Liver-specific autoantibodies in chronic hepatitis B virus infection

Anti-liver-specific protein (LSP) antibody and liver membrane autoantibody (LMA) have been evaluated in 88 patients with hepatitis B virus (HBV)-induced chronic liver disease by means of radioimmunoprecipitation and immunofluorescence. Among our patients, 38 presented circulating HBe antigen while 43 had HBe antibody and seven were negative for both. Anti-LSP was mainly found in HBeAg positive chronic active hepatitis (CAH), anti-HBe in positive CAH and in anti-HBe positive chronic persistent hepatitis (CPH). Similar prevalences of LMA (range 13-33%) were detected in the various groups studied. Taking into account the histological diagnosis of disease activity (periportal inflammation and piecemeal necrosis) no significant differences were found between active and inactive patients. Taking into account the HBeAg/anti-HBe status, no significant differences were found between the patients positive for 'e' antigen or 'e' antibody. Humoral autoimmune reactions may also play a role in HBV-induced chronic (active) liver disease irrespective of HBeAg/anti-HBe status and hence of the viral replication activity of the patients.     

Immunomodulatory therapy for chronic hepatitis B virus infection

Hepatitis B virus (HBV) is one of the most prevalent viral pathogens of man with around 350 million chronically infected patients. It has been postulated that in persistently infected individuals the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver disease. The primary aim in the treatment of chronic hepatitis B is to induce sustained disease remission and prevent serious complications like liver failure and/or hepatocellular carcinoma. The recent emergence of drug-resistant HBV mutants and post-treatment relapse as a consequence of nucleoside analogue monotherapy emphasizes that the principal goal should be to stimulate a successful immune response. In this paper we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines and Thymic derivates) and vaccine therapies using currently available recombinant anti-HBV vaccines, lipopeptide-based T cell vaccine and newly developed genetic vaccines.     

Therapeutic vaccination against chronic hepatitis B virus infection

Chronic liver disease and hepatocellular carcinoma associated with chronic hepatitis B virus (HBV) infection are among the most serious human health problems in highly endemic regions. Despite the existence for many years of effective vaccines against HBV, more than 370 million people remain persistently infected with HBV today. Currently available therapies fail to provide long-term control of viral replication in most patients. Viral persistence has been associated with a defect in the development of HBV-specific cell-mediated immunity. Strategies to boost or to broaden the weak virus-specific T-cell response of patients with chronic hepatitis B have been proposed as a means of terminating this persistent infection. The immunogenicity of HBV envelope- or capsid-based vaccines, new formulations for recombinant vaccines as well as DNA-based vaccines are currently under investigation in clinical trials. Although improvements are still required, vaccination would be the therapeutic procedure with the lowest cost and the potentially greatest benefit.     

Current therapies for chronic hepatitis B virus infection

Patients who are chronically infected with the hepatitis B virus are at an increased risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma. Therapeutic intervention offers the only means of interrupting this progression. Currently there are three licensed agents for the treatment of chronic hepatitis B virus infection. These are interferon-alpha, an immunomodulator, and two synthetic nucleos(t)ide analogs, namely lamivudine (Epivir, GlaxoSmithKline) and adefovir dipivoxil (Hepsera, Gilead Sciences). This review aims to summarize current experience with these drugs in the treatment and management of patients with chronic hepatitis B virus infection, their efficacy, and current problems of drug resistance. An outline of future treatment perspectives is also included.     

Current therapies for chronic hepatitis B virus infection

Patients who are chronically infected with the hepatitis B virus are at an increased risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma. Therapeutic intervention offers the only means of interrupting this progression. Currently there are three licensed agents for the treatment of chronic hepatitis B virus infection. These are interferon-α, an immunomodulator, and two synthetic nucleos(t)ide analogs, namely lamivudine (Epivir^®, GlaxoSmithKline) and adefovir dipivoxil (Hepsera^®, Gilead Sciences). This review aims to summarize current experience with these drugs in the treatment and management of patients with chronic hepatitis B virus infection, their efficacy, and current problems of drug resistance. An outline of future treatment perspectives is also included.     

