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.     

Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus-related chronic liver disease

Background and Aim: Hepatitis E virus (HEV) has recently been implicated in episodes of acute decompensation in patients having underlying chronic liver disease (CLD) of varying etiology. However, HEV as a cause of acute exacerbation of previously asymptomatic and unrecognized hepatitis B virus (HBV)‐infected patients is less well described. The aim of the present study was to investigate the etiology of acute exacerbation of previously asymptomatic and unrecognized HBV‐infected patients and to evaluate the relative role of HEV. We also investigated the effect of superinfection on the clinical spectrum of underlying HBV infection. Methods: Forty‐three patients presented with the following were retrospectively analyzed: (i) clinical features suggestive of acute hepatitis; (ii) with hepatitis B surface antigen (HBsAg) (+); (iii) IgM hepatitis B core antibody (IgM anti‐HBc) (?); (iv) no previous history of liver disease; (v) no features suggestive of CLD at presentation; (vi) HBsAg remaining (+) for at least 12 months on follow up; and (vii) having a follow‐up biopsy during the convalescent phase showing evidence of chronic hepatitis B. Results: Of the 43 patients, 21 were hepatitis e antigen (HBeAg) (+) (Gr.1) and 22 HBeAg (?) (Gr.2) at presentation. In Gr.1, only two (9.5%) had superinfection (both with hepatitis A virus), whereas in Gr.2, 11 (50%) had superinfection (27.3% hepatitis E, 13.6% hepatitis A and 9.1% both) (P = 0.007). In Gr.1, the remaining 19 (90.5%) patients had spontaneous exacerbation (immune clearance with spontaneous seroconversion) whereas in Gr.2, the remaining 11 (50%) had spontaneous exacerbation (due to reactivation). Overall, HEV superinfection contributed to 20% of acute exacerbation episodes and, in particular, 36% of episodes in initially HBeAg (?) patients. Time to alanine aminotransferase normalization was longer in patients with superinfection (n = 13) as compared to spontaneous exacerbation (n = 30) (median [range] 36 [8–48]vs 16 [6–36] weeks, P = 0.001). During convalescence, there was no significant difference between histological activity index score (median [range] 8 [4–11]vs 8 [4–16] weeks, P = 0.629) and fibrosis scores (median [range] 3.5 [1–4]vs 2 [1–4] weeks, P = 0.099] on liver biopsy after recovery among patients with acute exacerbation due to superinfection and spontaneous exacerbation. Conclusions: Acute exacerbations in HBeAg (+) patients are most often due to spontaneous viral activation, while in HBeAg (?) patients, superinfection with non‐B hepatitis viruses and spontaneous viral activation are equally common. HEV is an important cause of acute exacerbation in previously asymptomatic and unrecognized patients with HBV‐related CLD.     

Perioperative reactivation of hepatitis B virus replication in patients undergoing partial hepatectomy for hepatocellular carcinoma

Background and Aim: Reactivation of hepatitis B virus (HBV) replication happens in patients who receive transarterial chemoembolization or systemic chemotherapy for hepatocellular carcinoma (HCC). The incidence and risk factors of HBV reactivation during the perioperative period in HCC patients receiving hepatic resection is unknown. Methods: Between May 2009 and November 2010, 164 consecutive patients with HBV‐related HCC who underwent hepatic resection were prospectively enrolled in the study. Among these, 126 patients received antiviral treatment before the operation (the antiviral group) and 38 patients did not receive any antiviral treatment (the non‐antiviral group). Results: Ten patients (6.1%) developed HBV reactivation perioperatively (within 1 month after hepatectomy). The incidence of HBV reactivation in the antiviral group and non‐antiviral group were 1.6% (2/126) and 21.1% (8/38), respectively (P < 0.001). On univariate analysis, preoperative HBV DNA < 1.0 × 10³ copies/mL and non‐antiviral therapy were significantly correlated with the occurrence of HBV reactivation (P = 0.044 and P < 0.001, respectively). Only non‐antiviral therapy remained as a predictive factor on multivariate analysis (odds ratio, 15.46; 95% confidence interval, 2.80–85.46, P = 0.002). The recovery of liver function (defined as a decrease of alanine aminotransferase back to normal) was achieved in 86.8% (132/152) patients without HBV reactivation and in 37.5% (3/8) patients with HBV reactivation when evaluated on day 30 after hepatectomy (P < 0.001). Conclusion: Hepatectomy could reactivate HBV replication during the perioperative period, especially in patients who did not receive any antiviral therapy. A close monitoring of HBV DNA during the perioperative period was necessary irrespective of the preoperative HBV DNA level. Once HBV was reactivated, antiviral therapy should be given.     

