Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients

Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement -- with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.     

Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients

Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement – with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.     

Hepatitis B genotypes in chronic hepatitis B and lamivudine therapy

The influence of hepatitis B virus (HBV) genotypes on the natural history and the response to treatment of patients with chronic hepatitis B are of potential interest. Compared to the patients with HBV genotype C, those with genotype B were of a younger age and had a higher cumulative rate of hepatitis B e antigen (HBeAg) seroconversion during the initial 6 years of follow-up. The earlier HBeAg seroconversion in the patients with genotype B, however, did not provide them with a benefit in terms of a reduced risk of developing long-term complications. The response to lamivudine therapy was evaluated in 21 patients infected with HBV genotype B (all of subtype Ba) and 61 with genotype C. There were no differences in the virological response to lamivudine therapy, based on the reduction in median logarithmic HBV DNA titer as well as alanine aminotransferase (ALT) levels, normalization of ALT and the rate of HBeAg seroconversion between the patients with genotypes B and C. No differences were noted either, in the frequency of YMDD mutants at week 52 or the cumulative risk of HBV DNA breakthroughs with YMDD mutations during long-term lamivudine therapy (median 37.5 months). In conclusion, there is no influence of HBV genotypes on the development of long-term complications and lamivudine therapy in Hong Kong.     

Patient management and clinical decision making in HBV--aims of therapy and what we can achieve

International treatment guidelines for hepatitis B emphasize alanine aminotransferase (ALT) and serum HBV DNA thresholds, but strict adherence to these markers might lead to missed opportunities in some patients with acquisition in early life. Clinical trials have used improvement in liver histology, rate of hepatitis B e antigen seroconversion and sustained HBV DNA suppression as primary end points. These are potentially short-term end points because HBV infection can not be eradicated and delayed relapses might occur. The closest end point to a clinical cure of disease is the loss of hepatitis B surface antigen (HBsAg). The ability of interferon to stimulate the immune response of the host might explain the higher rate of early HBsAg clearance when compared with nucleoside analogues. Early studies suggest that combination therapy with interferon and long-term treatment with nucleoside analogues might lead to an even higher rate of HBsAg seroconversion. Measuring HBsAg concentration during therapy might provide an early indication that a durable virological response, including HBsAg clearance, is likely to occur. Thus far, this has been best studied using interferon. The relationship of this phenomenon to viral genotype will be discussed. There is a need for more flexible on-treatment criteria for hepatitis B. HBsAg clearance remains the best therapeutic end point, but is not readily achievable with current treatments. Future treatment paradigms should take into account the duration as well as the extent of viraemia, place less reliance on the ALT level to indicate the extent of liver injury and consider the possibility that maintenance therapy can prevent liver disease complications.     

拉米夫定治疗HBeAg阳性慢性乙型肝炎的疗效预测分析

目的分析拉米夫定治疗HBeAg阳性慢性乙型肝炎52周疗效与24周抑制HBVDNA程度的相关性,探讨临床疗效预测指标。方法回顾性分析拉米夫定治疗HBeAg阳性慢性乙型肝炎患者96例,根据治疗24周时HBVDNA是否阴转（HBVDNA〈10^3拷贝／ml）分为病毒学转阴组和未转阴组,比较两组治疗52周时HBVDNA、HBeAg、ALT和YMDD病毒变异。结果治疗52周时,转阴组和未转阴组HBVDNA、HBeAg转阴率、ALT复常率和YMDD变异率分别为87．7％、59．6％、93．0％、3．5％和48．7％、30．8％、2．6％、74．4％、28．2％,有统计学意义（P〈0．01）。结论拉米夫定治疗24周时,若HBVDNA〈10^3拷贝／ml,52周可获得较好疗效;若HBVDNA〉10^3拷贝／ml,则52周时疗效不佳且发生耐药的可能性增加。24周拉米夫定对HBVDNA的抑制程度可作为1年疗效的预测指标。     

Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B

The current available agents for the treatment of chronic hepatitis B (CHB) include immunomodulatory agents, such as interferon-α and pegylated interferon-α, and oral nucleoside/nucleotide analogues (NAs), including lamivudine, adefovir, telbivudine, entecavir and tenofovir. The NAs work mainly by inhibiting hepatitis B virus (HBV) DNA polymerase activity and thus suppress HBV replication. Oral NAs have become the mainstay of CHB treatment, mainly due to their profound viral suppressive effects and also due in part to the ease of single daily dosing and lack of significant side effects. One major drawback of NA therapy is the development of drug resistance mutations with long-term treatment. Lamivudine, the first oral NA approved for CHB patients, is associated with high rates of drug resistance, with resultant virological relapse and biochemical flare. Fortunately, newer and more potent NAs, such as entecavir and tenofovir, have very low resistance rates, with potent and durable viral suppression. This review is aimed at the current developments in NAs for CHB treatment, detailing the mechanisms of antiviral activity of the different agents, the efficacy of viral suppression, the achievement of treatment endpoints, the development of drug resistance and the optimal strategies for using these drugs.     

