乙型肝炎患者的病毒血症病毒血症在抗病毒治疗中可以忽略

StephenW

www.natap.org


EditorialLow-level viremia in hepatitis b patients on antiviral treatment: Can we ignore it?Hepatology june 2017 - Albert Min MD





In the landmark REVEAL study on the natural history of patients infected with hepatitis B virus (HBV), an association between baseline HBV DNA levels and the risk of cirrhosis and hepatocellular carcinoma (HCC) was established.[1] With the goal of antiviral treatment being to decrease the morbidity and mortality associated with chronic hepatitis B (CHB), the first-line antiviral agents recommended for treating CHB patients by the American Association for the Study of Liver Diseases (AASLD) include pegylated interferon, entecavir, and tenofovir.[2] With their easy tolerability and efficacy in suppressing viral replication associated with high genetic barrier to resistance, many patients with HBV worldwide were treated with either oral agent, often achieving reversal of cirrhosis and reduced incidence of HCC.[3, 4]
One question posed in the recently updated AASLD guidelines for management of CHB was whether there would be a role for adding a second antiviral agent with persistent low-level viremia (LLV; <2000 IU/mL) while on entecavir or tenofovir. The guidelines suggest that such CHB patients with LLV continue monotherapy.[2] This approach was demonstrated in a European cohort study in which long-term entecavir monotherapy led to a virologic response in the vast majority of treatment-naïve patients, including those with a partial virologic response after 48 weeks of treatment.[5] In this issue of Hepatology, a large retrospective study by Kim and Sinn et al. indicates that among patients on antiviral therapy, LLV, defined as persistent or intermittent episodes of HBV DNA greater than the lower detection limit of 12 IU/mL but <2000 IU/mL, was associated with a higher risk of developing HCC when compared with those who maintained virologic response (MVR) with persistently undetectable HBV DNA levels.[6] Previously treatment-naïve 875 patients were treated with entecavir for at least 1 year. During a median follow-up of 4.5 years, 85 patients (9.7%) developed HCC. Overall, the development of HCC was more frequent in patients with LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.016). On multivariate analysis, LLV was an independent risk factor associated with HCC development (HR = 1.98, P = 0.002). However, although patients who have cirrhosis with LLV had a higher risk of developing HCC than those with cirrhosis and MVR, among patients without cirrhosis there was no statistically significant difference in the risk of HCC occurrence between patients with LLV and those with MVR, possibly due to a lower risk of HCC in that population than in patients with cirrhosis. Achieving MVR even in noncirrhotic patients may still be important, but we would need a study with a much larger sample size and/or a longer follow-up to show such impact, including stratified analysis by age and sex that may be helpful in accounting for the effect of those strong covariates. Thus, at least for CHB patients with cirrhosis, presence of LLV while on entecavir or tenofovir may not be ignored with a higher risk of developing HCC than those with MVR.
-----------------------
Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatmentRISK OF HCC ACCORDING TO THE VIROLOGICAL RESPONSEThe cumulative incidence rates of HCC were 3.2% and 7.5% at 3 and 5 years for patients with MVR, respectively, which were lower than those for patients with LLV (6.2% and 14.3% at 3 and 5 years, respectively; P = 0.016; Fig. 3). LLV was associated with a higher risk for developing HCC than MVR. LLV and cirrhosis were independent risk factors for HCC (Table 3). When stratified according to cirrhosis, the cumulative incidence rate of HCC was higher (10.3% versus 23.4% at 5 years for MVR versus LLV; P = 0.001), and LLV was an independent risk factor for HCC in patients with cirrhosis (hazard ratio = 2.20, 95% confidence interval 1.34-3.60, adjusted for age, sex, HBeAg, and baseline HBV DNA levels; P = 0.002). However, for those without cirrhosis, there was no significant difference in HCC incidence rate (4.0% versus 6.9% at 5 years for MVR versus LLV, P = 0.44). LLV was not an independent factor for HCC in the multivariable model (hazard ratio = 1.65, 95% confidence interval 0.65-4.17, adjusted for age, sex, HBeAg, and baseline HBV DNA levels; P = 0.29) (Fig. 4).













