Recent advances in the treatment of chronic hepatitis B

Introduction: At present, two strategies exist for the treatment of chronic hepatitis B (CHB): i) standard or pegylated interferon alpha (IFN) with mainly immune modulatory effects; and ii) nucleos(t)ide analogues (NA) with direct antiviral effects. The optimal treatment for an individual patient remains controversial.

Areas covered: The treatment efficacy and prediction of response to antiviral agents for chronic hepatitis B are reviewed and discussed.

Expert opinion: The rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss or seroconversion are continuously increasing in CHB patients after stopping a finite course of IFN, whereas long-term NA therapy is usually required to improve the adverse outcomes of CHB. Lower baseline HBV DNA level is a strong predictor for both sustained viral suppression and HBeAg seroconversion in patients receiving IFN-based as well as NAs therapy. In addition, HBeAg-positive patients with genotype A or B infection have better responses to IFN-based therapy than those with genotypes C or D infection. Furthermore, on-treatment predictors such as declines of serum HBV DNA, HBsAg and HBeAg levels may be helpful in making decisions of subsequent therapy. Regarding the association of host genetic factors with responses to antiviral therapy, current evidence is limited.     

Emerging pipeline drugs for hepatitis B infection

INTRODUCTION: Chronic hepatitis B virus (HBV) infection continues to represent a global health concern with an estimated 350 - 400 million people infected worldwide. Current treatment options are either of two IFN-based therapies or either of five oral nucleos(t)ide analogs which are used as monotherapy or in combination. Control of viral replication can be achieved basically in all patients today. However, despite the clinical efficacy of antivirals, long-term management remains a clinical challenge mainly due to the slow kinetics of HBsAg clearance. Emergence of viral resistance has been a challenge in the past with some but not all oral therapies. The development of novel therapeutic agents with different mechanisms of action might provide new opportunities to clear HBsAg and achieve HBsAg seroconversion which could be maintained off therapy. The long-term efficacy of combinations of IFN and/or nucleos(t)ide analogs might achieve antiviral synergy, preventing drug resistance and clearing viral covalently close circular DNA and infected cells. AREAS COVERED: This article provides a review of recent data on the safety and efficacy of existing and emerging agents for the treatment of chronic hepatitis B infection. EXPERT OPINION: Currently, entecavir and tenofovir offer a safe and effective treatment option for patients with chronic HBV with minimal to no resistance. Although entecavir and tenofovir are able to suppress replication in essentially all patients, achieving HBsAg seroconversion remains suboptimal among all antiviral therapy. There are a number of new therapies in the pipeline for the treatment of chronic HBV infection as well as revisiting IFN combined or sequential to antiviral therapy.     

聚乙二醇干扰素α-2a单用与联合阿德福韦酯治疗慢性乙璎肝凌疗效的meta分析

目的系统评价聚乙二醇干扰素α-2a（PEG IFNα-2a）单用与联合阿德福韦酯（Adefovir dipivoxil,ADV）治疗慢性乙型肝炎的疗效。方法检索2001年1月至2011年9月Medline、PubMed、CBM、CNKI、VIP和万方数据库,纳入PEG IFNα-2a联合ADV与单用PEG IFNα-2a治疗慢性乙型肝炎的随机对照试验（RCTs）。采用RevMan5．0软件作进行meta分析,根据不同的疗程和观察时间进行亚组分析。结果共纳人6篇文献,合计379例患者。分析结果显示,在治疗24周时,hepatitis B virus（HBV）-DNA阴转率、HBV．DNA下降率、hepatitis Beantigen（HBeAg）阴转率和alanine aminotransferase（ALT）复常率,联合治疗组均优于对照组（P〈0．05）。尽管HBeAg转换率两组相比无统计学意义,但联合治疗组的转换率大于对照组（34．4％／23．6％）。在治疗48周时,HBV-DNA阴转率、HBV—DNA下降率、HBeAg阴转率、HBeAg转换率和AIJT复常率,联合治疗组均优于对照组（P〈0．05）,而hepatitis B Santigen（HBsAg）阴转率和HBsAg转换率两者相比无统计学意义。在治疗后随访（72周）,除HBV—DNA阴转率和HBeAg转换率外,HBV-DNA下降率、HBeAg阴转率、ALT复常率、HBsAg阴转率和HBsAg转换率两组相比均无统计学意义（P〉0．05）。在耐药性和不良反应方面,联合治疗并不增加不良反应发生率,未发现耐药菌株。结论在短疗程（24周）和长疗程（48周）中,PEG IFNα-2a联合ADV治疗慢性乙型肝炎的疗效均明显优于单药治疗,且不增加不良反应发生率和耐药菌株。但在停药时间、远期疗效和对HBsAg的疗效上还有待进一步探究。     

