Clevudine: a promising therapy for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection, affecting ～ 350 million people worldwide, is associated with significant morbidity and mortality. In the past 10 years, hepatitis B therapy research has led to a multitude of available antiviral therapies: IFN-α, pegylated IFN-α_2a, lamivudine, adefovir, entecavir, telbivudine and tenofovir. To further improve reductions in viral load and resistance profiles, development of new HBV therapeutic strategies has been an important focus. One such therapy is clevudine, an analogue of the β-L configuration. Clevudine is already licensed in Korea for anti-HBV therapy (Bukwang Pharmaceuticals, Seoul, Korea). Unique to clevudine is its ability to maintain antiviral activity following discontinuation of therapy. Typically, hepatitis B treatment requires continuous therapy to prevent reactivation. Sustained response is uncommon except in hepatitis B antigen (HBeAg)-positive patients who developed HBeAg seroconversion. This article reviews chronic HBV and its therapy options. Specifically, it describes clevudine's potent and sustained antiviral activity as observed in vitro and in vivo.     

Clevudine for the treatment of chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a major health problem that is responsible for < or = 1 million deaths and 500,000 cases of hepatocellular carcinoma worldwide each year. Drugs that are currently approved by the FDA for the treatment of chronic HBV consist of two groups: the immunomodulators, such as conventional IFN-alpha and pegylated IFN-alpha2a; and nucleoside/nucleotide analogues, such as lamivudine, adefovir dipivoxil and entecavir. However, due to the limitations of these agents, newer agents with improved efficacy are currently being developed. One nucleoside/nucleotide analogue that is drawing a wide range of interest is clevudine, which is an analogue of the unnatural beta-L configuration. In the woodchuck hepatitis virus (WHV), clevudine 10 mg/kg has proven to be effective in suppressing viral replication with < or = 9 log10 decreases in WHV. At this dose, a significant reduction of intrahepatic WHV RNA and covalently closed circular WHV DNA levels can also be observed. Treatment with clevudine 10 mg/kg can confer additional antiviral benefit in the form of a more sustained reduction in WHV replication, serum woodchuck hepatitis surface antigen and intrahepatic woodchuck hepatitis core antigen expression following the withdrawal of clevudine. In humans, clevudine 10, 50, 100 or 200 mg/day for 28 days can reduce the median HBV DNA by -2.5, -2.7, -3 and -2.6 log10, respectively. More importantly, this suppression of antiviral activity is maintained at 12 and 24 weeks post treatment. Based on the early results of clevudine, more large-scale human studies with clevudine monotherapy or combination therapy is eagerly awaited.     

慢性HBV感染患者HBV DNA前C区变异的临床意义

目的:探讨慢性HBV感染患者HBVDNA前C区变异的临床意义。方法:采用ELISA测定99例HBV感染患者血清肝炎病毒标志物,并采用RT-PCR检测HBVDNA前C区变异。结果:99例HBV感染患者中,乙型肝炎病毒携带26例,慢性乙型病毒性肝炎61例,慢性重型病毒性肝炎(乙型)11例和急性乙型病毒性肝炎1例。乙型肝炎病毒携带,慢性乙型病毒性肝炎和慢性重型病毒性肝炎中,变异株组HBVDNA前C区变异发生率与混合株组、野生株组相比,差异均无显著性(P>0.05)。与混合株和野生株两组相比,HBVDNA变异株组肝功能变化差异均无显著性(P>0.05)。结论:HBVDNA前C区变异可发生于HBV感染的不同临床状态。HBVDNA前C区变异可能与肝炎程度和病情进展无明显关系。     

Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection

Introduction: In April 2017 tenofovir alafenamide (TAF) was added to the list of first-line therapies recommended for chronic hepatitis B (CHB). TAF has pharmacology similar to tenofovir disoproxil fumarate (TDF) with higher cell delivery to the hepatocytes but less systemic exposure.