Natural history of hepatitis B virus infection: an update for clinicians

Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma.     

Efficacy of lamivudine therapy and factors associated with emergence of resistance in chronic hepatitis B virus infection in Japan

OBJECTIVE: Several reports have examined the efficacy of long-term lamivudine therapy and the risk factors involved in emergence of viral resistance in Japanese patients with hepatitis B virus (HBV) infection. However, the patient cohorts in such studies are relatively small. METHODS: We analyzed 234 chronically HBV-infected Japanese patients who were treated with lamivudine for more than 12 months. They comprised patients with HBV genotype A (n = 8), genotype B (n = 21), genotype C (n = 203) and other HBV genotypes (n = 2). RESULTS: In most patients, lamivudine resulted in normalization of alanine transaminase (ALT) levels at 6 and 12 months, and suppression of serum HBV DNA to undetectable levels by the branched chain DNA probe assay (bDNA). Rates of ALT normalization and non-detection of HBV DNA were higher among patients with genotype B than genotype C disease. The proportions of patients who achieved HBeAg loss were 27, 42 and 45% after 6 months, 1 year and 2 years, respectively. The emergence of mutations was not different among genotypes A, B and C by the Kaplan-Meier method. Multivariate analyses identified high HBV DNA level (bDNA >or=100 MEq/ml) as an independent factor associated with emergence of the YMDD motif mutation in all patients. Among patients with genotype C disease, which is the predominant HBV genotype in Japan, multivariate analysis also identified high HBV DNA level and HBeAg positivity as factors associated with emergence of resistance. CONCLUSION: Patients exhibiting these factors at the commencement of lamivudine treatment must be monitored carefully at regular intervals for emergence of viral resistance.     

Late failure of combined recombinant hepatitis B vaccine and lamivudine in treatment of a patient with chronic hepatitis B

We report the first case of a woman having chronic hepatitis B treated with a combination therapy of recombinant hepatitis B vaccine and lamivudine for 18 months. The main aims of such a combined therapy were to assess whether the concomitant anti-hepatitis B virus (HBV) vaccination might prevent the emergence of a mutant HBV and lead to sustained hepatitis B e antigen seroconversion with undetectable serum HBV DNA. The data from the present case demonstrated that combination of anti-HBV vaccine and lamivudine did not eliminate viral DNA despite prolonged treatment and did not have any effect on preventing resistant-type HBV. Although the combined therapy failed to reach the therapeutic endpoints, it concerned a single and unique patient. Hepatitis B vaccine and lamivudine for HBV treatment should be further investigated in randomized controlled trials.     

Entecavir for the long-term treatment of chronic hepatitis B

Hepatitis B virus is a major cause of chronic liver disease worldwide and is associated with an increased risk of hepatocellular carcinoma, progressive hepatic fibrosis and end-stage liver disease. Suppression of HBV replication is recognized as the primary on-treatment goal of antiviral therapy, as reduction of serum HBV DNA to low or undetectable levels is highly likely to have a positive impact on long-term clinical outcomes in HBV-associated chronic liver disease. Entecavir is an oral nucleoside analogue that effectively inhibits HBV polymerase, resulting in rapid viral suppression. Long-term data on patients receiving entecavir for chronic hepatitis B have demonstrated high potency, a low incidence of antiviral drug resistance and good tolerability, making entecavir an ideal first-line agent for the treatment of chronic hepatitis B.     

