Efficacy of Prophylactic Entecavir for Hepatitis B Virus- Related Hepatocellular Carcinoma Receiving Transcatheter Arterial Chemoembolization

Background and Aims: Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE. Methods: A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints. Results: Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation. Conclusion: Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients.     

原发性肝癌三维适形放疗致乙型肝炎病毒再激活相关研究

目的：探讨原发性肝癌患者中三维适形放疗（three dimensional conformal radiotherapy,3D-CRT）致乙型肝炎病毒（HBV）再激活的相关因素。方法入组56例接受3D-CRT治疗的原发性肝癌患者为研究对象,并按放疗后是否接受抗病毒治疗分为A组（抗病毒治疗组,32例）和B组（未接受抗病毒治疗组,24例）。统计HBV再激活率、HBV再激活危险因素、HBV再激活相关性肝炎、丙氨酸氨基转移酶（alanine aminotransferase, ALT）升高情况、肝功能损伤程度、放射性肝损伤（radiation-induced liver disease,RILD）发生率及转归等情况。结果3D-CRT治疗后12周,A组患者的HBV再激活率低于B组（13.64%vs 41.67%）,差异有统计学意义（P＜0.05）;两组ALT升高2倍的患者比例的差异无统计学意义（P＞0.05）;A组再激活相关性肝炎发生率低于B组（6.25% vs 25.0%）,差异有统计学意义（P＜0.05）;两组患者的肝功能损伤程度的差异无统计学意义（P＞0.05）;随访3个月时A组和B组的RILD发生率（6.25%vs 16.67%）的差异无统计学意义（P＞0.05）。B组患者中,HBV再激活患者和HBV未激活患者的Child-Pugh分级构成、HBV DNA水平的差异差异均具有统计学意义（均P＜0.05）。结论3D-CRT技术是治疗肝癌的重要方案,HBV再激活及RILD是肝癌3D-CRT治疗时较为常见的并发症,3D-CRT治疗后的抗病毒治疗可以降低HBV再激活率及HBV再激活相关性肝炎的发生率。     

拉米夫定预防B细胞非霍奇金淋巴瘤患者利妥昔单抗化疗后乙型肝炎病毒再激活的临床分析

 【摘要】　目的　研究利妥昔单抗联合化疗治疗B细胞非霍奇金淋巴瘤（B-NHL）合并乙型肝炎病毒（HBV）携带患者的安全性,探讨拉米夫定预防性治疗的价值。方法　回顾性分析含利妥昔单抗联合化疗前后B-NHL患者乙型肝炎五项、HBV-DNA和肝功能指标变化。将39例HBV核心抗体（HBcAb）（+）／HBV表面抗体（HBsAb）（-）的B-NHL患者分为拉米夫定预防组和对照组,比较两组化疗后HBV再激活、肝功能损害等指标。结果　108例接受利妥昔单抗联合化疗的B-NHL患者中,15例患者为HBV表面抗体（HBsAg）（+）,占所有患者的13.89 %;39例为HBsAg（-）／HBcAb（+）患者,占所有患者的36.11 %。15例HBsAg（+）的患者中HBV再激活率为13.3 %,13例拉米夫定预防患者中1例（7.7 %）HBV再激活,2例未预防的患者中1例HBV再激活。39例HBsAg（-）／HBcAb（+）患者中HBV再激活率为7.7 %（3例）,14例拉米夫定预防组HBV再激活率为0,25例未预防的患者中3例（12 %）HBV再激活。结论　B-NHL合并HBV携带患者在利妥昔单抗联合化疗导致HBV再激活的风险是可控的,预防性使用拉米夫定能明显降低HBV再激活。     

Hepatitis B virus reactivation after radiofrequency ablation or hepatic resection for HBV-related small hepatocellular carcinoma: A retrospective study

Background and purpose

Reactivation of hepatitis B virus (HBV) happens after systemic chemotherapy, transarterial chemoembolization (TACE) or hepatic resection for HBV-related hepatocellular carcinoma (HCC) patients. The incidence and risk factors of HBV reactivation after radiofrequency ablation (RFA) are unclear.

Patients and methods

From August 2006 to August 2011, 218 consecutive patients with HBV-related small HCC treated with RFA (n = 125) or hepatic resection (n = 93) were retrospectively studied. The incidence of HBV reactivation and risk factors were analyzed.

