AASLD2012:核苷类似物降低B型肝炎肝癌的风​​险，肝硬化仍令

StephenW

AASLD 2012: Nucleoside Analogs Reduce Hepatitis B Liver Cancer Risk, Cirrhosis Remains a Concern

   
    Category: HBV Treatment   
    Published on Sunday, 25 November 2012 00:00
    Written by Liz Highleyman


Treatment of chronic hepatitis B with nucleoside/nucleotide analogs including lamivudine (Epivir-HBV) and entecavir (Baraclude) can reduce the risk of developing hepatocellular carcinoma, including cancer recurrence after successful resection, according to studies presented at the recent American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) and published in the Journal of the American Medical Association.

Over years or decades, chronic hepatitis B virus (HBV) infection can lead to severe liver disease including advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), a form of primary liver cancer. It is thought that the liver's ongoing attempt to repair itself after injury can trigger abnormal cell growth.

Chun-Ying Wu from National Yang-Ming University in Taipei and colleagues looked at the effect of HBV treatment on HCC recurrence following curative resection, or successful surgical removal of liver tumors. While resection is among the most effective HCC treatments for people with isolated tumors, liver cancer recurs at least half the time.

As described at an oral session on liver cancer at the AASLD meeting and in the November 14, 2012, Journal of the American Medical Association, the researchers conducted a nationwide cohort study using data from the Taiwan National Health Insurance Research Database collected between October 2003 and September 2010.

Out of a total 100,938 newly diagnosed HCC patients, they identified 4569 with HBV-related liver cancer who underwent curative resection. More than 80% were men and the mean age was about 55 years. Patients with hepatitis C coinfection and those who had undergone previous HCC treatment or liver transplantation were excluded. Data on HBV viral load and liver function were not available, but the researchers noted that Taiwan's national health program only reimburses nucleoside analogs for people considered to be at high risk for liver disease progression.

Wu's team compared therisk of tumor recurrence between people taking nucleoside analogs and those not taking antiviral drugs. In the treated cohort, 487 patients received just 1 nucleoside analog, including 159 who took lamivudine, 292 who took entecavir, and 36 who took telbivudine (Tyzeka); the rest received more than 1 nucleoside drug. Treated participants used antiviral therapy for a mean duration of 1.5 years.

Results

    People treated with nucleoside analogshad a significantly lower risk of HCC recurrence and death than untreated patients, despite a higher prevalence of liver cirrhosis:

o   Liver cirrhosis: 48.6% treated vs 38.7% untreated;

o   HCC recurrence: 20.5% vs 43.6%, respectively;

o   Overall mortality: 10.6% vs 28.3%, respectively.

    After adjusting for competing causes of mortality, treated patients had a significantly lower 6-year HCC recurrence rate (45.6% vs 54.6%, respectively).
    6-year overall mortality rates were 29.0% for treated patients compared with 42.4% for untreated individuals.
    The primary identifiable causes of death for both nucleoside-treated and untreated patients were HCC or HCC treatment-related mortality, liver cirrhosis, sepsis, and pneumonia.
    In a multivariate analysis, factors independently associated with reduced risk of HCC recurrence included:

o   Nucleoside analog use: hazard ratio (HR) 0.67, or 33% risk reduction;

o   Statin use (drugs typically used to manage elevated blood lipid): HR 0.68, or 32% risk reduction;

o   Non-steroidal anti-inflammatory drug (NSAID) or aspirin use: HR 0.80, or 20% risk reduction.

    A stratified analysis showed that these associations were seen in all patient sub-groups, including those without liver cirrhosis.

Based on these findings, the researchers concluded, "Nucleoside analog use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection."

In their discussion, they noted that while prior studies had linked statin use and lower liver cancer risk, this study was the first to see such an association for NSAIDs or aspirin.

In an accompanying editorial, Anna Lok from the University of Michigan at Ann Arbornoted that surgical resection is the treatment of choice for HCC patients with solitary tumors and no evidence of cirrhosis. While only 5% of HCC cases in western countries exhibit this pattern, it reaches 40% in Asia, where HBV is endemic and is the primary cause of liver cancer.

HCC recurrence after resection is common, occurring in 50% to 70% of patients within 5 years. Early recurrence is usually due to metastasis from the original primary tumor, Lok explained, while late recurrence is often due to newly developed primary tumors in people with ongoing active HBV infection or cirrhosis.

"Given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1 to 2 years can prevent HCC recurrence, particularly because early recurrence is likely due to previously undiscovered metastasis from the primary tumor," Lok wrote.

