慢性乙型肝炎长期抗病毒治疗中的问题和解决策略

慢性乙型肝炎(chronic hepatitis B, CHB)的抗病毒治疗是关键的观点已经深入人心,通过2005年12月中华医学会肝病学分会、感染病学分会联合发布中国《慢性乙型肝炎防治指南》[1]以及2006年下半年全国25个城市的指南推广学术会议,取得了很大的成绩.     

慢性乙型肝炎抗病毒治疗新策略

慢性乙型肝炎（CHB）是一种免疫缺陷性疾病。近10多年来，抗病毒治疗取得了很大的进展。当今，抗病毒治疗药物有二大类，即核苷（酸）类（NAs）和干扰素类。已上市的NAs有拉米夫定（LAM）、阿德福韦（ADV）、替比夫定（LDT）、恩替卡韦（ETV）以及替诺福韦（TDF）；干扰素有普通干扰素（IFN）和聚乙二醇干扰素（PegIFN）-α。     

儿童慢性乙型肝炎抗病毒治疗新进展

通常血清HBsAg阳性超过6个月称为慢性HBV感染。我国约有1．25亿慢性HBV感染者,其中绝大多数是母婴传播或儿童期感染所致。尽管乙型肝炎疫苗能有效阻断乙型肝炎的传播,但由于感染人群基数庞大,儿童慢性HBV感染仍然是严重的社会问题。慢性乙型肝炎（CHB）是指HBV持续感染造成的肝脏慢性坏死性炎性反应,表现为血清HBV DNA升高,伴ALT水平持续或间歇升高或肝组织活检显示慢性肝炎。大约1／4的CHB患者可发展至肝硬化和肝细胞癌。     

慢性乙型肝炎抗病毒治疗专家共识

自2005年12月中国《慢性乙型肝炎防治指南》发布以来,国内外对于乙型肝炎病毒（HBV）及其相关慢性肝病的研究不断深入。亚太肝脏学会（APASL）、欧洲肝脏学会（EASL）及美国肝脏病学会（AASLD）陆续发布了各自更新的慢性乙型肝炎（CHB）临床指南及共识。     

重视慢性乙型肝炎核苷(酸)类似物抗病毒治疗的耐药

慢性乙型肝炎(chronic hepatitis B, CHB)抗病毒治疗的地位和作用已经得到了确立,未来几年这一领域的发展方向就是新型核苷(酸)类似物的研发.随着对于CHB抗病毒治疗临床研究的不断深入,在核苷(酸)类似物抗乙型肝炎病毒(hepatitis B virus, HBV)治疗临床研究中发现HBV的耐药是一个普遍和突出的问题,只有充分重视HBV耐药的研究,才能更有效地贯彻长期抗病毒治疗的方针.     

慢性乙型肝炎抗病毒治疗研究现状与热点

乙型肝炎病毒（乙肝病毒，HBV）感染极为广泛，60亿世界人口中有20亿人感染HBV，其中3．5亿～4．0亿人为慢性HBV携带者。慢性HBV感染引起慢性并发病发生，其中15％～40％将发展为肝硬化、肝衰竭或肝细胞癌，且有15％～40％患者死于肝硬化，有或无肝细胞癌。病死率男50％，女15％。据统计全世界每年死于慢性乙型肝炎（CHB）包括它的并发病者约100万人，代偿性肝硬化的5年病死率为16％，失代偿性肝硬化为86％。     

慢性乙型肝炎抗病毒治疗的停药问题

随着核苷（酸）类似物在慢性乙型肝炎（CHB）治疗中的长期应用,其停药方面的问题较为突出.首先,在定义治疗目标、治疗终点及停药标准上,如何掌握理想和现实的停药标准、最佳停药时机、使广大CHB患者获得最大疗效等问题都是当前值得我们关注和研究的热点课题.现将有关研究进展介绍如下.     

慢性乙型肝炎并肝硬化的抗病毒治疗

据北京2005年全国肝炎及肝病会议的资料，乙型肝炎（简称乙肝）是一个严重的公共卫生问题。全球60亿人口中约1／2的人生活在HBV高流行区，约20亿人被证明有HBV感染，3．4亿人为HBV慢性感染，其中25％．40％最终将死于肝硬化和肝癌。据世界卫生组织（WHO）报道，在全球10位疾病死因中，乙肝占第7位，每年因乙肝死亡者约为75万例。所以乙肝并肝硬化的治疗非常重要。     