Results

HBV reactivation developed in 20 (9.2%) patients after treatment. The incidence of HBV reactivation was significantly lower in the RFA group (5.6%, 7/125) than the hepatic resection group (14.0%, 13/93, P = 0.034). On univariate and multivariate analyses, no antiviral therapy (OR 11.7; 95% CI 1.52–90.8, P = 0.018) and treatment with RFA/hepatic resection (OR3.36; 95% CI 1.26–8.97, P = 0.016) were significant risk factors of HBV reactivation. On subgroup analysis, the incidence of HBV reactivation was lower in patients who received antiviral therapy than those who did not receive antiviral therapy in both the hepatic resection group (2.9% vs. 20.7%, P = 0.027) and the RFA group (0% vs. 7.6%, P = 0.188), although the difference was not significant in the latter group.

Conclusion

The incidence of HBV reactivation after RFA was relatively low when compared with hepatic resection. Prophylactic antiviral therapy is recommended, especially for patients who are going to receive hepatic resection for HBV-related HCC to decrease the incidence of post-treatment HBV reactivation.     

长、短疗程口服抗病毒药预防急性髓系白血病患者乙型肝炎病毒再激活的观察研究

背景与目的：乙型肝炎病毒(hepatitis B virus,HBV)再激活是急性髓系白血病(acute myeloid leukemia,AML)合并HBV感染的患者接受诱导和巩固化疗期间严重并发症之一,核苷类抗HBV药物(包括拉米夫定和恩替卡韦等)已成为预防和抢先治疗HBV再激活主要抗病毒药物。该研究观察并探究AML合并HBV感染患者化疗前后长疗程和短疗程口服核苷类抗HBV药物预防病毒再激活的临床疗效和安全性。方法：回顾性分析29例AML合并HBV感染并接受至少4个疗程化疗患者的临床资料。根据患者口服核苷类抗HBV药物预防治疗前HBV表面抗原(hepatitis B surface antigen,HBsAg)含量以及抗HBV药物持续服用时间分为4个亚组,系统分析和比较不同亚组患者HBV再激活情况和药物不良反应。结果：长疗程预防(long course prophylaxis group,LCP)组,即口服抗HBV药物持续至化疗结束后6个月以上,该组患者的HBV再激活率和HBV相关性肝炎发生率分别为5.56%(1/18)和0%(0/18),明显低于短疗程预防(short course prophylaxis group,SCP)组患者(即口服抗HBV药物持续至化疗结束后1个月以内)的45.45%(5/11)和36.36%(4/11),差异有统计学意义(P=0.018和P=0.014),而LCP和SCP组患者的HBV原发耐药率分别为11.11%(2/18)和9.09%(1/11),差异无统计学意义(P>0.05)。进一步亚组分析显示,预防治疗前HBsAg阳性患者(HBsAg大于等于0.05 IU/mL)经长疗程预防,其HBV再激活率和HBV相关性肝炎发生率分别为8.33%(1/12)和0%(0/12),明显低于SCP组,66.67%(4/6)和66.67%(4/6),差异有统计学意义(P=0.022和P=0.005);同时,LCP和SCP组中HBsAg(+)患者的HBV原发耐药率分别为8.33%(1/12)和16.67%(1/6),差异无统计学意义(P>0.05)。此外,LCP组中HBsAg阴性患者(HBsAg小于0.05 IU/mL)的HBV再激活率、肝炎发生率和原发耐药率与SCP组中HBsAg(-)患者比较,差异无统计学意义(P>0.05)。LCP和SCP组患者均未发生3级以上药物毒性反应。结论：长疗程口服核苷类抗HBV药物是降低AML合并HBsAg(+)感染患者化疗后病毒再激活以及病毒相关事件发生率有效而且安全性良好的预防治疗方案。     

Why, when, and how to prevent hepatitis B virus reactivation in cancer patients undergoing chemotherapy

Hepatitis B virus (HBV) reactivation is a serious clinical problem in HBV carriers undergoing chemotherapy. The clinical course of HBV reactivation can be separated into 2 phases: 1) an increase in HBV replication and 2) hepatic injury. Patients with resolved HBV infections (negative for hepatitis B surface antigen [HBsAg], and positive for both hepatitis B core antibody [anti-HBc] and/or hepatitis B surface antibody) can experience HBV reactivation, and Western guidelines recommend that not only HBsAg but also anti-HBc be screened before initiation of chemotherapy or immunosuppressive therapy. Several meta-analyses have repeatedly confirmed the prophylactic role of lamivudine in preventing HBV reactivation. In conclusion, screening for HBV is required before chemotherapy, and prophylactic antiviral therapy can reduce not only the incidence of HBV reactivation but also HBV-related morbidity and mortality.     

