对干扰素a无效应慢性乙肝患者的其它治疗选择

刘德华影子

无影清风

天哪，我看不懂！

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这文章我认了，稍后发布译文，人工翻译……仅供参考……

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能够发了……看来已经翻译了两个小时了……呵呵，还有几段……

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Journal of Hepatology 38 (2003) 853–855（本期刊2006年影响因子6.703）
Editorial
Treatment options for chronic hepatitis B not responding to interferon
Stephanos J. Hadziyannis*
Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, Athens, Greece

肝病学杂志 38（2003）853-855
社论
不相应干扰素的慢性乙肝的治疗选择
1. The natural course of chronic hepatitis B and the need for treatment
1. 慢性乙肝的自然过程和治疗的需要

Chronic hepatitis B (CHB) defined by the presence of hepatitis B surface antigen (HBsAg) in serum, high levels of circulating hepatitis B virus (HBV) DNA and chronic necroinflammation of the liver is separated into two forms based on the hepatitis B e antigen (HBeAg) and antibody (anti-HBe) status [1,2]. The HBeAg-positive CHB considered as the typical, prototype form of the disease, occurs in earlier phases of chronic HBV infection than HbeAg negative CHB, it prevails in European and North American patients infected with HBV genotype A and is characterized by persistently high serum aminotransferases (ALT) and hepatitis B viraemia levels [1,3]. In perinatally acquired HBV infection, which is common in geographical areas of high HBV prevalence like Asia, it appears to follow a period of immune tolerance of HBV during which HBV DNA levels are high while ALT levels keep normal or nearly normal and liver necroinflammtion is minimal or absent [4]. When HBeAg-positive CHB develops serum ALT levels increase and liver damage progresses to severe necroinflammation with advancing fibrosis. If HBeAg-positive CHB is left untreated it may subside spontaneously terminating into loss of HBeAg, seroconversion to anti-HBe, suppression of HBV replication to non-detectability by molecular hybridization techniques or to ,103–104 copies/ml by polymerase chain reaction, return of ALT to normal and resolution of liver disease activity. However, the probability of spontaneous resolution of HBeAg-positive CHB is limited to approximately 10–12% per year (ranging in the various studies from 2 to 24%) [2]. Thus, a large number of untreated patients with HBeAg-positive CHB are left with severe liver necroinflammation which persists for several years and results in an increased likelihood of progression of liver damage to advanced stages of fibrosis, cirrhosis and even development of hepatocellular carcinoma (HCC), the most dire consequence in the natural history of CHB [2].

慢性乙肝（CHB）的定义是血清中存在乙肝表面抗原（HbsAg），高水平的血液循环乙肝病毒（HBV）DNA，并且根据乙肝e抗原（HbeAg）和抗体（anti-HBe）状态，肝脏的慢性坏死性炎症分为两种形式[1,2]。HbeAg阳性CHB被认为是疾病的典型和原型，与HbeAg阴性CHB在慢性HBV感染的较早阶段发生，这种形式在欧洲和北美感染HBV基因型A的患者中流行，其特征是血清氨基转移酶（ALT）水平和乙肝病毒血液水平持续较高[1,3]。在高HBV流行地理区域，例如亚洲，在围产期获得HBV感染非常常见，其表现为HBV感染后出现了一段HBV免疫耐受期，即HBV DNA水平很高但是ALT水平保持正常或接近正常，并且肝脏坏死性炎症很少却根本没有[4]。当HbeAg阳性CHB发展到血清ALT水平增加，以及肝脏损伤发展到伴有不断纤维化的严重坏死性炎症时。如果HbeAg阳性CHB不予治疗，其可能自发消退，HbeAg消失，血清转化为anti-HBe，HBV复制抑制到分子杂交技术不可检测的水平，或者通过聚合酶链式反应（PCR）检测为103-104拷贝/酶LALT返回到正常水平，并且肝脏疾病活性消退。但是，HbeAg阳性CHB自发消退的概念限制在大约每年10-12%（各种研究在2到24%之间变化）[2]。因此，大量未治疗的HbeAg阳性CHB患者落下了持续数年的肝脏坏死性炎症，并导致肝损伤发展为肝纤维化，肝硬化晚期，甚至发展成CHB自然过程最可怕的结果——肝细胞癌（HCC）[2]。

In a recent study, the relative risk of HCC among men positive both for HBsAg and HBeAg was 60.2 compared to 9.2 in those with only HBsAg [5]. The need, therefore, for early and effective therapeutic intervention in HbeAg positive CHB is obvious, but unfortunately it has remained an unresolved issue of clinical hepatology for more than 20 years now.

