慢性乙型肝炎抗病毒治疗重在规范:口服核苷(酸)类似物类药物的临床应用原则

口服核苷(酸)类似物应用于慢性乙型肝炎的抗病毒治疗已近10年.从1998年拉米夫定到2003年阿德福韦酯,再到2006年恩替卡韦和2007年替比夫定,乃至不久后的替诺福韦、克拉夫定、恩曲他滨等药物的引入和广泛应用业已证明,口服核苷(酸)类药物已使慢性乙型肝炎抗病毒治疗获得巨大进展.口服核苷(酸)类似物在慢性乙型肝炎抗病毒治疗中的"有效性"、"可行性"、"安全性"已获得临床的广泛认同,其耐药性的产生也引起高度重视.单一或联合核苷(酸)类似物的使用,可使临床上90%以上的患者达到持续抑制HBV复制这一慢性乙型肝炎治疗的基本目标.     

抗病毒治疗对慢性乙型肝炎患者肝脏组织学的影响

目的分析慢性乙型肝炎患者的不同抗病毒治疗方式与疗程对肝组织学的影响,探讨临床用药的最佳方案。方法回顾性总结142例慢性乙型肝炎患者,分析其用药方式、疗程、肝脏生化学、病毒学、血清学、肝组织学等相关指标。结果病毒学完全应答:干扰素组58.93%(33/56),核苷(酸)类似物组90.20%(46/51),未抗病毒组0;HBeAg转阴率:干扰素组39.29%(22/56),核苷(酸)类似物组15.68%(7/51),未抗病毒组6%(2/35);HBsAg转阴率:干扰素组21.43%(12/56),核苷(酸)类似物组1.96%(1/51),未抗病毒组0;组织学应答:炎症改善方面,疗程≤1年者为干扰素组核苷(酸)类似物组未抗病毒组,疗程1年者为核苷(酸)类似物组干扰素组未抗病毒组,而肝组织纤维化改善方面,不论疗程长短均为核苷(酸)类似物组干扰素组未抗病毒组。结论抗病毒治疗获得病毒学应答者肝脏组织学均能得到不同程度的改善;核苷(酸)类似物抗病毒治疗2年以上者肝组织学改善程度优于干扰素。     

慢性乙型肝炎联合抗病毒治疗研究进展

抗病毒治疗是慢性乙型肝炎治疗的重要手段。目前单一药物的疗效不令人满意,越来越多的研究数据表明药物联合抗病毒治疗,包括干扰素α和核苷（酸）类似物联合治疗以及两种核苷（酸）类似物联合治疗可以减少耐药发生、提高抗病毒疗效,因而联合抗病毒治疗可能是控制乙肝的有效策略。     

干扰素与替比夫定序贯疗法治疗慢性乙型肝炎43例

干扰素α作为较为有效的抗病毒药物之一,疗程相对较短,耐药率低,但疗效仍不够理想,总的持久应答率仅为40％[1].核苷类药物疗程虽相对较长,但安全性和耐受性良好,且适用于干扰素治疗无效的患者.对于干扰素疗效欠佳的慢性乙型肝炎患者口服核苷类似物的选择,目前各类慢性乙型肝炎指南中尚无推荐方案.与拉米夫定、阿德福韦酯相比,替比夫定具有强效抑制HBV复制及HBeAg血清转换率高等双重特点[2].本研究对干扰素α治疗疗效不佳的患者,选用序贯替比夫定再治疗,探讨其临床疗效.     

HBV感染：有病毒复制就抗病毒治疗

作为在临床一线长期从事乙型肝炎诊疗的专科医师, 我们亲身经历了乙型肝炎治疗理念发展变化的全过程:从"对症治疗"进展至"病因治疗"(抗病毒治疗);抗乙型肝炎病毒(HBV)药物, 从单一的普通干扰素发展到多种核苷(酸)类似物和聚乙二醇干扰素, 特别是高效、高耐药屏障的恩替卡韦(ETV)、富马酸替诺福韦二吡呋酯(TDF)、富马酸丙酚替诺福韦(TAF)和艾米替诺福韦(TMF)等核苷(酸)类似物的广泛应用, HBV抑制的疗效满意, 大多数经过抗病毒治疗的慢性乙型肝炎(CHB)患者病情得到有效控制、肝功能持续正常, 肝纤维化逆转者亦屡见不鲜, 发展至肝癌的患者显著减少。即使是乙型肝炎肝硬化患者, 抗病毒治疗后的预后亦明显改善。     