-----------------------------

Whether or when a compliant CHB patient with LLV on treatment with entecavir or tenofovir should add another agent is not clear.[2, 7] Entecavir or tenofovir fails to achieve HBV DNA undetectability after 48 weeks in 10% and 30% in HBeAg-negative and HBeAg-positive patients, respectively.[2] In light of the Kim and Sinn et al. study, we should consider a potential alternative strategy, at least in patients with cirrhosis. There is no prospective, well-designed study in answering what is the best strategy among the three options in compliant patients with LLV on entecavir or tenofovir—whether to continue the initial agent, switch to the other agent or add the second agent. It will be difficult to design a study to determine the optimal timing of the alternative strategy while trying to correlate it with the risk of HCC development. Undoubtedly, any strategy to manage such patients who have cirrhosis with LLV on treatment should be optimally evaluated in a scientifically rigorous study. One may opt to narrow a focus of any potential study using a specific antiviral agent in a cirrhotic population and wait for viral response to plateau before implementing a predefined alternative strategy. However, as is the case for the above hypothetical study in the noncirrhotic population, the number of patients and time required to arrive at a meaningful answer would still be immensely prohibitive for such study to be performed. Thus, one has to rely upon indirect evidence, as has been the case for answering most challenging issues in management of CHB patients.[7] For example, in trying to ascertain whether to treat CHB patients with compensated cirrhosis and LLV (<2000 IU/mL) with an antiviral agent, Lok et al. did not find any comparative studies to guide their decision but found one specific study (performed by the same group as the authors of the Kim and Sinn et al. article) examining the benefit of antiviral therapy in CHB patients with compensated cirrhosis and LLV with reduced incidence of HCC in the treated group.[7, 8] Despite the presence of confounding factors such as differences in the characteristics between the treated and untreated groups in that retrospective study and absence of other randomized controlled trials, the AASLD guidelines recommend that such patients with compensated cirrhosis and LLV should be treated with antiviral therapy to reduce the risk of decompensation.[2]
One cautionary note is that we cannot extrapolate Kim and Sinn et al.'s findings to treatment-naïve HBV patients without cirrhosis who are considered to be in the inactive phase, demonstrated by either intermittently or persistently detectable HBV DNA levels but always <2000 IU/mL and normal alanine aminotransferase values. The REVEAL study showed that CHB patients having LLV (between 60 and 2000 IU/mL) at baseline are not at a higher risk of developing HCC than those whose baseline viral levels are below the lower limit of quantitation.[1] Unlike patients on antiviral treatment in the Kim and Sinn et al. study, most patients with LLV in the inactive phase of CHB have minimal evidence of liver injury. In the 2016 AASLD annual meeting, a large retrospective cohort study compared the risk of developing HCC between patients with CHB who achieved virologic response with antiviral therapy and patients in the inactive CHB phase (HBV DNA <2000 IU/mL) after adjusting for fibrosis status.[9] Clinical outcomes were comparable between CHB patients with virologic response using oral antiviral therapy and those in the inactive phase of CHB when adjusted for fibrotic burden. Moreover, it is reassuring that among noncirrhotic patients on antiviral therapy in the Kim and Sinn et al. study, there was no significant difference in the risk of developing HCC between CHB patients with LLV and those with MVR.
However, half of the patients in the Kim and Sinn et al. study had cirrhosis at baseline, and most patients with HBV and HCC have cirrhosis.[10] In addition, having undetectable viral level rather than a loss of HBsAg was associated with a lower risk of HCC.[11] Even those CHB patients who ultimately achieve “functional cure” with loss of HBsAg, albeit an uncommon occurrence with or without antiviral therapy, remain at risk for HCC development.[11] With cirrhosis as the major risk factor of HCC development, and in light of the Kim and Sinn et al. study's findings, we may no longer be able to ignore the significance of LLV in patients with compensated cirrhosis who are already on antiviral therapy. However, in considering how to convert those being treated from LLV to MVR camp, without well-designed comparative studies available we would have to make a decision based on indirect evidence, incorporating data from observational studies, individual patient preference, and available resources.[7] Fortunately, the good news is that with currently available effective antiviral agents that are associated with high genetic barrier to resistance, the number of HBV-related patients who have cirrhosis with LLV on treatment will account for a small portion of CHB patients in clinical practice. However, we are once again reminded that in managing CHB patients, we should remain vigilant in continuing regular HCC surveillance indefinitely, regardless of whether undetectable HBV DNA levels and/or even loss of HBsAg have been achieved, particularly in patients with cirrhosis.

