评论:长期替诺福韦治疗肝硬化回归

StephenW

Regression of Cirrhosis With Long–Term Tenofovir Treatment

    Vincent Wai-Sun Wong
    ,
    Francis Ka-Leung Chan

published online 24 June 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Section Editor

   

Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381:468–475.

Cirrhosis is the common final path of different chronic liver diseases. A couple of decades ago, cirrhosis was considered an irreversible state. Since the development of antiviral therapy for chronic hepatitis B and C, it has been observed that liver fibrosis, and to certain extent cirrhosis, can regress if the underlying etiology is under control. However, high-quality data to document this phenomenon are scarce.

In a recent paper, Marcellin et al reported the results of long-term tenofovir disoproxil fumarate treatment in patients with chronic hepatitis B (Lancet 2013;381:468–475). Tenofovir is among the most potent antiviral agents against hepatitis B virus (HBV). In the original registration trial involving 266 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and 375 patients with HBeAg-negative chronic hepatitis B, tenofovir demonstrated superior antiviral efficacy to adefovir dipivoxil (N Engl J Med 2008;359:2442–2455). Among HBeAg-positive patients, 76% of those treated with tenofovir and 13% of those treated with adefovir had HBV DNA suppressed below 69 IU/mL at week 48 (P < .001). Corresponding figures in HBeAg-negative patients were 93% and 63%, respectively (P < .001).

After week 48, patients in both groups continued tenofovir regardless of initial treatment assignment and were prospectively followed for 8 years. The current report by Marcellin et al was a planned analysis at 5 years (Lancet 2013;381:468–475). Although follow-up liver biopsy was optional, this study was remarkable in that 489 of the original 641 randomized patients completed 5 years of follow-up, and 348 patients (54% of the original cohort) also agreed to repeat liver biopsy at 5 years. Therefore, this study provided valuable data on the histologic benefits of long-term antiviral therapy.

The majority of patients had marked reduction in hepatic necroinflammation. The proportion with no or mild necroinflammation (Knodell score ≤ 3) increased from 8% at baseline to 80% at 5 years. Similarly, fibrosis also improved with time. No or mild fibrosis was found in 39% at baseline and 63% at 5 years. The proportion with pronounced bridging fibrosis or cirrhosis (Ishak stage 4–6) decreased from 38% to 12%. Altogether, 51% had improvement in fibrosis stage. Among 96 patients with cirrhosis at baseline, 71 (74%) had regression of cirrhosis, 70 of whom also showed improvement in Ishak fibrosis score by ≥2 points. Low body mass index (<25 kg/m2) was the only independent factor associated with regression of cirrhosis.

In addition, 73% of HBeAg-positive and 85% of HBeAg-negative patients had normal alanine aminotransferase at 5 years. By intention-to-treat analysis, 65% of HBeAg-positive and 83% of HBeAg-negative patients had HBV DNA suppressed to <69 IU/mL. Of HBeAg-positive patients, 40% achieved HBeAg seroconversion. No drug-resistant mutant was detected.

Because of structural similarities between tenofovir and adefovir, nephrotoxicity and bone loss have been a concern. However, in this 5-year study, only 1 of 585 patients had creatinine clearance of <50 mL/min, and 7 (1%) patients had serum phosphorus of <0.65 mmol/L.


Comment

Regression of fibrosis has been observed ever since effective antiviral therapy became available. In a small study of 20 chronic hepatitis B patients treated with lamivudine for 1 year, 7 had improvement in fibrosis, 12 had static disease, and only 1 had progression from Knodell stage 0 to stage 1 disease (J Hepatol 1999;30:743–748). Subsequent studies largely supported the initial observation. In another study of 69 patients treated with entecavir, liver biopsy was repeated after a median of 6 years (range, 3–7; Hepatology 2010;52:886–893). Overall, 88% had improvement in fibrosis, and 58% had a reduction in Ishak fibrosis score by ≥2 points. All 10 patients with advanced fibrosis or cirrhosis at baseline had improvement in fibrosis stage. The current study by Marcellin et al adds further proof by including a large number of patients with repeated liver biopsies. In particular, the study included a sizable cohort of cirrhotic patients.

Is this unequivocal evidence of cirrhosis regression? Although there is little doubt that fibrosis can improve with treatment, the reversibility of cirrhosis remains controversial. Cirrhosis involves not only deposition of fibrous tissue, but also changes in liver architecture. In addition, studies with serial liver biopsies are not foolproof. Because a typical liver biopsy specimen only represents 1/50,000 of the entire liver volume, sampling variability is common. If the less severe area is biopsied at the second assessment, a patient may erroneously be labeled to have regression of cirrhosis despite no change in disease status.