DC-CIK细胞疗法联合干扰素治疗慢性乙肝临床研究

目的观察DC-CIK细胞疗法联合干扰素对慢性乙型肝炎的治疗效果。方法 134例CHB患者随机分成治疗组（DC-CIK细胞疗法联合干扰素）50例和对照组（干扰素）84例,观察2组患者肝功能、HBV-DNA、HBeAg的变化,同时观察治疗组3个月和6个月时患者肝功能、HBV-DNA、HBeAg的变化。结果治疗组HBV-DNA转阴率与对照组差异无统计学意义（P〉0.05）,治疗组HBeAg阴转率（56%）、抗-HBe阳转率（40%）以及ALT复常率（88%）均明显高于对照组（分别为38.1%、19.1%、57.1%）,治疗组治疗6个月时,其HBV-DNA转阴率（48%）、HBeAg转阴率（56%）、抗-HBe阳转率（40%）以及ALT复常率（88%）均明显高于治疗3个月时（分别为24%、32%、18%、70%）,差异有统计学意义（P〈0.05）。结论 DC-CIK细胞疗法联合干扰素治疗慢性乙肝较单用干扰素疗效更佳。     

HBsAg水平与抗乙型肝炎病毒药物治疗远期效果相关性分析

目的:通过观察HBeAg/HBeAb血清转换率与HBsAg定量的关系,探讨抗病毒治疗的远期疗效预测指标。方法:慢性乙型肝炎患者66例随机分为2组,即干扰素组、拉米夫定组。在治疗前后不同时间分别检测血清HBVDNA、HBsAg、HBeAg/HBeAb。根据治疗前HBsAg水平分级,计算治疗3个月时HBsAg抑制率和HBeAg/HBeAb血清转换率。结果:HBsAg初始水平低于100ng·L-1时,干扰素组HBeAg/HBeAb血清转换率显著提高,P<0.05。治疗3个月时,HBsAg抑制率超过50%,HBeAg/HBeAb血清转换率为47%。结论:HBsAg初始水平或治疗3个月后下降幅度是治疗慢性乙型病毒性肝炎疗效的预测指标。     

Efficacy of HBV-pulsed DCs in combination with entecavir in patients with chronic hepatitis B infection

Dendritic cells (DCs) are multifunctional cells that initiate adaptive immune responses. Patients with chronic hepatitis B virus (HBV) infection have reduced numbers of DCs which may be functionally impaired, a defect that may contribute to viral persistence. Autologous DC-based immunotherapy is considered to be a treatment option for chronic HBV infection (CHB). We evaluated the therapeutic efficacy of HBV-pulsed DCs in combination with the antiviral drug entecavir in patients with CHB. Eighty patients were divided into four groups: HBV-pulsed DCs only, HBV-pulsed DCs plus entecavir, entecavir only, and an untreated control group. Patients on combination therapy exhibited greater antiviral responses than patients on either monotherapy. The combination of HBV-pulsed DCs and entecavir resulted in the largest reduction in serum viral DNA levels and the highest percentage of virologic response. In addition, combination therapy resulted in viral e antigen (HBeAg) loss and seroconversion. These results suggest that the combination of HBV-pulsed autologous DCs and entecavir could be therapeutically advantageous for patients with CHB.     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 - 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in approximately 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-alpha. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 - 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.     

Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 – 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in ～ 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-α. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 – 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.     

Treatment of chronic hepatitis B: from research to clinical practice via the consensus conferences

The aim of antiviral therapy of chronic hepatitis B is to control Hepatitis B Virus (HBV) replication and to cure liver disease avoiding the progression of chronic hepatitis to cirrhosis and the end stage complications of cirrhosis. HBeAg/anti-HBe seroconversion is the hallmark of response in hepatitis B "e" antigen (HBeAg) positive patients. In the patients with antibody against HBeAg (anti-HBe positive) the combination of HBV DNA and anti-HBc IgM tests provides adequate diagnostic accuracy. Patients with biochemical and/or histological disease activity are eligible to therapy. The drug choice is based on age, disease severity, risk of complications, side effects and compliance, particularly in anti-HBe positive patients where prolonged treatment is needed. Interferon (5-6 MU daily or 9-10 MU thrice weekly for 4-6 months) is the first line therapy for HBeAg positive patients and (5-6 MU thrice weekly for 12-24 months) for anti-HBe positive patients. When IFN is contraindicated or ineffective, Lamivudine (100 mg) or Adefovir Dipivoxil (10 mg) are given as long as 4-6 months after HBeAg/anti-HBe seroconversion or for long-term treatments in HBeAg positive non-responders and anti-HBe positive patients. Patients with more advanced forms of cirrhosis and portal hypertension are to be treated within liver transplantation programs. Fifteen to 30% of treated patients achieve sustained response and more than 60% of them experience long-term disease remission during therapy. In perspectives, currently available molecular and immunologic tools and modelling of viral dynamics will help to address the therapy issue with more complex, efficacious and individually tailored treatment schedules.     

Adefovir dipivoxil in chronic hepatitis B: history and current uses

INTRODUCTION: The nucleotide analogue adefovir dipivoxil (ADV) was approved in 2002 for the treatment of chronic infection with hepatitis B virus (HBV), in both hepatitis B e antigen (HBeAg)-positive and -negative patients. ADV 10 mg daily has been associated with improved liver histology, decreased levels of HBV DNA and alanine aminotransferase (ALT), and seroconversion of HBeAg. AREAS COVERED: This paper reviews the use of ADV as a first-line treatment for chronic hepatitis B and as an add-on therapy in chronic HBV-infected patients with lamivudine resistance. In the years since its launch, clinical resistance to ADV has emerged, and tenofovir and entecavir have shown greater efficacy in reducing viral load. EXPERT OPINION: Many patients who started antiviral therapy with ADV (either as monotherapy or in combination with lamivudine) remain on this agent because they have undetectable viremia, but its future use will probably diminish because of the availability of more potent drugs. ADV is generally well tolerated, though the 10 mg dose is associated with low risk of nephrotoxicity.     

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.     

Is combination therapy with lamivudine and interferon-alpha superior to monotherapy with either drug?

For the treatment of chronic hepatitis B (CHB) two drugs have been licensed world-wide: interferon-alpha (IFN) and lamivudine. Both drugs significantly increase the hepatitis B e-antigen (HBeAg) seroconversion rate, but a sustained treatment response occurs in less than 40% of patients. To explore whether there is an additional benefit of combining these two drugs, we reviewed the literature on lamivudine-IFN combination therapy in comparison to the two monotherapies in compensated, HBeAg-positive, CHB patients. We focussed on two clinically relevant outcome measures: HBeAg seroconversion, and change in liver histology. Candidates for lamivudine-IFN combination therapy were, previously untreated, patients with moderately elevated alanine aminotransferase (ALT). Such regimen should still be considered experimental. Viral kinetics may provide insight into how long therapy should be continued; prolongation of therapy to 52 weeks currently appears a reasonable approach. According to principles of anti-viral therapy today, simultaneously dosing of both drugs is to be preferred, since rapid maximal virus suppression is thought to be essential to prevent drug resistance and enhance seroconversion. From an immunological point of view, pre-treatment with lamivudine or IFN may alter the virus-host balance and set the stage for the other drug to enhance the effect of treatment. Further clinical research on lamivudine-IFN combination therapy appears warranted.     

