma.The high-level viral load will lead to not only HCC recurrence but also end-stage liver diseases.The Recommendation on antiviral therapy to hepatitis B/C virus related hepatocellular carcinoma gives a panoramic review of application of antiviral therapy for patients with hepatitis B/C virus related HCC.The schemes help to reduce HCC recurrence rate and HBV reactivation caused by treatment??protecting the hepatic function.However??large randomized control studies in this field are still needed.     

Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection

BACKGROUND/AIMS:  To identify the risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after resection.
METHODS:  Seventy-two patients who underwent liver resection for HBV-related HCC were recruited. Demographic, biochemical, tumor, and viral factors at the time of resection were evaluated by univariate and multivariate analyses to identify risk factors associated with recurrence after resection.
RESULTS:  The median follow-up period was 18.9 months and the median age was 53 yr, with male-to-female ratio of 59:13. Age >60 yr, tumor size >5 cm, poorly differentiated tumor, lymphovascular permeation, the presence of microsatellite lesions, α-fetoprotein (AFP) level >1,000 ng/mL and HBV viral load >2,000 IU/mL (4 log₁₀ copies/mL) at the time of tumor resection, HBV genotype C, core promoter mutations, and patients with no antiviral treatment after tumor resection were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV viral load >2,000 IU/mL (4 log₁₀ copies/mL) ( P = 0.001, odds ratio [OR] 22.3), AFP >1,000 ng/mL ( P = 0.02, OR 7.4), tumor size >5 cm ( P = 0.02, OR 5.1), and age >60 yr ( P = 0.01, OR 4) at the time of tumor resection remained to be the independent risk factors.
CONCLUSIONS:  Viral load of >2,000 IU/mL (4 log₁₀ copies/mL) is the most important correctable risk factor for HCC recurrence after resection. Whether antiviral therapy in these patients can decrease tumor recurrence requires further investigations.     

Impact of antiviral therapy on post-hepatectomy outcome for hepatitis B-related hepatocellular carcinoma

The outcome after curative resection for hepatocellular carcinoma (HCC) remains unsatisfactory due to the high recurrence rate after surgery. In patients with hepatitis B virus (HBV)-related HCC, which is the majority of patients with HCC in Asia, a high viral load is a strong risk factor for HCC recurrence. It is logical to believe that antiviral therapy may improve the post-operative outcome by promoting viral clearance and hepatocyte regeneration, as well as improving residual liver volume in HCC patients with hepatitis B. However, the effect of antiviral therapy on clinical outcomes after liver resection in patients with HBV-related HCC remains to be established. There are two main groups of antiviral treatment for HBV-oral nucleos(t)ide analogues and interferon. Interferon treatment reduces the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Nucleos(t)ide analogues carry fewer side effects and are potent in terms of viral suppression when compared to interferon and are typically implemented for patients with more advanced liver diseases. They may also improve the outcome after curative resection for HBV-related HCC. There are increasing evidence to suggest that antiviral therapy could suppress HBV, decrease the perioperative reactivation of viral replication, reduce liver injury, preserve the liver function before and after operation, and may lower the risk of HCC recurrence. After all, antiviral therapy may improve the survival after liver resection by reducing recurrence and delaying the liver damage by the virus, resulting in a higher chance of receiving aggressive salvage therapy during HCC recurrence.     

Hepatitis B core‐related antigen levels predict recurrence‐free survival in patients with HBV‐associated early‐stage hepatocellular carcinoma: results from a Dutch long‐term follow‐up study

Prognosis of hepatitis B (HBV)‐associated hepatocellular carcinoma (HCC) is poor due to high rates of HCC recurrence and progression of underlying liver disease. We studied whether serum hepatitis B core‐related antigen (HBcrAg) levels could predict HCC recurrence and outcome in HBV associated. Higher HBcrAg levels at HCC diagnosis were independently associated with reduced overall and recurrence‐free survival in patients with early, but not advanced, stage HCC.     