术前抗病毒治疗对HBV-DNA 阴性肝细胞癌患者术后病毒再激活及肝功能的影响*

目的:评估术前抗病毒治疗对术后乙肝病毒再激活以及肝功能的影响。方法:2012年7 月至2016年3 月将广西医科大学附属肿瘤医院肝胆胰脾外科乙肝病毒DNA 阴性的HCC 患者分成抗病毒组（66例）及对照组（108 例）,抗病毒组术前给予恩替卡韦分散片抗病毒治疗,对照组未给予抗病毒治疗。统计分析术后HBV 再激活及肝功能指标变化情况。结果:抗病毒组HBV 激活率为3%（2/ 66）,对照组为27.8%（30/ 108）。 多因素分析显示小部分肝切术（HR= 4.695;95%CI:1.257- 17.537,P = 0.021）及术前未抗病毒治疗（HR= 8.164;95%CI:1.831- 36.397,P = 0.006）是术后HBV 再激活的危险因素。抗病毒组与未抗病毒组,激活组与未激活组术后7 天内肝功能指标差异无统计学意义（P > 0.05）,术后30天比较,ALT 及ALB 差异有统计学意义（P < 0.05）。 结论:对于DNA阴性的HCC 患者,肝切除术可导致HBV 再激活,术前抗病毒治疗能有效降低HBV 再激活风险及保护肝功能。      

Hepatitis B virus reactivation in hepatocellular carcinoma patients undergoing transcatheter arterial chemoembolization therapy

Aim: The effect of transcatheter arterial chemoembolization (TACE) therapy on hepatitis B virus (HBV) reactivation in hepatocellular carcinoma (HCC) patients with prior resolved hepatitis B is not fully understood. Methods: From January 2006 to December 2010, 43 hepatitis B surface antigen (HBsAg)‐negative/anti‐hepatitis B core antigen (HBc) positive patients with newly diagnosed unresectable HCC were enrolled in the study. All underwent TACE therapy. Results: Four patients (9.3%) developed HBV reactivation with mild/moderate hepatitis. The median number of TACE cycles received was 3.5 (range 3–4 cycles). The median time interval between the occurrence of HBV reactivation and the completion of TACE therapy was 3 months (range 1–5 months) and their median HBV DNA level was 1.58 × 10⁴ IU/mL (range, 1.65 × 10³–6.42 × 10⁴ IU/mL). After the introduction of lamivudine at the occurrence of HBV reactivation, all had resolution of hepatitis. An exploratory analysis indicated that significant predictors of HBV reactivation included increased serum total bilirubin coexisting with cirrhosis and the total number of cycles of TACE received. Conclusion: The administration of TACE therapy may increase the risk of HBV reactivation in HBsAg‐negative/anti‐HBc‐positive patients diagnosed with unresectable HCC. Further studies are warranted to explore the optimal management of HBV reactivation in patients with prior resolved hepatitis B.     

Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy.

BACKGROUND: Cancer patients who are hepatitis B virus (HBV) carriers and undergoing chemotherapy (CT) may be complicated by HBV reactivation. Over 80% of hepatocellular carcinoma (HCC) patients are HBV carriers; however, the incidence of HBV reactivation during CT has not been well-reported. A prospective study was conducted to determine the incidence of HBV reactivation, the associated morbidity and mortality, and possible risk factors. PATIENTS AND METHODS: 102 HBsAg-positive patients with inoperable HCC underwent systemic CT. Patients received either combination cisplatin, interferon, doxorubicin and fluorouracil (PIAF) or single-agent doxorubicin. They were followed up during and for 8 weeks after CT. RESULTS: In 102 patients, 59 (58%) developed hepatitis amongst whom 37 (36%) were attributable to HBV reactivation. Twelve (30%) died of HBV reactivation. CT was interrupted in 32 patients (86%) with reactivation and 54 (83%) without reactivation (P>0.05). The median survivals were 6.00 and 5.62 months, respectively (P=0.694). Elevated baseline alanine aminotransferase (ALT) was found to be a risk factor. CONCLUSION: HBV reactivation is a common cause of liver damage during CT in HBsAg-positive HCC patients. The only identifiable associated risk factor was elevated pre-treatment ALT. Further studies into the role of antiviral and novel anticancer therapies are required to improve the prognosis of these patients.     

Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy.

PURPOSE: For cancer patients receiving cytotoxic chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during chemotherapy. PATIENTS AND METHODS: Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing chemotherapy. The historical controls consisted of 193 consecutive patients who underwent chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. RESULTS: In the controls, lymphoma and anthracycline usage were factors identified to be associated with reactivation. The two groups were comparable in most baseline characteristics, although in the prophylactic lamivudine group, there were significantly more patients with lymphoma and receiving anthracyclines. In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P <.001), fewer incidences of hepatitis (17.5% v 44.6%; P <.0001) that were less severe (4.8% v 18.7%; P =.0005), and less disruption of chemotherapy (15.4% v 34.6%; P =.0029). The reduction in overall mortality was not statistically different. CONCLUSION: Prophylactic lamivudine significantly reduced the incidence of HBV reactivation and the overall morbidity of cancer patients undergoing chemotherapy.     

原发性肝癌精确放疗致乙型肝炎病毒再激活分析

目的 探讨原发性肝癌(PLC)患者精确放疗后乙型肝炎病毒(HBV)再激活的临床特点,并分析其危险因素。
方法 回顾分析69例HBsAg阳性PLC患者行精确放疗并发HBV再激活的临床特点。所有患者放疗前均做基线血常规、肝功能、肾功能、甲胎蛋白、HBV标志物、HBV DNA定量测定。放疗中及后血常规检查每2周检测1次,肝功能、甲胎蛋白、HBV标志物、HBV DNA定量测定每4周检测1次,持续至放疗完成后至少12周。Logistic法评估临床各项指标对HBV再激活的影响。
结果 69例中发生放射性肝病12例(17%),HBV再激活发生17例(25%),HBV再激活相关肝炎发生15例(22%)。Logistic法评估结果显示基线血清HBV DNA水平为HBV再激活发生的危险因素。
结论 PLC患者精确放疗后可引起HBV再激活,基线血清HBV DNA水平为其独立危险因素。发生HBV再激活相关肝炎患者即使及时采用抗病毒治疗预后仍不良。     

拉米夫定结合胸腺肽治疗对合并活动性肝炎肝癌术后复发的影响

目的　观察拉米夫定结合胸腺肽治疗对合并活动性肝炎肝癌术后复发的影响。方法33例合并活动性肝炎的肝癌随机分为两组 :对照组 17例 ,为单纯手术切除 ;治疗组 16例 ,为手术切除加术后拉米夫定结合胸腺肽治疗。观察两组的乙型肝炎病毒DNA(HBV DNA)清除率、乙型肝炎e抗原 (HBeAg)转阴率、复发时间和生存时间。结果　治疗组和对照组比较 ,1年后HBV DNA清除率分别为 10 0 .0 %和 6 .0 % (P <0 .0 1) ,HBeAg转阴率分别为 6 2 .5 %和 5 .9% (P <0 .0 5 ) ,1年肿瘤复发率分别为 81.3%和 95 .5 % (P >0 .0 5 ) ,中位复发时间分别为 7.0个月和 5 .0个月 (P <0 .0 1) ,中位生存时间分别为 10 .0个月和 7.0个月 (P <0 .0 1)。结论　拉米夫定结合胸腺肽治疗有助于合并活动性肝炎的肝癌患者术后清除病毒复制 ,延迟肿瘤复发 ,提高患者生存时间。     

Hepatitis B Virus DNA Negativity Acts as a Favorable Prognostic Factor in Hepatocellular Carcinoma Patients

Background: This retrospective study was aimed to investigate the efficacy of prophylactic agents inhepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine andentecavir. Materials and Methods: A consecutive series of 203 HBV-related HCC patients receiving TACE wereanalyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBVDNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation andprogression free survival (PFS) were the main endpoints. Results: Some 48 (69.6%) reached virologic response.Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%,p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as comparedto those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significantvariables associated with virologic events. In addition, prophylaxis was the only independent protective factor forhepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver ItalianProgram score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudinedemonstrated similar efficacy as entecavir. Conclusions: Prophylactic agents are efficacious for prevention ofHBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayeda significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA andhepatitis B flares might be causes of tumor progression in these patients.     