在一项最近的研究中，HbsAg和HbeAg阳性的人与只有HbsAg阳性的人患HCC的相对风险是60.2比9.2[5]。因此，对HbeAg阳性CHB进行有效地早期治疗性干预的必要性是明显的，但是不幸的是，直到现在，20多年多这一直是临床肝病学上没有解决的难题。

In the HBeAg-negative form of CHB, which prevails in the Mediterranean Area and Asia and is mostly due to precore HBV mutants, serum HBV DNA levels are lower than in HBeAg-positive CHB, generally between 104 and 108 copies/ml. Both HBV DNA and serum ALT levels are often fluctuating [1]. However, spontaneous remissions are extremely rare and prognosis is poor with frequent progression to cirrhosis and HCC. Therefore, similar to HBeAg-positive CHB, the need for effective therapeutic intervention is again obvious [6].

在地中海区域和亚洲流行的CHB的HbeAg阴性形式，主要是由提前成熟的核心HBV突变体引起的，血清HBV DNA水平比HbeAg阳性CHB要低，一般在104到108拷贝/mL。HBV DNA和血清ALT水平都经常波动[1].但是，自发性缓解非常罕见，对于经常发展为肝硬化和HCC的预测也很不容易。因此，与HbeAg阳性CHB类似，有效地治疗性干预的必要性再一次是明显的[6]。

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2. Efficacy of currently available therapies in chronic hepatitis B
2. 目前对慢性乙肝已有疗法的有效性

Treatment of CHB is aiming to suppress HBV replication and to induce remission in liver disease before cirrhosis and HCC develop [4]. Biochemical, virologic and histological responses achieved under any treatment should be durable after discontinuation of therapy (sustained responses or SR) [2,7].

CHB的治疗是为了抑制HBV复制并且诱导在肝硬化和HCC发展前肝脏疾病的消退[4]。任何治疗在生化上的，病毒上的，以及组织上的获得的成绩必须在不间断治疗之后仍能保持（持续性相应，或SR）[2,7]。

Currently there are three approved treatments for CHB aiming at SR: interferon alfa (IFNa), lamivudine and recently adefovir dipivoxil. The efficacy of these therapies differs greatly between HBeAg-positive and HbeAg negative CHB. In general, the goal of SR appears to be achievable in HBeAg-positive CHB, albeit at low frequencies, by finite courses of treatment with any of the three existing drugs whereas in HBeAg-negative CHB only IFNa may be able to induce SR but only in a small percentage of patients [2,7].

为了实现SR，当前对CHB存在三种推荐的治疗：干扰素alfa（IFNa），拉米夫定【lamivudine】和最近的阿德福韦二匹伏酯【adefovir dipivoxil】。这些疗法的效力在HbeAg阳性和HbeAg阴性CHB之间差异非常大。通常，对HbeAg阳性CHB实现SR的目标可能可以实现的，虽然频率较低，但是对HbeAg阴性CHB，三种现存的药物在有效的疗程内只有IFNa可能能够在一小部分患者中能够诱导SR[2,7]。

In HBeAg-positive CHB therapy with IFNa, lamivudine, and adefovir dipivoxil of defined duration, ranging from 12 to 24 weeks for IFNa and for 24–52 weeks for the nucleos(t)ide analogs, appears to achieve loss of HBeAg, seroconversion to anti-HBe, normalizaion of ALT and loss of HBV DNA by molecular hybridization techniques at roughly comparable frequencies of 20–30%, two to three times higher compared to untreated controls [2,4,8]. Responses to IFNa seem to be durable, probably more than responses to lamivudine, being subsequently followed by loss of HBsAg in approx 8% [2,9]. The efficacy of IFNa treatment in HBeAg-positive CHB seems to increase with longer duration of therapy [10] and probably with the administration of pegylated IFNa2a [11]. Extension of lamivudine treatment in HBeAg-positive CHB from 1 to 3 and more years has also been reported to increase the HBeAg seroconversion rate [12].

