在乙型肝炎患者中更好的治疗是否能减少肝癌？

StephenW

Hepatitis B
Is better treatment reducing liver cancer among people with hepatitis B?
Liz Highleyman

Published:
    23 February 2017

Produced in collaboration with hivandhepatitis.com
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    Mortality and liver transplants

The incidence of hepatocellular carcinoma (HCC) appears to be decreasing and mortality improving among people with chronic hepatitis B treated with suppressive antiviral therapy, according to studies presented at the recent 2016 AASLD Liver Meeting in Boston. However, liver cancer remains a major indication for liver transplants and has a negative effect on survival of people with hepatitis B.

Over years or decades chronic hepatitis B virus (HBV) infection can lead to advanced liver disease including cirrhosis and HCC, and it is a leading cause of liver cancer worldwide. Antiviral therapy using nucleoside/nucleotide analogues such as entecavir (Baraclude) or tenofovir disoproxil fumarate (Viread) is the mainstay of treatment for chronic hepatitis B. While these drugs can suppress HBV replication during therapy – and can thereby reduce the risk of liver disease progression – they usually do not lead to a cure and long-term treatment is generally required.

Yao-Chun Hsu of E-Da Hospital and colleagues looked at changes in the risk of HCC over time among people with chronic hepatitis B in Taiwan who received optimal antiviral therapy.

This retrospective cohort study looked at more than 65,000 Taiwanese residents who received entecavir or tenofovir DF between 2008 and 2013, identified in Taiwan’s national healthcare database. People treated for less than three months, those previously exposed to other nucleoside/nucleotide analogues such as lamivudine (Epivir), those with pre-existing malignancies and those who developed HCC within three months of starting therapy were excluded. The final analysis included 27,820 eligible people. Nearly three-quarters were men, the median age was 48 years, a third had cirrhosis and 7% had co-infection with hepatitis C.

A total of 802 people developed HCC over a median follow-up period of 29 months. Cumulative incidence rates during the first, second and third years were 1.82%, 3.05% and 4.06%, respectively.

HCC incidence declined significantly with more time on treatment (adjusted incidence rate ratio [IRR] 0.73, or about a 27% reduction per year). Cirrhosis was the strongest predictor of developing HCC in a multivariate analysis (adjusted hazard ratio [HR] 4.91), followed by male sex (adjusted HR 1.73), older age (adjusted HR 1.65 per decade), diabetes (adjusted HR 1.25) and hepatitis C co-infection (adjusted HR 1.23).

"The incidence rate of HCC decreased year by year in chronic hepatitis B patients on entecavir or tenofovir," the researchers concluded. They suggested their study could inform a surveillance strategy to more intensively monitor those at greatest risk, as well as identify modifiable factors to reduce liver cancer risk.

In a related study, George Papatheodoridis of the University of Athens Medical School and colleagues assessed HCC incidence beyond the first five years on entecavir or tenofovir DF. The researchers had previously shown that HCC could still develop within the first five years of treatment despite viral suppression.

This analysis included more than 1900 Caucasian adults with chronic hepatitis B at ten centres in Europe. About 70% were men, the mean age was 53 years, 18% were HBeAg-positive, most reported little alcohol use and just over a quarter had compensated cirrhosis. People with pre-existing HCC, decompensated cirrhosis, or hepatitis C or HIV co-infection were excluded.

Participants were treated with entecavir or tenofovir DF for at least a year; about 40% had previously used other antivirals and about 20% had used pegylated interferon. Of these, 1205 people who did not develop HCC within the first five years on therapy were followed for at least an additional five years.

HCC was diagnosed in 5% of participants within the first five years of therapy, and in 17 of the 1205 people (1.4%) still at risk beyond the first five years. Nine people with cirrhosis (2.8%) and eight without cirrhosis (0.9%) developed liver cancer after five years on treatment. The annual HCC incidence rate was 1.22% within the first five years and 0.73% after five years.

