AASLD2012:抗病毒治疗取得抑制病毒抗，肝癌的风险

StephenW

在慢性乙型肝炎患者抗病毒治疗取得抑制病毒抗，肝癌的风险
CONTROL ID: *1424601

*PRESENTATION TYPE: *Oral or Poster

*CURRENT CATEGORY: *Hepatitis B

*CURRENT DESCRIPTORS: *I01. Patient-centered, Natural History and Effectiveness Research

*TITLE: *Hepatocellular Carcinoma Risk In Chronic Hepatitis B Patients Achieving Viral Suppression With Antiviral Therapy.

*AUTHORS (FIRST NAME, LAST NAME): *_Simon Ghaly_^1 , Raghubinder S. Gill^2 , Mathew J. Keegan^2 , Peter W. Angus^3 , Jacob George^4 , Amanda J. Nicoll^5 , Matthew Law^6 , Marie Sinclair^7 , Lucy Y. Lim^3 , Hasanka Ratnayake^5 , Anna Dunn^5 , Simone I. Strasser^2 , Amany Zekry^1

*Institutional Author(s): *

*INSTITUTIONS (ALL): *1. Gastroenterology and Hepatology, St. George Hospital, Sydney, NSW, Australia.
2. AW Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
3. Gastroenterology and Liver Transplant Unit, The Austin Hospital , Melbourne, VIC, Australia.
4. Storr Liver Unit, Millennium Institute, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.
5. Gastroenterology and Hepatology, Royal Melbourne Hospital, Melbourne, VIC, Australia.
6. The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
7. Gastroenterology and Hepatology, Monash Medical Center, Melbourne, VIC, Australia.

*ABSTRACT BODY: *Effective viral suppression with antiviral therapy has been shown to reduce the development of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected patients. Scarce data exist however, on the group of patients who still develop HCC despite achieving HBV viral suppression with therapy. We aimed therefore, to characterise the risks and predictors for the development of HCC in this patient cohort.

Methods: This was a multicentre, retrospective analysis of HCC development in chronic hepatitis B over an 11-year period. HBV infected patients who achieved viral suppression (defined by HBV DNA <200IU/ml persistently) on antiviral therapy for at least 6 month and yet developed HCC were identified from hospital records. These were compared to a group of HBV infected patients achieving viral suppression with antiviral therapy and who did not develop HCC during follow-up. These were matched for duration of antiviral therapy and follow up from the time of therapy initiation.

Results: 537 patients with hepatitis B-related HCC were identified. Of these, 101 patients with viral suppression on antiviral therapy were identified and compared to a matched group of 99 HBV-patients with virological suppression, but without HCC development. Among these 200 patients, mean age at HCC diagnosis was 54.9±10.4 year old, the majority were of Asian background (66%), and were predominately male (80%). The median follow-up was 35.5 (range 6-144) months. Of the HCC group 30% were non cirrhotic. Among the HCC and the control group, 77% and 55% respectively had received initial lamivudine therapy. By univariate analysis, those who developed HCC were more likely to be male (OR 2.21 p=0.031), age >60 (OR 2.32, p= 0.034), HBeAg negative (OR 1.9, p=0.037) and have been exposed to lamivudine (OR 2.713 p=0.001). Baseline viral load, time taken to achieve viral suppression, and the development of lamivudine resistance (as defined by the need to switch to other therapy due to failure to achieve undetectable viral load during follow up), did not reach statistical significance. On multivariate analysis age>60, male gender and lamivudine exposure (OR 3.12, 95%CI: 1.61-6.05) remained independent predictors of HCC development.

Conclusions. In our cohort, despite achieving viral suppression with anti viral therapy, there was still an increased risk of HCC primarily related to older age, and exposure to lamivudine therapy. The association with lamivudine exposure raises the possibility of drug-induced mutations associated with an increased risk of HCC development - this possibility is currently under investigation.