HbeAg阳性CHB使用IFNa，拉米夫定，以及阿德福韦二匹伏酯的有限治疗过程中，对于IFNa是12到24周，而核苷（酸）类似物为24-52周，似乎能够以大约20-30%的可比频率，比未治疗对照相比高两道三倍的实现HbeAg消失，血清转换为anti-HBe，ALT正常化，以及分子杂交技术检测的HBV DNA消失[2,4,8]。对IFNa的响应可能是持久性的，可能比拉米夫定的影响更持久，并且IFNa随后伴随有大约8%的HbsAg消失[2,9]。IFNa对HBeAg阴性CHB治疗的效力可能在更长的治疗时间后能够增加[10]，并可能在给予聚乙二醇化的IFNa后效力也增加[11]。已经报道，对于HbeAg阳性CHB，延长拉米夫定的治疗1年到3年或更多年能够降低HbeAg血清转换速率[12]。

IFNa treatment of HBeAg-negative CHB for 12 and more months has also been effective in inducing SR in 15–20% of treated and retreated patients followed, in some of them, by clearance of HBsAg as well [2,6,13]. On the other hand, SR to lamivudine treatment in HBeAg-negative CHB, whatever its duration, have hitherto been reported only in rare instances while no information regarding SR after stopping adefovir dipivoxil treatment in HBeAg-negative CHB is available yet [7]. Thus, several investigators are currently treating patients with HBeAg-negative CHB indefinitely with nucleos(t)ide analogs to achieve longlasting virologic, biochemical and histological responses.

对于跟随IFNa治疗的治疗和再治疗HbeAg阴性CHB患者，15-20%的患者在12个月或更长的治疗后同样能够有效的诱导SR，并且其中的一些也能清除HbsAg[2,6,13]。另一反面，对于HbeAg阴性CHB拉米夫定治疗获得的SR情况是，无论经过多长时间，迄今只在罕见的例子中报道过的，并且目前没有在HbeAg阴性CHB停用阿德福韦二匹伏酯治疗后SR情况的信息[7]。因此，当前有数个研究者不确定的使用核苷（酸）类似物治疗HbeAg阴性CHB患者以获得长效的病毒学，生物化学和组织学响应。

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3. Treatment options for chronic hepatitis B refractory to IFNa
3. 对IFNa抵抗的慢性乙肝的治疗选择

For patients with CHB not responding to a first course of IFNa there are three possible options aiming at SR: (a) retreatment with IFNa, preferably pegylated IFNa and for longer periods of time; (b) treatment course with lamivudine or adefovir dipivoxil; and (c) some short of combination therapy. However, for the time being, few if any evidence based recommendations can be made for the management of IFNa non-responders.

对于在第一轮IFNa治疗中不相应的CHB患者，为了实现SR还有3个可能的选择：（a）在使用IFNa治疗，选择聚乙二醇化的IFNa和更长的时间周期；（b）使用拉米夫定或阿德福韦二匹伏酯治疗；（c）一些组合疗法。但是，但目前为止，对于IFNa不响应者的治疗很少能够提出基于任何证据的建议。

Since SR to IFNa may be achieved several months after therapy has been discontinued [2,4,8,14], patients should not be considered as IFNa non-responders prior to at least 6 months of post-treatment follow-up. A second treatment regimen may then be initiated with the aim to reduce the duration of active liver disease. But what type of treatment can be effective in these patients? There are few available data and these should be considered separately for HbeAg positive and HBeAg-negative patients.

因为IFNa实现的SR可能在治疗中断后数月内获得[2,4,8,14]，对于治疗后至少跟踪6个月之前，患者不应该被认为是IFNa非响应者。第二个治疗方法可以在这之后开始，目标是降低肝脏疾病活动的过程。但是哪种治疗对于这些患者是有效的呢？能够获得的资料很好，而且对于HbeAg阳性和HbeAg阴性患者要单独考虑。

In HBeAg-positive patients with CHB who did not respond to a first course of IFNa, re-treatment for 6 months with 9MU of IFNa thrice weekly has been associated with a 33% SR rate compared to 10% in untreated controls [15]. In an earlier study of a small group of patients who failed a first course of IFNa only 11% responded to a 16-week regimen with a daily dose of 1.5–5 MU of IFNa [16].