Hepatitis B virus genotypes and hepatocellular carcinoma in Taiwan

With phylogenetic analysis of hepatitis B virus (HBV) isolates, eight different genotypes (A to H) have been recognized worldwide. The impact of HBV genotypes on the clinical aspects of HBV infection in Taiwan, including the clinical outcome of chronic infection and therapeutic response to antiviral treatments, has been clarified. Our data showed that genotypes B and C are the predominant HBV strains in Taiwan, and genotype C is associated with more severe liver disease including cirrhosis and hepatocellular carcinoma (HCC), whereas genotype B is associated with the development of HCC in young noncirrhotic patients. Serologically, genotype C tends to have a higher frequency of hepatitis B e antigen (HBeAg) positivity and a higher serum HBV DNA level than genotype B. In addition, genotype C patients, compared to genotype B patients, have a delayed HBeAg seroconversion in the immune clearance phase of chronic HBV infection. Virologically, genotype C bears a higher frequency of basal core promoter mutation than genotype B. Our recent data further indicated that patients with basal core promoter mutation are significantly more associated with the development of HCC than those without, which applies to both genotypes B and C. In addition, the prevalence of basal core promoter mutation in young HCC patients is comparable to older HCC patients but is significantly higher than that in age-matched inactive carriers, irrespective of genotypes. Although superinfection of HBV on hepatitis B carriers indeed occurs in Taiwan, it is rarely associated with acute exacerbations. As to the response to antiviral treatments, genotype C is associated with a lower response rate to interferon therapy compared to genotype B. In addition, genotype B seems to have a better virological response to lamivudine as compared to genotype C, but both genotypes have a similar risk in the development of lamivudine resistance. These lines of evidence highlight the remarkable differences in the clinical and virological characteristics between Taiwanese patients infected with different genotypes. In conclusion, pathogenic and therapeutic differences do exist among HBV genotypes in Taiwan, and determining the genotype in patients with chronic HBV infection would help gain further information in anthropologic, clinical, virological and prognostic investigations.     

HCV-HBV infection

Chronic infection of hepatitis C (HCV) and B virus (HBV) frequently causes viral hepatitis. Patients with chronic viral hepatitis are at risk for liver cirrhosis and even hepatocellular carcinoma. In patients with chronic hepatitis C, the most effective therapy is elimination of HCV with interferon (IFN). The most effective initial IFN therapy is the combination of pegylated IFN alpha-2b plus ribavirin. Forty-eight weeks of this combination therapy produces sustained viral response rates of approximately 50%. Moreover, several reports showed that long-term IFN therapy also reduced the risk of liver carcinogenesis. In patients with chronic hepatitis B, seroconversion from HBeAg to anti-HBe antibodies suppresses viral replication and attenuates the hepatitis. Twenty-four weeks of IFN therapy produces HBeAg seroconversion rates approximately 30%.     

Management of hepatitis B

Treatment of chronic hepatitis B needs to consider two aspects. First, a certain proportion of patients will spontaneously undergo a stable remission of the underlying liver disease, i.e. without therapeutic intervention, on occasion of the HBeAg --> anti-HBe seroconversion. Second, all drugs that have been used so far in the treatment of HBV have rarely resulted in the definitive eradication of the viral infection, i.e. a permanent disappearance of HBsAg with development of anti-HBs. Thus, the most reasonable, albeit surrogate endpoint of treatment is the acceleration towards HBeAg --> anti-HBe seroconversion and/or the stable suppression of HBV replication at levels below 500000 copies/ml, which is associated with disappearance of intrahepatic necrosis and inflammation and slowing down of the fibrosis progression. Two drugs are currently available--interferon-alpha and lamivudine--and a third antiviral compound (adefovir dipivoxil) will soon appear in the market. Advantages and disadvantages of different therapeutic options are discussed below.     

Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence

OBJECTIVE: Standard treatment for hepatitis B is either based on interferon or on nucleos(t)ide analogues. Available evidence on treatment outcome by hepatitis B virus genotype was summarized and analysed to determine whether the genotype has a substantial role in selecting treatment. METHODS: Abstracts from PubMed, the European Association for the Study of the Liver and the American Association for the Study of the Liver Diseases were screened for publications with at least 30 patients and reporting hepatitis B treatment results (hepatitis B e antigen [HBeAg] seroconversion, loss of HBeAg or loss of HBV DNA) broken down by hepatitis B genotypes. Twenty reports were identified and included. Forest-plot techniques were applied to visualize the association of HBV genotypes (A versus D and B versus C) with treatment outcome given by type of treatment and HBeAg status. The potential size of a treatment by genotype interaction was estimated. RESULTS: Treatment response to nucleos(t)ide analogues is not significantly influenced by HBV genotype in HBeAg-positive or HBeAg-negative individuals. In contrast, HBV genotypes are informative concerning responses to interferon treatment in all patients with genotype A versus D and in HBeAg-positive patients with genotype B versus C. CONCLUSION: If no contraindications are present, interferon may be considered as first-line therapy in all genotype A patients and in individuals with genotype B who are HBeAg positive. However, confirmation of this observation in a prospective clinical trial is warranted, because this analysis is explorative and hypothesis generating only.     