Risk stratification for hepatitis B virus related hepatocellular carcinoma

Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, especially in the Asia–Pacific region. Several hepatitis B viral factors predictive of clinical outcomes in HBV carriers have been identified. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐HBV (REVEAL‐HBV) study from Taiwan illustrated the strong association between HBV‐DNA level at study entry and risk of HCC over time. In this community‐based cohort study, male gender, older age, high serum alanine aminotransferase level, positive hepatitis B e antigen, higher HBV‐DNA level, HBV genotype C infection, and core promoter mutation are independently associated with a higher risk of HCC. Another large hospital‐based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers cohort of Taiwanese patients further validated the findings of REVEAL‐HBV. The risk of HCC started to increase when HBV‐DNA level was higher than 2000 IU/mL. Both HBV‐DNA and HBsAg levels were shown to be associated with HCC development. While HBV‐DNA level had better predictive accuracy than HBsAg level, when investigating the overall cohort in patients with HBV‐DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL was identified as a new independent risk factor for HCC. With the results from REVEAL‐HBV, a risk calculation for predicting HCC in non‐cirrhotic patients has been developed and validated by independent cohorts (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B).Taken together, ample evidence indicates that HBsAg level can complement HBV‐DNA level in predicting HCC development, especially in HBV carriers with low viral load. In conclusion, HBV treatment guidelines should include the risk stratification of HCC to individualize the management of HBV carriers with different levels of HCC risk.     

Hepatitis B viral load affects prognosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a complex disease that is dually challenging to treat due to underlying chronic liver disease in addition to the cancer itself.The prognosis of patients with HCC is determined by intrahepatic tumor status and reserved hepatic function.Hepatitis B virus(HBV)is an established major risk factor of HCC development,and HBV viral load is being increasingly recognized as a prognostic factor in the presence of established HCC.High HBV viral load may affect the prognosis of HBV-related HCC patients in several ways.First,it is associated with more frequent recurrence of HBV-related HCC after treatment.Second,it is associated with more occurrence and severity of potentially life-threatening HBV reactivation.Last,it is associated with more worsened liver function,which limits the therapeutic options for HBV-related HCC.HBV,directly or indirectly,can induce hepatocarcinogenesis.In patients with a high HBV DNA level and subsequent active hepatitis,adhesion molecules expressed on the sinusoidal cells are up-regulated and may increase intrahepatic metastasis.HCC progression after treatment can lead to a poor prognosis by reducing number of normal functioning hepatocytes.Thus,high HBV viral load can affect the prognosis of patientswith HCC by frequent recurrence after treatment for HCC and deterioration of hepatic function associated with HCC progression.Recent meta-analysis showed that antiviral treatment reduces HCC recurrence and liver-related mortality after curative therapy of HCC.Given the strong relationship between high HBV DNA load and poor survival outcome of HCC patients due to cancer progression,it is expected that long-term antiviral therapy results in the sustained HBV suppression,control of inflammation,reduction in HCC progression,and eventually in improved overall survival.     

Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus‐related hepatocellular carcinoma

Background/Aims: Treatment of patients with hepatocellular carcinoma (HCC) depends on the tumour extent and underlying liver function. Antiviral therapy with nucleoside/nucleotide analogues has been shown to be effective in improving the liver function of chronic hepatitis B (CHB) patients. We assessed whether lamivudine could induce biochemical and virological improvements in patients with hepatitis B virus‐related HCC. Patients/Methods: Of 148 CHB patients treated with 100 mg/day lamivudine for at least 6 months, 80 had HCC (CHB/HCC group) and 68 did not (CHB group). Biochemical and virological parameters were serially monitored. Results: Compared with the CHB group, the CHB/HCC group was older, had higher male predominance, bilirubin levels and liver cirrhosis rate, and lower albumin and hepatitis B virus (HBV) DNA levels and hepatitis B e antigen (HBeAg) positivity (P<0.05 each). The two groups showed similar cumulative rates of alanine aminotransferase normalization, HBV DNA seroconversion, HBeAg loss and viral breakthrough during 12 months of lamivudine treatment. After 12 months, the CHB/HCC group showed, relative to baseline, increased albumin levels (3.51±0.5 vs. 3.72±0.5 mg/ml) and decreased ascites scores (1.63±0.7 vs. 1.45±0.6) and Child–Pugh scores (6.92±1.9 vs. 6.02±1.38) (P<0.05 each). Conclusion: Lamivudine had comparable antiviral effects both in patients with CHB and CHB/HCC, and improved underlying liver function in the latter group. Treatment of HBV may increase the chance of curative treatments in patients with HBV‐related HCC.     

