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标题: 替诺福韦治疗具有较低的肝细胞癌风险比恩替卡韦治疗慢性 [打印本页]

作者: StephenW 时间: 2019-7-8 16:14 标题: 替诺福韦治疗具有较低的肝细胞癌风险比恩替卡韦治疗慢性

本帖最后由 StephenW 于 2019-7-8 16:16 编辑

Tenofovir treatment has lower risk of hepatocellular carcinoma
than entecavir treatment in patients with chronic hepatitis B

Reported by Jules Levin
EASL 2019 April 10-14 Vienna (home of gelato)

Terry Cheuk-Fung Yip1,2, Vincent Wai-Sun Wong1,2,3, Yee-Kit Tse1,2,
Henry Lik-Yuen Chan1,2,3, Grace Lai-Hung Wong1,2,3
1Institute of Digestive Disease,
2Department of Medicine and Therapeutics, and
3State Key Laboratory of Digestive Disease,
The Chinese University of Hong Kong

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作者: StephenW 时间: 2019-7-8 16:17

Risk of Hepatocellular Carcinoma in Patients Treated With Entecavir vs Tenofovir for Chronic Hepatitis BA Korean Nationwide Cohort Study

JAMA Oncol. 2019

Question Are entecavir and tenofovir disoproxil fumarate, the first-line antiviral agents for chronic hepatitis B infection, associated with similar risks of hepatocellular carcinoma during long-term treatment?

Findings In a Korean nationwide population cohort of 24 156 treatment-naive adult patients with chronic hepatitis B infection, tenofovir treatment was associated with a significantly lower risk of hepatocellular carcinoma and mortality compared with entecavir treatment. The data were validated in a hospital cohort of 2701 treatment-naive adult patients with chronic hepatitis B infection.

Meaning Given the poor prognosis of patients who developed hepatocellular carcinoma, this study's findings may have considerable clinical implications in the prevention of this cancer in patients with chronic hepatitis B infection.

Results Among the population cohort of 24 156, the mean (SD) age was 48.9 (9.8) years, and 15 120 patients (62.6%) were male. Among the hospital cohort of 2701, the mean (SD) age was 48.8 (10.5) years and 1657 patients (61.3%) were male. In the population cohort, the annual incidence rate of HCC was significantly lower in the tenofovir group (0.64 per 100 person-years [PY]) than in the entecavir group (1.06 per 100 PY). By multivariable-adjusted analysis, tenofovir therapy was associated with a significantly lower risk of HCC (hazard ratio [HR], 0.61; 95% CI, 0.54-0.70) and all-cause mortality or transplant (HR, 0.77; 95% CI, 0.65-0.92) compared with entecavir. The tenofovir group also showed a significantly lower risk of HCC in the 10 923-pair propensity score-matched population cohort (HR, 0.62; 95% CI, 0.54-0.70) and 869-pair propensity score-matched hospital cohort (HR, 0.68; 95% CI, 0.46-0.99) compared with the entecavir group.

The mechanism of our main finding on the association of tenofovir with a significantly lower risk of HCC compared with entecavir might be explained in part by the better VR profiles of the tenofovir group as shown in the hospital cohort, which are in line with the results of previous studies.16-18 However, considering that VR was not an independent risk factor for HCC, the differences in HCC risk between the 2 treatments cannot be fully explained by their antiviral potency. A recent study showed that higher serum interferon λ3 levels were induced in patients treated with nucleotide analogues (adefovir dipivoxil and tenofovir), but not in those treated with nucleoside analogues (lamivudine and entecavir).19 Interferon lambda showed potent antitumor activity in murine models of cancer, including hepatoma,20,21 and this antitumor activity could presumably contribute to the difference in the HCC risk that we observed.