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.     

Virological and clinical implication of core promoter C1752/V1753 and T1764/G1766 mutations in hepatitis B virus genotype D infection in Mongolia

Background and Aim: The aim of the present study was to reveal virological and clinical features of hepatitis B virus (HBV) genotype D infection. Methods: One hundred and twenty‐two Mongolian chronic liver disease (CLD) patients infected with HBV were subjected for serological HBV‐markers screening and HBV‐enzyme immunoassay (EIA) genotyping. Nucleotide sequences were analyzed for 48 HBV/D strains (23 isolated from hepatocellular carcinoma (HCC) and 25 from CLD patients). Results: Prevalence of hepatitis B e antigen (HBeAg) positivity was low (25.9%) in young patients (≤30 years old) indicating early HBeAg seroclearance in HBV/D carriers. The T1764/G1766 double mutation was the most common basal core promoter (BCP) mutation (29.2%) and was frequent in HBeAg‐negative patients (39.3%). Patients harboring T1764/G1766 mutants exhibited lower HBV‐DNA and HBV core antigen (HBcAg) levels than those with wild‐type BCP strains (P = 0.024, 0.049, respectively). C1752 and/or V (not T) 1753 mutation was significantly prevalent in HCC patients (HCC vs CLD; 52.2% vs 20%, P = 0.033). T1762/A1764 mutation was detected in 75.0% of HCC patients with high viral load (≥5 log copies/mL). Precore stop codon mutation A1896 was detected in (70.8%) of HBV/D‐infected patients. Conclusions: In Mongolians infected with HBV/D, C1752 and/or V1753 mutation was associated with HCC.     

Viral level is an indicator of long-term outcome of hepatitis B virus e antigen-negative carriers with persistently normal serum alanine aminotransferase levels

Summary. The association between viral level and the long‐term outcomes of hepatitis B virus (HBV) carriers who test negative for hepatitis B virus e antigen (HBeAg) but have persistently normal serum alanine aminotransferase levels (PNALT) remains unclear. We examined hepatocarcinogenesis, hepatitis reactivation, predictive factors and the time course of HBV DNA levels during follow‐up in 104 HBeAg‐negative Japanese carriers with PNALT. During a mean follow‐up period of 6.4 ± 3.4 years, 5 patients (4.8%) had hepatocarcinogenesis and 14 (13.5%) had hepatitis reactivation. At 5 and 10 years, the cumulative rates of hepatocarcinogenesis were 2.4% and 9.9%, while those of hepatitis activation were 13.7% and 15.5%, respectively. An HBV DNA level of ≥5 log₁₀ copies/mL was the sole predictor of hepatocarcinogenesis with a univariate analysis. An HBV DNA level of ≥5 log₁₀ copies/mL and an alanine aminotransferase (ALT) level of >20 to ≤40 IU/L were independent predictors of hepatitis reactivation in a Cox model. Because there was no association between hepatocarcinogenesis and ALT activity, the HBV DNA level was considered an essential predictor. In addition, the baseline HBV DNA level was related to the future level and was not subject to wide fluctuations. Our results showed that an HBV DNA level of ≥5 log₁₀ copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg‐negative carriers with PNALT. As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

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.     