Case-control study of hepatitis B virus infection in chronic liver disease and hepatocellular carcinoma

Summary The prevalence of serum hepatitis B virus markers was studied in three groups of age- and sex-matched patients:a. 31 patients with liver cirrhosis and hepatocellular carcinoma (c-HCC);b. 31 patients with chronic liver disease (CLD) andc. 62 hospitalized control subjects. The overall exposure rate to the hepatitis B virus was 90% in c-HCC, 80% in CLD and 58% in control subjects. The prevalence of hepatitis B surface antigen (HBsAg) was 29%, 13% and 1.6% in the three groups, respectively. The prevalence of hepatitis B surface antibody was significantly lower in c-HCC (9.6%) than CLD (42%) and control subjects (40%). The serological evidence of continuous viral replication (HBsAg positivity or isolated high titre hepatitis B core antibody positivity) was more common in c-HCC (39%) than CLD (12%) and control subjects (1.6%). The prevalence and patterns of aggregation of serum hepatitis B virus markers were similar in the 31 patients with c-HCC and in 11 patients with HCC without concomitant liver cirrhosis (n-HCC). In conclusion, the overall exposure rate to the hepatitis B virus is similar in c-HCC and CLD. However, serological evidence of continuous viral replication is more common in the former group. A defective clearance of the hepatitis B virus in hepatocellular carcinoma is a possible explanation of the phenomenon. The strength of the association between hepatitis B virus infection and hepatocellular carcinoma appears to be similar in c-HCC and n-HCC.     

Serum HBV-DNA (hepatitis B virus DNA) in acute and chronic hepatitis B infection

HBV DNA was measured in the sera of 69 patients with hepatitis B virus infections. Sixteen patients had acute hepatitis B, 24 had chronic active hepatitis (CAH), 6 had chronic persistent hepatitis (CPH), 5 had cirrhosis without CAH and 18 were asymptomatic HBsAg carriers. In patients with acute hepatitis B who recovered, HBV DNA was present in the serum transiently early in the illness. HBV DNA persisted in the serum in the two patients who developed chronic hepatitis. Sera of 23 of 24 patients with CAH were persistently positive for HBV DNA. There was no relationship between the quantity of HBV DNA in the serum and the histological intensity of activity. Thirteen of the 24 patients with CAH had histological evidence of cirrhosis in addition to CAH and HBV DNA was detected in the sera of all 13. The sera of 2 of 6 patients with CPH were positive for HBV DNA. In one it was positive only where there was clinical evidence of reactivation of HBV infection. The other patient subsequently developed CAH. Sera of 5 patients with established HBsAg positive cirrhosis but without evidence of CAH were negative for HBV DNA. Two of these patients had hepatocellular carcinoma. Sera of 18 asymptomatic anti-HBe positive carriers with normal ALT were negative for HBV DNA. HBeAg and HBV DNA were not always found in the serum together. In acute hepatitis 5 patients with HBV DNA in the serum were HBeAg positive, but in 6 patients the sera were HBeAg positive inthe absenceof HBV DNA.     

Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection

Adefovir dipivoxil (Hepsera^®, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir^®, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.     

Adefovir dipivoxil in the treatment of chronic hepatitis B virus infection

Adefovir dipivoxil (Hepsera, Gilead Sciences) is a prodrug of adefovir, with potent antiviral activity against hepatitis B virus. Adefovir dipivoxil therapy, 10 mg daily for 48 weeks, is effective in hepatitis B e antigen-positive and -negative chronic hepatitis B. In hepatitis B e antigen-negative chronic hepatitis B, adefovir dipivoxil was recently found to maintain its efficacy even after 3 years of therapy. Adefovir dipivoxil is effective in patients with compensated or decompensated chronic viral B liver disease, and in pre- and post-transplant hepatitis B virus patients who develop resistance to lamivudine (Epivir, GlaxoSmithKline). It is well-tolerated and safe even after the third year of long-term therapy, and is associated with low rates of viral resistance. All these characteristics make adefovir dipivoxil an important drug for the treatment of hepatitis B virus infection and an excellent candidate for long-term maintenance therapy in chronic viral B liver disease.     