Areas covered: We review here studies leading to TAF’s approval and comparing it to TDF. In two major clinical trials, TAF was non-inferior to TDF in achieving HBV DNA levels below 29 IU/ml. TAF-treated patients had significantly smaller decreases in bone mineral density (BMD) at the hip and spine in both HBeAg-positive and HBeAg-negative patients, and smaller mean increases in serum creatinine, although the difference was only statistically significant in HBeAg-positive patients. Patients treated with TDF for 96 weeks and then switched to TAF had improvements in renal and BMD measures only 24 weeks after switching.

Expert commentary: With clear evidence from major studies showing that TAF is safe, tolerable, and non-inferior to TDF, its recommendation as a first-line therapy is appropriate. Longer term follow up will be required to determine if the differences in adverse bone and kidney effects seen with TAF in comparison to TDF will be clinically relevant.     

Evolving therapies for the treatment of chronic hepatitis B virus infection

Despite the availability of prophylactic vaccines lamivudine and IFN-alpha, chronic hepatitis B remains an enormous global health problem. Several promising nucleosides/nucleotides are undergoing clinical trials, including adefovir dipivoxil, the latter of which is active against lamivudine-resistant hepatitis B virus (HBV). In addition to nucleosides/nucleotides, it will be important to develop new agents with different modes of action. Novel small molecule inhibitors, as well as gene therapy approaches, have produced encouraging results in vitro and in animal models. Additional immunomodulatory therapies, including thymosin-alpha 1, IL-12 and several therapeutic vaccines, are also being explored. Combination therapy with multiple nucleosides/nucleotides and other agents will play an important role in the treatment of hepatitis and may help achieve complete viral suppression, host-mediated elimination of infected cells and lasting immunity.     

双环醇治疗慢性乙型肝炎患者52例

目的:对比双环醇及拉米夫定治疗慢性乙型肝炎的疗效.方法:慢性乙型肝炎患者随机分成双环醇组(52例)和拉米夫定组(30例),分别服用双环醇25 mg,tid或拉米夫定100 mg,qd,共24周.结果:治疗结束时,e抗原转阴率两组分别为7.4%与8.8%(P>0.05),总有效率两组分别为83.3%及67.3%(P>0.05).HBV DNA阳性但e抗原阴性或ALT正常的患者亦适合双环醇治疗.疗前病毒定量的高低、性别及年龄并不影响疗效.结论:双环醇对乙型肝炎患者降低转氨酶及抗病毒疗效与拉米夫定类似,无明显不良反应.     

Adefovir dipivoxil in chronic hepatitis B infection

Adefovir dipivoxil, an acyclic nucleotide analogue, is effective for the treatment of chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and -negative patients, with improvement in liver histology, hepatitis B virus (HBV) DNA levels, alanine aminotransferase levels, and HBeAg seroconversion (for HBeAg-positive patients). It is also effective against lamivudine-resistant strains of hepatitis B mutations. It has been studied in pre- and post-liver transplant patients. Compared to lamivudine, adefovir dipivoxil is associated with a much lower risk of emergence of drug-resistant HBV. Adefovir-associated resistant virus is susceptible to lamivudine therapy. The recommended dose of adefovir dipivoxil 10 mg is associated with low risk of nephrotoxicity. Adefovir dipivoxil can be recommended as a first-line treatment but can also be used in patients with chronic hepatitis B infection who are failing lamivudine therapy.     

Recent developments in the treatment of chronic hepatitis B virus infection

Infectious diseases are the major cause of death worldwide; in developing countries such diseases are responsible for nearly half the burden of premature death and disability. Therefore, the need for the development of new vaccine strategies aimed at preventing or limiting disease is extremely urgent. Important successes have been achieved against some infectious diseases that were once endemic or, even, epidemic (e.g., polio, smallpox, diptheria). Advances in our knowledge of the pathogenesis and immune correlates of protections are needed to develop novel vaccinal approaches to diseases such as hepatitis C, AIDS and malaria. In this review we will analyse the biological problems associated with the prevention of development and/or improvement of vaccine strategies for infectious diseases, focusing on the difficulties facing the creation of new effective vaccines for HIV infection and malaria.     