Entecavir was shown to be carcinogenic in mice and rats when administered at doses higher than those used in humans.22 It was also shown to potentially incorporate into the human genome, which may contribute to a putative mechanism of carcinogenicity, especially if the embedded genomes have higher error rates during subsequent rounds of replication.23-25 These data raise concern about the carcinogenic potential of entecavir even at clinical doses during long-term treatment, especially in patients with cirrhosis who have increased chromosomal instability of hepatocytes.26,27

Nevertheless, given that HBV replication itself is a strong independent risk factor for HCC, assessing the carcinogenic potential of entecavir should be balanced by considering its protective role against HCC development via suppression of HBV replication. Many observational studies and meta-analyses have shown that in patients with CHB, entecavir therapy significantly reduced HCC risk compared with no treatment.18,22,28 However, a previous cohort study demonstrated that HCC risk with entecavir was not lower than that with lamivudine.7 Nonetheless, the effect of entecavir on HCC risk would be better compared with tenofovir because both drugs have similar potencies in suppressing HBV replication.16,18,28 Based on our data, 185 HCC cases were estimated to have been preventable at 4 years' follow-up if the 11 464 patients in the entecavir group had used tenofovir (eTable 15 in the Supplement).

Pdfs attached above

作者: StephenW 时间: 2019-7-8 16:17

恩替卡韦与替诺福韦治疗慢性肝炎患者肝细胞癌的风险BA全国队列研究

JAMA Oncol。 2019

问题恩替卡韦和替诺福韦地索普西富马酸盐是慢性乙型肝炎感染的一线抗病毒药物，与长期治疗期间肝细胞癌的相似风险相关吗？

结果在一项韩国全国人群中，有24 156名未接受治疗的成年慢性乙型肝炎患者，与恩替卡韦治疗相比，替诺福韦治疗与肝细胞癌和死亡率的风险显着降低相关。该数据在2701例未接受治疗的成人慢性乙型肝炎感染患者的医院队列中得到验证。

意义鉴于患有肝细胞癌的患者预后不良，本研究的结果可能对慢性乙型肝炎患者预防这种癌症具有相当大的临床意义。

结果在24 156人群中，平均（SD）年龄为48.9（9.8）岁，15 120名患者（62.6％）为男性。在2701名医院队列中，平均（SD）年龄为48.8（10.5）岁，1657名患者（61.3％）为男性。在人群中，替诺福韦组的HCC年发病率显着低于每100人年[PY] 0.64，而非恩替卡韦组（1.06 / 100 PY）。通过多变量校正分析，替诺福韦治疗与HCC风险显着降低（风险比[HR]，0.61; 95％CI，0.54-0.70）和全因死亡率或移植（HR，0.77; 95％CI， 0.65-0.92）与恩替卡韦相比。替诺福韦组在10 923对倾向评分匹配的人群组（HR，0.62; 95％CI，0.54-0.70）和869对倾向评分匹配的医院队列中显示出显着较低的HCC风险（HR，0.68）与恩替卡韦组相比，95％CI，0.46-0.99）。

与恩替卡韦相比，我们对替诺福韦与HCC风险显着降低的关联的主要发现机制可能部分地由医院队列中显示的替诺福韦组的更好的VR曲线解释，这与结果一致。之前的研究[16-18]然而，考虑到VR不是HCC的独立危险因素，2种治疗之间HCC风险的差异不能通过其抗病毒效力来完全解释。最近的一项研究表明，在用核苷酸类似物（阿德福韦酯和替诺福韦）治疗的患者中诱导了更高的血清干扰素λ3水平，但在用核苷类似物（拉米夫定和恩替卡韦）治疗的患者中没有.19干扰素λ在小鼠模型中显示出强有力的抗肿瘤活性。癌症，包括肝癌，20,21，这种抗肿瘤活性可能会导致我们观察到的HCC风险的差异。

恩替卡韦在小鼠和大鼠体内的剂量高于人类使用的剂量时显示出致癌性.22它也被证明可能与人类基因组结合，这可能有助于推定致癌机制，特别是如果嵌入的基因组有在随后几轮复制过程中错误率较高.23-25这些数据引起人们对恩替卡韦即使在长期治疗期间的临床剂量也具有致癌可能性的担忧，尤其是肝硬化肝细胞染色体不稳定性增加的患者.26,27