There was no difference in pre- and post-five year HCC incidence among people without cirrhosis, but the risk dropped significantly after five years for people with cirrhosis (from 3.21% to 1.57%). All HCC cases diagnosed after five years occurred in people who were older than 50 when they started treatment, and being over 50 was a significant predictor of late HCC.
"The difference in the HCC incidence rates between initially cirrhotic and non-cirrhotic patients becomes less pronounced after year five, when older age, especially age >50 years, represents the main risk factor for HCC development," the researchers concluded.

StephenW

乙型肝炎
在乙型肝炎患者中更好的治疗是否能减少肝癌？
Liz Highleyman

发布时间：
    2017年2月23日

生产与hivandhepatitis.com的合作
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    死亡率和肝移植

根据最近在波士顿举行的2016年AASLD肝会议上提出的研究，肝细胞癌（HCC）的发病率似乎在减少，并且在用抑制性抗病毒治疗治疗的慢性乙型肝炎患者中的死亡率改善。然而，肝癌仍然是肝移植的主要适应症，并且对乙型肝炎患者的存活具有负面影响。

多年或几十年，慢性乙型肝炎病毒（HBV）感染可导致晚期肝病，包括肝硬化和HCC，并且它是全世界肝癌的主要原因。使用核苷/核苷酸类似物（如恩替卡韦（Baraclude）或替诺福韦地索普西富马酸盐（Viread））的抗病毒治疗是慢性乙型肝炎治疗的主要方法。虽然这些药物可以在治疗期间抑制HBV复制，从而降低肝病进展的风险 - 它们通常不会导致治愈，通常需要长期治疗。

E-Da医院的Yao-Chun Hsu和同事观察了接受最佳抗病毒治疗的台湾慢性乙型肝炎患者的HCC风险随时间的变化。

这项回顾性队列研究观察了在台湾的国家医疗数据库中发现的在2008年至2013年期间接受恩替卡韦或替诺福韦DF的65,000多台台湾居民。治疗少于三个月的人，先前暴露于其他核苷/核苷酸类似物例如拉米夫定（Epivir），具有预先存在的恶性肿瘤的那些人和那些在开始治疗的三个月内发展HCC的人被排除。最终分析包括27,820名合格的人。近四分之三是男性，中位年龄是48岁，三分之一是肝硬化，7％是丙型肝炎共感染。

在中位随访29个月中，共有802人发展HCC。第一，二，三年的累积发病率分别为1.82％，3.05％和4.06％。

HCC发病率随治疗时间的延长显着降低（调整发生率比率[IRR] 0.73，或每年降低约27％）。肝硬化是在多变量分析（调整的风险比[HR] 4.91），随后男性（调整的HR 1.73），老年（调整的HR 1.65每十年），糖尿病（调整的HR 1.25）和肝炎C共感染（调整HR 1.23）。

“在恩替卡韦或替诺福韦的慢性乙型肝炎患者中，HCC的发病率逐年下降，”研究人员总结说。他们建议他们的研究可以通知监测策略，以更密集地监测最大风险的患者，以及确定可降低肝癌风险的可能因素。

在一项相关研究中，雅典大学医学院的George Papatheodoridis及其同事评估了恩替卡韦或替诺福韦DF在头五年内的HCC发病率。研究人员以前表明，HCC仍然可以在治疗的前五年内发展，尽管病毒抑制。

这项分析包括在欧洲十个中心的超过1900名白种人成人与慢性乙型肝炎。约70％为男性，平均年龄为53岁，18％为HBeAg阳性，多数报告少量酒精使用，刚刚超过四分之一已经补偿肝硬化。排除了具有预先存在的HCC，失代偿性肝硬化或丙型肝炎或HIV共感染的人。

参与者用恩替卡韦或替诺福韦DF治疗至少一年;约40％以前使用过其他抗病毒药物，约20％使用聚乙二醇化干扰素。其中，在治疗的前五年内没有发展HCC的1205个患者被跟踪至少另外五年。

在治疗的前五年内，5％的受试者中诊断出HCC，在1205人中有17人（1.4％）在头五年内仍然处于风险之中。 9名肝硬化患者（2.8％）和8名无肝硬化（0.9％）的患者在治疗5年后出现肝癌。 HCC年发病率在前五年为1.22％，五年后为0.73％。