慢性乙型肝炎抗病毒治疗进展

本文从干扰素α、核苷（酸）类似物和免疫调节药物三方面论述了慢性乙型肝炎抗病毒的治疗进展，对乙肝治疗颇有帮助。     

中国慢性乙型肝炎患者抗病毒治疗的耐药现况

目前我国已批准了4种结构不同的核苷（酸）类似物用于慢性乙型肝炎（CHB）患者的抗病毒治疗,分别是胞嘧啶核苷类似物拉米夫定（LAM）、腺嘌呤核苷磷酸酯类似物阿德福韦酯（ADV）、鸟嘌呤核苷类似物恩替卡韦（ETV）和胸腺嘧啶核苷类似物替比夫定（LdT）[1]。这些药物在乙型肝炎病毒（HBV） DNA逆转录酶的作用下,掺入HBV DNA链,终止DNA     

慢性乙型肝炎的免疫调节治疗：挑战与机遇

慢性乙型肝炎的抗病毒治疗药物主要包括核苷类似物和干扰素，其中核苷类似物主要抑制HBV复制；普通干扰素以抑制病毒为主，兼有免疫调节作用。值得关注的是长效干扰素（PEG—IFNOt2a）在5％-8％的HBeAg转阴并发生HBeAb转换的慢性乙型肝炎患者治疗中，出现HBsAg血清转换，显示其可能具有通过诱导免疫应答来清除病毒的作用。由于目前应用的抗病毒治疗药物不能彻底清除病毒，而且在停药后易复发，     

慢性乙型肝炎及其相关肝硬化抗病毒治疗:单药还是联合?

目前慢性乙型肝炎的抗病毒治疗应答率仍有待提高,不少学者开始尝试联合用药,包括核苷和核苷酸类药物之间的联用和干扰素与核苷和核苷酸类药物的联用。回顾近期国内外经验发现,初治慢性乙型肝炎患者可首选强效低耐药核苷和核苷酸类药物单药治疗,普通核苷和核苷酸类药物耐药患者可换用替诺福韦。高病毒载量及HBe Ag阳性的患者,推荐核苷和核苷酸类药物的联合治疗。既往经治甚至多重耐药的患者可以选择恩替卡韦与替诺福韦联用。核苷和核苷酸类药物经治、期待HBe Ag和HBs Ag血清学转换的患者,可以考虑加用长效干扰素。     

干扰素α-1b联合恩替卡韦治疗HBeAg阳性慢性乙型肝炎33例48周疗效观察

慢性乙型肝炎是危害人类健康的严重传染病之一,我国属高发地区.抗病毒治疗是阻止慢性乙型肝炎进展的主要方法.目前抗病毒药物主要有干扰素和核苷(酸)类似物两大类,单用一种药物疗效往往不佳.自2008年1月以来,我们应用干扰素α-1b联合恩替卡韦治疗HBeAg阳性慢性乙型肝炎,发现联合用药的治疗效果优于单用恩替卡韦.现将结果报道如下.     

难治性慢性乙型肝炎

"难治性慢性乙型肝炎"的定义:符合慢性乙型肝炎的诊断标准,因各种原因/因素导致在现有指南或建议治疗方案指导下,使用了包括核苷(酸)类似物和(或)干扰素在内的抗HBV药物治疗失败或疗效不佳、或不规范抗病毒治疗所致、或已有循证医学依据证实疗效不佳的慢性乙型肝炎.难治性慢性乙型肝炎概念的提出,有利于乙型肝炎患者接受临床规范化...     

