替诺福韦在降低慢性乙型肝炎肝细胞癌风险方面优于恩替卡

StephenW

Is Tenofovir Superior to Entecavir in Reducing the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B? The Controversy Continues
Pietro Lampertico∗,'Correspondence information about the author Pietro LamperticoEmail the author Pietro Lampertico
CRC “A. M. and A. Migliavacca” Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
George V. Papatheodoridis
Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens, Greece
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DOI: https://doi.org/10.1053/j.gastro.2019.11.007 |
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See “Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China,” by Yip TC-F, Wond VW-S, Chan HL-Y, et al, on page 215.

The article by Yip et al1 published in this issue of Gastroenterology fuels the discussion on whether different nucleos(t)ide analogues may modulate the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). This large retrospective territory-wide cohort study that included 29,350 patients with CHB who started entecavir (ETV) or tenofovir disoproxil fumarate (TDF) in Hong Kong between 2008 and 2018 has several strengths, such as a large sample size, relevant good follow-up, sophisticated statistical analysis, baseline assessment of liver disease severity and all major virologic variables, 1-year virologic and biochemical responses and determination of several HCC risk scores. In contrast, study findings must be taken with caution for several reasons. The 2 groups differed significantly in several well-known strong baseline HCC risk factors; the TDF-treated patients were younger, more frequently hepatitis B e antigen positive, and less frequently male, cirrhotic, and diabetic. Only 4.5% of 29,350 patients and particularly only 1% of 3860 patients with cirrhosis received TDF as a likely consequence of the fact that this drug became available in Hong Kong years after ETV. In addition, the number of TDF-treated patients who developed HCC was very limited: only 8 of 1394 HCCs developed in TDF-treated patients (6 patients with and 2 without baseline cirrhosis), questioning the robustness of a comparative analysis with so few events. The cumulative HCC incidence in this study started to diverge very early, immediately after week 48 (but HCC diagnosed within the first 48 weeks were excluded), which is more in line with different baseline HCC risks between the 2 groups rather than with a usually more delayed different drug effect on the HCC risk.

To adjust for significant differences in baseline characteristics and HCC risk factors between the 2 groups, Yip et al1 used several statistical tools such as multivariable adjustment, propensity score (PS) weighting and matching, inverse probability of treatment weighting, and competitive risk analysis. In 1200 TDF-treated patients finally matched with ETV-treated patients, TDF was associated with significantly lower HCC risk after PS weighting and 1:5 matching (weighted subdistribution hazard ratio [HR], 0.36 and 0.39; P ≤ .016). These findings were confirmed by other subanalyses. However, sophisticated statistical methods cannot replace randomization, because they cannot completely adjust for all the differences in HCC risk factors. Even if an excellent balance can be achieved by PS, the matching will be only for identified and available rather than all possible confounders. In fact, the exact phase of chronic HBV infection and the appropriate treatment indication represent 2 related HCC risk factors2 that cannot be accurately assessed in such territory-wide studies using code based diagnosis extracted from large databases and therefore cannot be considered in any matching method.

The possible mechanisms explaining the lower HCC risk in patients with CHB treated with TDF are unclear. It has been suggested that TDF, but not ETV, may activate the interferon lambda 3 pathway.3 Interestingly, in the PS-matched cohort of the current study, virologic response rate at year 1 was significantly lower with ETV than TDF (69.7% vs 77.6%; P < .001), although the biochemical response rate was higher with ETV (71% vs 59%; P < .001). This finding is unexpected, because a virologic response is usually the major driver of biochemical response. The activation of the interferon lambda 3 pathway by TDF could justify, at least partly, the suboptimal biochemical response in TDF patients, as the persistence of mildly elevated alanine aminotransferase in patients with suppressed HBV replication could play some role in reducing HCC development, for example, by nonspecific killing or deaths of hepatocytes committed to neoplastic transformation. In contrast, observations even from the same group that elevated on-therapy alanine aminotransferase is associated with higher HCC risk complicate the interpretation of such findings.4

The results of the Hong Kong study are in line with the initial report from South Korea by Choi et al,5 suggesting a lower HCC risk with TDF (adjusted HR, 0.68), but 2 large well-performed independent studies again from South Korea failed to confirm these findings.6,7 Kim et al6 reported that the annual HCC incidence did not differ between 1484 ETV-treated and 1413 TDF-treated patients (1.92 vs 1.69 per 100 person-years); by multivariable (adjusted HR, 0.975; P = .852) or PS-matched and ITPW analyses. Similar findings were reported by Lee et al7 in a study enrolling 7015 consecutive patients with CHB, both in the entire cohort (PS-matching model HR, 1.03; P = .880) and in the subgroups of chronic hepatitis and cirrhotic patients. A third recently published study from a large international consortium of CHB also did not show any significant difference in the 5-year HCC risk between 520 paired matched patients treated with TDF or ETV.8

