Carriers of inactive hepatitis B virus are at increased risk of hepatocellular carcinoma and liver-related death, compared with noncarriers, findings from a large, prospective cohort study suggest, reported Dr. Jin-De Chen and colleagues in an article in the May issue of Gastroenterology.

The annual incidence rates of hepatocellular carcinoma and liver-related death in 20,069 participants in the study, which had a mean follow-up of more than 13 years, were 0.06% and 0.04%, respectively, among 1,932 carriers of inactive hepatitis B virus (HBV). The annual incidence rates were 0.02% for hepatocellular carcinoma and 0.02% for liver-related death among 18,137 controls, wrote Dr. Jin-De Chen of National Taiwan University Hospital, Taipei, and colleagues.

Multivariate-adjusted hazard ratios for carriers, compared with controls, were 4.6 and 2.1 for hepatocellular carcinoma and liver-related death, respectively, the investigators reported (Gastroenterology [doi: 10.1053/j.gastro.2010.01.042]).

The authors used data from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL–HBV) Study for their analysis. Inactive HBV carriers were those who had seronegative hepatitis B e antigen status, anti–hepatitis C virus (HCV)-seronegative status, serum levels of HBV DNA less than 10,000 copies/mL without cirrhosis, hepatocellular carcinoma, or increased serum alanine transaminase (ALT) levels. Controls were participants who were seronegative for HB surface antigen and antibodies against HCV, but who had similar clinical liver features (normal serum ALT, without cirrhosis or hepatocellular carcinoma at study entry). Together, the groups contributed 262,122 person-years of follow-up.

Significant predictors of hepatocellular carcinoma in the entire cohort, compared with controls, were older age (hazard ratio of 2.7/10-year increment), high-normal baseline ALT level (HR 2.2), and alcohol drinking habit (HR 2.4). Significant predictors in inactive HBV carriers, compared with controls, were older age (HR 2.6/10-year increment) and drinking habit (HR 3.7).

The risk of hepatocellular carcinoma was higher in those with baseline serum HBV DNA levels of 300-10,000 copies/mL, compared with those with undetectable serum HBV DNA at baseline, but the difference did not reach statistical significance (HR 1.6). In inactive carriers with undetectable serum HBV DNA at baseline, alcohol drinking habit was a significant predictor of hepatocellular carcinoma (HR 6.9).

Significant predictors of liver-related death in the entire cohort, compared with controls, were similar to those for hepatocellular carcinoma, and included older age (HR 2.3/10-year increment), high-normal baseline serum ALT level (HR 1.9) and alcohol drinking habit (HR 2.1). Among inactive HBV carriers, only older age (HR 2.6/10-year increment) and alcohol drinking habit (HR 5.8) were significant predictors.

The inclusion of hepatocellular carcinoma as a time-dependent event in the analysis revealed that it was the most striking risk predictor for liver-related death (HR 611 for the entire cohort, and 451 for inactive HBV carriers), as would be expected, the investigators noted.

In those without newly developed hepatocellular carcinoma, older age (HR 2.0/10-year increment) and alcohol drinking habit (HR 2.3) were significant risk factors for liver-related death; in inactive carriers without hepatocellular carcinoma, only older age was a significant predictor (HR 2.4).

No significant differences were seen in the development of hepatocellular carcinoma or liver-related death between inactive carriers with undetectable and detectable serum HBV DNA, the investigators noted.

The study is limited by a lack of histologic data, since liver biopsies were not applicable in the large community-based study. Also, serial HBV DNA measurements were not taken to assess for continued inactive carriage, and other risk factors, such as HBV genotypes, were not assessed in those with HBV DNA levels greater than 100,000 copies/mL to determine an association with hepatocellular carcinoma in inactive carriers.

Future studies that include serial measurement of hepatitis B surface antigen serostatus and serum HBV DNA levels would help clarify the natural history of inactive HBV carriage, they concluded.