在没有肝硬化的人群中，5年前和5年后HCC发病率没有差异，但是肝硬化患者5年后的风险显着降低（从3.21％到1.57％）。在五年后诊断的所有HCC病例发生在他们开始治疗时大于50岁的人中，超过50岁是晚期HCC的显着预测因子。
研究人员得出结论：“在第5年后，初期肝硬化和非肝硬化患者HCC发病率的差异变得不明显，当年龄较大，特别是年龄> 50岁时，代表HCC发生的主要危险因素。

StephenW

Mortality and liver transplants

Dr Papatheodoridis and his team also looked at survival of people with and without cirrhosis in this cohort of 1951 people on long-term entecavir or tenofovir DF. All were treated for at least one year (median six years). Follow-up continued to April 2016.

Over a median follow-up period of six years, 37 people without cirrhosis (2.7%) and 44 people with cirrhosis (8.4%) died from any cause; 10 (0.7%) and 23 (4.4%) of these deaths were due to liver-related causes. Thirty-seven people without cirrhosis (2.7%) and 80 people with cirrhosis (15.2%) developed HCC, and eight (0.6%) and nine (1.7%), respectively, received liver transplants.

Cumulative survival probability for the whole patient population at 1, 3, 5, 8 and 10 years was high: 99.7%, 97.8%, 95.9%, 94.1% and 94.1%, respectively. However, survival rates were significantly higher for people without cirrhosis (100%, 98.5%, 97.3%, 96.2% and 96.2%) compared to those with cirrhosis (99.1%, 95.9%, 92.8%, 89.3% and 89.3%).

Development of liver cancer was the major factor affecting overall mortality – and was in fact the only factor affecting liver-related mortality in this cohort, according to the researchers.

Among people with HCC, 45.9% of people without cirrhosis and 32.5% of those with cirrhosis either died from a liver-related cause or got a liver transplant. In contrast, this occurred in just 0.01% of people without cirrhosis and 1.3% of people with cirrhosis without HCC. Having HCC gave a hazard ratio of 5.47 – more than five times higher risk of all-cause death – but after adjusting for HCC in a multivariate analysis, cirrhosis had a much smaller though still significant effect (HR 1.08).

Finally, Kellie Young of the Santa Clara Valley Medical Center in California, Robert Wong of the Alameda Health System and colleagues used data from the United Network for Organ Sharing registry to evaluate trends in liver transplant wait-list registrations, survival while wait-listed, and the likelihood of receiving transplants among adults with chronic hepatitis B in the US.

This retrospective study looked at approximately 6700 people (about 80% men) waitlisted during three time periods:

    Era 1: 1992-1996, before treatment with nucleoside/nucleotide analogues
    Era 2: 1997-2004, lamivudine and adefovir (Hepsera) available
    Era 3: 2005-2015, current therapies available (entecavir starting in 2005 and tenofovir DF in 2008).

The number of waitlisted individuals more than doubled from Era 1 (about 900) to Era 2 (about 2800), but then stabilised in Era 3 (about 3000). The proportion of white individuals fell over time (from nearly two-thirds to a third) while the proportion of Asians rose (from about a quarter to about half); black and Hispanic people accounted for a small proportion of transplant candidates across time.

Overall, about a quarter of waitlisted individuals had HCC. But the number of candidates with liver cancer rose steadily, from just 5% in Era 1 to 15% in Era 2 and 39% in Era 3, although HCC dipped somewhat in the last two years. The proportion of Asians with HCC reached two-thirds in Era 3. Dr Wong suggested this might be because HBV genotypes found in Asia (B and C) may be more likely to cause liver cancer.

During Era 1, 0.9% of waitlisted individuals died and 46.6% received transplants within a year; the average time to death on the waitlist was 1432 days and the mean time to transplantation was 273 days. During Era 2, 8.4% died and 40.3% got transplants within a year; the mean times to death and transplantation were 569 and 311 days, respectively. And during Era 3, 6.2% died while waiting and 47.5% got transplants; the mean times to death and transplantation were 350 and 178 days.