Current data, however, suggest that regression of cirrhosis is genuine at least in some cases. In a study of 195 chronic hepatitis B patients who underwent per-protocol paired liver biopsies in clinical trials, 100 had histologic response defined as a ≥2-point improvement in Knodell histologic activity index without worsening of fibrosis (Clin Gastroenterol Hepatol 2009;7:1113–1120). Hepatocellular carcinoma or cirrhotic complications only occurred in 1% of the patients with histologic response, compared with 12% of those without after a median follow-up of 7 years. No patient with regression of cirrhosis developed complications, compared with 30% of those who continued to have cirrhosis at the second biopsy. In addition, lamivudine monotherapy in patients with advanced fibrosis or cirrhosis is superior to placebo in preventing hepatocellular carcinoma and worsening of Child-Pugh score (N Engl J Med 2004;351:1521–1531). Among patients with decompensated liver cirrhosis, antiviral therapy may also result in delisting from transplantation list because of clinical improvement, and seems to improve the overall survival (Gastroenterology 2002;123:719–727; Hepatology 2011;54:91–100; J Viral Hepat 2012;19:732–743). Antiviral therapy also reduces portal pressure in some cirrhotic patients (J Hepatol 2009;51:468–474). Although none of these studies provide unequivocal evidence of cirrhosis regression, the clinical benefit of antiviral therapy is consistently observed.

If we agree that antiviral therapy can improve the histology and clinical outcome of cirrhotic patients, what is next? A number of observational studies suggest that cirrhotic patients with incomplete HBV DNA suppression are still at increased risk of hepatocellular carcinoma and cirrhotic complications (Gut 2013;62:760–765; Hepatology 2013 Feb 6 doi:10.1002/hep.26301 [Epub ahead of print]). Unfortunately, a proportion of patients will still have incomplete HBV DNA suppression despite potent antiviral drugs like entecavir and tenofovir (Aliment Pharmacol Ther 2012;35:1326–1335; Lancet 2013;381:468–475). The optimal treatment strategy in this setting, including the possibility of combination therapy (Gastroenterology 2012;143:619–628), remains to be defined.

It is also interesting to note that patients who failed to achieve regression of cirrhosis in the study by Marcellin et al were more likely to be overweight or obese. In recent years, nonalcoholic fatty liver disease has emerged as the most common cause of abnormal liver biochemistry worldwide (Gastroenterology 2011;140:124–131; Gut 2012;61:409–415) and the third leading indication for liver transplantation in United States (Gastroenterology 2011;141:1249–1253). It is important to remember that HBV may not be the sole driver of disease activity in some patients.

Finally, although we are satisfied with the safety and efficacy of entecavir and tenofovir, we should not forget the financial and psychological burden of long-term antiviral therapy on our patients. In the years ahead, efforts should be made to develop effective yet finite treatment for chronic hepatitis B. In addition, antiviral therapy lowers but does not eliminate the risk of hepatocellular carcinoma. Further knowledge in fibrosis and hepatocarcinogenesis will allow us to develop effective secondary prevention against hepatocellular carcinoma and cirrhotic complications.

StephenW

甘恩Marcellin等P，ë，布提等。富马酸替诺福韦酯治疗慢性乙型肝炎肝硬化患者在治疗过程中的回归：有5年的开放标签的随访研究。柳叶刀“杂志2013，381:468-475。

不同的慢性肝病，肝硬化是常见的最终路径。一对夫妇十年前，肝硬化被认为​​是一个不可逆的状态。自慢性乙型和丙型肝炎的抗病毒治疗的发展，已经观察到，肝纤维化，肝硬化在一定程度上，可以倒退，如果潜在的病因是在控制之下。然而，高品质的数据记录这种现象是稀缺的。

在最近的一篇文章中，Marcellin等等报道长期富马酸替诺福韦酯治疗慢性乙型肝炎患者（柳叶刀“杂志2013; 381:468-475）的结果。其中最有力的抗乙型肝炎病毒（HBV）的抗病毒药物替诺福韦。在原登记试验，涉及266乙型肝炎e抗原（HBeAg）阳性的慢性乙型肝炎患者和375例HBeAg阴性慢性乙型肝炎患者中，替诺福韦表现出卓越的抗病毒疗效，阿德福韦酯（新英格兰医学杂志2008; 359:2442 -2455）。 HBeAg阳性患者中，替诺福韦治疗的76％和13％用阿德福韦治疗HBV DNA抑制到低于69 IU / mL的48周（P <0.001）。 HBeAg阴性患者的相应数字分别为93％和63％，分别为（P <0.001）。

48周后，两组患者继续替诺福韦，无论初始治疗分配，并进行前瞻性随访了8年。 Marcellin等等人目前的报告是有计划的分析，5年（柳叶刀“杂志2013; 381:468-475）。虽然随访肝活检是可选的，这项研究是显着的，489原641随机患者完成5年的随访，348例（54％原来的队列）还同意在5年重复肝活检。因此，这项研究提供了宝贵的数据，在长期的抗病毒治疗的组织学的好处。

多数患者有显着减少肝坏死性炎症。无或轻度炎症坏死（Knodell评分≤3）的比例在基线从8％上升至80％，为5年。同样，纤维化也随时间的改善。无或轻度纤维化被发现在基线和39％，63％，5年。明显的桥接纤维化或肝硬化的比例从38％下降至12％（伊沙克阶段4-6）。总之，51％有改善纤维化阶段。其中96例肝硬化患者在基线，71（74％）有肝硬化，70人亦有改善Ishak纤维化评分≥2分的回归。低体重指数（<25 kg/m2）中伴有肝硬化的回归是唯一的独立因素。