• Albert D. Min, M.D.

• Division of Digestive Diseases

• Mount Sinai Beth Israel

• Icahn School of Medicine at Mount Sinai

• New York, NY

  
  

StephenW

www.natap.org



社论
乙型肝炎患者的病毒血症病毒血症在抗病毒治疗中可以忽略吗？

肝病学2017年6月 - 阿尔伯特敏医学博士

在对乙型肝炎病毒（HBV）感染患者自然病史的里程碑式REVEAL研究中，建立了基线HBV DNA水平与肝硬化和肝细胞癌（HCC）风险之间的关联[1]为了降低与慢性乙型肝炎（CHB）相关的发病率和死亡率，抗病毒治疗的目标是推荐用于美国肝病研究协会（AASLD）治疗CHB患者的一线抗病毒剂包括聚乙二醇化干扰素，恩替卡韦，替诺福韦[2]由于它们容易耐受和有效地抑制与高遗传阻力相关的病毒复制，所以许多HBV患者全部用口服药物治疗，通常会导致肝硬化逆转，HCC的发生率降低[3,4]

最近更新的AASLD管理CHB指南中提出的一个问题是在恩替卡韦或替诺福韦期间是否会添加持续低水平病毒血症（LLV; <2000 IU / mL）的第二种抗病毒药物。该指南表明，这种CHB患者LLV继续单药治疗[2]在欧洲队列研究中证实了这种方法，其中长期恩替卡韦单药治疗导致绝大多数治疗无效患者的病毒学应答，包括治疗48周后具有部分病毒学应答的患者[5]在本期“肝病学”杂志上，Kim和Sinn等人进行了大量回顾性研究。表明在抗病毒治疗的患者中，定义为HBV DNA持续或间歇发作大于12 IU / mL但<2000 IU / mL的检测下限的LLV与发生HCC的风险相比较高谁维护病毒学应答（MVR）持续不可检测的HBV DNA水平[6]治疗初治875例患者接受恩替卡韦治疗至少1年。在4.5年的中位随访中，85例（9.7％）发展为HCC。总体而言，LLV患者的发病率比MVR更高（14.3％，5年时为7.5％，P = 0.016）。在多变量分析中，LLV是与HCC发展相关的独立危险因素（HR = 1.98，P = 0.002）。然而，虽然肝硬化患者与肝硬化和MVR发生HCC的风险较高，但在没有肝硬化的患者中，LLV患者和MVR患者HCC发生风险之间差异无统计学意义在该人群中HCC的风险低于肝硬化患者的风险。甚至在非肝硬化患者中获得MVR可能仍然很重要，但是我们需要一个具有更大样本量和/或更长时间随访的研究来显示这种影响，包括年龄和性别的分层分析，可能有助于会计那些强协变量的影响。因此，至少对于肝硬化的CHB患者，在恩替卡韦或替诺福韦期间LLV的存在可能不被忽略，发生HCC的风险高于具有MVR的风险。
-----------------------
接受恩替卡韦治疗的患者的低水平病毒血症和肝细胞癌的风险增加
肝硬化风险根据病毒学应答

MVR患者3年和5年HCC累积发生率分别为3.2％和7.5％，低于LLV患者（分别为3年和5年时分别为6.2％和14.3％; P = 0.016 ;图3）。与MVR相比，LLV与发展HCC的风险相关。 LLV和肝硬化是HCC的独立危险因素（表3）。根据肝硬化分层，肝硬化患者HCC的累积发病率较高（10.3％，MVR为5年时为23.4％，P = 0.001），LLV为肝硬化患者HCC的独立危险因素（风险比= 2.20,95％置信区间1.34-3.60，根据年龄，性别，HBeAg和基线HBV DNA水平进行调整; P = 0.002）。然而，对于没有肝硬化的患者，HCC发生率（MVR与LLV相比，在5年时分别为4.0％和6.9％，P = 0.44）无显着性差异。 LLV在多变量模型中不是HCC的独立因素（风险比= 1.65,95％置信区间0.65-4.17，根据年龄，性别，HBeAg和基线HBV DNA水平进行调整; P = 0.29）（图4）。