The likelihood of dying while on the waitlist was significantly higher in Era 1 compared to Era 2 (HR 4.55), but fell from Era 2 to Era 3 (HR 3.63 vs Era 1). Waitlist mortality was affected by both the number of people who died and time to death on the transplant list. Era 1 had both the smallest number of deaths and the longest mean time to death, which the researchers said might be due to selection bias in favour of healthier individuals, as transplant outcomes were poor for people with hepatitis B prior to the 1990s.

The researchers noted that studies have shown that MELD scores at the time of transplantation have increased in recent years, suggesting people on the waitlist are now sicker. But the decline in the likelihood of death on the waitlist from Era 2 to Era 3 may reflect the improvement in hepatitis B treatment. A subgroup analysis of Era 3 showed that survival increased from 2005-2007 to 2008-2011 (HR 0.77) and 2012-2015 (HR 0.61), even after controlling for disease severity.

StephenW

死亡率和肝移植

Papatheodoridis博士和他的团队还研究了在1951年长期恩替卡韦或替诺福韦DF人群中，患有和不伴有肝硬化的患者的生存。所有患者至少治疗一年（中位6年）。后续活动继续至2016年4月。

在中位随访6年中，37例无肝硬化（2.7％）和44例肝硬化（8.4％）死于任何原因; 10（0.7％）和23（4.4％）的死亡是由于肝脏相关的原因。 37例无肝硬化（2.7％）和80例肝硬化（15.2％）发生肝癌，8例（0.6％）和9例（1.7％）分别接受肝移植。

在1,3,5,8和10年的整个患者群体的累积生存概率高：分别为99.7％，97.8％，95.9％，94.1％和94.1％。然而，与没有肝硬化的患者（99.1％，95.9％，92.8％，89.3％和89.3％）相比，没有肝硬化的患者的存活率（100％，98.5％，97.3％，96.2％和96.2％

肝癌的发展是影响整体死亡率的主要因素，事实上是影响肝脏相关死亡率的唯一因素，根据研究人员。

在肝癌患者中，45.9％的无肝硬化的人和32.5％的肝硬化的人死于肝脏相关的原因或得到肝移植。相比之下，这仅发生在0.01％的没有肝硬化的人和1.3％的肝硬化没有肝癌的人。 HCC的危险比为5.47 - 是全因死亡风险的五倍以上 - 但是在多变量分析中校正HCC后，肝硬化具有更小但仍然显着的作用（HR 1.08）。

最后，加利福尼亚州圣克拉拉谷医疗中心的Kellie Young，Alameda健康系统的Robert Wong和同事使用来自联合网络的器官共享登记系统的数据来评估肝移植等待名单注册，等待上市的生存，以及美国慢性乙型肝炎患者接受移植的可能性。

这项回顾性研究观察了约6700人（约80％的男性）在三个时间段等候：

    Era 1：1992-1996，在用核苷/核苷酸类似物处理之前
    Era 2：1997-2004，拉米夫定和阿德福韦（Hepsera）
    时代3：2005-2015，目前可用的治疗（恩替卡韦从2005年开始，替诺福韦DF在2008年）。

等候名单人数从时代1（约900）到时代2（约2800）增加了一倍以上，但后来在时代3（约3000）稳定下来。白人的比例随时间下降（从近三分之二到三分之一），而亚洲人的比例上升（约四分之一到约一半）;黑人和西班牙裔人在一段时间内占移植候选人的一小部分。

总体而言，约四分之一的候选人患有HCC。但肝癌候选人的数量稳步上升，从时代1的5％到时代2的15％和时代3的39％，虽然HCC在过去两年略有下降。肝癌亚洲人的比例在时代3达到三分之二。黄医生认为这可能是因为在亚洲（B和C）发现的HBV基因型可能更有可能导致肝癌。

在时代1，0.9％的候选人死亡，46.6％在一年内接受移植;在等候名单上的平均死亡时间为1432天，移植的平均时间为273天。在时代2，8.4％死亡和40.3％在一年内移植;死亡和移植的平均时间分别为569天和311天。在时代3期间，6.2％的患者在等待期间死亡，47.5％的患者移植;死亡和移植的平均时间为350天和178天。