Prognosis of hepatitis B-related liver cirrhosis in the era of oral nucleos(t)ide analog antiviral agents

Background and Aim: We investigated long‐term outcomes and prognostic factors in patients with hepatitis B virus (HBV)‐related liver cirrhosis in the era of oral nucleos(t)ide analog antiviral agents. Methods: Between January 1999 and February 2009, a total of 240 consecutive patients who had HBV‐related cirrhosis without malignancy were treated with lamivudine and second line nucleos(t)ide analogs. The group of historical controls consisted of 481 consecutive patients with HBV‐related cirrhosis who were managed without any antiviral treatment prior to 1999. Results: In 78% of the patients who received antiviral treatment, sustained viral suppression (serum HBV DNA < 10⁵ copies/mL) was achieved during a mean follow‐up period of 46 months. The occurrences of death, hepatic decompensation, and hepatocellular carcinoma (HCC) were less frequent in the treated cohort than in untreated historical controls, with the 5‐year cumulative incidences being 19.4% versus 43.9% (log‐rank P < 0.001), 15.4% versus 45.4% (P = 0.001), and 13.8% versus 23.4% (P = 0.074), respectively. For patients who received antiviral treatment, suboptimal viral suppression (HBV DNA > 10⁵ copies/mL at last follow‐up) was an important independent risk factor of death (P < 0.001) and hepatic decompensation (P = 0.019), and was linked to an increased risk of HCC (P = 0.042). Although the Child–Pugh grade remained a useful prognostic factor, no significant differences were found between patients with Child–Pugh grade B and C cirrhosis at the beginning of antiviral treatment (P = 0.656). Conclusions: Oral antiviral agents have improved the prognosis of patients with HBV‐related cirrhosis and affected the prognostic values of factors constituting the Child–Pugh system, necessitating a more efficient prognostic system.     

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside‐naïve HBeAg‐positive patients with chronic hepatitis B*

Summary. This retrospective analysis was conducted to describe the characteristics of nucleoside‐naïve hepatitis B e antigen (HBeAg)‐positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg‐positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double‐blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off‐treatment follow‐up. Through a maximum duration of 96 weeks on‐treatment and 24 weeks off‐treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside‐naïve HBeAg‐positive patients treated with entecavir, and that HBsAg loss is associated with sustained off‐treatment suppression of HBV DNA.     

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.     

Long-term follow-up of patients with hepatitis B e antigen negative chronic hepatitis B

Background and Aim: After hepatitis B virus (HBV) e antigen (HBeAg) seroconversion, HBV‐DNA continues to replicate, and HBeAg‐negative patients still face the risk of liver disease progression. We investigated the predictive factors for alanine aminotransferase (ALT) elevation, antiviral drug use, and hepatocellular carcinoma (HCC) occurrence in HBeAg‐negative patients. Methods: Age, sex, ALT, platelet counts, HBV‐DNA levels, genotype, antidiabetic drug use, body mass index, smoking, and alcohol consumption were analyzed for a total of 244 HBV carriers who were HBeAg‐negative. Results: Of 244 HBeAg‐negative patients, 158 (64.8%) showed normal ALT levels at baseline. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels and high ALT at baseline as independent risk factors for ALT elevation in the patients with normal ALT at baseline. The threshold ALT and HBV‐DNA levels were determined to be 31 IU/L and 5.3 logcopies/mL, respectively. Seventeen (7.0%) patients used antiviral drugs. Multivariate Cox hazard regression analysis identified high HBV‐DNA levels (threshold, 5.7 log copies/mL), the use of antidiabetic drugs, and daily alcohol consumption at baseline as an independent risk factor for the use of antiviral drugs in HBeAg‐negative patients. In 10 patients (4.1%), HCC was detected, and a low platelet count (threshold, 10.0 × 10⁴/mm³) was associated with the occurrence of HCC. Conclusion: This study identified predictors of future active liver disease in HBeAg‐negative patients, i.e. ALT elevation, unavoidable use of antiviral drugs, and occurrence of HCC.     