Agents in clinical development for the treatment of chronic hepatitis B

Chronic hepatitis B remains a public health problem of global importance despite the availability of an effective vaccine. Between 350 and 400 million people, approximately 6% of the world’s population, suffer from chronic hepatitis B and face a 30% likelihood of developing cirrhotic liver disease or hepatocellular carcinoma. Current treatment options include three monotherapies of subcutaneous interferon, oral nucleoside lamivudine and oral nucleotide adefovir dipivoxil. Unfortunately, these agents have not effectively and frequently been able to attain a ‘cure’ or complete eradication of the virus. Consequently, the expectation of current therapies is confined to the achievement of clinically beneficial and durable responses defined by lasting suppression of virus replication, histological improvement and increased survival for patients with decompensated liver diseases. Other disadvantages include the undesirable tolerability of interferon, the rapid resistance to lamivudine and the compromise between efficacy and toxicity that led to the development of the 10 mg dose of adefovir dipivoxil. Clearly, better therapeutics and treatment strategies are needed. Increased potency, activity against current treatment-refractory viruses, as well as efficacy in difficult-to-treat populations will be critical to meeting the therapeutic challenge of chronic hepatitis B.     

乙肝病毒携带者与职业相关性的探讨

目的 探讨成人乙肝病毒感染与职业的相关性。方法 分析２１３６名志愿捐血者的职业及其血液ＨＢｓＡｇ检测情况。结果 ２１３６人中共８６人ＨＢｓＡｇ阳性，阳性率４．０２％，不同职业在ＨＢｓＡｇ阳性方面差异有显著意义（Ｘ＾２＝３１．２４，Ｐ〈０．００１）。结论 乙肝病毒携带与职业具有相关性。     

乙肝病毒大蛋白在乙型病毒性肝炎诊断中的临床意义

目的探讨乙肝病毒大蛋白（HBV-LP）与HBV DNA、HBeAg的相关性及其检测意义。方法共检测416例乙肝患者血清标本,采用酶联免疫吸附试验检测HBV-LP、乙肝病毒标志物（HBV M）;FQ-PCR定量检测HBVDNA。结果416例HBV感染者血清中,HBV-LP浓度与HBVDNA含量（拷贝数对数）间呈正相关（r=0.358,P〈0.05）;在253份HBV DNA阳性标本中HBV-LP阳性率（90.51%）高于乙肝病毒前S1抗原（HBV PreS1Ag）的阳性率（77.08%）,两者差异有统计学意义（P〈0.05）;在44例HBV感染组中,HBV-LP、HBV DNA、HBV PreS1Ag与乙肝病毒前S2抗原（HBV PreS2Ag）间均有显著相关性（χ2=4.793、3.927、6.769、P〈0.05）;HBeAg阴性组中HBV-LP与HBV DNA间差异有统计学意义（P〈0.05）。结论HBV-LP是判断HBV感染者体内病毒复制程度的可靠指标,HBV-LP与HBVDNA呈正相关,是反映HBeAg阴性HBV感染者体内病毒复制情况新的敏感监测指标。     

Novel treatment options for hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection affects between 350 and 400 million people globally. Interferon-alpha, lamivudine and adefovir (Hepsera) are approved for the treatment of chronic hepatitis B; however, the use of interferon-alpha is limited. Lamivudine and adefovir have excellent antiviral activity and oral bioavailability, although viral rebound after cessation of therapy and development of resistance after long-term therapy with lamivudine are major clinical limitations. Adefovir has proven to be effective against lamivudine-resistant strains in vitro and in vivo. The various steps of HBV replication provide opportunities for new antiviral drugs to interact with the virus. Recent developments, including new antivirals that interfere with viral DNA replication, hold promise for the future. Sustained reduction in viral load and improved treatment of chronic HBV infection could, in future, be achieved by the development of new drugs with different mechanisms of action and resistance profiles, and with combination therapy involving two or more nucleosides with or without immunomodulators.     

Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection

Background: 170 to 200 million people worldwide are believed to suffer from chronic hepatitis C virus (HCV) infection, a blood-born disease that targets the liver and progresses to organ cirrhosis and primary cancer in a significant proportion of patients. The currently available treatment has limited efficacy and suffers from restricting side effects. HCV infection is the principal cause of liver transplant in industrialized nations and between 8000 and 10,000 deaths result annually from the disease in the United States alone. Virus-specific, more efficacious, and better-tolerated anti-HCV therapies are thus required to address the unmet medical need. Objective: To review progress achieved since 2005 in the development of HCV NS5B polymerase inhibitors as potential therapy for the treatment of HCV infection with a primary focus on available patent and medical literature. Results/conclusion: Several classes of small-molecule inhibitors of HCV NS5B have progressed into clinical development and demonstrated efficacy in reducing viral load in infected patients. The results so far provide an encouraging foundation for the development of novel, more tolerable therapies and addressing emergence of resistance through combination of antiviral agents with complementary mechanisms of action.     

贺普丁治疗慢性乙型肝炎的病例对照研究

目的：研究贺普丁治疗慢性乙型肝炎的治疗作用及其特点,方法：采用1：1病例配对方法,比较贺普丁（治疗组）和护肝片＋当飞利肝宁（对照组）对患血清ALT、HBeAg、抗－HBe及HBVDNA的作用。结果：治疗组ALT较对照组下降的慢,但在6个月时,两接近（P＞0．05）;治疗组在治疗后1、3、6月HBVDNA的阴转率分别是51．3％、78．1％和84．4％,对照组相比差异有显性（P＜0．001）;但HBeAg的阴性,与对照组相比,无统计学意义,结论贺普丁治疗慢性乙型肝炎HBV DNA转阴率高,ALT下降的慢,而对HBeAg作用不太理想。     

Experimental and emerging therapies for chronic hepatitis C virus infection

Hepatitis C virus infection is prevalent throughout the world and is associated with substantial morbidity, mortality and health economic burden. No effective preventative measure, including vaccination, is currently available. Incremental and substantial progress in the rate of viral eradication using interferonbased therapies has been made over the past decade. The most recent advance has been related to the development of a pegylated form of IFN-α by two independent pharmaceutical companies. Pegylation of IFNα appears to prolong its halflife, allowing for less frequent dosing. Reports have suggested that pegylated interferons are also associated with better efficacy for viral eradication in patients with hepatitis C virus. Slower progress also has been made in developing noninterferonbased therapeutic agents against hepatitis C virus, including protease inhibitors, helicase inhibitors, ribozymes, antisense therapies, cytokinebased therapies and Tcellbased therapeutic vaccines.     