Prophylactic use of lamivudine for hepatitis B exacerbation in post-operative breast cancer patients receiving anthracycline-based adjuvant chemotherapy

Background:

With the increasing incidence of breast cancer worldwide, in particular in southeast Asia (including Korea), and the common use of anthracyclines in the adjuvant and metastatic settings, the occurrence of Hepatitis B virus (HBV) reactivation may develop in this patient population. The use of prophylactic antiviral agents in cancer patients may result in a reduced HBV exacerbation. The purpose of the current study was to assess the efficacy of prophylactic lamivudine in reducing the incidence and severity of HBV reactivation in post-operative breast cancer patients undergoing adjuvant doxorubicin-containing chemotherapy.

Methods:

The medical records of patients undergoing anthracycline-based adjuvant chemotherapy at Samsung Medical Center between January 2001 and September 2008 were reviewed.

Results:

From the database, 1912 breast cancer patients who had received anthracycline-based adjuvant chemotherapy were identified. Of 131 patients who were HBV surface antigen positive, 55 and 76 did and did not receive prophylactic lamivudine, respectively. In all, 30 patients (23%) developed hepatitis during doxorubicin-containing adjuvant chemotherapy. Of the 30 patients, 5 (9%) were in the prophylactic lamivudine group and 25 (33%) in the control group (P=0.001). In the prophylactic lamivudine group, there was significantly less HBV reactivation (1 patient (2%) vs 20 patients (16%); P=0.002), less disruption of chemotherapy (7 vs 14% P=0.04), and less severe hepatitis (0 vs 17% P=0.002).

Conclusion:

Prophylactic lamivudine significantly reduced the incidence and severity of HBV reactivation in breast cancer patients undergoing anthracycline-based adjuvant chemotherapy.     

Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: Analysis from the Asia Lymphoma Study Group

BackgroundHepatitis B virus (HBV) reactivation is increasing, as rituximab has become widely used for B-cell lymphoma. Thus, prevention and management of HBV reactivation are important in HBV-endemic areas.MethodsHepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-positive patients and HBsAg-negative/HBV core antibody (HBcAb)-positive patients who received rituximab-containing chemotherapy was investigated by the Asia Lymphoma Study Group via retrospective (n = 340), and the results were compared to cross-sectional analysis with patients who were prospectively monitored in a single institute (n = 127). The goal of the study was to define the frequency of HBV reactivation and the efficacy of antiviral prophylaxis.ResultsHBV reactivation was found in 27.8% of HBsAg-positive patients (45/162) in the retrospective analysis, being significantly less frequent in patients receiving antiviral prophylaxis than those not (22.9%, 32/140 versus 59.1%, 13/22; p < 0.001). Lamivudine was most commonly used (96/162, 59.3%), but more than 20% of HBsAg-positive patients showed breakthrough HBV reactivation. In the cross-sectional analysis, a reduced rate of HBV reactivation occurred for entecavir as compared with lamivudine prophylaxis (6.3% versus 39.3%; p < 0.05). HBV DNA monitoring of HBsAg-negative/HBcAb-positive patients in the cross-sectional analysis showed HBV reactivation in only 2.4% of cases.ConclusionsThis is the largest study of HBV reactivation in patients receiving rituximab-containing chemotherapy to date, and we defined the probability of HBV reactivation in an HBV-endemic region.     

Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma

This study investigated whether conformal radiotherapy affects hepatitis B virus (HBV) reactivation, and the risk factors for HBV reactivation in patients with HBV‐related hepatocellular carcinoma (HCC). Sixty‐nine patients with HCC were included in this retrospective study. Before radiotherapy (RT), all patients underwent imaging examinations and some baseline examinations, including CBC, liver function test, renal function test, α‐fetoprotein level, hepatitis B (HB) surface antigen, HB surface Ab, HB e antigen, HB e Ab, and serum HBV DNA quantification. During the period of RT and at least 16 weeks after the end of RT, CBCs were carried out weekly and the other tests were monitored monthly or more frequently if necessary. The clinical features and dosimetric parameters of RT were recorded. Univariate and multivariate logistic regression algorithms were used to analyze the risk factors of HBV reactivation. The incidence of complications in the study population was as follows: radiation‐induced liver disease, 17.4%; HBV reactivation, 24.6%; and HBV reactivation‐induced hepatitis, 21.7%. The HBV DNA level and dose volume parameters including normal liver volume, V20, and mean dose were associated with HBV reactivation. There was a relatively high incidence of HBV reactivation in HCC patients after the end of conformal RT. The serum HBV DNA level and some dosimetric parameters related to normal liver, including normal liver volume, V20, and mean dose, were the prognosis factors of HBV reactivation and should be carefully considered before conformal RT.     

Radiation-induced hepatitis B virus reactivation in liver mediated by the bystander effect from irradiated endothelial cells.

PURPOSE: Hepatitis B virus (HBV) reactivation is one unique pathogenesis in Asian carriers with liver toxicity after radiotherapy for hepatobiliary malignancies. This study attempts to delineate the biological mechanism of radiation-induced HBV reactivation. EXPERIMENTAL DESIGN: Primary cultures of hepatocytes (PCC) were prepared from the noncancerous liver tissue removed perioperatively from 12 HBV carriers with hepatocellular carcinoma (HCC). The conditioned medium of irradiated PCCs, HCC, and endothelial cells from patients was transferred to PCCs or HepG2.2.15 cells (a human hepatoblastoma cell line transfected with HBV DNA) before subsequent irradiation. Forty-eight hours after irradiation, HBV DNA was measured by real-time quantitative PCR. Specific cytokines were determined by cytokine array and ELISA analysis. Preradiotherapy and postradiotherapy sera from 10 HBV carriers and 16 non-HBV carriers were analyzed for viral loads and cytokine activities. RESULTS: Radiation induced HBV DNA replication in (a) irradiated PCCs cultured with the conditioned medium from irradiated PCCs (2.74-fold; P=0.004) and endothelial cells (9.50-fold; P=3.1x10(-10)), but not from HCCs (1.07-fold), and in (b) irradiated HepG2.2.15 cells (17.7-fold) cocultured with human umbilical vascular endothelial cells. Cytokine assay revealed increased expression of interleukin-6 (IL-6) in conditioned medium from irradiated human umbilical vascular endothelial cells. All 16 patients with liver irradiated had the increased serum IL-6 compared with 3 of 10 patients with irradiation excluding liver (P<0.001). All nine HBV carriers with liver irradiated had postradiotherapy increases in both HBV DNA and IL-6. CONCLUSIONS: Radiation-induced liver toxicity with HBV reactivation is from a bystander effect on irradiated endothelial cells releasing cytokines, including IL-6.     

Type 2 diabetes and hepatocellular carcinoma: a case-control study in patients with chronic hepatitis B

Type 2 diabetes has been suggested as an independent risk factor for the development of hepatocellular carcinoma (HCC). However, the role of Type 2 diabetes on the development of HCC in the presence of chronic hepatitis B (CHB) remains inconclusive. We conducted this hospital-based case-control study to evaluate the roles of Type 2 diabetes in HCC development in patients with CHB. From January 2004 to December 2008, a total of 6,275 eligible consecutive patients with chronic hepatitis B virus (HBV) infection were recruited. A total of 1,105 of them were patients with HBV-related HCC and 5,170 patients were CHB but without HCC. We used multivariate logistic regression models to investigate the association between Type 2 diabetes and HCC risk. The prevalence of Type 2 diabetes is higher among HCC patients without cirrhosis than among those with cirrhosis (12.1% vs. 6.7%, p=0.003). Type 2 diabetes was associated with a significantly high risk of HCC in female patients after adjusting for age, family history of HCC, city of residence, hepatitis B e antigen and cirrhosis with an odds ratio (95% confidence interval, CI) of 1.9 (1.1-3.4). Restricted analyses among female patients without cirrhosis indicated that Type 2 diabetes was strongly associated with HCC risk with adjusted odds ratio (95% CI) of 5.6 (2.2-14.1). In conclusion, Type 2 diabetes is independently associated with the increased risk of HCC in female CHB patients. Female CHB patients with Type 2 diabetes are of a high HCC risk population and should be considered for HCC close surveillance program.     