Telbivudine for the management of chronic hepatitis B virus infection

BACKGROUND: Telbivudine (LdT) is an L-nucleoside that is structurally related to lamivudine. It is highly selective for hepatitis B virus (HBV) and inhibits viral DNA synthesis. LdT was approved by the US Food and Drug Administration on October 25, 2006, for the treatment of chronic HBV infection in adults who have active viral replication and either elevations in liver transaminases or signs of active liver disease on histologic examination. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and therapeutic efficacy of LdT. Potential drug interactions and adverse events associated with the use of LdT are also reviewed. METHODS: Relevant publications were identified from searches of MEDLINE (1996-June 2007), the Cochrane Library, and BIOSIS (1993-June 2007). Search terms included, but were not limited to, telbivudine, beta-L-thymidine, LdT, pharmacology, pharmacokinetics, adverse events, resistance, drug interactions, hepatitis B, and therapeutic use. Additional publications were identified from the reference lists of the identified papers, meeting abstracts, and correspondence with the manufacturer of LdT. RESULTS: After 52 weeks of therapy in the Phase III GLOBE study, HBV resistance (breakthrough and resistance mutations) to LdT occurred in 3% of patients who were hepatitis B e antigen (HBeAg) positive and 2% of patients who were HBeAg negative. After 104 weeks of therapy, 17.8% to 21.6% of HBeAg-positive and 7.3% to 8.6% of HBeAg-negative LdT-treated patients had a rebound in HBV DNA associated with breakthrough and resistance mutations. After 24 weeks of treatment, the risk of resistance was greater in patients with HBV DNA titers >3 log(10) copies/mL than in those with lower numbers of copies. LdT is not active against lamivudine-resistant HBV. The proportion of HBeAg-positive patients with undetectable HBV DNA (by polymerase chain reaction assay) after 104 weeks of therapy in the GLOBE study was significantly greater with LdT compared with lamivudine (56% vs 39%, respectively; P < 0.05). After 104 weeks of therapy, the corresponding proportions of HBeAg-negative patients with undetectable HBV DNA were 82% and 57% (P < 0.05). Patients who failed lamivudine therapy in the GLOBE study showed cross-resistance to LdT. The most common adverse events associated with LdT are upper respiratory tract infection (14%-17%), fatigue and malaise (12%-14%), nasopharyngitis (11%-15%), headache (11%-12%), and abdominal pain (6%-12%). Grade 3/4 adverse events included elevations in serum creatine kinase, which were more common in patients receiving LdT than in those receiving lamivudine (9% vs 3%, respectively). Elevations in creatine kinase are typically asymptomatic; however, myopathy has been reported in 3 of 680 patients receiving LdT. CONCLUSIONS: LdT joins the increasing number of antiviral agents for the management of chronic HBV infection. Questions concerning the optimal length of therapy and long-term efficacy await the results of on-going clinical trials. Concerns about increasing resistance over time may relegate LdT to second-line status in the management of chronic HBV infection. The role of LdT in combination therapy is under investigation.     

Entecavir for the treatment of chronic hepatitis B virus infection

OBJECTIVE: This article reviews the pharmacology/pharmacokinetics and therapeutic efficacy of entecavir, which was approved on March 29, 2005, for the management of adult patients with chronic hepatitis B virus (HBV) infection who have active viral replication and/or elevations in liver transaminases or signs of active liver disease on histologic examination. Potential drug interactions and adverse events associated with the use of entecavir are also reviewed. METHODS: Relevant literature was identified through searches of MEDLINE (1996-July 2005) and BIOSIS (1993-July 2005). Search terms included, but were not limited to, entecavir, BMS-200475, hepatitis B, pharmacology, pharmacokinetics, adverse events, and therapeutic use. Further publications were identified from the reference lists of the identified articles and through correspondence with the manufacturer of entecavir. RESULTS: Entecavir is highly selective for the HBV and inhibits all 3 steps of viral replication. Results of early studies indicated a 6% resistance potential after 48 weeks of therapy, although the potential may be higher in patients who harbor lamivudine-resistant mutants. The approved dosage in treatment-naive patients is 0.5 mg/d p.o., administered on an empty stomach; in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg/d p.o.. The oral tablet and solution can be used interchangeably. Entecavir is well absorbed orally, achieving a dose-related Cmax between 0.6 and 1.5 hours after administration. It is metabolized to a small extent and is not a substrate for the cytochrome P450 enzyme system. The mean elimination t(1/2) ranges from 77 to 149 hours in patients with normal kidney function. Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%-73%). No dose adjustment appears to be necessary in patients with moderate to severe liver disease alone. The potential for drug interactions with entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg, probenecid) may be expected to prolong serum concentrations of entecavir. One of the Phase III studies of entecavir found statistically significant benefits compared with lamivudine in terms of improvements in liver histology after 48 weeks of therapy (72% vs 62%, respectively; P<0.009), the proportions of patients with undetectable HBV DNA titers on branched DNA signal amplification assay after 48 weeks of therapy (91% vs 65%; P<0.001), and the proportion with undetectable HBV DNA on polymerase chain reaction (PCR) assay after 48 weeks of therapy (69% vs 38%; P<0.001). In another Phase III study, patients who had failed to respond to lamivudine therapy responded to entecavir: after 48 weeks of therapy, significant differences between entecavir and lamivudine were seen in histologic improvement (55% vs 28%; P<0.001) and the proportion of patients with undetectable HBV DNA on PCR assay (21% vs 1%; P<0.001). Adverse events associated with entecavir therapy were similar in character, severity, and incidence to those associated with placebo or lamivudine therapy. The most common adverse events in clinical trials of entecavir were headache (17%-23% of patients), upper respiratory tract infection (18%-20%), cough (12%-15%), nasopharyngitis (9%-14%), fatigue (10%-13%), dizziness (9%), upper abdominal pain (9%-10%), and nausea (6%-8%). CONCLUSIONS: Entecavir is a new antiviral agent for the management of chronic HBV infection. Questions concerning the ideal length of therapy, long-term efficacy, and resistance rates over time await the results of ongoing clinical trials.     