替比夫定治疗e抗原阳性慢性乙型肝炎的疗效预测因素研究

目的探讨替比夫定酯治疗HBeAg（＋）慢性乙型肝炎的疗效预测指标,为个体化治疗提供依据。方法选取广州医学院第一附属医院HBeAg阳性慢性乙型肝炎患者60例,均予替比夫定600 mg治疗48周,检测治疗前及治疗后24、48周的HBsAg、HBeAg、HBV DNA定量及丙氨酸氨基转移酶（ALT）水平。根据治疗24周时血清HBV DNA水平,将患者分为两组,聚合酶链反应（PCR）低于检测下限（〈300拷贝/m l）的A组和高于检测下限（≥300拷贝/m l）的B组。结果治疗24周时HBV DNA水平越低,HBsAg下降幅度越大,在48周HBV DNA达到PCR检测不到的水平、HBeAg血清转换率和ALT复常率越高。A组患者在48周时HBeAg血清转换率为44.1%,B组患者则为8.3%,两组比较差异有统计学意义（χ2=22.1,P〈0.01）。结论乙型肝炎患者应用替比夫定治疗24周时HBV DNA水平及HBsAg下降幅度可作为48周疗效的预测指标。     

Hepatitis B virus genotype-associated variability in antiviral response to adefovir dipivoxil therapy in Chinese Han population

It is well known that different genotypes of hepatitis B virus (HBV) have a different sensitivity to interferon-alpha or lamivudine (nucleoside analogue) antiviral therapy. However, for adefovir dipivoxil (ADV, a nucleotide analogue), the antiviral response of the different genotypes remains to be clarified. In order to evaluate the response of HBV genotypes to ADV therapy and to identify factors that might affect initial virological response, we performed a retrospective analysis on patients with chronic hepatitis B (CHB) in Chinese Han population. The study included 183 patients, who had been tested positive for hepatitis B e antigen (HBeAg) and had been treated with ADV (10 mg/day) for 48 weeks. The numbers of patients infected with HBV genotype B and genotype C were 98 and 75 cases, respectively, and the remaining 10 patients were mixture infection of genotypes B plus C or genotypes B plus D. The mean HBV-DNA reduction and HBV-DNA seroclearance of genotypes B and C at 48 weeks were 3.6 log(10) and 3.1 log(10) copies/ml (p < 0.05) and 41.8% and 34.6% (p < 0.05), respectively. There were no statistically significant differences between genotypes B and C in terms of HBeAg loss, anti-HBe seroconversion and normalization of serum alanine aminotransferase (ALT). Multivariate analysis showed that young age, low pretreatment HBV-DNA and/or elevated ALT level might be independent predictive factors associated with initial virological response. Thus, in Han CHB patients who are HBeAg-positive, HBV genotype B shows a better virological response to ADV therapy than does genotype C.     

Role of lamivudine in the treatment of chronic hepatitis B virus infection.

OBJECTIVE: To examine the evidence regarding the therapeutic effectiveness of lamivudine in the treatment of chronic hepatitis B virus (HBV) infection in immunocompetent patients. DATA SOURCES: Using chronic hepatitis B and lamivudine as MeSH headings, MEDLINE was searched from 1966 to September 1998 for all published randomized controlled trials evaluating lamivudine in chronic HBV infection. Relevant articles from selected bibliographies were also retrieved. STUDY SELECTION: Only randomized, single- and double-blind trials in human HBV carriers published in the English language were included. DATA SYNTHESIS: Evidence from the controlled trials suggests that lamivudine has a therapeutic effect in suppressing HBV replication in immunocompetent patients. Lamivudine 100 mg/d appears to suppress HBV replication in as many as 97% of patients within two weeks after the initiation of therapy and is capable of suppressing histologic damages. However, viral suppression is effective only during the therapy; on discontinuation of lamivudine therapy, most patients return to the pretreatment condition. Viral resistance to lamivudine has been observed. Most patients with chronic HBV infection appear to tolerate 100 mg/d of lamivudine therapy. CONCLUSIONS: Evidence has shown that oral lamivudine 100 mg/d will produce rapid and significant suppression of viral replication in immunocompetent patients with chronic HBV infections. Treatment periods up to one year have been effective and well tolerated. The suppression of viral replication may not be sustained after cessation of lamivudine therapy, and very few patients have complete elimination of HBV during therapy. Therefore, long treatment periods may be necessary. Efficacy and tolerability of treatment beyond one year need to be investigated. Resistance to lamivudine has been reported in patients receiving therapy. A combination anti-HBV regimen using lamivudine and other agents with different mechanisms of action should be investigated to maximize the elimination of the viral infection while minimizing or preventing damage to the liver cells and tissues and the development of viral resistance.     

