High levels of hepatitis B virus DNA are a strong predictive factor for hepatic decompensation in chronic hepatitis B patients with acute hepatic flares, reported Dr. Yun-Fan Liaw and colleagues in the June issue of Clinical Gastroenterology and Hepatology.

The authors determined that a specific cutoff value for HBV-DNA can be used in patients with acute exacerbations of chronic HBV infection to assess decompensation risk, allowing for immediate treatment with antiviral medication to prevent decompensation in those patients above the cutoff, the researchers wrote (Clin. Gastroenterol. Hepatol. 2010 June [doi:10.1016/j.cgh.2010.02.023]).

For their investigation – part of an ongoing multiyear cohort study of more than 1,400 patients treated at Chang Gung Memorial Hospital in Taipei – Dr. Liaw and colleagues isolated 138 episodes of abrupt alanine aminotransferase (ALT) elevation that occurred in 110 hepatitis B e antigen seropositive patients with chronic disease of at least 6 months. Patients with simultaneous anti-HB e seropositivity, with evidence of cirrhosis or other liver disease, or who were taking antiviral medication, were excluded.

The 110 patients were monitored every 1-2 weeks at the hospital’s outpatient hepatitis clinic, in accordance with the clinic’s normal protocols for hepatic flares in patients with chronic infections. Researchers recorded serum ALT and HBV-DNA levels, as well as bilirubin, albumin, prothrombin time, and the cause (spontaneous, or a relapse from antiviral treatment) at the first sign of the exacerbations.

The median patient age during the 138 exacerbations was 34.7 years (range, 16-58.3 years); 81.2% of flares occurred in males and 58% were in genotype B HBV-infected patients. Median value of ALT was 419 U/L at enrollment; bilirubin was 1.1 mg/dL, prothrombin time prolongation was 0.4 seconds, and HBV-DNA level was 5.657 x 10⁸ copies/mL.

Of the 138 flares, 7 (5.1%) resulted in decompensation before the antiviral drug could be administered. And in all seven episodes, “serum HBV-DNA level was the only significant risk factor,” Dr. Liaw and colleagues wrote, although ALT levels were marginally higher for the cases that developed decompensation. The decompensation patients also had higher bilirubin levels and prothrombin time at enrollment than did those who did not subsequently develop decompensation (1.3 vs. 1.1 mg/dL and 0.9 vs. 0.4 seconds, respectively). No significant differences were noted with regard to sex, age, or albumin level at entry.

The investigators used a receiver operating characteristic (ROC) curve to determine the optimal cutoff point for serum HBV-DNA, and found 1.55 x 10⁹ copies/mL to be the ideal value in predicting decompensation, with a sensitivity of 85.7%, a specificity of 85.5%, a negative predictive value of 99.1% and a positive predictive value of 24%.

Although normal protocols for the treatment of hepatitis B flare in Asia generally consist of monitoring and awaiting an immune-mediated seroconversion, the ability to predict the rare occurrence of decompensation and to administer antiviral drugs before its onset is important, the investigators wrote, as decompensation can result in liver damage and death.

HBV-DNA has not been previously isolated as a predictor of decompensation, the authors wrote. “Earlier case-controlled studies have identified preexisting cirrhosis, high Child-Pugh score, low albumin level, high bilirubin level, prolonged PT and high HBV-DNA as factors associated with hepatic decompensation during an acute exacerbation,” they wrote. “However, except preexisting cirrhosis, these so-called factors are actually the presenting features of overt hepatic decompensation.”

By using the predictive value of 1.55 x 10⁹ copies/mL for HBV-DNA, antiviral medicines can be administered in time to prevent onset of decompensation in patients with acute exacerbations, the researchers concluded. Patients with levels of less than 1.55 x 10⁹ copies/mL are at low risk and can continue to be monitored for spontaneous HBeAg seroconversion, they recommended.

The research was carried out using funds from Taiwan’s Prosperous Foundation and Chang Gung University. Neither Dr. Liaw nor colleagues reported any competing interests related to their research, although Dr. Liaw has served as an adviser to Roche, Bristol-Myers Squibb, Novartis Pharmaceuticals Corp., and Gilead Sciences Inc.