Association of type 2 diabetes mellitus with incidences of microvascular invasion and survival outcomes in hepatitis B virus-related hepatocellular carcinoma after liver resection: A multicenter study

BackgroundMicrovascular invasion (MVI) adversely affects long-term survival in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study aimed to examine the association between preoperative type 2 diabetes mellitus (T2DM) with incidences of MVI and prognosis in HBV-related HCC after liver resection (LR).Material and methodsData of HBV-related HCC patients who underwent LR as an initial therapy from four hospitals in China were retrospectively collected. Clinicopathological factors associated with the incidence of MVI were identified using univariate and multivariate logistic regression analysis. The recurrence-free survival (RFS) and overall survival (OS) curves between different cohorts of patients were generated using the Kaplan-Meier method and compared using the log-rank test.ResultsOf 1473 patients who were included, 219 (14.9%) patients had T2DM. Preoperative T2DM, HBV DNA load, antiviral treatment, AFP level, varices, and tumor encapsulation were identified to be independent predictors of the incidence of MVI. Patients with HBV-related HCC and T2DM had a higher incidence of MVI (65.8%) than those without T2DM (55.4%) (P = 0.004). The RFS and OS were significantly worse in patients with T2DM than those without T2DM (median RFS: 11.1 vs 16.7 months; OS: 26.4 vs 42.6 months, both P < 0.001). Equivalent results were obtained in HCC patients with MVI who had or did not have T2DM (median RFS: 10.0 vs 15.9 months; OS: 24.5 vs 37.9 months, both P < 0.001).ConclusionsPreoperative T2DM was an independent risk factor of incidence of MVI. Patients with HBV-related HCC and T2DM had worse prognosis than those without T2DM after LR.     

The effect of prophylactic lamivudine on hepatitis B virus reactivation in HBsAg-positive patients with diffuse large B-cell lymphoma undergoing prolonged rituximab therapy

The association of prolonged rituximab therapy and hepatitis B virus (HBV) reactivation in diffuse large B-cell lymphoma (DLBCL) and the role of lamivudine prophylaxis remain undefined. The prevalence and mortality of HBV reactivation in HBsAg-positive patients with DLBCL undergoing rituximab-based treatment, who received prophylactic treatment with or without lamivudine, were retrospectively analyzed. From January 2003 to December 2009, there were 50 patients enrolled in the study, among of which 30 received the prophylactic treatment of lamivudine and 20 without prophylactic treatment of lamivudine. Among of the 50 patients, seven patients received further rituximab maintenance, once every 3 months for 2 years. Compared with lamivudine treatment group, it showed that there was significantly higher prevalence of HBV reactivation (60.0% vs 13.3%, P = .001), severe hepatitis (45.0% vs 6.7%, P = .004), and mortality (25.0% vs 3.3%, P = .032) in non-lamivudine prophylactic group; however, there was no statistically significant difference in the HBV DNA levels at reactivation (3.94 × 10⁶ vs 8.30 × 10⁵ copies/ml, P = .47) and the time from first dose of rituximab to HBV reactivation(207 vs 386 days, P = .28). For patients undergoing further rituximab maintanence treatment, the prevalence and mortality of HBV reactivation were 71.4 and 28.6%, respectively. The prevalence and mortality of HBV reactivation are 66.7% vs 75.0% (P = 1.00) and 0 vs 50.0% (P = .43) in lamivudine prophylactic and non-lamivudine prophylactic groups, respectively. The effect of lamivudine prophylaxis on preventing HBV reactivation was found to be less in patients undergoing longer duration of rituximab treatment. A longer duration of rituximab treatment contributed to higher morbidity and mortality of HBV reactivation in HbsAg-positive patients with DLBCL. Further study is warranted for the optimal management of hepatitis caused by HBV reactivation