尽管如此，鉴于HBV复制本身是HCC的一个强大的独立危险因素，评估恩替卡韦的致癌潜力应通过考虑其通过抑制HBV复制对HCC发展的保护作用来平衡。许多观察性研究和荟萃分析显示，在CHB患者中，与未治疗相比，恩替卡韦治疗显着降低了HCC风险[18,22,28]。然而，之前的一项队列研究表明恩替卡韦的HCC风险并不低于拉米夫定的风险.7尽管如此，与替诺福韦相比，恩替卡韦对HCC风险的影响会更好，因为两种药物在抑制HBV复制方面具有相似的效力[16,18,28]。根据我们的数据，估计185例HCC病例可在4年内预防。如果恩替卡韦组的11 464名患者使用替诺福韦（补充中的eTable 15），则进行随访。

上面附有Pdfs

作者: StephenW 时间: 2019-7-8 16:19

Editorial
January 2019 JAMA Oncol. 2019

Current guidelines for the treatment of chronic hepatitis B (CHB) recommend as first-line line therapy entecavir (ETV), tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide fumarate.1-3 Both ETV and TDF achieve similar rates of hepatitis B virus (HBV) DNA suppression and alanine aminotransferase normalization over time and have an excellent safety record. However, ETV and TDF have not been directly compared except in patients with decompensated cirrhosis4; to our knowledge, no other head-to-head randomized trials exist. Yet, there is strong interest in understanding if one drug might be superior to the other in specific clinical settings or subpopulations. In the absence of randomized comparator trials, high-quality "real world" cohorts can be quite informative. In this issue of JAMA Oncology, Choi and colleagues5 report the results of 2 retrospective cohort studies of patients with CHB from Korea that evaluated the association between the type of nucleoside or nucleotide analogue and the development of hepatocellular carcinoma (HCC).5 Using both a large administrative data set (24 156 patients with CHB and 984 with HCC) and a tertiary hospital-based cohort (2701 patients with CHB and 154 with HCC), the authors found that the risk of HCC was consistently about 35% lower in those treated with TDF than in those treated with ETV. This association persisted even when stratified by cirrhosis status and after very thorough adjustment for available confounders. These striking findings raise the question of whether the current CHB guidelines should be updated to reflect this observed superior anticancer benefit of TDF over ETV.

Multiple studies have shown that treatment with either ETV or TDF reduces the incidence of HCC in patients with CHB when compared with untreated patients.6,7 Prior studies examining the use of ETV vs TDF, though limited in numbers, did not find a difference between these 2 first-line agents.8,9 Based on the observed adjusted hazard ratios in the study by Choi and colleagues,5 these other cohort studies would have needed more than 200 cases of HCC to have adequate power to detect a 35% reduction in HCC risk. Therefore, since the largest known study had only 56 incident cases of HCC,8 these earlier studies may have been underpowered to detect a difference in HCC rates by antiviral drug.

There remains a concern that the observed difference in HCC rates is due to residual confounding. This is a limitation of all observational studies, but Choi and colleagues5 used a robust analytic approach that included multiple subgroup analyses, the use of propensity scores and competing risks, as well as validation in a hospital-based cohort having data on disease severity and virologic responses. Remarkably, the association of ETV vs TDF and HCC risk was minimally changed by any of these adjustments. However, adherence to antiviral therapy and surveillance programs was not captured and may have influenced rates of HCC. Indeed, adherence of less than 90% to antiviral therapy in patients with CHB has been associated with a higher risk of HCC.10 Moreover, especially in countries where prior lamivudine exposure is prevalent, patients treated with ETV may be at increased risk of virologic breakthrough with time, and this, in turn, affects risk for HCC. Indeed, in the study by Choi and colleagues, there was a substantially higher rate of changing therapy in patients treated with ETV (12%) vs TDF (0.2%). Might reduced adherence and increasing rates of ETV resistance represent unmeasured confounders that contribute to the divergence in rates of HCC evident 2 years after initiation of therapy? Ideally, a randomized study design would help overcome these challenges and provide stronger evidence of the association between type of antiviral agent and HCC outcomes. As such a study seems unlikely, at least in the near term, we would advocate for additional observational cohorts with data on liver disease severity, virologic response, and adherence to surveillance to evaluate this important question.