核苷(酸)类似物治疗慢性乙型肝炎部分应答后加用α干扰素继续治疗疗效分析

目的比较核苷(酸)类似物(NA)治疗慢性乙型肝炎(CHB)部分应答后加用α-干扰素组与未加用干扰素组的疗效。方法筛选出71例经NA抗病毒治疗后出现HBV DNA转阴,ALT复常半年以上,但持续未出现HBeAg血清转换的HBeAg阳性CHB患者,随机分为联合干扰素组(n=38例)和单用NA组(n=33例),观察治疗4、12、24、36和48周两组患者HBeAg阴转率、HBeAg血清转换率、生化及HBV DNA水平的变化。结果在治疗36周时,联合组HBeAg阴转率为36.8%,高于单用NA组的15.2%(P=0.039);在治疗48周时,联合组HBeAg阴转率和HBeAg血清转换率分别为42.1%和36.8%,明显高于单用NA组的18.2%和15.2%(P=0.030和0.039);治疗过程中两组均未出现ALT、HBV DNA波动及明显的不良反应。结论干扰素可辅助NA治疗,提高患者HBeAg血清转换率,是一种有效的治疗方法。     

Combination treatment in HBeAg-negative chronic hepatitis B

Chronic hepatitis B (CHB) represents an important public health problem. HBeAg-negative CHB is frequently associated with advanced liver disease and its prevalence is increasing. Monotherapy with either interferon (conventional or pegylated) or nucleoside/nucleotide analogues has its limitations. It has been suggested that a combination of these agents might increase antiviral efficacy. However, existing data do not support this hypothesis, even though combination treatment appears to reduce the risk for emergence of lamivudine resistance. Nevertheless, most existing combination studies are small, and it is possible that they have not been designed to detect significant differences between combination treatment and monotherapies. Another limitation of these studies is that, in most of them, lamivudine treatment was discontinued after 1 year, a strategy that is not followed in clinical practice. It was thought to be interesting to evaluate the combination of a short course of interferon (particularly pegylated) with the long-term administration of nucleotide or nucleoside analogues. The efficacy of combining pegylated interferon with the newer nucleotide or nucleoside analogues or of nucleotide with nucleoside analogues could also be evaluated. However, findings show that until more data are available, combination therapy cannot be recommended as first-line treatment in patients with CHB. On the other hand, add-on therapy with adefovir or tenofovir is the treatment of choice in patients who develop resistance to lamivudine. In patients with cirrhosis, a combination of lamivudine/adefovir may also be used as initial treatment; another option would be to add tenofovir in patients with an insufficient response to entecavir.     

儿童慢性乙型肝炎的诊治现状及进展

对慢性乙型肝炎儿童进行抗病毒治疗可以阻止肝脏炎症、纤维化的进展,部分可以达到临床治愈。应选择免疫清除期、再活动期进行治疗,出现疾病进展、严重并发症时也应治疗。目前儿童可及抗病毒药物有干扰素、核苷(酸)类似物。其中,干扰素是治疗的一线药物,核苷(酸)类似物是二线用药,联合使用效果值得期待。合理选择适应证进行个体化治疗才能使患儿获益最大化。     

The effectiveness of nucleoside analogues in chronic hepatitis B patients unresponsive to interferon therapy: our clinical trials for one year

Background and Aims

We aimed to evaluate the effectiveness of nucleoside analogues such as Lamivudine, Adefovir,Entacavir, and Tenofovir in patients with chronic hepatitis B who failed to respond to interferon therapy and relapsed.

Materials and Methods

We followed a total of 73 patients with hepatitis B in the hepatitis outpatient clinic in our hospital. The patients subsequently received nucleoside analogues therapy and their treatment data were evaluated retrospectively. The biochemical and virological response rates were evaluated at 3 and 12 months, and we compared these results with the results of treatment-naive patients.

Results

There were 29 (39.7%) HbeAg-positive and 44 (60.3%) HbeAg-negative patients, and their mean age was 35.8 (±13.4) years. Of these patients, 33, 18, 13 and 9 received Entacavir, Tenofovir, Lamivudine, and Adefovir treatment,respectively. In HbeAg-negative patients, at 3 months the biochemical and virological response (early response) rates were observed to be 91% and 98%), and at 12 months the two rates were 93% and 73%, respectively. In HbeAg-positive patients, the biochemical and virological response rates at 3 months were 83% and 97%, and the rates at 12 months were 90% and 48%, respectively.