乙型肝炎患者治疗前后检测HBV抗原蛋白特异性T细胞的反应

目的探讨HBV抗原蛋白特异性T细胞在乙型肝炎患者治疗前后变化的临床意义。方法收集本院2008年1月至2011年9月的58例慢性乙型肝炎患者进行抗病毒等内科治疗3个月后,检测其治疗前后的外周血单个核细胞,并以HBv特异性抗原蛋白HBsAg、HbcAg和HBeAg为刺激物,酶联免疫斑点检测其分泌1FN-γ产生斑点的情况。同时对血清HBV DNA和HBsAg、HBeAg等病毒学指标及丙氨酸转氨酶(ALT)等生化学指标进行检测。以10例接种过乙型肝炎疫苗的健康人为对照组,均为HBsAg、HBeAg、抗-HBe、抗-HBc阴性,抗-HBs阳性。结果治疗前所有患者的HBV-DNA>104拷贝/mL,经过3个月治疗后,45例患者的HBV-DNA的水平降到正常值范围内。结论 HBV抗原蛋白特异性T细胞的反应可能做为乙型肝炎病毒复制和抗乙型肝炎病毒疗效评定实验室敏感指标。     

Peginterferon-alpha 2a for the treatment of hepatitis B infection

Chronic hepatitis B is one of the world's most common serious diseases with > 300 million patients worldwide. Currently recommended treatments include conventional interferon (IFN), lamivudine and adefovir. Recently, peginterferon-alpha2a (PEG-IFN-alpha2a, Pegasys; Hoffmann-La Roche & Co.) has been approved for use in patients with chronic hepatitis B in the US, the EU, Switzerland, Turkey and in several countries in the Asia-Pacific region. Several trials have been carried out using PEG-IFN-alpha2a (40 kDa) compared with conventional IFN, lamivudine monotherapy and a combination of PEG-IFN-alpha2a and lamivudine in patients with hepatitis Be antigen- (HBeAg) positive chronic hepatitis B, and patients with HBeAg-negative chronic hepatitis B. PEG-IFN-alpha2a was shown to be superior to conventional IFN in HBeAg-positive disease and to lamivudine in both HBeAg-positive and HBeAg-negative chronic hepatitis B. Although there was greater suppression of virus while on therapy, the combination of lamivudine and PEG-IFN-alpha2a did not enhance sustained response at the end of the 24-week follow-up period, compared with PEG-IFN monotherapy. In addition, approximately 3% of patients underwent hepatitis B surface antigen (HBsAg) seroconversion - the ultimate marker of therapeutic response, which is rarely seen following treatment with antiviral agents. The side effect profile was reasonable. PEG-IFN-alpha2a could become the treatment of choice in many patients with both HBeAg-positive and HBeAg-negative disease and, in those who fail to respond, consideration could then be given to the use of antiviral agents.     

Hepatitis B virus antigens impair NK cell function

An inadequate immune response of the host is thought to be a critical factor causing chronic hepatitis B virus (CHB) infection. Natural killer (NK) cells, as one of the key players in the eradication and control of viral infections, were functionally impaired in CHB patients, which might contribute to viral persistence. Here, we reported that HBV antigens HBsAg and HBeAg directly inhibited NK cell function. HBsAg and/or HBeAg blocked NK cell activation, cytokine production and cytotoxic granule release in human NK cell-line NK-92 cells, which might be related to the downregulation of activating receptors and upregulation of inhibitory receptor. Furthermore, the underlying mechanisms likely involved the suppression of STAT1, NF-κB and p38 MAPK pathways. These findings implicated that HBV antigen–mediated inhibition of NK cells might be an efficient strategy for HBV evasion, targeting the early antiviral responses mediated by NK cells and resulting in the establishment of chronic virus infection. Therefore, this study revealed the relationship between viral antigens and human immune function, especially a potential important interaction between HBV and innate immune responses.     