与Era 2（HR 4.55）相比，Era 1在等待名单上死亡的可能性显着更高，但从Era 2降至Era 3（HR 3.63 vs Era 1）。等待名单死亡率受移植名单上的死亡人数和死亡时间的影响。时代1具有最小的死亡数量和最长的平均死亡时间，研究人员说，这可能是由于选择偏向有利于更健康的个体，因为在90年代之前乙型肝炎患者的移植结果很差。

研究人员指出，研究表明，移植时的MELD评分近年来有所增加，这表明在候诊者中的人现在更加严重。但是从时代2到时代3的候选人死亡可能性的下降可能反映了乙型肝炎治疗的改善。 Era 3的亚组分析显示，即使在控制疾病严重程度后，生存从2005 - 2007年增加到2008 - 2011年（HR 0.77）和2012 - 2015年（HR 0.61）。

StephenW

"While current therapies are effective in suppressing HBV and reducing risk of cirrhosis and hepatocellular carcinoma, our current study demonstrates that HBV-related hepatocellular carcinoma is still a major concern," Dr Wong said in an AASLD press release. "[W]ith the many potential HBV therapies on the horizon, it will be interesting to understand what treatment endpoints are most effective at reducing HBV disease progression and hepatocellular carcinoma (e.g. viral suppression, normalization of alanine aminotransferases and HBV surface antigen loss)."
References

Hsu Y-C et al. Risk of hepatocellular carcinoma decreases over time in chronic hepatitis B patients on antiviral therapy with entecavir or tenofovir. The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, Boston, abstract 103, 2016. View abstract

Papatheordoridis GV et al. The risk of hepatocellular carcinoma (HCC) is decreasing after the first 5 years of entecavir (ETV) or tenofovir (TDF) therapy in Caucasian chronic hepatitis B (CHB) patients. The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, Boston, abstract 1867, 2016. View abstract

Papatheodoridis GV et al. Hepatocellular carcinoma (HCC) is the only factor affecting the excellent survival of Caucasian chronic hepatitis B (CHB) patients with or without cirrhosis under long-term entecavir (ETV) or tenofovir (TDF) therapy. The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, Boston, abstract 68, 2016. View abstract

Young K et al. Despite plateauing of chronic hepatitis b virus (HBV) patients listed for liver transplantation, the proportion of patients with HBV-related hepatocellular carcinoma continues to rise. The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, Boston, abstract 211, 2016. View abstract

StephenW

Wong博士在AASLD的新闻稿中说：“虽然目前的治疗有效抑制HBV并降低肝硬化和肝细胞癌的风险，但我们目前的研究表明，HBV相关的肝细胞癌仍然是一个主要关注。 “在许多潜在的HBV治疗方面，有趣的是，了解什么治疗终点最有效地减少HBV疾病进展和肝细胞癌（例如病毒抑制，丙氨酸氨基转移酶和HBV表面抗原损失的正常化）。 “。
参考文献

徐YC等在使用恩替卡韦或替诺福韦的抗病毒治疗的慢性乙型肝炎患者中，肝细胞癌的风险随时间降低。第67届美国肝病研究协会：肝脏会议，波士顿，摘要103，2016.查看摘要

Papatheordoridis GV et al。在高加索慢性乙型肝炎（CHB）患者中恩替卡韦（ETV）或替诺福韦（TDF）治疗的前5年后，肝细胞癌（HCC）的风险降低。美国肝病研究协会第67次会议：肝脏会议，波士顿，摘要1867年，2016年。查看摘要

Papatheodoridis GV等人在长期恩替卡韦（ETV）或替诺福韦（TDF）治疗期间，肝细胞癌（HCC）是影响具有或不具有肝硬化的白人慢性乙型肝炎（CHB）患者的优良存活的唯一因素。第67届美国肝病研究协会：肝脏会议，波士顿，摘要68，2016.查看摘要

Young K et al。尽管列入肝移植的慢性乙型肝炎病毒（HBV）患者平稳期，HBV相关肝细胞癌患者的比例继续上升。第67届美国肝病研究协会会议：肝脏会议，波士顿，摘要211，2016.查看摘要

StephenW

http://www.infohep.org/Is-better ... ?platform=hootsuite