Risk of hepatitis B exacerbation is low after transcatheter arterial chemoembolization therapy for patients with HBV-related hepatocellular carcinoma: report of a prospective study

OBJECTIVES: Systemic chemotherapy may lead to immune suppression and possible reactivation of hepatitis B virus (HBV), suggesting prophylactic antiviral therapy in cancer patients with HBV. Transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) is not a systemic chemotherapy, but has been partially associated with HBV reactivation. The aim of this study was to evaluate whether TACE aggravates HBV hepatitis in patients with HBV-related HCC. METHODS: Eighty-nine patients with HBV-related HCC were studied prospectively. Patients treated with TACE were enrolled in the case group (n = 69), and patients in follow-up or awaiting treatment were enrolled in the control group (n = 20). TACE was performed with doxorubicin (20-60 mg) and lipiodol (2-20 mL). RESULTS: Three (4.3%) patients in the TACE group and 2 (10%) patients in the control group showed HBV reactivation (p= 0.334). A twofold or more increase in serum HBV DNA was detected in 21 (30.4%) patients in the TACE group and 4 (20%) patients in the control group (p= 0.361). Exacerbation of viral hepatitis B was found in 4 (5.8%) patients in the TACE group and no patients in the control group, but the difference between the two rates was not statistically significant (p= 0.271). Three of the four reactivated patients showed spontaneous recovery within 1 month, and one showed tumor-progression-related exacerbation. CONCLUSIONS: One session of TACE using doxorubicin and lipiodol does not significantly aggravate HBV hepatitis in patients with HBV-related HCC.     

原发性肝癌局部化疗后肝炎及乙型肝炎抗病毒治疗的临床研究

目的分析肝癌化疗后肝炎发生的病因,探讨核苷类似物抗病毒治疗对化疗后乙肝病毒再激活肝炎疗效。方法收集明确诊断乙型肝炎后肝细胞癌患者120例,男108例,女12例,年龄28~85岁,平均（53.88±12.16）岁。肝癌患者均接受1次经导管肝动脉化疗栓塞（TACE）治疗;并分为抗病毒治疗组35例;未行抗病毒治疗组85例。抗病毒组中TACE前2周23例服拉米夫定;12例服阿德福韦酯,维持抗病毒治疗TACE后4周为观察终点。随访4周后,监测2组患者TACE前后肝功能及HBV载量水平变化和肝炎发生情况,观察核苷类似物抗病毒治疗HBV再激活肝炎的疗效。结果肝细胞癌患者化疗后HBV再激活33例,化疗后未再激活87例,HBV再激活发生率为27.50%。HBV再激活肝炎23例,发生率为69.70%;化疗药物性肝炎11例,发生率为12.64%,2种肝炎的发生之间差异有统计学意义（P=0.00）。抗病毒治疗组与未抗病毒组之间HBV再激活肝炎的发生差异有统计学意义（2χ=5.78,P〈0.05）,2组间药物性肝炎的发生差异无统计学意义。结论肝细胞癌化疗后发生HBV再激活肝炎和化疗药物性肝炎;HBV再激活肝炎的发生较化疗药物性肝炎多。核苷类似物（拉米夫定/阿德福韦酯）抗病毒治疗可明显降低肝细胞癌患者化疗后HBV再激活肝炎的发生。     

Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

Clinical outcome of 251 patients with extrahepatic metastasis at initial diagnosis of hepatocellular carcinoma: Does transarterial chemoembolization improve survival in these patients?