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B

Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus(HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC,the molecular basis for this association has not been fully elucidated. In addition,a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis,recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agentsin achieving profound and durable suppression of HBV DNA levels while improving liver function and histology,robust evidence of other long-term clinical outcomes,such as prevention of HCC,are limited.     

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.     

Significance of viral status on occurrence of hepatitis B-related hepatocellular carcinoma

Hepatitis B virus (HBV) infection remains a challenging global health problem, with more than 350 million people chronically infected and at risk of developing hepatocellular carcinoma (HCC). Interactions that occur among host, environmental, and viral factors determine the natural course and predict the prognosis of patients with chronic HBV infection. In the past decades, several important viral factors of predictive of HCC have been identified, such as high hepatitis B surface antigen level, seropositivity of hepatitis B e antigen, high viral load, viral genotype, and specific viral sequence mutations. Identification of certain viral risk factors for HCC development and stratification of patient risk are very important to perform future surveillance programs. In this article, we thus reviewed the risk of viral factors involved in hepatocarcinogenesis.     

Influence of hepatitis B virus reactivation on the recurrence of HBV‐related hepatocellular carcinoma after curative resection in patients with low viral load

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B‐related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV‐related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre‐operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV‐related HCC after curative resection were investigated. Fifty‐three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV‐related HCC in patients with low viral load.     

Antiviral therapy and primary and secondary prevention of hepatocellular carcinoma

Viral hepatitis due to chronic hepatitis B and C virus (HBV/HCV) infects more than 500 000 000 individuals worldwide. These chronic viral diseases are highly linked to the development of hepatocellular carcinoma (HCC), the fifth most common cause of cancer death worldwide. HCC is much more common in Asia and Africa than in the USA and Europe, although HCC is one of the few cancers with a rising incidence in the USA. There are 530 000 cases of HCC worldwide of which 82% are related to viral hepatitis. 316 000 cases of HCC are HBV-associated, 118 000 are HCV-associated. The most effective way to prevent HCC is to prevent viral infection through immunization. Currently there are effective vaccinesagainst hepatitis B and A, but not against HCV, the virus that accounts for most HCC in the USA. The published work supporting the use of antiviral therapy in preventing liver cancer is limited. Data supporting the use of antiviral therapy in preventing recurrence of HCC after initial anticancer approaches is even less available. Nevertheless, the weight of evidence suggests that treatment of HBV/HCV-related fibrosis will reduce the risk of developing HCC.     

Evaluation of current treatment recommendations for chronic hepatitis B: a 2011 update

Background and Aim: Guidelines for the treatment of chronic hepatitis B have been recently updated in the 2009 European Association for the Study of the Liver consensus statement, the 2008 US Panel, the 2008 Asian–Pacific consensus statement, and the 2009 American Association for the Study of Liver Disease practice guidelines. We sought to determine whether these guidelines identified patients who developed hepatocellular carcinoma (HCC) or who died of non‐HCC liver‐related deaths for antiviral therapy. Methods: The criteria described in the new treatment guidelines were matched to the database of 369 hepatitis B surface antigen‐positive patients, in whom 30 developed HCC and 37 died of non‐HCC liver‐related deaths during a mean follow up of 84 months. Results: Using criteria for antiviral therapy as stated by the four current guidelines, 19–30% of patients who died of non‐HCC liver‐related complications, and 23–53% of patients who developed HCC, would have been excluded for antiviral therapy. If baseline serum albumin levels of ≤ 3.5 g/dL or platelet counts of ≤ 130 000 mm³ were included into the treatment criteria, then 85–94% of patients who developed liver‐related complications would have been recommended for antiviral therapy. Also, the addition of precore A1896 mutants and basal core promoter T1762/A1764 mutants would have identified 98.5–100% of these patients. Conclusion: The updated treatment guidelines for hepatitis B still excluded patients who developed serious liver‐related complications. The inclusion of baseline serum albumin and platelet counts to current criteria would have identified a majority of these patients for antiviral therapy. These tests should be included into hepatitis B treatment strategies.     

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.     

Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment

Aim

Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)‐DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment.

Methods

A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV‐DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV‐DNA disappearance.

Results

Thirteen patients developed HCC during the follow‐up period. The 1‐, 3‐, and 5‐year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220–17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438–21.519; P = 0.013), and higher HBV core‐related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683–108.815; P = 0.014) at the time of HBV‐DNA disappearance were significantly associated with the development of HCC.

Conclusion

Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV‐DNA disappearance.