StephenW

*有效抑制病毒的抗病毒治疗乙型肝炎病毒（HBV）感染的患者已被证明是减少肝细胞肝癌（HCC）的发展。然而，稀缺的数据存在，对本集团的开发HCC尽管实现病毒抑制治疗的患者。因此，我们的目的是，以发展为肝细胞癌这个病人队列的风险特征和预测因子。

方法：这是一项多中心，回顾性分析在慢性B型肝炎的肝癌发展超过11年的时间。 HBV感染患者的抗病毒治疗至少6个月达到病毒抑制（持续HBV DNA <200IU/ml）和尚未开发的HCC患者从医院的记录标识。这些进行了比较，一组HBV感染的患者达到抑制病毒的抗病毒治疗，谁没有在后续开发HCC。这些相匹配的抗病毒治疗的持续时间和后续治疗开始的时间。

结果：537 B型肝炎相关的肝癌患者进行了鉴定。抑制病毒的抗病毒治疗，其中101例被确定和比较的匹配组的99 HBV-患者的病毒学抑制，但无肝癌发展。在这200名患者中，平均，肝癌诊断年龄为54.9±老10.4年，大多数的亚洲背景（66％），并以男性为主（80％）。中位随访时间为35.5个月（范围6-144）。 30％的肝癌组，非肝硬化。在HCC和对照组，分别为77％和55％，收到了初步拉米夫定治疗。单因素分析显示，那些谁开发HCC更可能是男性（OR 2.21，P = 0.031），年龄> 60岁（OR 2.32，P = 0.034），HBeAg阴性（OR 1.9，P = 0.037）和已暴露于拉米夫定（OR 2.713，P = 0.001）。基线病毒载量，所需的时间，以达到抑制病毒，和拉米夫定耐药性的发展（定义见的需要切换到其他治疗，由于未能实现随访过程中检测不到病毒载量），没有达到统计意义。多变量分析显示年龄> 60岁，男性性别和拉米夫定暴露（OR 3.12，95％CI：1.61-6.05）仍然HCC发展的独立预测因子。

结论。在我们的研究中，尽管实现抑制病毒的抗病毒治疗，主要与年龄增长，接触拉米夫定治疗肝癌的危险性增加。与拉米夫定曝光引起了药物引起的基因突变与肝癌发展的危险性增加的可能性 - 这种可能性目前正在调查中。

疯一点好

看不太懂，应该是说抗病毒治疗可以减少肝癌的发生，但后面的结论又说拉米治疗肝癌的危险性增加，不知道是不是这个意思。

StephenW

回复 疯一点好 的帖子

抗病毒治疗应该可以减少肝癌的发生，但取得坚持的HBVDNA<200 IU / ml, 至少6个月,肝癌仍有发生. 研究比较2组: 101 有肝癌, 99 没有肝癌. 多元统计分析，年龄>60岁，男性性别和
之前用过拉米夫定的（OR3.12，95％CI：1.61-6.05）是肝癌发生的独立预测因子。
用过拉米治疗肝癌的危险性增加 - 是否拉米夫定药诱发突变有关吗？正在调查中.

咬牙硬挺

难道抗病毒会诱发肝癌？有点可怕…

疯一点好

我有点怀疑，抗病毒持续dna阴性可能就好，但当病毒变异发生耐药后可能会加快癌变速度，其实那个阿德帖子后面也有个别案例，只是拉米耐药率高，其促发癌变的苗头已经显现。而其他抗病毒药耐药的案例数据还未足以满足统计学的需要，嗯，还不好说吧？总之抗病毒治疗只是救眼前罢了，长远疗效还是未知数啊。

StephenW

这个讨论是从论文:

慢性乙型肝炎患者接受核苷（酸）IDE治疗肝癌的发病率：系统回顾
Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: A systematic reviewGeorge V. Papatheodoridis,Pietro Lampertico,Spilios Manolakopoulos,Anna Lokhttp://www.journal-of-hepatology.eu/article/S0168-8278%2810%2900331-4/fulltext