对于第一轮不响应的HbeAg阳性CHB患者，每周三次9MU IFNa再次治疗6个月能够获得33%的SR速率，相比于未治疗对照组的10%[15]。在较早的研究中，在第一轮IFNa治疗中失败的一小组患者只有11%对16周的每天1.5-5MU的IFNa饮食疗法产生响应[16]。

Data on IFN re-treatment of patients with HbeAg negative CHB are very limited. A recent study reported a SR of 31% after a second course of IFNa among 51 patients with HBeAg-negative CHB who had relapsed or had no response to previous IFNa treatment [13].

HbeAg阴性CHB患者的IFN再治疗的数据是非常有限的。最近的一项研究报道在51为HbeAg阴性CHB患者中有31%在第二轮IFNa治疗后获得了SR，而他们在先前的IFNa治疗中出现复发或不响应[13]。

HBeAg–positive patients who had previously failed IFNa monotherapy have been included in trials of lamivudine and adefovir dipivoxil monotherapy [17,18]. Of 17 IFNa failures treated with lamivudine, five achieved sustained HBV DNA clearance and three HBeAg seroconversion to anti-HBe [17]. In the recently published adefovir studies response rates under therapy did not differ between treatment-naive and previously IFNa-treated patients both in the HBeAg-positive and HBeAg-negative groups [18,19].

对于先前IFNa 单一疗法失败的HbeAg阳性患者参与了拉米夫定和阿德福韦二匹伏酯单一疗法试验[17,18]。在17位IFNa治疗失败又给予拉米夫定治疗的患者中，有5位获得了持续性的HBV DNA清除，而3位的HbeAg血清转换为anti-HBE[17]。在最近发表的阿德福韦研究中，在第一次治疗和以前进行过IFNa治疗的患者之间，不管是在HbeAg阳性还是HbeAg阴性组，治疗后的效应速率没有差异[18,19]。

Finally Mutimer et al. [20] have used combination of IFNa with lamivudine for 16 weeks in 20 patients who had previously failed IFN monotherapy. Its efficacy was disappointing, however, only one patient out of four achieving HBeAg seroconversion during treatment with maintaining this response after stopping treatment. However, in a recent pilot study of sequential treatment with lamivudine and IFNa monotherapies in CHB patients not responding to IFNa alone, sustained serum HBV DNA clearance 6 months after the end of sequential treatment was achieved in eight out of 14 patients, HBeAg to anti-HBe seroconversion in five out of 11 and HBsAg seroconversion to anti-HBs in three out of 14 patients [21].

最终，Mytimer等[20]使用IFNa与拉米夫定结合，在20位前期IFNa治疗失败的患者中，在4位在治疗中获得了HbeAg血清转换的患者中只有1位在停止治疗后仍能维持这种相应。但是，在一项最近进行的初步研究中，在对单独使用IFNa无响应的CHB患者中相继使用拉米夫定和IFNa单一疗法，相继治疗结束后的6个月中，14位患者中有8位获得了持续性的HBV DNA去除，11位患者中的5为HbeAg发生了向anti-HBe的血清转换，而14位患者中的3位发生了HbsAg向anti-HBs的血清转换[21]。

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In this issue of the Journal, Schiff et al. [22] report the results of a multicenter trial on the efficacy of lamivudine monotherapy versus combination of lamivudine with IFNa or no treatment in 238 HBeAg-positive CHB patients who were non-responders to a previous course of IFNa. Lamivudine given for 52–68 weeks was found to be as effective in IFNa non-responders as in previously reported treatment-naive patients and significantly superior than the combination of lamivudine for 24weeks and IFNa for 16 weeks, both in terms of histologic response and HBeAg loss (52 and 33% versus 32 and 21%, respectively). In the placebo group the rates of histologic improvement and of spontaneous HBeAg loss were 25 and 13%, respectively. However, seroconversion to anti-HBe was not statistically better in the lamivudine (18%) than in the combination (13%) and the placebo group (12%).