-----------------------------

[2,7]恩替卡韦或替诺福韦48周后未能达到HBeAg阴性的10％和30％的HBV DNA检测不到（或）何时符合CHB患者的LLV治疗恩替卡韦或替诺福韦和HBeAg阳性患者[2]鉴于Kim和Sinn等人研究中，我们应该考虑一个潜在的替代策略，至少在肝硬化患者中。没有任何准确的设计研究来回答在依诺卡韦或替诺福韦治疗合并LLV患者的三个方案中最好的策略是 - 是否继续使用初始药剂，转用其他药物或添加第二药物。设计研究将难以确定替代策略的最佳时机，同时试图将其与HCC发展的风险相关联。毫无疑问，在科学严谨的研究中，应该对治疗患有LLV肝硬化的患者进行治疗的任何策略进行最佳评估。人们可能会选择使用特定的抗病毒剂在肝硬化人群中缩小任何潜在研究的焦点，并在实施预定义的替代策略之前等待对高原的病毒反应。然而，与上述非肝硬化患者的假设研究一样，患者的数量和达成有意义的回答所需的时间对于进行这种研究仍将是非常高的。因此，人们必须依赖间接证据，就像回答CHB患者管理中最具挑战性的问题一样。[7]例如，在试图确定是否用抗病毒药物治疗补偿性肝硬化和LLV（<2000IU / mL）的CHB患者时，Lok等人没有发现任何比较研究来指导他们的决定，但发现一项具体研究（由Kim和Sinn等人的文章作者同一组进行）检查抗病毒治疗在具有补偿性肝硬化和LLV的CHB患者中的益处，减少治疗组中HCC的发生率[7,8]尽管在回顾性研究中没有存在混杂因素，例如治疗组和未治疗组之间的差异，而没有其他随机对照试验，AASLD指南建议这样的患者补偿性肝硬化和LLV应接受抗病毒治疗，以降低失代偿的风险[2]

一个值得注意的是，我们不能将Kim和Sinn等人的研究结果推广到治疗无效的无肝硬化的HBV患者，被认为处于非活动期，通过间歇或持续检测的HBV DNA水平证实，但总是<2000IU / mL和正常丙氨酸氨基转移酶值。 REVEAL研究显示，在基线时具有LLV（60至2000IU / mL）的CHB患者与基线病毒水平低于定量下限的患者相比，没有发生HCC的风险更高[1]与Kim和Sinn等人的抗病毒治疗患者不同研究中，大部分患有LLV无症状CHB患者的肝损伤证据很少。在2016年AASLD年会上，一项大型回顾性队列研究比较了在调整纤维化状态后，获得病毒学应答与抗病毒治疗的CHB患者与无活性CHB期患者（HBV DNA <2000 IU / mL）之间发生HCC的风险[9]。使用口服抗病毒治疗的CHB患者与CHB无活性期的CHB患者之间的临床结果可比较，以调整纤维化负担。此外，在Kim和Sinn等人的非肝硬化患者中进行抗病毒治疗是令人放心的。研究发现，CHB患者LLV与MVR患者HCC发生风险无显着性差异。

然而，Kim和Sinn等人的一半患者研究发现肝硬化患者基线，大部分HBV和HCC患者均有肝硬化。[10]此外，具有不可检测的病毒水平而不是HBsAg的丧失与较低的HCC风险相关[11]即使是那些最终实现“功能治愈”与失去HBsAg的CHB患者，尽管在有或没有抗病毒治疗的情况下是罕见的发生，仍然有HCC发展的风险[11]随着肝硬化是HCC发展的主要危险因素，并且鉴于Kim和Sinn等人。研究结果显示，我们可能无法忽视已经进行抗病毒治疗的补偿性肝硬化患者LLV的意义。然而，在考虑如何将被视为LLV的人转换为MVR阵营时，如果没有精心设计的比较研究，我们将不得不基于间接证据作出决定，纳入观察性研究的数据，个人患者偏好和可用资源。 7]幸运的是，好消息是，目前有效的抗病毒药物与遗传性阻力较高有关，与临床实践中CHB患者相比，治疗肝硬化的HBV相关患者数量将占CHB患者的一小部分。然而，我们再次提醒，在管理CHB患者时，我们应该保持警惕，无限期地继续定期进行HCC监测，无论HBV DNA水平检测是否可检测到，甚至HBsAg甚至失去HBeAg，特别是肝硬化患者。

    阿尔伯特·闵敏

    消化疾病科

    西奈山贝斯以色列

    西奈山伊坎医学院

    纽约纽约市