In addition to these 5 recently fully published studies, several as yet unpublished reports have addressed the same topic with contrasting results. In the PAGE-B cohort, which included approximately 2000 Caucasian patients, the 5-year HCC risk was 5.4% in ETV-treated and 6.0% TDF-treated patients (adjusted HR, 1.00; 95% confidence interval, 0.70–1.42).9 In a French cohort including 2658 patients, the annual HCC risk was also not significantly different between ETV-treated and TDF-treated patients (0.91 vs 0.88 per 100 person-years; adjusted HR, 1.41; 95% confidence interval, 0.65–3.03).10 At variance, a recent US study demonstrated that, after adjustment of baseline variables and PS weighting, TDF (6145 patients) was associated with significantly decreased risk of HCC compared with ETV therapy (4060 patients) (HR, 0.56; 95% confidence interval, 0.37–0.86).11

In summary, whether patients treated with TDF have a lower risk of HCC compared with those treated with ETV remains unsettled, because different studies, even from the same country, reached opposite conclusions.12,13 The only exception is Europe, where 2 large independent studies reported no difference in the HCC risk between the 2 agents. To improve the quality of the data and subsequently the validity of the results, carefully collected individual data from large cohorts of homogeneous and clinically relevant subpopulations, such as compensated cirrhotics or patients with different stages of disease severity or hepatitis B e antigen profiles, should be analyzed. Thus, investigators are encouraged to merge their cohorts, because only careful collaborative efforts could unravel this interesting clinical issue.

StephenW

替诺福韦在降低慢性乙型肝炎肝细胞癌风险方面优于恩替卡韦吗？争议仍在继续
Pietro Lampertico *，'作者的通讯信息Pietro Lampertico发电子邮件给作者Pietro Lampertico
CRC“ A. M.和A. Migliavacca”，意大利米兰大学UniversitCS degli Studi di Milano的IRCCS胃肠病学和肝病学研究中心，胃肠病学和肝病学研究中心，IRCCSCàGranda Ospedale Maggiore Policlinico
乔治五世·帕帕特奥多里迪斯
雅典国立卡普迪斯安大学医学院消化科，雅典“莱科”总医院，希腊雅典
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DOI：https：//doi.org/10.1053/j.gastro.2019.11.007 |
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请参阅Yip TC-F，Wond VW-S，Chan HL-Y等人在第215页上的文章“在中国慢性HBV感染患者中，替诺福韦的肝细胞癌风险比恩替卡韦低”。

Yip等人在这一期《胃肠病学》上发表的文章引发了关于不同核苷酸类似物是否可调节慢性乙型肝炎（CHB）肝癌（HCC）风险的讨论。这项大型回顾性队列研究纳入了29,350名CHB患者，他们于2008年至2018年在香港开始使用恩替卡韦（ETV）或替诺福韦二富马酸富马酸（TDF），具有多个优势，例如样本量大，相关的良好随访，复杂的统计分析，肝病严重程度和所有主要病毒学变量的基线评估，1年病毒学和生化反应以及几个HCC风险评分的确定。相反，出于以下几个原因，必须谨慎对待研究结果。两组在几个众所周知的强基线HCC危险因素上有显着差异。 TDF治疗的患者较年轻，乙型肝炎e抗原阳性的频率更高，而男性，肝硬化和糖尿病的频率更低。在29,350名肝硬化患者中，只有4.5％接受了TDF，特别是3860名肝硬化患者中只有1％接受了TDF，这可能是由于ETV在香港上市后几年即可获得。此外，发生HCC的经TDF治疗的患者数量非常有限：在接受TDF治疗的患者中，只有1394例HCC中有8例发生了肝癌（6例有基线肝硬化的患者和2例没有基线肝硬化的患者），这质疑了如此少发生事件的比较分析的有效性。在这项研究中，累积的HCC发生率开始很早就开始分散，在第48周后开始出现差异（但排除了在前48周内诊断出的HCC），这与两组之间不同的基线HCC风险相符，而不是通常更高延迟了不同药物对HCC风险的影响。