此外，还有73％的HBeAg阳性和HBeAg阴性患者中有85％在5年的谷丙转氨酶正常。意向性治疗分析，65％的HBeAg阳性和HBeAg阴性患者有83％的抑制HBV DNA <69 IU /毫升。 HBeAg阳性的患者中，40％实现HBeAg血清学转换。无耐药突变检测。

由于替诺福韦和阿德福韦结构之间的相似性，肾毒性和骨质流失一直关注的问题。然而，在这5年的研究中，只有1 585例患者的肌酐清除率<50毫升/分钟，7（1％）<0.65 mmol / L的患者血清磷


评论

已观察到纤维化回归自从提供有效的抗病毒治疗成为。在一项小规模研究对20例慢性乙型肝炎患者拉米夫定治疗1年，7纤维化改善，12例静态疾病，只有1 Knodell进展，从0级，1级，疾病（肝1999，30:743  - 748）。随后的研究在很大程度上支持了初步观察。在另一项研究中，恩替卡韦治疗69例，肝活检后重复中位数为6年（范围3-7; 2010年肝病; 52:886-893）。总体而言，88％有纤维化改善，58％减少Ishak纤维化评分≥2分。所有10例晚期肝纤维化或肝硬化基线有改善纤维化阶段。目前的研究等Marcellin等通过反复肝活检的患者在内的大量增加进​​一步证明。尤其是肝硬化患者，研究包括一个庞大的队列。

这是明确的证据表明，肝硬化的回归？虽然有一点是无可置疑的纤维化可改善与治疗，肝硬化的可逆性​​仍存在争议。肝硬化不仅涉及沉积的纤维组织，但肝组织结构的变化。此外，与串行肝活检的研究并非万无一失。因为一个典型的肝活检标本仅占1/50，000的整个肝脏体积，抽样变异是常见的。如果不太严重的区域在第二次评估活检，可能会错误地被贴上一个病人有肝硬化的回归，尽管在疾病状态没有变化。

然而，目前的数据表明至少在某些情况下，肝硬化是真正的回归。在一项研究中，195例慢性乙肝患者接受每个协议的配对肝活检在临床试验中，100例组织学应答定义为Knodell组织学活动指数≥2点改善无恶化纤维化（临床胃肠肝脏病杂志2009; 7： 1113-1120）。肝癌或肝硬化并发症只发生在组织学反应的患者的1％，相比那些没有一个中位随访7年后的12％。没有病人相比，那些谁继续在第二次活检有肝硬化，30％肝硬化并发症的回归。此外，先进的肝纤维化或肝硬化患者拉米夫定单药治疗是优于安慰剂在预防肝癌恶化，Child-Pugh评分（新英格兰医学杂志2004; 351:1521-1531）。在肝硬化失代偿期的患者，抗病毒治疗也可能导致退市移植的名单，因为临床症状明显改善，似乎提高总生存期（2002年消化; 123:719-727，2011年肝病54:91-100研究病毒Hepat 2012，19:732-743）。抗病毒治疗也减少了在某些肝硬化患者的门静脉压力（肝2009，51:468-474）。虽然这些研究没有提供明确的证据肝硬化回归，抗病毒治疗的临床获益持续观察。

如果我们同意抗病毒药物治疗可改善肝硬化患者的组织学和临床结果，下一步是什么？许多的观测研究表明，肝硬化患者仍处于不完整的HBV DNA抑制肝癌和肝硬化并发症的风险增加（GUT 2013，62:760-765肝病2013年2月6日期：10.1002/hep.26301 [EPUB的提前打印]）。不幸的是，患者的比例仍将有不完整的HBV DNA抑制，尽管有强大的抗病毒的药物如恩替卡韦和替诺福韦（中华消化杂志，2012，35:1326-1335;柳叶刀“杂志2013; 381:468-475）。在此设置的最佳治疗策略，包括联合治疗的可能性（2012年消化; 143:619-628），还有待定义。

它也是值得注意Marcellin等等人的研究中，未能实现回归肝硬化的患者更可能是超重或肥胖。近年来，酒精性脂肪性肝病已成为最常见的原因肝脏生化异常全世界（2011年消化; 140:124-131，2012年肠道61:409-415）和肝移植在美国的第三代领导指示（2011年消化; 141:1249-1253）。重要的是要记住，乙肝病毒，可能无法在一些患者疾病活动的唯一驱动力。

最后，虽然我们感到满意，恩替卡韦和替诺福韦的安全性和有效性，我们不应该忘记长期的抗病毒治疗对患者的经济和心理负担。在未来的岁月中，应作出努力此外，制定有效但有限的治疗慢性乙型肝炎的抗病毒治疗肝癌的风险降低，但并不能消除。进一步纤维化和肝癌的知识将使我们能够制定有效的二级预防的抗肝癌和肝硬化并发症。