This study received grant support from Bristol-Myers Squibb Co.; Department of Health, Executive Yuan, National Health Research Institutes, Taiwan; and Academia Sinica, Taiwan. The investigators reported that there were no financial or other disclosures related to the study.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

Jin-De Chen博士及其同事进行的一项大规模前瞻性队列研究发现，非活动性乙肝病毒(HBV)携带者发生肝细胞癌和肝脏相关死亡的风险高于非携带者。该研究发表于《胃肠病学》(Gastroenterology) 5月刊。

 

台北台大医院的Jin-De Chen博士及其同事表示，该研究对20,069名受试者平均随访13年以上发现，1,932名非活动性HBV携带者的肝细胞癌和肝相关死亡年发生率分别为0.06%和0.04%，而18,137名对照者的肝细胞癌和肝相关死亡年发生率均为0.02%。

 

研究者指出，对多因素校正后分析显示，与对照者相比，携带者发生肝细胞癌和肝相关死亡的危险比(HR)分别为4.6和2.1(Gastroenterology [doi: 10.1053/j.gastro.2010.01.042])。

 

研究者进行分析的数据来自乙肝病毒载量增加与相关肝病/癌症的风险评估(REVEAL-HBV)研究。非活动性HBV携带者定义为血清乙肝病毒e抗原阴性、血清抗丙肝病毒(HCV)阴性、HBV DNA血清水平低于10,000 拷贝/ml、无肝硬化和肝细胞癌，且血清丙氨酸转氨酶(ALT)水平无升高。对照者定义为血清HB表面抗原和抗HCV抗体阴性，但具有与携带者相似的临床肝脏特征(入组时，血清ALT正常，无肝硬化和肝细胞癌)。总随访时间为262,122人年。

 

与对照者相比，整个队列的肝细胞癌显著预测因子为老龄(HR每10年增加 2.7)、基线时ALT处于正常高水平(HR 2.2)和饮酒习惯(HR 2.4)。与对照者相比，非活动性HBV携带者的显著预测因子为老龄(HR每10年增加2.6)和饮酒习惯(HR 3.7)。

 

与基线时血清中未检出HBV DNA的受试者相比，基线血清HBV DNA水平为300~10,000 拷贝/ml的受试者发生肝细胞癌的风险更高，但差异无统计学意义(HR 1.6)。在基线血清未检出HBV DNA的非活动性携带者中，饮酒习惯是发生肝细胞癌的显著预测因子(HR 6.9)。

 

与对照者相比，整个队列的肝相关死亡显著预测因子与肝细胞癌预测因子相似，包括老龄(HR每10年增加2.3)、基线时ALT处于正常高水平(HR 1.9)和饮酒习惯(HR 2.1)。在非活动性HBV携带者中，仅老龄 (HR每10年增加2.6)和饮酒习惯(HR 5.8)为显著预测因子。

 

研究者指出，当将肝细胞癌作为时间依赖性事件纳入分析中时，发现肝细胞癌是肝相关死亡的最显著风险预测因子(整个队列的HR为611，非活动性HBV携带者的HR为451)，这与预期一致。

 

在无新发肝细胞癌的受试者中，老龄(HR每10年增加2.0)和饮酒习惯(HR 2.3)为肝相关死亡的显著危险因素；在无肝细胞癌的非活动性携带者中，仅老龄为显著预测因子(HR 2.4)。

 

研究者指出，在发生肝细胞癌和肝相关死亡方面，血清中未检出与检出HBV DNA的非活动性携带者之间无显著差异。

 

该研究的局限性在于缺乏组织学数据，之所以缺乏这方面的数据，是因为肝活检不适用于该大规模社区研究。此外，在HBV DNA水平高于100,000 拷贝/ml的非活动性HBV携带者中，未进行连续HBV DNA测定来评价持续非活动性HBV携带状态，也未对HBV基因型等其他危险因素进行评价，因此无法确定这些因素是否与肝细胞癌存在关联。

 

他们总结说，在未来研究中，对乙肝表面抗原血清状况和血清HBV DNA水平进行连续测定将有助于明确非活动性HBV携带的自然病史。

 

该研究获得百时美施贵宝公司、台湾行政院卫生署卫生研究院和台湾中央研究院的资金支持。 研究者声明无任何与该研究相关的经济利益关系或其他关系。

 

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