In considering HBV therapy as prevention of HCC, a critical question remains. How important is the achievement and maintenance of undetectable HBV DNA during treatment? Current HBV guidelines do not recommend changing or adding another antiviral agent in patients with low-level intermittent or persistent viremia during treatment with first-line agents, as long as criteria for virologic breakthrough are not met. In terms of HCC risk, natural history studies show that HCC risk is highest among those with HBV DNA levels of 200 000 IU/mL or higher but not different from uninfected controls if HBV DNA levels are lower than 2000 IU/mL.11 More recent studies of patients undergoing long-term antiviral therapy provide conflicting results on the importance of low-level viremia and HCC risk. In a Korean study of patients with CHB and cirrhosis on ETV therapy for up to 5 years, rates of HCC were 2.2-fold higher in patients with persistent or intermittent HBV DNA viral loads less than 2000 IU/mL compared with those with persistently undetectable HBV DNA (<12 IU/mL), though this did not hold true for those without cirrhosis.12 In a study of patients with decompensated cirrhosis, maintained virologic response (<20 IU/mL) vs suboptimal responses (<2000 but >20 IU/mL) influenced transplant-free survival but not HCC risk over 10 years.13 These studies highlight the importance of cirrhosis as a primary driver of HCC risk, independent of effective therapy.12,13 However, for those without cirrhosis, which represent the majority of patients with CHB, the level of viremia may be relevant to treatment decisions. While the study by Choi et al5 includes information on virologic response in the first year with the validation cohort, the absence of longitudinal virologic response over the duration of follow-up is a shortcoming of the larger observational cohort, and could be the major explanatory variable for the differences in HCC outcomes in the ETV vs TDF groups. Collectively, recent studies suggest that viral suppression is important, and thus selecting an antiviral agent that achieves and maintains suppression is highly desirable, but the findings do not dictate that one drug should be preferred over the other.

Finally, if TDF is superior to ETV in reducing HCC risk, the big question is why. Choi and colleagues5 offer 2 potential explanations, neither of which is well supported by human data. They suggest that ETV may be procarcinogenic and/or that nucleotide analogues (vs nucleoside analogues) may induce higher antitumor cytokines. That viral clearance may induce an altered intrahepatic milieu that influences risk of hepatocarcinogenesis is possible, though the rapidity of viral and antigen decline may be more important than the specific drug type (nucleoside vs nucleotide) used. The hypothesis that ETV may be procarcinogenic is based on preclinical studies in mice and rats treated with high-dose ETV; there are no human correlative data to support this. Indeed, if this were the case, one would have expected to see increasing rates of HCC with increasing duration of drug exposure; a feature not seen in this cohort or others.5,6,14 The study by Choi et al with just over 4 years of follow-up data does not provide a yearly HCC incidence, but visual inspection of the survival curves in ETV-treated patients suggests that the rate of incident HCC is not increasing. Another Korean cohort of almost 2000 patients treated with ETV showed that the annual HCC incidence in the first 5 years of treatment was similar to the rate after 5 years of ETV exposure (2.29% vs 1.66%, P = .22).14 Additionally, in a cohort of over 1900 white patients with CHB undergoing long-term treatment with either ETV or TDF with a median follow-up of 6 years, HCC incidence was similar beyond 5 years in those without cirrhosis, while there was a significant decrease in HCC incidence after 5 years of therapy in those with cirrhosis at baseline.6 Thus, there is no clinical support for a procarcinogenic tendency with ETV, and the biologic underpinnings of the observed difference in HCC rates between ETV and TDF remain obscure.