IL-28B 基因多态性对慢性 HBV 患者抗病毒治疗疗效的预测价值

目的：探索 IL-28B 基因在慢性 HBV 患者抗病毒疗效中的作用。方法对 HBV 病毒 e 抗原（HBeAg）阳性的205例慢性乙型肝炎患者采用干扰素（PEG-IFN）的抗病毒治疗方法,采用 TapManSNP 基因分析法检测 IL-28Brs12980275和rs12979860的基因型,并分析基因型与 HBeAg 血清转化的关系。结果205例患者中有6例基因型不确定,剩余的199例患者IL-28B 的 rs12980275和 rs12979860基因型比率分别为 AA 77％、AG 19％、GG 5％和 CC 76％、CT 20％、TT 4％。IL-28B 基因型与 HBeAg 血清转化显著相关（P ＜0．01）。在 rs12980275基因型上,通过 HBV 基因型、年龄、HBV 水平及丙氨酸转氨酶和联合治疗,血清转化调整 AA 和 AG/GG 的优势比为3．16。对于 rs12979860也得到了相似的结果。IL-28B 也与乙型肝炎表面抗原清除有关。结论 IL-28B 与 HBeAg 阳性慢性乙型肝炎患者抗病毒治疗疗效有关系。     

Antivirals for the treatment of chronic hepatitis B: current and future options

Despite effective vaccination programmes, new hepatitis B virus (HBV) infections remain common and there are many millions of individuals already infected. Therapeutic agents are needed to reverse existing liver disease and prevent future disease progression. This article reviews recently published clinical data on the two currently available antivirals for the treatment of chronic hepatitis B infection, lamivudine and adefovir dipivoxil. Lamivudine, a nucleoside analogue, is currently the only licensed antiviral for the treatment of chronic hepatitis B in Asia. Extensive clinical trials have shown that lamivudine is effective and well tolerated in a wide range of patients. YMDD variants have been identified in some patients with reduced sensitivity to lamivudine after extended therapy. Adefovir dipivoxil, a nucleotide analogue, will soon be commercially available in Asia. Adefovir dipivoxil 10 mg is well tolerated and is as effective as lamivudine in reducing serum HBV DNA and alanine aminotransaminase levels and increasing seroconversion in patients with hepatitis B e antigen. No adefovir-resistant mutants have been reported during 48-week clinical trials. The addition of adefovir dipivoxil to ongoing lamivudine therapy, in patients with YMDD variants and a reduced response to lamivudine, leads to significant inhibition of viral replication and improvement in liver function after 1 year of therapy.     

Sequential combination therapy leads to biochemical and histological improvement despite low ongoing intrahepatic hepatitis B virus replication

BACKGROUND: We previously reported that 48 weeks of combination therapy with pegylated interferon-alpha2b (PEG-IFN-alpha2b) and adefovir dipivoxil (ADV) in patients with chronic hepatitis B led to marked decreases of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) (-2.4 log10 copies/ml). Combination therapy was followed by 96 weeks of ADV monotherapy. METHODS: Here, we report on the final outcome after 144 weeks of sequential antiviral treatment. Twenty-four patients were analysed, triplet liver biopsies (taken at baseline, week 48 and week 144) were available from 16 patients. RESULTS: At week 144, 12/15 patients positive for hepatitis B virus e antigen (HBeAg) had lost HBeAg, alanine transaminase (ALT) levels were normal in 23 patients (96%), median serum HBV DNA had decreased by -4.9 log10 copies/ml and was undetectable (<100 copies/ml) in 11/24 individuals (46%). Median total intrahepatic HBV DNA had decreased by -2.2 log. Although no further significant cccDNA changes occurred between week 48 and week 144, two years of ADV monotherapy proved capable of controlling cccDNA levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that combination therapy with PEG-IFN-alpha2b and ADV inhibited viral productivity by 99% and subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability within the first 12 weeks of treatment was strongly associated with long-term virological response and HBeAg and hepatitis B virus surface antigen HBsAg seroconversion. Histological improvement was determined in 11/16 patients at week 144. Two patients developed ADV resistance during the third year of treatment. CONCLUSIONS: Reduction of intrahepatic viral load achieved after 48 weeks of combination therapy with PEG-IFN-alpha2b and ADV was maintained in the following 96 weeks of ADV monotherapy and translated into long-term clinical benefit for most of the treated patients.