拉米夫定联合阿德福韦酯对慢性乙型肝炎的疗效分析

目的 探讨并分析拉米夫定联合阿德福韦酯对阿德福韦酯初始治疗不佳的慢性乙型肝炎患者的临床疗效.方法 选择2011年1月～ 2013年6月收治的81例慢性乙型肝炎患者,均为经阿德福韦酯初始治疗后又出现了慢性乙型肝炎血清标志物,所有患者均给予常规护肝治疗并随机分为3组:Ⅰ组:27例,患者使用阿德福韦酯联合拉米夫定用药48周;Ⅱ组:27例,患者使用阿德福韦酯联合拉米夫定12周后继续单独使用阿德福韦酯用药36周;Ⅲ组:27例,常规护肝治疗基础上,患者使用拉米夫定单独用药48周.分别于第12、24、48周的每周末检测并观察各组患者的HBV-DNA应答率、HBeAg转阴率、ALT复常率等相关指标及患者病情好转情况.结果 治疗时间在12周时各组HBV-DNA应答率、HBeAg转阴率、ALT复常率的比较均无统计学差异.但随着治疗时间的持续增加,患者经过48周治疗后,Ⅰ组的HBV-DNA应答率、HBeAg转阴率、ALT复常率均显著高于Ⅲ组(P＜0.05),而Ⅱ组与Ⅲ组相比这些指标差异无统计学意义.结论 拉米夫定联合阿德福韦酯持续使用48周后,慢性乙型肝炎患者的抗病毒治疗要比单纯使用拉米夫定治疗效果更好,而2者联合使用12周的治疗效果并不是十分理想.因此,对治疗初次口服阿德福韦酯治疗失败的患者应持续使用拉米夫定与阿德福韦酯联合治疗48周以上具有较好的临床疗效.     

慢性乙型肝炎治疗的研究进展

慢性乙型病毒性肝炎是一个严重威胁人类健康的疾病,呈世界性流行。抗病毒治疗是减少肝硬化、肝癌等严重肝病发生的关键治疗,目前公认有效的抗病毒药物包括干扰素和核苷(酸)类似物。抗病毒药物治疗的持续应答率仅有20%-30%,病毒耐药率高,且停药后容易反弹或复发。那么对CHB的抗病毒治疗时机的把握、药物的选择、治疗的目标、治疗效果的评价及终点的界定就显得尤为重要。     

Treatment paradigms on hepatitis B e antigen-negative chronic hepatitis B patients

The primary goal of treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) is potent and durable suppression of hepatitis B virus (HBV) replication. It results in biochemical and histological remission of CHB and is the prerequisite for the prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Responses that are durable after the cessation of treatment are referred to as sustained virological responses, whereas those persisting under therapy are referred to as treatment-maintained virological responses. Treatment paradigms of sustained virological response in HBeAg-negative CHB are practically restricted to conventional IFN-α and pegylated interferons (peg-IFNs), and are limited only to patients with compensated liver disease. Long-lasting maintained virological responses without HBV resistance in HBeAg-negative CHB are achievable by all approved nucleos(t)ide analogues (lamivudine, adefovir and entecavir) in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to resistance. The maintenance of response under 5 years of adefovir treatment represents the most effective treatment paradigm for HBeAg-negative CHB, whereas such long-term data with entecavir and tenofovir monotherapy may become available in the near future. In patients with lamivudine-resistant HBV mutants, the recommended treatment strategy is to add adefovir at the same time as continuing treatment with lamivudine. There are no treatment paradigms as yet of combination therapy from the very outset with two nucleoside analogues for use in treatment-naive patients.     

替比夫定治疗HBeAg阳性慢性乙型肝炎的效果观察

目的观察替比夫定治疗HBeAg阳性慢性乙型肝炎的效果。方法回顾性分析2010年2月～2012年2月于沈阳市第六人民医院传染科治疗的HBeAg阳性慢性乙型肝炎患者104例的临床资料。将采用替比夫定治疗的52例患者作为替比夫定组,将采用拉米夫定治疗的52例患者作为拉米夫定组,观察并比较两组治疗12、24、52周ALT复常、HBV DNA转阴、HBeAg血清学转换情况。结果治疗12周,两组ALT复常率、HBV DNA转阴率及HBeAg血清学转换率,差异均无统计学意义（P〉0.05）;治疗24周时,替比夫定组HBeAg血清学转换率（13.5%）高于拉米夫定组（5.8%）,差异有统计学意义（P〈0.05）;治疗52周时,替比夫定组ALT复常率、HBV DNA转阴率及HBeAg血清学转换率均高于拉米夫定组,差异均有统计学意义（P〈0.05）。结论采用替比夫定治疗HBeAg阳性慢性乙型肝炎的效果较好,安全性较高,值得临床推广应用。