Three safe and effective oral antivirals are endorsed by experts as first-line therapy for CHB: ETV, TDF, and tenofovir alafenamide fumarate.1,2 These antiviral agents share the qualities of high efficacy in reducing HBV DNA levels and excellent tolerability and safety. In deciding on the best option for a given patient with CHB, the clinician should consider the treatment history, comorbidities, including renal disease or human immunodeficiency virus, and cost and accessibility. Prevention of liver-related complications requires adherence to the treatment regimen and a therapy achieving viral load suppression. The work of Choi and colleagues5 is the first to our knowledge to suggest that TDF offers advantages over ETV in terms of HCC prevention, but given the inherent limitations of observational data, this study should not lead to a widespread paradigm shift in selecting TDF over ETV. Rather, it should spur more investigators to address the issue of whether one of these HBV drugs is not like the other.

作者: StephenW 时间: 2019-7-8 16:21

社论
2019年1月JAMA Oncol。 2019

目前的慢性乙型肝炎（CHB）治疗指南推荐为一线治疗恩替卡韦（ETV），替诺福韦地索普西富马酸盐（TDF）或替诺福韦艾拉酚酰胺富马酸盐.1-3 ETV和TDF均达到相似的乙型肝炎病毒率（HBV）DNA抑制和丙氨酸氨基转移酶随时间正常化并具有极好的安全记录。然而，除了失代偿期肝硬化患者外，尚未直接比较ETV和TDF4;据我们所知，没有其他头对头的随机试验存在。然而，人们对了解一种药物在特定临床环境或亚群中是否优于另一种药物具有浓厚的兴趣。在没有随机比较试验的情况下，高质量的“真实世界”队列可以提供相当丰富的信息。在本期JAMA肿瘤学杂志中，Choi及其同事[5]报道了韩国CHB患者的2项回顾性队列研究结果，该研究评估了核苷类或核苷酸类似物与肝细胞癌（HCC）发展之间的关系。大型行政数据集（24 156名CHB患者和984名HCC患者）和一家三级医院队列（2701名CHB患者和154名HCC患者），作者发现HCC的风险在治疗组中始终低约35％使用TDF比使用ETV治疗的患者。即使在肝硬化状态分层和对可用混杂因素进行非常彻底的调整后，这种关联仍然存在。这些引人注目的研究结果提出了一个问题，即目前的CHB指南是否应该更新，以反映TDF优于ETV的抗癌益处。

多项研究表明，与未治疗的患者相比，ETV或TDF治疗可降低CHB患者的HCC发病率[6,7]。之前的研究检查ETV与TDF的使用虽然数量有限但未发现差异。根据Choi及其同事在研究中观察到的调整风险比，5这些其他队列研究需要200多例HCC才能有足够的能力来检测35％的减少。 HCC风险。因此，由于已知的最大研究仅有56例HCC事件，8这些早期研究可能无法通过抗病毒药物检测HCC发病率的差异。

仍然存在一种担忧，即观察到的HCC率差异是由于残留的混杂因素造成的。这是所有观察性研究的局限性，但Choi及其同事使用了一种强大的分析方法，包括多个亚组分析，倾向评分和竞争风险的使用，以及基于医院的队列中的验证，其中包含疾病严重程度和病毒学数据。响应。值得注意的是，ETV与TDF和HCC风险的关联在这些调整中几乎没有变化。然而，没有捕获抗病毒治疗和监测计划，可能会影响HCC的发病率。事实上，CHB患者对抗病毒治疗的依从性低于90％与HCC风险增加有关.10此外，特别是在拉米夫定暴露普遍存在的国家，接受ETV治疗的患者可能会增加病毒学突破的风险。随着时间的推移，这反过来会影响HCC的风险。事实上，在Choi及其同事的研究中，接受ETV治疗的患者（12％）与TDF（0.2％）相比，改变治疗的比率要高得多。可能降低依从性和增加ETV耐药率代表未测量的混杂因素，这些混杂因素导致治疗开始2年后HCC发生率明显不同？理想情况下，随机研究设计有助于克服这些挑战，并为抗病毒药物类型与HCC结局之间的关联提供更有力的证据。由于这样的研究似乎不太可能，至少在近期内，我们会提倡额外的观察性队列，其中包括肝病严重程度，病毒学应答和遵守监测的数据，以评估这一重要问题。