"However, nucleoside/nucleotide analogs may decrease short-term mortality after liver resection, particularly among patients with underlying cirrhosis, high levels of HBV replication, or active hepatic inflammation," she continued. "For patients who do not experience early HCC recurrence, continued therapy with nucleoside/nucleotide analogs may prevent de novo primary tumors and further progression of liver disease, thereby decreasing late HCC recurrence and long-term mortality."
Risk Factors for HCC

At the Liver Meeting, Tetsuya Hosakafrom Toranomon Hospital in Tokyo and colleagues presented findings showing that long-term treatment with entecavir reduces HCC incidence in chronic hepatitis B patients. This retrospective cohort study included 472 formerly treatment-naive hepatitis B patients who received entecavir and 1568 untreated patients.

About 3% of participants in the entecavir group developed liver cancer over a mean follow-up period of about 3 years, compared with about 14% of untreated patients over about 10 years of follow-up. Cumulative 5-year HCC rates were about 4% and about 12%, respectively. In a multivariate analysis, entecavir use significantly reduced the risk of HCC (HR 0.40. or 60% risk reduction).

"Long-term entecavir treatment reduces the incidence of HCC in chronic hepatitis B patients," the researchers concluded. "The treatment effect was greater in patients with higher risks."

However, other studies presented at the meeting found that antiviral treatment does not always do the trick.

Liu-Qing Yang from the Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China, and colleagues conducted a retrospective/prospective cohort study of more than 500 chronic hepatitis B patients treated with nucleoside/nucleotide analogs who were followed from 2007 through March 2012.

A total of 22 cases of HCC were diagnosed, most presenting with small single tumors. All patients who developed HCC had cirrhosis, and a multivariate analysis showed that baseline cirrhosis before starting antiviral therapy was the only independent risk factor for HBV-related HCC in this study. Antiviral treatment for 1-2 years did not significantly reduce the risk of HCC, even for patients with good virological and biochemical (ALT normalization) response.

Finally, Adriano Pellicelli and fellow investigators with the Italian CLEO Group (Gruppo Epatologi Ospedalieri) studied the effect of liver fibrosis on development of HCC in hepatitis B "e" antigen (HBeAg) negative patients receiving nucleoside/nucleotide analog treatment.

This retrospective/prospective analysis looked at HCC incidence among people with HBV genotype D -- the predominant type in Southern and Eastern Europe and the Middle East -- treated with nucleoside/nucleotide analogs for at least 18 months, with a median of about 60 months.

During follow-up, 2 people without cirrhosis developed HCC, for an incidence rate of 0.36 per 100 person/years, compared with 20 cases among patients with compensated cirrhosis, an incidence rate of 4.80 per 100 person/years.

In a multivariate analysis, only age > 60 years (HR 4.85, or about 5-fold higher risk) and liver cirrhosis were independent predictors of developing HCC, with cirrhosis increasing the risk by about 13-fold (HR 13.3). Lack of virological response and resistance to nucleoside/nucleotide analogs upped HCC risk somewhat, but the difference did not reach statistical significance.

"Long-term therapy with [nucleoside/nucleotide analogs] does not eliminate HCC risk in HBeAg negative genotype D patients with liver cirrhosis," the researchers concluded.

Taken together, these studies indicate that although HCC can occur in the absence of advanced fibrosis, cirrhosis is a key risk factor. Short-term treatment with nucleoside/nucleotide analogs may not be enough to diminish HCC risk, but long-term therapy can reduce the likelihood of both initial liver cancer and HCC recurrence after resection. Early antiviral therapy that prevents advanced fibrosis or cirrhosis from developing in the first place may have an even greater beneficial effect.

11/27/12

References

C-Y Wu, Y-J Chen, HJ Ho, et al. Association Between Nucleoside Analogues and Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma Recurrence Following Liver Resection. Journal of the American Medical Association 308(18):1906-1913. November 14, 2012.

C-Y Wu, Y-C Hsu, and J-T  Lin. Effect of lamivudine on hepatitis B virus-related hepatocellular carcinoma following liver resection: a nationwide experience in Taiwan. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 166.

AS Lok. Does Antiviral Therapy Prevent Recurrence of Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection?(Editorial) Journal of the American Medical Association 308(18):1922-1924. November 14, 2012.

T Hosaka, F Suzuki, M Kobayashi, et al.Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with chronic hepatitis B. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 357.

L-Q Yang, X-Y Li, Y Wu, and Y Chong. Risk Factor Analysis of HCC for Chronic Hepatitis B Patients with Nucleos(t)ide Analogues Therapy. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 344.

A Pellicelli, P Vignally, E Mazzoni, et al. Impact of liver fibrosis in development of hepatocellular carcinoma in HBeAg negative genotype D patients with chronic hepatitis B treated with nucleos(t)ide analogues. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 21.

Other Source

JAMA. Patients With HBV-Related Liver Cancer Who Receive Antiviral Therapy Have Lower Risk of Tumor Recurrence. Media advisory. November 12, 2012.