Drugs in development for hepatitis B

The management of chronic hepatitis B (CHB) has improved dramatically over the last decade with the development of new drugs such as lamivudine and adefovir dipivoxil, in addition to the now standard interferon (IFN)-alpha therapy. These new drugs can achieve a significant reduction or inhibit replication of hepatitis B virus (HBV) DNA during therapy. However, in the majority of patients, particularly in those who are hepatitis B e antigen (HBeAg)-negative, the sustained off-therapy suppression of HBV DNA is rare. For this reason, several new antiviral and immunomodulatory agents are currently being evaluated. Among the immunomodulatory agents, pegylated IFNalpha (peginterferon-alpha) has been shown to be more effective for HBeAg-positive CHB than either lamivudine or standard IFNalpha monotherapy, particularly in those patients infected by HBV genotypes A and B. The new antivirals entecavir, tenofovir disoproxil fumarate and telbivudine exhibit a more potent viral inhibitory effect than the currently approved drugs (IFNs, lamivudine and adefovir dipivoxil). However, the emergence of viral resistance has been witnessed and this could be one of the major limitations to the clinical use of these new drugs, particularly during prolonged therapy. In HBeAg-negative patients it is more and more common for oral antiviral therapy to be administered for prolonged periods, as the sustained off-therapy response rates of short-term therapy are very low. Different studies are currently evaluating combination therapy, using lamivudine with adefovir dipivoxil or peginterferon-alpha with lamivudine; the preliminary results show virological responses no better than those achieved by monotherapy. However, as combination therapy is associated with a low likelihood of developing HBV drug resistance, this could result in a higher virological response during prolonged therapy. In the near future the most realistic therapeutic option for the majority of patients with CHB will be long-term use of these new, more potent antiviral drugs, if they can achieve good safety profiles while maintaining low resistance rates at affordable costs.     

Long-term lamivudine therapy for chronic hepatitis B in patients with and without cirrhosis

STUDY OBJECTIVE: To evaluate the effects and safety of 52-week lamivudine therapy in Korean patients with chronic hepatitis B virus (HBV), with and without cirrhosis. DESIGN: Long-term retrospective study. SETTING: Ajoo University Medical Center, Soowon, Korea. PATIENTS: Twenty-seven men and two women who had received oral lamivudine 100 mg/day for 52 weeks for treatment of biopsy-proven chronic HBV; 11 patients had cirrhosis, 18 did not. MEASUREMENTS AND MAIN RESULTS: All 29 patients were positive for HBV DNA and hepatitis B surface antigen (HBsAg) before treatment began; 25 (86%) patients were positive for hepatitis B e antigen (HBeAg). Lamivudine therapy suppressed serum HBV DNA to undetectable levels in 26 (90%) patients within a median of 4 weeks. Serum HBV DNA of 28 patients (97%) fell significantly to undetectable levels within 12 weeks and remained undetectable in 24 (83%) patients after 52 weeks, and HBeAg had converted to negative in 10 (40%) of the 25 patients who were positive. Mean serum alanine aminotransferase (ALT) levels of the 29 patients decreased to within the normal range by 12 weeks and remained at 33-48 IU/L thereafter. Differences in responses of HBV DNA and ALT to lamivudine therapy in HBeAg-positive and -negative patients were negligible (p = 0.786 and p = 0.225, respectively). Pretreatment HBV DNA and ALT levels had no effect on the efficacy of lamivudine (p = 0.9116). Furthermore, differences in responses of HBV DNA (p = 0.641), HBeAg seroconversion (p = 0.386), and ALT (p = 0.689) and in development of drug resistance (p = 0.617) between patients with and without cirrhosis were negligible. No serious adverse effects were reported. CONCLUSION: Lamivudine is an effective and well-tolerated therapeutic agent for treating chronic HBV in patients with and without cirrhosis.     

Review article: chronic hepatitis B – anti‐viral or immunomodulatory therapy?

