逆转肝纤维化的临床证据

StephenW

http://www.medscape.com/viewarticle/772507_5
Clinical Evidence of Reversibility of Fibrosis
Hepatitis B

In chronic HBV infection, liver damage appears to be immune-mediated, with HBV-specific T cells playing a key role both in disease pathogenesis and viral clearance. CD4-positive T cells tend to predominate CD8-positive T cells in chronic hepatitis B.[30] When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology.[31] Inflammation is minimal in the immune-tolerant and inactive carrier phases, but is prominent in the immune-reactive phase. It is typically associated with scarring, which can vary from a mild portal expansion to periportal fibrous strands, bridging fibrosis and cirrhosis.[32]

Histological studies based on paired biopsies obtained before and after HBeAg seroconversion have consistently demonstrated that seroconversion of antibody to HBeAg (anti-HBe) is followed by a significant improvement or even disappearance of disease activity, and this improvement seems to be irrespective of the extent of the liver damage in the baseline biopsy.[33] When sustained, these changes are associated with excellent long-term prognosis.[34]

Five different oral nucleoside and nucleotide analogues have been approved. Such therapy can not only retard the progression of fibrosis and reverse both fibrosis and cirrhosis,[35–38] but also salvage patients with decompensated chronic hepatitis B[39] and prevent hepatic decompensation in patients with advanced fibrosis and cirrhosis.[40]

The most extensive evidence is in favour of lamivudine, the first oral agent licensed for treatment of hepatitis B. Clinical trials indicate that lamivudine can retard the progression of fibrosis, reduce progression to cirrhosis and also reverse cirrhosis.[39–42] In studies where lamivudine was compared with telbivudine or entecavir, Ishak fibrosis scores were improved by 35–73% in HBeAg-positive patients and by 38–46% in HBeAg-negative patients taking lamivudine.[41, 43–46] With extended therapy, patients are at an increasing risk of developing lamivudine-resistant variants, leading to increased viral replication prior to clinical relapse.

Long-term treatment (over 3 years) with entecavir has been associated with histological improvement including at least 1-point reduction in the Ishak fibrosis score in 88% of patients with chronic hepatitis B.[47] In another recent study, 10 patients with advanced fibrosis or cirrhosis (Ishak fibrosis score ≥4) were followed during 6 years of cumulative entecavir therapy. All showed improvement in Ishak fibrosis score (mean: −2.2). A reduction in Ishak fibrosis score to 4 or less was observed for all four patients who had cirrhosis at baseline.[48] Among patients with advanced liver fibrosis or cirrhosis treated with entecavir for 1 year, improvement in Ishak scores after 1 year was observed in 57% of HBeAg-positive patients, 59% of HBeAg-negative patients and 43% of lamivudine-refractory patients.[44, 46, 49]

In a long-term study of adefovir in which 15 patients had liver biopsies before treatment and after 5 years, seven of 12 patients (58%) with pre-treatment bridging fibrosis or cirrhosis improved their Ishak scores by at least 2 points, and three of the four patients with cirrhosis improved by 4 points, demonstrating that 5 years of adefovir therapy can reverse fibrosis (including cirrhosis) in most patients.[50]

In a large randomised, controlled trial in patients with chronic hepatitis B, after 1 year of telbivudine therapy, among the patients with marked pre-treatment bridging fibrosis or cirrhosis and Ishak fibrosis scores of 4–6, the Ishak scores improved to between 0 and 3 in 68% of HBeAg-positive and 56% of HBeAg-negative patients.[44]

A recent 5-year follow-up of patients treated with tenofovir was presented in the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), in November 2011. A total of 641 patients had baseline liver biopsies, 154 of which (24%) had cirrhosis (Ishak score ≥5). Of the 96 cirrhotic patients who had paired baseline and 5-year biopsies, 71 patients (74%) had decreases of ≥2 points at year 5.[51] Reversibility of HBV-related compensated cirrhosis has also been reported with the use of interferon alpha;[38] however, treatment of HBV-related cirrhosis with interferon alpha is currently not recommended because of the risk of hepatic decompensation associated with interferon-related flares of hepatitis.[52]