在考虑将HBV治疗作为预防HCC时，仍存在一个关键问题。治疗期间检测到的HBV DNA的成功和维持有多重要？目前的HBV指南不建议在用一线药物治疗期间改变或添加另一种抗病毒药物用于低水平间歇性或持续性病毒血症患者，只要不符合病毒学突破的标准。就HCC风险而言，自然史研究表明，如果HBV DNA水平低于2000 IU / mL，那么HBV DNA水平为200 000 IU / mL或更高的患者的HCC风险最高，但与未感染的对照无差异.11最近对长期抗病毒治疗患者的研究提供了低水平病毒血症和HCC风险重要性的相互矛盾的结果。在韩国一项关于CHB和肝硬化患者接受ETV治疗长达5年的研究中，持续或间歇性HBV DNA病毒载量低于2000 IU / mL的患者与持续检测不到HBV的患者相比，HCC发生率高2.2倍DNA（<12 IU / mL）虽然对于没有肝硬化的患者不适用.12在对失代偿性肝硬化患者的研究中，维持病毒学应答（<20 IU / mL）与次优应答（<2000但> 20 IU）这些研究强调了肝硬化作为HCC风险的主要驱动因素的重要性，与有效治疗无关[12,13]。然而，对于那些没有肝硬化的患者，这代表了无肝移植存活率。大多数CHB患者，病毒血症的水平可能与治疗决策有关。虽然Choi等[5]的研究包括验证队列在第一年的病毒学应答信息，但在随访期间缺乏纵向病毒学应答是较大观察性队列的缺点，可能是主要的解释变量对于ETV与TDF组中HCC结果的差异。总的来说，最近的研究表明，病毒抑制很重要，因此选择能够实现和维持抑制的抗病毒药物是非常需要的，但研究结果并不能说明一种药物应优先于另一种药物。

最后，如果TDF在降低HCC风险方面优于ETV，那么最重要的问题就是原因。 Choi和他的同事们提供了2种可能的解释，这两种解释都没有得到人类数据的充分支持。他们提出ETV可能是致癌的和/或核苷酸类似物（相对于核苷类似物）可能诱导更高的抗肿瘤细胞因子。尽管病毒和抗原下降的速度可能比使用的特定药物类型（核苷对核苷酸）更重要，但病毒清除可能诱导肝内环境改变，从而影响肝癌发生的风险。 ETV可能是致癌的假设是基于小鼠和大剂量ETV治疗的大鼠的临床前研究;没有人类相关数据来支持这一点。事实上，如果是这种情况，人们可能会预计随着药物暴露时间的延长，HCC的发病率会上升;这个队列或其他人未见过的特征.5,6,14 Choi等人的研究仅用了4年多的随访数据，并未提供年度HCC发生率，但目测检查ETV治疗后的生存曲线患者表明HCC事件发生率没有增加。另外一组近2000名接受ETV治疗的患者表明，治疗前5年的年度HCC发病率与ETV暴露5年后的发生率相似（2.29％vs 1.66％，P = .22）.14此外，在一组1900多名白内障患者中，接受ETV或TDF长期治疗，中位随访时间为6年，HCC发病率在无肝硬化的患者中超过5年，而HCC显着下降因此，对于ETV的致癌倾向没有临床支持，并且ETV和TDF之间观察到的HCC发生率差异的生物学基础仍然模糊不清。

三种安全有效的口服抗病毒药物被专家认可为CHB的一线治疗药物：ETV，TDF和替诺福韦艾拉酚酰胺富马酸盐.1,2这些抗病毒药物在降低HBV DNA水平和优异的耐受性和安全性方面具有高效的特性。在确定给定CHB患者的最佳选择时，临床医生应考虑治疗史，合并症，包括肾病或人体免疫缺陷病毒，以及成本和可及性。预防肝脏相关并发症需要坚持治疗方案和实现病毒载量抑制的疗法。 Choi及其同事的工作5是我们的第一个知识，表明TDF在预防HCC方面优于ETV，但考虑到观察数据的固有局限性，本研究不应导致选择TDF优于ETV的广泛范式转变。相反，它应该刺激更多的调查人员来解决这些HBV药物中的一种是否与另一种不同的问题。

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