为了调整两组之间基线特征和HCC危险因素的显着差异，Yip等[1]使用了多种统计工具，例如多变量调整，倾向评分（PS）权重和匹配，治疗权重的逆概率以及竞争风险分析。在最终与ETV治疗的1200名接受TDF治疗的患者中，PS加权和1：5匹配后，TDF与降低的HCC风险相关（加权分分布危险比[HR]，0.36和0.39； P≤.016）。这些发现被其他子分析所证实。但是，复杂的统计方法无法代替随机化，因为它们无法完全针对HCC危险因素的所有差异进行调整。即使PS可以实现出色的平衡，该匹配也仅适用于已确定和可用的匹配，而不是所有可能的混杂因素。实际上，慢性HBV感染的确切阶段和适当的治疗适应症代表2个相关的HCC危险因素2，在此类全区域研究中无法使用从大型数据库中提取的基于代码的诊断来准确评估，因此无法以任何匹配方法加以考虑。
用TDF治疗的CHB患者较低的HCC风险的可能机制尚不清楚。有人提出，TDF，而不是ETV，可能会激活干扰素λ3途径。3有趣的是，在本研究的PS匹配队列中，ETV在1年级的病毒学应答率显着低于TDF（69.7％vs 77.6％； P <.001），尽管ETV的生化反应率更高（71％对59％； P <.001）。这一发现是出乎意料的，因为病毒学应答通常是生化应答的主要驱动力。 TDF对lambda 3干扰素的激活至少可以部分证明TDF患者的生化反应欠佳，因为在HBV复制抑制的患者中，丙氨酸氨基转移酶轻度升高的持续性可能在减少HCC发生中起一定作用。通过非特异性杀伤或致死性转化的肝细胞死亡。相反，即使来自同一组的观察结果也表明，治疗中丙氨酸氨基转移酶水平升高与较高的HCC风险相关，使这些发现的解释变得复杂4。

香港的研究结果与Choi等人[5]从韩国的最初报告相一致，表明TDF降低了HCC的风险（校正后的HR，0.68），但韩国进行的两项大型且良好的独立研究再次失败6,7 Kim等[6]报道，在1484名接受ETV治疗的患者和1413名接受TDF治疗的患者中，每年的HCC发生率没有差异（每100人年1.92比1.69）；通过多变量（校正后的HR，0.975； P = .852）或PS匹配和ITPW分析。 Lee等[7]在一项研究中纳入了7015名连续性CHB患者，在整个队列（PS匹配模型HR，1.03； P = .880）中以及在慢性肝炎和肝硬化患者的亚组中都报告了类似的发现。大型国际CHB联盟最近发表的第三项研究也未显示520名配对患者接受TDF或ETV治疗后5年HCC风险有任何显着差异[8]。

除了最近发表的这5篇研究报告以外，还有几篇尚未发表的报告针对同一主题进行了对比研究。在包括大约2000名白种人患者的PAGE-B队列中，经ETV治疗的患者和经TDF治疗的患者的5年HCC风险为5.4％（校正后的HR，1.00； 95％的置信区间，0.70-1.42）。 9在包括2658名患者的法国人群中，ETV治疗和TDF治疗患者的年度HCC风险也无显着差异（每100人年0.91比0.88；校正后的HR为1.41； 95％的置信区间为0.65-3.03 ）.10方差方面，最近的一项美国研究表明，在调整基线变量和PS权重之后，与ETV治疗（4060例）相比，TDF（6145例）与HCC风险显着降低有关（HR，0.56； 95％置信区间0.37–0.86）.11

总之，与ETV治疗相比，接受TDF治疗的患者是否具有较低的HCC风险，因为即使来自同一国家的不同研究也得出相反的结论。12,13唯一的例外是欧洲，欧洲有2个大型独立研究机构。研究报告说两种药物之间的HCC风险无差异。为了提高数据质量并随后提高结果的有效性，应仔细收集来自同质和临床相关亚人群的大量队列中的个体数据，例如代偿性肝硬化或疾病严重程度或乙型肝炎e抗原谱不同阶段的患者。分析。因此，鼓励研究者合并他们的研究组，因为只有认真合作才能揭示这个有趣的临床问题。

小牡丹

根据服用Taf与恩替时血常规化验结果，TAF时指标正常率高。服用恩替时化验很多次，几乎没有变化。服用TAF化验一次，某些指标变化大。再次化验，就能说明问题。

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小牡丹什么意思？二代比一代抑制癌更好？

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