Conclusions

In CHB therapy with treatment-resistent patients, nucleoside analogues may be preferable. There are disadvantages to nucleoside analogues, such as a risk of developing resistance during therapy, reduced HBeAg seroconversion compared to interferons, and the therapy’s ambiguous duration. In our study, in HbeAg-negative patients who received nucleoside analogues, a lower biochemical response rate was detected in patients with 1 year of Lamivudine therapy compared to other therapies. For HbeAg-positive patients, the virological response rate was higher in 1 year of Tenofovir therapy than with other therapies.     

Antiviral therapy for chronic hepatitis B: Combination of nucleoside analogs and interferon

The ideal goal of chronic hepatitis B (CHB) treatment should be suppression of emergence of hepatocellular carcinoma through the disappearance of hepatitis B s antigen (HBsAg) rather than the control of serum hepatitis B virus-DNA level. For this purpose, various types of combination therapies using nucleoside analogs (NAs) and interferon (IFN) have been conducted. The therapeutic effects of combination of two different kinds of agents are better than those of the monotherapy using NAs or IFN alone, probably because different pharmaceutical properties might act in a coordinated manner. Recently, combination therapies with NAs and IFN and sequential therapies with NAs administration followed by IFN therapy have been routinely employed. We previously reported that combination therapy using entecavir (ETV) and pegylated (PEG)-IFN showed antiviral effects in 71% of CHB patients; the effect of this combination was better than that using lamivudine (LAM) and PEG-IFN. This is partially explained by the better antiviral effects of ETV than those of LAM. In our analysis, the cohort of CHB consisted of the patients who showed a flare-up of hepatitis before antiviral therapy, and their baseline HBsAg levels were relatively low. Therefore, in addition to the combination of the agents, the appropriate selection of patients is critical to achieve a good viral response.     

核苷类抗病毒药预防治疗糖皮质激素诱导的HBV再激活临床回顾性分析

目的：回顾性分析因免疫性基础疾病等使用糖皮质激素的慢性HBV感染者,应用核苷类药物预防治疗HBV再激活及免疫性疾病活动的临床效果。方法随机选取131例HBV感染并因免疫性疾病应用糖皮质激素治疗的患者,分为3组：A组41例,血清ALT正常,HBV DNA载量≤1×103 copies/ml;B组67例,ALT＜2倍正常值上限（upper limits of normal, ULN）,1×103 copies/ml＜HBV DNA载量＜1×104 copies/ml;C组23例,ALT≥2×ULN,HBV DNA载量≥1×104 copies/ml,应用拉米夫定、恩替卡韦或拉米夫定＋阿德福韦酯治疗,每3个月随访HBV DNA载量和ALT水平。结果口服核苷类药物可明显抑制病毒复制,有利于控制免疫性疾病活动。如不给予核苷类药物治疗,当HBV DNA载量〉1×103 copies/ml时HBV DNA复制和免疫性疾病活动风险更高。但无论病毒载量高低,采用单药拉米夫定/恩替卡韦,或拉米夫定＋阿德福韦酯均出现良好应答。对拉米夫定单药或加用阿德福韦酯应答不良者,恩替卡韦治疗仍可获得理想应答。结论因免疫性疾病采用糖皮质激素治疗的患者,无论HBV DNA载量是否高于正常值,均应给予核苷类药物治疗,且应尽早使用强效、低耐药的药物。     

替诺福韦酯挽救治疗对核苷（酸）类药物耐药的慢性乙型肝炎研究进展

核苷（酸）类似物已广泛应用于慢性乙型肝炎的治疗,其中替诺福韦酯（TDF）具有安全性高和耐药率低的特点,对慢性乙型肝炎（CHB）初治、经治患者,甚至是肝硬化肝功失代偿期患者均具有较强的抗病毒作用,成为经治耐药患者补救治疗的最佳选择。本文综述了TDF在拉米夫定、阿德福韦酯、恩替卡韦治疗慢性乙型肝炎无效或其他核苷（酸）类药物耐药患者中的抗病毒疗效。     

Efficacy of lamivudine on hepatitis B viral status and liver function in patients with hepatitis B virus‐related hepatocellular carcinoma