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

《临床胃肠病学和肝脏病学》杂志在6月号上发表了Yun-Fan Liaw医生和其同事的研究成果。乙肝病毒DNA水平增高是预测慢性乙肝患者急性发作时发生肝脏失代偿的重要指标。

 

文章作者确定了一个特异的HBV-DNA水平截断值，用以评估慢性乙肝病毒感染急性发作患者发生肝脏失代偿的危险性。若患者HBV-DNA水平高于该截断值，应立即给予抗病毒治疗，以预防肝脏失代偿的发生（参见Clin. Gastroenterol. Hepatol. 2010 June [doi:10.1016/j.cgh.2010.02.023]）。

 

上述研究是一项正在进行中的多年期队列研究的一部分。该研究以在台北长庚纪念医院接受治疗的超过1,400名患者为研究对象。Liaw医生和同事筛选出110名血清HBe抗原阳性的患者，共出现138次突发性丙氨酸转氨酶（ALT）水平增高。患者慢性乙肝病程至少6个月。若患者同时出现血清抗HBe阳性，且有肝硬化或其他肝脏疾病的征象，或接受了抗病毒治疗，则不纳入研究。

 

研究者根据临床诊治慢性乙肝患者急性发作的常规方案，每隔1~2周对该110名患者在医院肝炎门诊进行监测。记录项目包括血清ALT和HBV-DNA水平，还有胆红素、白蛋白、凝血酶原时间（PT）以及首次发作的原因（自发的，或抗病毒治疗后复发的）。

 

138次发作时患者中位年龄为34.7岁（范围为16~58.3岁）；急性发作的患者中81.2%为男性，58%感染的乙肝病毒的基因型为B型。发作时ALT水平中位值为419 U/L，胆红素为1.1 mg/dl，PT延长0.4 s，HBV-DNA水平为5.657×10⁸拷贝/ ml。

 

138次发作中仅有7次（5.1%）在应用抗病毒药物治疗前出现肝脏失代偿。Liaw医生和同事在文章中称，尽管ALT水平在发生肝脏失代偿的病例中偏高，但上述7次发作中，“血清HBV-DNA水平是唯一有显著性的危险因素”。肝脏失代偿患者发作时胆红素水平和PT较未发展到失代偿的患者有所增加（分别为1.3比1.1 mg/dl和0.9比0.4 s）。未提出患者性别、年龄或白蛋白水平有显著差异。

 

研究者应用受试者工作特性（ROC）曲线确定血清HBV-DNA水平最佳截断值，结果发现预测肝脏失代偿的理想值为1.55×10⁹拷贝/ ml，其特异性为85.5%，阴性预测值为99.1%，阳性预测值为24%。

 

研究者在文章中指出，虽然在亚洲地区，通常对乙肝发作的诊疗方案包括监测和等待免疫介导的血清转换，但鉴于肝脏失代偿能导致肝损伤和死亡，故具有预测肝脏失代偿这种少见病症的能力并在其发生前进行抗病毒药物治疗是非常重要的。

 

文章作者称，以前从未将HBV-DNA水平筛选出来作为肝脏失代偿的预测指标。“早期的病例对照研究确定肝硬化、高Child-Pugh评分、低白蛋白水平、高胆红素水平、PT延长以及高HBV-DNA水平是乙肝急性发作期发生肝脏失代偿的相关因素。但除了肝硬化，这些所谓相关因素都是肝脏严重失代偿的特征表现。”

 

研究者总结称，通过应用1.55×10⁹拷贝/ ml这个HBV-DNA水平预测值，可及时对慢性乙肝急性发作患者进行抗病毒药物治疗以预防肝脏失代偿的发生。他们建议，若HBV-DNA水平低于1.55×10⁹拷贝/ ml，则患者处于低危险性，可继续进行监测，以等待自发性HBe抗原血清转换。

 

该研究由台湾繁荣基金会和长庚大学提供基金资助。Liaw医生及其同事未报告任何与其研究相关的利益冲突，不过Liaw医生是罗氏公司、百时美施贵宝公司、诺华制药公司以及吉利德科学公司的顾问。

 

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