StephenW

治疗慢性乙型肝炎的核苷/核苷酸类似物，包括拉米夫定（拉米HBV）和恩替卡韦（博路定）可以减少肝癌发展的危险，包括成功切除后复发的癌症，根据研究发表在最近的美国协会的研究肝病肝会（AASLD 2012），并发表在美国医学协会杂志“上。

过去几年或几十年，慢性乙型肝炎病毒（HBV）感染可导致严重的肝脏疾病，包括先进的肝纤维化，肝硬化和肝细胞癌（HCC），原发性肝癌的一种形式。它被认为是，不断试图肝脏的自我修复损伤后可以触发异常细胞的生长。

春英吴阳明大学，台北和他的同事们看着HBV治疗的效果，对肝癌复发根治性切除，或手术切除的肝脏肿瘤成功。虽然切除的人孤立肿瘤的最有效的肝癌治疗，肝癌复发，至少有一半的时间。

如对肝癌在美国肝病学会会议上的口头报告，并在2012年11月14日的美国医学协会杂志中，研究人员进行了一项全国性的队列研究使用的数据来自2003年10月间收集的台湾全民健康保险研究资料库2010年9月

出共100,938新诊断的肝癌患者，他们确定了4569与HBV相关的肝癌根治性切除。超过80％为男性，平均年龄约55年。 C型肝炎合并感染和那些谁经历了以前的肝癌治疗或肝移植的患者被排除在外。 HBV病毒载量和肝功能上的数据无法获得，但研究人员指出，台湾的国民健康保险只报销核苷类似物的人被认为是高风险的肝脏疾病进展。

吴的团队therisk肿瘤复发服用核苷类似物和那些不服用抗病毒药物，人与人之间的。在治疗的人群中，仅有1 487例患者接受核苷类似物，包括159了，292了恩替卡韦，拉米夫定和36谁替比夫定（Tyzeka），其余超过1核苷类药物。治疗使用的抗病毒药治疗的平均时间为1.5年。

结果

    与核苷治疗analogshad一个比未接受治疗的患者肝癌复发和死亡的风险显着降低，尽管肝硬化的发病率较高：

Ø肝硬化48.6％和38.7％未经处理的处理;

Ø复发，分别为20.5％和43.6％;

O总死亡率，分别为10.6％和28.3％。

    调整后的竞争死亡原因，接受治疗的患者有显着降低6年HCC的复发率（45.6％和54.6％，分别）。
    6年的总死亡率分别为29.0％，治疗的患者相比，有42.4％未经处理的个人。
    核苷处理和未经处理的病人可识别的主要死亡原因是肝癌或肝癌的治疗相关死亡率，肝硬化，败血症和肺炎。
    多变量分析显示，HCC复发的风险降低独立相关因素包括：

Ø采用核苷类似物的危险比（HR）0.67，或减少33％的风险;

Ø使用他汀类药物（药物通常用于管理血脂升高）：HR 0.68，32％的风险减少;

o非甾体类抗炎药（NSAID）或使用阿司匹林：HR 0.80，或减少20％的风险。

    分层分析表明，这些协会在所有患者亚组，包括那些没有肝硬化。

基于这些发现，研究人员得出结论，“核苷类似物的使用与HBV相关的肝癌肝切除后的患者肝癌复发的风险较低。”

在他们的讨论中，他们指出，以前的研究已经与他汀类药物的使用，并降低肝癌的风险，这项研究是第一次看到这样的非甾体抗炎药或阿司匹林协会。

在随后的社论中，安娜乐从美国密西根大学安Arbornoted，手术切除是治疗的首选单发性肿瘤和肝癌患者无肝硬化的证据。虽然只有5％的肝癌病例在西方国家表现出这种模式，它达到了40％在亚洲，其中，乙肝病毒流行和肝癌的首要原因。

肝癌切除术后复发是常见的，在50％〜70％的患者在5年内发生。通常是由于早期复发转移从原来的原发肿瘤，乐解释说，而晚期复发往往是由于新开发的原发肿瘤的持续活跃的乙肝病毒感染或肝硬化的人。

“细胞损伤之间的间隔较长，恶性转化，肿瘤的发生发展，这是不切实际的期望，政府的抗病毒治疗1〜2年可预防肝癌复发，特别是因为早期复发可能是由于以前未发现的转移，从主肿瘤，“乐写的。

然而，核苷/核苷酸类似物，可能会降低短期死亡率肝切除后，尤其是基础性肝硬化，HBV复制水平高，或主动肝脏炎症的患者，“她继续说。” “谁没有经历过早期肝癌复发的患者，继续治疗的核苷/核苷酸类似物可以防止从头原发肿瘤和肝脏疾病的进一步恶化，从而降低晚期肝癌复发和长期的死亡率。”
为HCC的危险因素