在这一期杂志中，Schiff等[22]报道了一个多通道试验，在238位对先前一轮的IFNa 无响应的HbeAg阳性CHB患者中，对拉米夫定单一疗法，与拉米夫定和IFNa结合，或者不治疗进行对比。52-68周的拉米夫定治疗对IFNa无响应者的效果与以前报道的对未治疗患者的效果一样有效，并且不管是在组织学响应还是在HbeAg消失上均显著的优于24周拉米夫定和16周IFNa组合治疗（分别是52和33%比32和21%）。在安慰剂组中，组织上的改善和自发HbeAg消失分别是25和13%。但是，向anti-HBe的血清转换在统计上拉米夫定（18%）并不优于组合（13%）和安慰剂小组（12%）。

The results of this study bring again into the therapeutic scenery the existing controversy over the efficacy of various schemes and dosages of combination therapies of interferon and lamivudine or other antiviral agents for patients with CHB [23].

这个研究的结果使得对现存的对于CHB患者进行的各种干扰素和拉米夫定或其他抗病毒试剂程序和剂量结合疗法的治疗情形的效力的再一次引发了争论。

Schiff et al. [22], constrained by regulatory considerations, could not include a pegylated-IFNa regimen, and had to restrict the duration of IFNa only to the approved period of 16 weeks. They have also considered that IFNa nonresponders were unlikely to respond to re-treatment with standard IFNa because the promising results of two recent studies on IFNa re-treatment [13,15] were not available at the time this trial was designed. Thus, 8 weeks of lamivudine treatment followed by a 16-week period of combination of lamivudine with IFNa were compared to a full year and more of lamivudine monotherapy. The authors recognize these problems and in a thoughtful discussion they stress the need for other approaches to combination therapies of IFNa with nucleoside analogs in treatment naive patients and IFNa non-responders with CHB. In this context the results of two large multi-center trials with combination therapy for 1 year with pegylated IFNa and lamivudine versus lamivudine and pegylated IFNa monotherapy also for 1 year both in HBeAg-positive and - negative patients are anxiously awaited.

Schiff等[22]，受到调节性考虑的限制，不可能包括聚乙二醇化IFNa饮食疗法，这使得IFNa的疗程需要限制在批准的16周。他们同样考虑到IFNa不响应者可能能够对标准IFNa治疗再响应，因为在这个实验设计的时候最近的两项关于IFNa再治疗研究[13,15]的有前途的结论还不存在。因此，对8周拉米夫定治疗后紧接着16周拉米夫定与IFNa的组合治疗与一个全年或更长时间的拉米夫定单一疗法进行了对比。作者意识到这些问题，并在一个深思的讨论中他们强调了需要另一个途径将IFNa的疗法和对未接受过治疗的患者使用核苷酸类似物的治疗结合起来，以及将IFNa不响应者与CHB结合起来。在这种背景下，我们焦急的等待在HbeAg阳性和阴性患者中，进行聚乙二醇化IFNa和拉米夫定组合治疗1年和聚乙二醇化IFNa以及拉米夫定单独治疗1年的两项大型多通道试验的结果。

Regardless of existing conjectures, it is becoming increasingly obvious that the strategy of combining IFNa with nucleoside analogs whatever the order and duration of application of the two drugs, may improve the efficacy of finite courses of treatment but is not expected to revolutionize the management of CHB neither in treatment- naive nor in IFNa resistant patients. Therefore many investigators are turning from the IFNa based therapeutic approaches to long-term suppression of HBV replication by safe nucleoside analogs with little or no viral resistance. The recent availability of adefovir with an excellent safety and resistance profile [19] makes this approach realistic and attractive [18].

不管存在多少猜想，越来越明显的是不管在两种药物的应用中顺序的还是一同将IFNa与核苷酸类似物结合起来的策略，都可能促进有限治疗的效力，但是不管是在初次治疗或是IFNa抵抗患者中，均不能期待能够对CHB的治疗产生革命。因此，很多研究者从基于IFNa的治疗途径转移到通过安全而带有极少或完全没有病毒抵抗性的核苷酸类似物对HBV复制的长期抑制。最近，具有有效安全性和抵抗特性的阿德福韦[19]的获得使得这种途径成为现实并很吸引人[18]。

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感谢biostar ，辛苦了！！！