Background/Aims: Treatment of patients with hepatocellular carcinoma (HCC) depends on the tumour extent and underlying liver function. Antiviral therapy with nucleoside/nucleotide analogues has been shown to be effective in improving the liver function of chronic hepatitis B (CHB) patients. We assessed whether lamivudine could induce biochemical and virological improvements in patients with hepatitis B virus‐related HCC. Patients/Methods: Of 148 CHB patients treated with 100 mg/day lamivudine for at least 6 months, 80 had HCC (CHB/HCC group) and 68 did not (CHB group). Biochemical and virological parameters were serially monitored. Results: Compared with the CHB group, the CHB/HCC group was older, had higher male predominance, bilirubin levels and liver cirrhosis rate, and lower albumin and hepatitis B virus (HBV) DNA levels and hepatitis B e antigen (HBeAg) positivity (P<0.05 each). The two groups showed similar cumulative rates of alanine aminotransferase normalization, HBV DNA seroconversion, HBeAg loss and viral breakthrough during 12 months of lamivudine treatment. After 12 months, the CHB/HCC group showed, relative to baseline, increased albumin levels (3.51±0.5 vs. 3.72±0.5 mg/ml) and decreased ascites scores (1.63±0.7 vs. 1.45±0.6) and Child–Pugh scores (6.92±1.9 vs. 6.02±1.38) (P<0.05 each). Conclusion: Lamivudine had comparable antiviral effects both in patients with CHB and CHB/HCC, and improved underlying liver function in the latter group. Treatment of HBV may increase the chance of curative treatments in patients with HBV‐related HCC.     

Viral infection parameters not nucleoside analogue itself correlates with host immunity in nucleoside analogue therapy for chronic hepatitis B

AIM: To determine the relationship between host immunity and the characteristics of viral infection or nucleoside analogues (NAs) themselves in patients with chronic hepatitis B (CHB) receiving NA therapy.METHODS: Fifty-two hepatitis B envelope antigen (HBeAg) positive CHB patients were enrolled and divided equally into two groups. One group received telbivudine (LDT, 600 mg/d), and the other group received lamivudine (LAM, 100 mg/d). Clinical, virological and immunological parameters were assessed at the baseline and at 4, 12, 24, 36 and 48 wk.RESULTS: Both groups achieved significant hepatitis B virus (HBV) replication inhibition and alanine aminotransferase normalization at 48 wk. At the baseline, compared to healthy controls, CHB patients had a lower circulating CD8 T cell frequency (29.44% ± 11.55% vs 37.17% ± 7.30%, P = 0.03) and higher frequencies of programmed death 1 positive CD8 T cells (PD-1+ CD8 T) (16.48% ± 10.82% vs 7.02% ± 3.62%, P = 0.0001) and CD4+ CD25+ FoxP3+ T regulatory cells (Tregs) (23.64% ± 9.38% vs 13.60% ± 6.06%, P = 0.001). On therapy, at the beginning 24 wk with the levels of hepatitis B virus deoxyribonucleic acid (HBV DNA) and HBeAg declining, the frequencies of PD-1+ CD8 T cells and Treg cells gradually and significantly declined at 12 and 24 wk in both therapy groups. At treatment week 4, patients treated with LDT had a lower frequency of PD-1+ CD8 T cells compared to patients treated with LAM (10.08% ± 6.83% vs 20.51% ± 20.96%, P = 0.02). The frequency of PD-1+ CD8 T cells in all of the CHB patients was significantly correlated with both the HBV DNA level (r = 0.45, P = 0.01) and HBeAg level (r = 0.47, P = 0.01) at treatment week 24, but the frequency of Treg cells was only significantly correlated with the HBeAg level (r = 0.44,P = 0.02). Furthermore, the ability of CD8 T cells to secrete pro-inflammatory cytokines was partially restored after 24 wk of therapy.CONCLUSION: NA-mediated HBV suppression could down-regulate the production of negative regulators of host immunity during the first 24 wk of therapy and could partially restore the ability of CD8 T cells to secrete pro-inflammatory cytokines. This immune modulating response may be correlated with the levels of both HBV DNA and HBeAg.