Discussion The results of our systematic review show that the medium-term risk of HCC is significantly lower in chronic hepatitis B patients receiving effective oral antiviral therapy. In three studies including untreated controls, HCC developed in 2.8% of treated and in 6.4% of untreated chronic hepatitis B patients (p=0.003). Although only one of these three studies was randomised [22], the untreated controls had many similar characteristics with the treated patients in the second study [26] and were selected to match the treated patients in the third study [32]. It should be noted that treatment significantly reduced the HCC incidence in the only randomised trial [22]. Given the benefits of antiviral therapy, it is unethical not to offer treatment to chronic hepatitis B patients who meet treatment criteria. These data therefore represent the best evidence supporting the efficacy of nucleos(t)ide analogue therapy in reducing the incidence of HCC in chronic hepatitis B patients.
Achievement of virological remission after the initial treatment course was found to be extremely important for the reduction of HCC incidence. In studies including nucleos(t)ide naive patients, HCC developed significantly less frequently in patients remaining in virological remission than in those with virological breakthrough or no response (2.3% vs 7.5%, p<0.001). This finding is in agreement with the well known association between levels of HBV replication and HCC risk [8]. It is not surprising that viral suppression decreased but did not eliminate the risk of HCC in chronic HBV patients because HBV DNA may have already integrated into the host genome before the onset of treatment and may have already resulted in genomic alterations and/or chromosomal instability [39], [40]. Furthermore, in patients who have been infected for a long time or who have already progressed to cirrhosis, malignant transformation of hepatocytes may be present before the onset of treatment. Finally, some of the tumours may have been present at the start of treatment and were not detected by routine clinical evaluations. The latter hypothesis is in agreement with the finding that approximately one fourth (23%) of HCC cases in nucleos(t)ide naive patients were diagnosed within the first year of treatment.
The rate of HCC was significantly higher in lamivudine resistance than in nucleos(t)ide naive patients (7.1% vs 3.8%, p=0.001) despite a shorter duration of follow-up. This is partly related to the more frequent presence of cirrhosis among patients with lamivudine resistance, but even among cirrhotics, the incidence of HCC was significantly higher in patients with lamivudine resistance than in those who were nucleos(t)ide naive (18% vs 11%, p=0.015). Achievement of virological response did not seem to significantly reduce the HCC risk in patients with lamivudine resistance, as HCC was detected in 9% of such patients with and in 6% of those without detectable viremia during rescue therapy (p=0.466). These data suggest that the maintenance of viral suppression over a long period of time is needed to reduce the risk of HCC. It has also been suggested that mutations associated with lamivudine resistance, in particular, changes at position 181 of the reverse transcriptase domain of the HBV polymerase have direct oncogenic potential [41], [42].
It is well known that the HCC risk is highest among untreated chronic HBV patients with cirrhosis and that severe fibrosis and cirrhosis predispose to the development of HCC [1], [2], [4]. Our data show that the risk of HCC remains high in cirrhotic patients receiving nucleos(t)ide analogue therapy. HCC developed in 11% of cirrhotic and in only 0.5% of non-cirrhotic chronic hepatitis B patients who were naive to nucleos(t)ide agents (p<0.001) and in 18% of cirrhotic and 0% of non-cirrhotic patients with lamivudine resistance (p<0.001). The effect of the severity of cirrhosis (compensated vs decompensated) on HCC risk could not be evaluated because of the small number of patients.
Other factors found to be associated with the risk of HCC were older age, regular HCC surveillance and inclusion of HBeAg negative cases. Older age is a well known risk factor for HCC [1], [2], [4], but the higher HCC rate in the studies with mean/median age 50years vs <50years might be, at least partly, related to the higher proportion of cirrhotic patients in the studies with older patients. Indeed, cirrhosis was present in a higher percent of patients in studies with mean/median age 50years (543/1085 or 50% vs 511/2202 or 23%, p<0.001) (Table 1). The association between HCC risk and HCC surveillance may be related to a higher proportion of patients with cirrhosis in studies with HCC surveillance. The proportion of nucleos(t)ide naive patients with cirrhosis was significantly higher in studies which reported regular HCC surveillance [19], [21], [22], [25], [26], [27], [32], [35], [36] than those which did not [18], [20], [23], [24], [28], [29], [34] (566/1200 or 47% vs 488/2087 or 23%, p<0.001). The association between HCC risk and HBeAg-negative status may be related to the older age and more frequent presence of cirrhosis in HBeAg-negative patients. The proportion of patients with cirrhosis was significantly higher in studies with almost exclusively HBeAg negative [19], [20], [21], [26], [28], [29], [35] than studies with predominantly HBeAg-positive patients [18], [32], [34] (536/1245 or 43% vs 97/1200 or 8%, p<0.001) (Table 1).
In conclusion, medium-term nucleos(t)ide analogue therapy significantly reduces but it does not completely eliminate the risk of HCC, particularly in patients with pre-existing cirrhosis. Patients with cirrhosis undergoing antiviral treatment should continue to undergo HCC surveillance. Maintenance of virological remission is important for the reduction of HCC risk. Our findings suggest that HCC risk is increased in patients who experience virologic breakthrough even if HBV replication is subsequently suppressed by rescue therapy. This observation provides further evidence that lamivudine is not an optimal first-line treatment for chronic hepatitis B, as it is associated with very high rates of drug resistance during long-term treatment. Our study is limited by the poor quality of many of the included studies, the heterogeneous patient populations, the variations in treatment regimens and patient monitoring, the differences in definitions of response, and the wide range in sensitivity of HBV DNA assays used to assess virological response and the different duration of follow-up. In addition, because incidence of HCC was not a primary outcome in these studies, details regarding screening of HCC at baseline and HCC surveillance during therapy, diagnostic criteria of HCC and timing of HCC diagnosis were not specified in most studies. Nevertheless, the large number of patients and the results of subgroup analyses reinforce the validity of our conclusions. The vast majority of the current data on HCC risk in chronic hepatitis B patients treated with nucleos(t)ide analogues come from studies on lamivudine. It is anticipated that the newer nucleos(t)ide analogues, such as entecavir and tenofovir, will further reduce the HCC incidence given their greater potency and better resistance profiles.