慢性乙型肝炎联合抗病毒治疗专家共识

干扰素α（IFN—α）、核苷（酸）类似物（NUC）抗病毒单药治疗是目前慢性乙型肝炎（chronichepatitisB，CHB）的主要治疗策略，且CHB患者远期预后经抗病毒治疗后获得了显著改善。然而单药治疗应答率较低，多数患者需长期用药，停药后维持应答率较低，长期治疗耐药变异率较高，限制了CHB患者单药治疗的临床应用。     

慢性乙型肝炎抗病毒治疗的现状与对策

全球约20亿人曾感染过乙型肝炎病毒（HBV），现在慢性HBV感染者为3．5～4．0亿人，其中15％～30％将发展为肝硬化、肝癌而过早死亡。抗病毒治疗的目的是抑制HBV复制，减少肝硬化的发生和肝癌的出现。     

核苷和核苷酸类药物治疗慢性乙型肝炎的长期性

核苷和核苷酸类药物（ NAs）已成功用于慢性乙型肝炎（ CHB）治疗。目前一致认为,乙型肝炎病毒（ HBV）复制是肝损伤和疾病进展的关键因素,因此CHB治疗的主要目的是最大限度地持续抑制HBV复制。现已证明,应用NAs长期治疗CHB可明显改善肝脏组织学、逆转肝纤维化或肝硬化,以及减少肝细胞癌的发生。该文对CHB长期治疗的必要性、临床获益及管理进行了综述。     

Long-term results of treatment of chronic hepatitis B, C and D with interferon-α in renal allograft recipients

Abstract The aim of this study was to evaluate the efficacy and safety of interferon-a (IFN-α) therapy of chronic hepatitis B, C and D (HBV, HCV and HDV, respectively) in renal transplant recipients. A group of 42 patients (30 males, 12 females, mean age 38 years) with documented viraemia and chronic active hepatitis (CAH) were studied, of whom 1 had HBV infection alone, 11 had HCV infection alone, 3 had HBV and HDV infection concomitantly, 12 had HBV and HCV infection concomitantly, and 2 had HBV, HCV and HDV infection concomitantly. Patients received 3 MU IFN-α three times weekly for 6 months. After IFN-α therapy, 18 patients (43 %) achieved normal alanine aminotransferase (ALT) activity and a partial response was observed in 12 (29%) patients. Two patients relapsed (one with HCV and one with HBV + HCV infection) immediately after the cessation of IFN-α therapy. Repeated liver biopsy was performed in 16 patients after 6–24 months of therapy and revealed progression to cirrhosis in five patients, remission in two and stable disease in nine. None of the patients cleared HCV RNA, four patients cleared HBeAg (two also HDV), and one both HBV and HCV. Five patients died during IFN-α therapy (one as a consequence of liver failure), and four died during the 6 months after therapy (two as a consequence of liver failure). During IFN-α therapy renal allograft function remained stable in 31 patients and acute rejection episodes occurred in 7, of whom 5 lost their graft and all had experienced rejection episodes before. In 16 patients normalization of ALT continued during long-term follow-up (median 22 months, range 0–84 months). IFN-α seemed to be moderately effective in the treatment of chronic HBV or HCV infections, but cannot be recommended for recipients infected with both HBV and HCV.     

替比夫定治疗慢性乙型肝炎的临床研究

目的探讨替比夫定治疗慢性乙型肝炎的疗效。方法将160例患者随机分为治疗组和对照组,各80例。治疗组给予替比夫定治疗,对照组给予拉米夫定治疗,疗程为24周。结果治疗组患者第4周、12周和24周各时间段HBVDNA低于检测下限的比率明显高于对照组(P0.01)。两组患者治疗第4周HBeAg低于检测下限的比率均为0,治疗组患者第12周、24周HBeAg低于检测下限的比率均明显高于对照组(P0.05)。治疗组和对照组患者第4周ALT复常率分别为5.0%和2.5%,无统计学意义;治疗12周、24周后治疗组患者ALT复常率均明显高于对照组(P0.05)。治疗24周后治疗组完全应答率明显高于对照组,无应答率明显低于对照组(P0.05)。两组不良反应发生率分别为10%和15%,无统计学差异。结论替比夫定能有效抑制HBV复制,提高HBVDNA、HBeAg低于检测下限的比率和ALT复常率,临床使用安全,耐受性好。     