Background and Aims: The therapeutic efficacy of transarterial chemoembolization (TACE) has not been evaluated in hepatocellular carcinoma (HCC) patients with extrahepatic metastasis. We investigated the efficacy of TACE with/without systemic chemotherapy (s‐chemo) in these patients. Methods: We performed a survival analysis of consecutive HCC patients with extrahepatic metastasis, diagnosed at initial presentation according to treatment modality after stratification, using the Child–Pugh classification and intrahepatic HCC T stage, retrospectively. Results: Between 2005 and 2007, 251 patients were newly diagnosed with HCC involving extrahepatic metastasis at our institution. Among those, 226 were classified as Child–Pugh A–B and the other 25, Child‐Pugh C. Within the Child–Pugh A–B group, repeated TACE or transarterial chemoinfusion (TACI) was performed with/without s‐chemo in 171 patients. Eight of 226 received s‐chemo alone, and 47, conservative management (CM) alone. The median survival time of patients treated with TACE/TACI with s‐chemo, TACE/TACI alone, and CM was 10, 5, and 2.9 months in patients classified as Child–Pugh A and T3‐stage HCC (TACE/TACI with s‐chemo vs CM, P = 0.0354; TACE/TACI alone vs CM, P = 0.0553) and 7.1, 2.6, and 1.6 months in Child–Pugh B and T3‐stage patients, respectively (TACE/TACI with s‐chemo vs CM, P = 0.0097; TACE/TACI alone vs CM, P < 0.0001). Individual treatment with TACE/TACI or sorafenib showed independent prognostic significance in the multivariate analysis. Conclusion: Repeated TACE could show significant survival benefits in metastatic HCC patients with conserved liver function and intrahepatic HCC T3 stage. The survival data of our study could be used as a historical control for TACE monotherapy in future clinical trials evaluating combination treatments containing TACE in these patients.     

Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long‐time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment‐naïve and had begun a 7‐year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real‐time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg‐negative rates also increased. After 48 weeks’ NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA‐positive. After 7 years of treatment, more HBV pgRNA‐negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA‐positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA‐positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75‐31.08). The median time to HBeAg clearance in the HBV pgRNA‐positive patients was longer than that of the HBV pgRNA‐negative patients (152 weeks vs 72 weeks). The HBV pgRNA‐positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33‐144.67 vs 48 weeks, 95% CI: 34.80‐61.20). The HBV pgRNA status after NA treatment can predict the long‐term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA‐positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.     

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.     

Hepatitis B virus genotype B results in better immediate, late and sustained responses to peginterferon-alfa in hepatitis-B-e-antigen-positive patients

Background and Aims: This study investigated outcome predictors in hepatitis‐B‐e‐antigen (HBeAg)‐positive chronic hepatitis B patients treated with peginterferon alfa‐2a. Methods: A total of 88 HBeAg‐positive patients receiving peginterferon alfa‐2a for 6 months and followed up for at least 24 weeks were prospectively analyzed. Precore and core promoter genes of hepatitis B virus (HBV) were sequenced from the serial serum samples of 88 patients. Results: After 24 weeks of follow up, 38.6% and 28.4% of patients achieved HBeAg clearance and combined response, respectively. Multivariate analysis disclosed that pretreatment HBeAg sample to cut‐off (S/Co) ratio ≤ 200, alanine aminotransferase > 200 IU/mL, HBV genotype B and T1846 were independent factors for HBeAg clearance, and HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for combined response. HBeAg S/Co ratio ≤ 10 at week 12 of therapy was the useful factor for treatment response and had a greater power (P = 0.012) to predict HBeAg clearance than HBV DNA. Patients with HBeAg clearance had a higher frequency of A1896 mutation at baseline and during therapy than those without HBeAg clearance, and the frequency of A1896 decreased during treatment. During follow up, delayed HBeAg seroconversion and reactivation of HBV after HBeAg clearance were observed in eight non‐responders and 20 patients with HBeAg clearance, respectively. HBV genotype B was a significant factor to predict both responses. Conclusions: Pretreatment HBeAg S/Co ratio ≤ 200 and HBV genotype B were major determinants for treatment response to peginterferon. Genotype‐B‐infected patients had higher probability of delayed HBeAg clearance and sustained response. Rapid decrease of HBeAg titer was useful on treatment predictor.