讨论

我们的系统的审查结果显示，中期肝癌的风险显着降低，慢性乙型肝炎患者接受有效的口服抗病毒药物治疗。在三年的研究，包括未经处理的对照组，HCC开发处理后的2.8％和6.4％，未经治疗的慢性乙肝患者（P = 0.003）。虽然只有一个是随机的这三个研究[22]，未经处理的对照组治疗的患者在第二项研究中有许多相似的特点[26]和选择，以配合治疗的患者在第三项研究[32]。应该指出的是治疗肝癌发病率显着降低了在唯一的随机试验[22]。由于抗病毒治疗的好处，这是不道德的，不提供治疗慢性乙型肝炎患者符合治疗标准的。因此，这些数据代表了最好的证据支持核苷（酸）类似物治疗，减少肝癌的发病率在慢性乙型肝炎患者的疗效。

成就的初始疗程的病毒学缓解后发现的肝癌发病率的降低是非常重要的。在包括核苷（酸）IDE初治患者的研究中，HCC的发展明显较少留在病毒学缓解的患者相比，那些与病毒学突破或无反应（2.3％对7.5％，P <0.001）。这一发现是在协议与著名的HBV复制水平之间的关系和肝癌的风险[8]。这并不奇怪，抑制病毒的下降，但在慢性乙肝患者中肝癌的危险并没有消除，因为HBV DNA已经整合到宿主基因组发病前的治疗，可能已经导致基因改变和/或染色体不稳定[ 39]，[40]。此外，在已经感染了很长一段时间，或已经进展到肝硬化的患者，肝细胞的恶性转化可能是在发病前的治疗。最后，某些肿瘤可能已经存在于开始治疗，并没有检测到由常规的临床评价。后者的假设是一致的发现，在第一年的治疗核苷（酸）IDE初治患者的肝癌病例中约四分之一（23％）被诊断。