哲也Hosakafrom在东京虎之门医院和他的同事在肝脏的会议上，提出调查结果显示，恩替卡韦降低肝癌发病率在慢性乙型肝炎患者的长期治疗。本回顾性队列研究纳入了472以前治疗初治乙肝患者接受恩替卡韦和1568年未经治疗的患者。

大约3％的肝癌，平均随访期为3年左右的恩替卡韦组的参与者中，约14％未经治疗的患者中，大约10年的后续。 5年累积HCC率分别为4％左右和12％左右。多变量分析显示，恩替卡韦的使用显着降低肝癌的风险（HR 0.40或减少60％的风险）。

“长期恩替卡韦治疗在慢性B型肝炎患者肝癌的发病率降低，研究人员得出结论。” “更大的风险较高的患者的治疗效果。”

然而，在会议上提出的其他研究发现，抗病毒治疗并不总是做的伎俩。

杨柳青从孙中山大学第三附属医院，广州，中国，和他的同事进行了一项回顾性/前瞻性队列研究的500多名慢性乙型肝炎患者核苷/核苷酸类似物治疗与随访从2007年到3月2012年。

一个总被确诊的22例原发性肝癌，多数小单瘤的呈现。谁开发HCC患者有肝硬化，多变量分析表明，在开始抗病毒治疗前的基线肝硬化HBV相关的肝癌在这项研究中是唯一的独立危险因素。的抗病毒治疗1-2年没有显着减少肝癌的危险，即使是具有良好的病毒学和生化指标（ALT正常化）反应的患者。

最后，阿德里亚诺Pellicelli的和同伴的调查与意大利CLEO集团（GRUPPO Epatologi Ospedalieri）研究了HCC肝纤维化的发展，在B型肝炎的“e”抗原（HBeAg）阴性患者接受核苷/核苷酸类似物治疗。

本回顾性/前瞻性分析研究了肝癌发病率之间的人与HBV基因型D  - 在南欧和东欧及中东的主要类型 - 核苷/核苷酸类似物治疗至少18个月，中位数约60个月。

在随访期间，2人无肝硬化肝癌，100人/年，发生率为0.36％，代偿性肝硬化，发病率为100人/年为4.80％（20例）的患者相比。

在多变量分析中，只有年龄> 60岁（HR 4.85，或约5倍的风险较高），肝硬化发展为HCC的独立预测因子，肝硬化的风险增加了约13倍（HR 13.3）。核苷/核苷酸类似物的病毒学应答和抗调升HCC风险缺乏一些，但差异并未达到统计显着性。

“[/核苷酸，核苷类似物长期治疗不消除HBeAg阴性D型肝硬化患者的HCC风险，研究人员得出结论。”

两者合计，这些研究表明，虽然发生HCC可以在没有先进的肝纤维化，肝硬化的主要危险因素。短期治疗的核苷/核苷酸类似物可能不会有足够的降低肝癌的风险，但长期治疗可降低初始肝癌，肝癌切除术后复发的可能性。及早使用抗病毒药物治疗，以防止晚期肝纤维化或肝硬化的发展摆在首位，可能有一个更有利的影响。

12年11月27日

参考文献

C-Y，Y-J陈武，HJ何，等。核苷类似物和B型肝炎病毒相关的肝癌复发的肝切除术的风险之间的关联。杂志美国医学协会，308（18）:1906-1913。 2012年11月14日。

吴C-Y，Y-C，许林J-T。拉米夫定对乙肝病毒相关的肝癌肝切除术：在台湾的经验在全国范围内的影响。第63届年度会议的美国协会肝病（AASLD 2012）的研究。波士顿，2012年11月9-13日。摘要166。

为乐。是否抗病毒治疗B型肝炎病毒相关的肝癌肝切除后疗效防止复发？（社论）杂志的美国医学协会308（18）:1922-1924。 2012年11月14日。

，M，F铃木Ţ保坂小林，等al.Long长期恩替卡韦治疗可降低肝癌的发生率在治疗慢性乙型肝炎第63届会议的美国协会肝病（AASLD 2012）的研究。波士顿，2012年11月9-13日。摘要357。

L-Q X-Y杨，吴，李，Y和Y冲。慢性乙型肝炎的核苷（酸）类似物治疗的患者肝癌的危险因素分析。第63届年度会议的美国协会肝病（AASLD 2012）的研究。波士顿，2012年11月9-13日。摘要344。

一个Pellicelli，P，E崇义，Vignally等。 HBeAg阴性D基因型患者核苷（酸）类似物治疗慢性乙型肝炎肝纤维化的肝细胞性肝癌的发展的影响。第63届年度会议的美国协会肝病（AASLD 2012）的研究。波士顿，2012年11月9-13日。摘要21。

其他资料来源

JAMA。与乙肝病毒有关的肝癌患者接受抗病毒治疗的肿瘤复发风险降低。媒体咨询。 2012年11月12日。

咬牙硬挺

就是要一直吃药