StephenW

临床证据可逆性
B型肝炎

在慢性HBV感染，肝功能损害，似乎是免疫介导的，无论是在疾病的发病机理和病毒的清除HBV特异性T细胞发挥了关键作用。往往占主导地位CD4阳性T细胞CD8阳性T细胞在慢性乙型肝炎[30]，当HBV特异性CD8响应是无法控制病毒复制，它可能会导致肝组织病理变化是最小的。[31]炎症免疫耐受和不活动的载波相位，但突出的免疫反应相。它通常与疤痕，它可以改变从一个温和的门户网站扩展到汇管区纤维束，桥接纤维化和肝硬化。[32]

组织学研究的基础上对切片前和HBeAg血清转换后的一贯表现出的抗体，e抗原（抗-HBe），血清转换后的重大疾病活动性的改善甚至消失，这种改善的程度似乎是不论基线活检对肝脏有损害的。持续，这些变化与卓越的长期预后[33] [34]

已批准了5个不同的口服核苷和核苷酸类似物。这样的治疗不仅能延缓肝纤维化的进展和逆转纤维化和肝硬化，[35〜38]，而且还挽救患者的代偿性慢性乙型肝炎[39]和防止肝脏失代偿，拥有先进的肝纤维化和肝硬化的患者。[40]

最广​​泛的证据是有利于拉米夫定，获发牌的第一个口服剂用于治疗B型肝炎的临床试验表明，拉米夫定能延缓肝纤维化的进展，减少发展为肝硬化和逆转肝硬化[39-42]在研究中。拉米夫定相比，替比夫定或恩替卡韦，Ishak纤维化评分的35-73％，HBeAg阳性患者和HBeAg阴性患者服用拉米夫定的38-46％。[41，43-46]延长治疗，患者在拉米夫定耐药变异，导致越来越多的风险增加病毒复制的临床前复发。

长期（3年以上），恩替卡韦治疗一直伴随着组织学改善，包括至少减少1点在Ishak纤维化评分在88％的患者与慢性乙型肝炎[47]在另一项最近的研究中，10例随后在6年的累计恩替卡韦治疗晚期肝纤维化或肝硬化（Ishak纤维化评分≥4）。所有显示Ishak纤维化评分（平均2.2）的改善。 Ishak纤维化评分的减少到4个或更少观察到的所有4名患者有肝硬化的基线。[48]在1年后患者1年恩替卡韦治疗晚期肝纤维化或肝硬化，改善Ishak评分观察57％的HBeAg阳性患者中，有59％的HBeAg阴性患者和拉米夫定难治性患者的43％。[44，46，49]

在长期的研究中，阿德福韦酯15例肝活检治疗前和治疗后5年，7桥接纤维化或肝硬化治疗前的12例（58％）提高了他们的Ishak评分至少有2点，提高了4个百分点，表明5年的阿德福韦治疗可以逆转纤维化（包括肝硬化），大多数患者的肝硬化患者。[50]

在一个大型的随机，对照试验在慢性乙型肝炎患者中，替比夫定治疗1年后，显着治疗前的桥接纤维化或肝硬化和Ishak纤维化评分4-6的患者中，Ishak评分提高到介于0和3在68％的HBeAg阳性和HBeAg阴性患者的56％。[44]

最近5年的随访中，与替诺福韦治疗的患者的肝病研究学会（AASLD）第62届会议的美国协会，于2011年11月。一个总的641例患者的基线肝活检，其中154（24％），肝硬化（Ishak评分≥5）。谁曾配对的96例肝硬化患者基线和5年的活组织切片检查，有71例（74％）下降≥2分5年。[51] HBV相关的代偿性肝硬化的可逆性​​也有报道使用干扰素阿尔法[38] [52]然而，与α-干扰素治​​疗HBV相关性肝硬化，目前不建议，因为与干扰素相关的flare的肝功能失代偿的风险。

咬牙硬挺

感谢分享，长期抗病毒才有效，希望有特效药物吧