Aliment Pharmacol Ther 2011; 33: 501–513

Summary

Background First‐line treatment options for chronic hepatitis B (CHB) consist of nucleos(t)ide analogues with a high barrier to resistance (entecavir and tenofovir) or the immunomodulatory agent peginterferon (PEG‐IFN). The optimal choice for individual patients remains controversial. Aim To review treatment options for CHB, with a focus on deciding between prolonged nucleos(t)ide analogue therapy or a finite course of PEG‐IFN. Methods A comprehensive literature search was undertaken. Results Long‐lasting, treatment‐maintained suppression of hepatitis B virus (HBV) DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off‐treatment response is, however, unlikely and long‐term therapy must be anticipated. PEG‐IFN offers a higher rate of sustained response in a subgroup of patients, but is frequently complicated by side effects. Pre‐treatment predictors of response, including HBV genotype, alanine aminotransferase and HBV DNA levels, aid in selecting patients for PEG‐IFN therapy. Furthermore, on‐treatment markers such as quantitative hepatitis B surface antigen may be applied to identify nonresponders early during the PEG‐IFN treatment course, thereby preventing unnecessary treatment. Conclusions Both nucleos(t)ide analogues and PEG‐IFN can be prescribed as first‐line treatment options for CHB. However, PEG‐IFN should only be considered for patients with a high chance of response based on pre‐treatment and on‐treatment factors.     

慢性乙型肝炎患者YMDD自然变异的临床观察

目的观察发生YMDD自然变异的慢性乙型肝炎（CHB）患者的临床特征,探讨HBVYMDD自然变异发生的可能机理,为CHB抗病毒治疗提供新思路。方法选择144例HBVDNA阳性、未经抗病毒治疗的CHB患者作为观察对象,采用PCR熔解曲线法检测其YMDD基因序列突变;同时对其进行HBVDNA定量、血清丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）和乙肝两对半等相关指标检测,并对患者性别、年龄及上述检测结果进行统计学分析。结果144例未经抗病毒治疗的CHB患者中,有30例出现YMDD自然变异,变异检出率为20．8％,其中YIDD阳性19例（占63．3％）,YVDD阳性8例（占26．7％）,YIDD＋YVDD同时阳性3例（占10％）。YMDD自然变异组CHB患者年龄明显小于未变异组;HBVDNA定量值在105copies／ml以上的CHB患者易发生YMDD自然变异,而HBVDNA定量低于105copies／ml的CHB患者不易发生YMDD自然变异。CHB患者的性别、HBeAg和抗一HBe状态及肝功能损害程度与YMDD自然变异无关。结论CHB患者中存在HBVYMDD自然变异,低龄和HBVDNA高值的患者易发生YMDD自然变异;自然变异与患者性别、HBeAg和抗一HBe状态及肝功能损害程度无关。     

Effect of telbivudine therapy on the cellular immune response in chronic hepatitis B

Weak T-cell reactivity to the hepatitis B virus (HBV) is believed to be the dominant cause of chronic HBV infection. Several lines of experimental evidence suggest that treatment with telbivudine increases the rate of HBV e antigen (HBeAg) loss, undetectable HBV DNA, and normalization of serum alanine aminotransferase (ALT) in chronic hepatitis B patients (CHB). However, it is still unclear how early antiviral therapy affects cellular immune responses during sustained telbivudine treatment. In order to investigate this issue, we measured detailed prospective clinical, virological, and biochemical parameters, and we examined the frequency of T cell subgroups as well as the ability of peripheral blood mononuclear cells (PBMC) to respond to stimuli at five protocol time points for 51 CHB patients who received telbivudine therapy for one year. The preliminary data from this study revealed that effective-treated patients showed an increased frequency of peripheral blood CD4⁺T lymphocytes, an augmented proliferative response of HBV-specific T-cells to the hepatitis B core antigen (HBcAg), and the induction of cytokines, such as interferon gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) release at the site of infection compared to non-responsive patients. Enhanced HBV-specific T-cell reactivity to telbivudine therapy, which peaked at treatment week 12, was confined to a subgroup of effective-treated patients who achieved greater viral suppression.