慢性乙型肝炎合并肾功能不全患者抗病毒治疗研究进展

慢性乙型肝炎(Chronic hepatitis B,CHB)是一种以肝脏损害为主要表现的感染性疾病,可进展为肝纤维化、肝硬化、肝衰竭或肝癌,危及患者生命。CHB患者易并发乙型肝炎病毒(Hepatitis B virus,HBV)相关性肾小球肾炎,或合并其他肾脏疾病,这类患者的抗病毒治疗需要充分考虑药物的肾脏安全性。根据目前相关指南推荐,合并肾功能不全或者有潜在肾功能损害的患者应优先选用替比夫定、恩替卡韦或丙酚替诺福韦,但这几种抗HBV药物各有利弊,如何在CHB合并肾脏损害的患者中进行抗病毒治疗值得进一步深入探究。同时,抗病毒治疗过程中应定期监测肾功能,以便早期识别肾功能损害。本文就CHB合并肾功能损害的原因,抗HBV治疗引起肾脏损害的风险,抗病毒治疗方案的选择,以及患者肾功能监测等作一综述。     

Adefovir treatment for chronic hepatitis B in heart transplant recipients

Chronic hepatitis B is prevalent in the transplant setting and may cause significant complications. Effective control of viral replication is needed. Besides lamivudine, very little data are available on safety and efficacy of other drugs. We describe our experience with adefovir dipivoxil (ADV) in eight heart transplant recipients. Studies included a baseline liver biopsy, thrice‐monthly clinical, biochemical, and virological evaluations, including genotyping and viral load, polymerase gene sequencing for resistance mutations, liver and kidney function tests, and liver ultrasound. Of eight patients, six had fibrosis score ≤2 and negative HBeAg and seven had hepatitis B virus (HBV) genotype D. Upon ADV start, median HBV‐DNA was 5.8 logs IU/mL and alanine aminotransferase (ALT) levels were mostly normal. All patients had prior mild‐to‐moderate renal functional impairment. Seven of eight patients started ADV after a previous course of lamivudine. Five of these seven patients became HBV‐DNA undetectable within eight months. One patient with low baseline viremia started ADV de novo and suppressed HBV‐DNA. Median treatment duration was 66 months. ADV daily dose was halved in one patient due to renal function worsening. No ALT flares, hypophosphatemia, liver decompensation, liver cancer, or emergence of resistance was observed. Our data suggest that ADV may be a safe and effective rescue treatment for heart transplant recipients with lamivudine‐resistant chronic hepatitis B.     

Long-term results of hepatitis B immunoglobulin and lamuvidine for hepatitis B prophylaxis after liver transplantation

Purpose

Recurrence of hepatitis B virus after a liver transplantation (OLT) is a risk factor affecting graft and patient survivals. Short-term hepatitis B virus reactivation rates after OLT range between 3% and 15%. Using combination prophylaxis, the outcomes of OLT among patients with liver disease related to hepatitis B virus have improved to levels comparable to those whose disease is not related to hepatitis B virus.

Materials and Methods

Since September 2001, we performed 288 OLT in 282 patients including 74 who had liver failure related to hepatitis B virus among whom 58 were followed for >12 months and analyzed retrospectively. Our protocol included lamivudine (100 mg orally per day beginning the day after surgery) and hepatitis B immunoglobulin (10,000 IU IV during the anhepatic phase, 2000 IU/d IV during the first week after surgery, 2000 IU IV/month from postoperative months 1 to 12). Using our protocol, the anti-hepatitis B surface antibodies (HBsAb) serum titer was maintained up to 100 IU/mL. The female:male ratio was 11:47. The mean age of patients was 43 ± 12.8 years.

Results

Five patients died of causes unrelated to hepatitis B virus. At the time of death, their hepatitis B surface antigens were negative, and serum titers of anti-HBsAb were 45, 35.3, 56.4, 79.6, and 123 IU/mL. Mean follow-up was 46.5 ± 18.9 months (range, 12-79). The hepatitis B surface antigen became positive in 4 patients; the remaining 49 had no evidence of hepatitis B surface antigen. In 18 patients, serum titer of anti-hepatitis B surface antigen was 0; in the remaining 31 patients, it was 69.2 ± 133 IU/mL.

Conclusion

Our combination protocol with hepatitis B immunoglobulin and lamivudine is a safe, cost-saving, and effective treatment for hepatitis B virus prophylaxis after liver transplantation.     

慢性乙型肝炎患者病毒准种的研究进展

由于乙型肝炎病毒（HBV）的逆转录酶缺乏校正活性,在病毒复制过程中产生大量核苷酸错配,故HBV在宿主体内表现为大量在遗传学上高度相关而又有差别的病毒群体,这一群体称为准种,宿主体内的病毒准种在宿主免疫压力和药物的选择压力下不断发生动态变化,因此HBV准种变化在慢性乙型肝炎的抗病毒治疗、耐药检测以及预后等方面均有重要作用。本文对HBV准种变化与慢性乙型肝炎进展的关系作一综述。