Diagnostic markers of chronic hepatitis B infection and disease

Recent advances in therapy for patients with chronic hepatitis B (CHB) infection offer the potential for a more successful treatment outcome, but also raise a number of questions in clinical practice regarding diagnosis and staging of CHB to ensure such potential is realized. In patients without cirrhosis, some forms of antiviral therapy can switch patients from an active disease phase into an inactive hepatitis B surface antigen (HBsAg) carrier state, and eventually lead to HBsAg clearance and HBsAg antibody seroconversion, the closest to a cure in CHB; thus, one of the most important diagnostic questions that clinicians face is the identification of patients with early forms of CHB within a large cohort of asymptomatic HBsAg-positive individuals, most of whom are inactive HBsAg carriers. Two major categories of diagnostic markers are currently available: virus-specific markers and liver disease markers. Most markers involve the use of non-invasive serological testing, but invasive diagnostic procedures, such as liver biopsy, are also an option. In this article, we review current opinions on the appropriate use of diagnostic procedures, answering some important questions for the clinician, such as why, how, when and in whom they might best be used.     

Incidence of hepatitis B virus infection in patients with blood disease

AIM: To define incidence of HBV infection in patients with blood diseases caused by blood components transfusion; correlation between infection rate and blood disease nosological entity, intensity of hemoreplacement therapy, time of hepatitis B incubation period in patients with hematological malignancies after the diagnosis and initiation of polychemotherapy (PCT). MATERIAL AND METHODS: In 2000-2007 a prospective clinicoepidemiological trial was made to detect markers of HBV infection among 303 patients 15 to 76 years of age treated in the department of acute leukemia chemotherapy of N.N. Burdenko Military Hospital for acute lymphoid and myeloblastic leukemia, chronic myeloid leukemia in a blastic crisis, myelodysplastic syndrome in blast transformation, lymphoproliferative diseases with bone marrow affection. Statistic processing was performed with standard methods. RESULTS: HBV infection markers were detected in 30 (9.9%) of 303 examinees. Among the infected patients there were 16 (53.4%) patients with different variants of acute myeloblastic leukemia, 12 (40.0%) with different immunophenotypes of acute lymphoblastic leukemia, 1 (3.3%) patient with acute biphenotypical leukemia and 1 (3.3%) with lymphoma/leukemia. HBV infection was registered in patients 2 to 32 months after the beginning of the treatment. Most of the patients - 23 (74%) of 30 - were infected with HBV within the first year after hematological diagnosis and PCT induction course. HBV was diagnosed within treatment year two in 5 (16%) patients and within year three after PCT in 3 (10%). CONCLUSION: High incidence of HBV infection in patients with hematological malignancies points to a high epidemiological risk of hemoreplacement therapy, unsatisfactory quality of donor blood testing and necessity of updating methods of donor infection detection. To lower the risk of HBV infection in patients with hematological malignancies it is necessary to perform vaccine prophylaxis of hepatitis B before PCT.     

调节性T细胞在乙型肝炎慢性化中的免疫调控作用

目的 探讨乙型肝炎慢性化的免疫调控机制.方法 用酶联免疫吸附实验测定慢性乙型肝炎患者(CHB)的辅助性T淋巴细胞(Th1/Th2)细胞因子IFN-γ、IL-2、IL-4和IL-10的血清浓度;同时用流式细胞术检测CHB的调节性.T细胞(Treg)在外周血中的分布频率.结果 与健康对照组相比,CHB组血清IL-2明显减低...