肝癌率显着较高的拉米夫定耐药的核苷（酸）IDE初治患者（7.1％对3.8％，P = 0.001）尽管持续时间较短的后续行动。这是较频繁的拉米夫定耐药的患者肝硬化有一定的关系，但即使是在肝硬化，肝癌的发病率显着高于拉米夫定耐药的患者比那些核苷（酸）IDE天真的（18％比11 ％，P = 0.015）。成就的病毒学应答似乎并没有显着降低肝癌的风险与拉米夫定耐药的患者，如肝癌中检测到9％的此类患者的抢救治疗过程中没有检测到病毒血症（P = 0.466），并在6％。这些数据表明，在很长一段时间内抑制病毒的维护是需要减少肝癌的危险。也有人认为，与拉米夫定耐药相关的基因突变，特别是在HBV聚合酶逆转录酶结构域的181位的变化有直接的致癌性[41]，[42]。

这是众所周知的，未经治疗的慢性乙肝患者肝硬化肝癌的风险是最高的，严重的肝纤维化和肝硬化易患肝癌的发展[1]，[2]，[4]。我们的数据显示，在肝硬化患者中，接受核苷（酸）类似物治疗肝癌的风险仍然很高。在11％的肝硬化和非肝硬化的慢性乙肝患者谁是天真的核苷（酸）IDE剂（P <0.001）和18％的肝硬化和非肝硬化患者0％，只有0.5％的HCC发展拉米夫定耐药性（P <0.001）。肝硬化（代偿与失代偿期），对肝癌风险的严重程度的影响无法评估，因为少数患者。

发现与肝癌的危险因素是年龄，定期肝癌监测和包容性的HBeAg阴性的病例。年龄是一个众所周知的HCC的危险因素[1]，[2]，[4]，但较高的HCC研究的平均数/中位数年龄50年率比<50年可能会对，至少部分地，涉及到较高的比例的肝硬化患者，老年患者的研究中。事实上，肝硬化是目前在一个较高％的患者在研究，平均/的中位数的年龄50年（的1085分之543与二千二百〇二分之五百十一50％或23％，P <0.001）（表1）。可能与肝癌风险之间的关联和肝癌监测与肝硬化的患者在研究肝癌监测到一个更高的比例。核苷（酸）IDE天真的肝硬化患者的比例显着较高的定期HCC监测的研究报告[19]，[21]，[22]，[25]，[26]，[27]，[32] [35]，[36]比那些没有[18]，[20]，[23]，[24]，[28]，[29]，[34]（566/1200或47％比二千〇八十七分之四百八十八或23％，P <0.001）。肝癌风险之间的关联和HBeAg阴性状态，可能与肝硬化HBeAg阴性患者年龄较大，较频繁的。肝硬化患者的比例显着较高的研究，几乎完全HBeAg阴性[19]，[20]，[21]，[26]，[28]，[29]，[35]的研究，主要是HBeAg阳性患者[18]，[32]，[34]（1245分之536或与一千二分之九十七43％或8％，P <0.001）（表1）。

总之，中期核苷（T）类似物治疗显着降低，但它并不能完全消除肝癌的危险，特别是在与预先存在的肝硬化患者。肝硬化患者进行抗病毒治疗应继续接受HCC监控。病毒学缓解的维修是很重要的肝癌风险减少。我们的研究结果表明，谁的经验病毒学突破，即使随后被抑制HBV复制的抢救治疗的患者中，HCC的风险增加。这个观察提供了进一步的证据，拉米夫定不是一个最佳的第一线治疗慢性乙型肝炎，因为它是与长期治疗过程中的耐药率非常高。质量差很多的研究，我们的研究是有限的异质的患者人群，不同的治疗方案，病人监护仪，定义响应的差异，以及广泛使用的HBV DNA检测的灵敏度，以评估病毒学响应和不同时间的随访。此外，由于肝癌的发病率是不是在这些研究的主要成果，在治疗过程中有关基线筛查肝癌和肝癌监测，肝癌诊断肝癌和时间的诊断标准并没有规定在大多数研究中。然而，大量的患者和亚组分析的结果加强了我们的结论的有效性。绝大多数当前的数据来自研究拉米夫定的核苷（酸）类似物治疗慢性乙型肝炎患者的HCC风险。可以预见，新的核苷（酸）类似物，如恩替卡韦和替诺福韦，将进一步降低肝癌发病率更大的效力和更好的抗型材。