pyrimidinones and Hepatitis-B--Chronic

The optimal oral anti-viral agent to use in patients with decompensated HBV cirrhosis remains unclear.. We performed a meta-analysis of the oral nucleos(t)ide analogues in patients with decompensated HBV cirrhosis.. One year efficacy and safety outcomes in 22 studies published in English between '95 and 2010 were analysed.. Substantial heterogeneity was noted in the inclusion/exclusion criteria, controls, and sensitivity of the HBV DNA assay used. Pooled 1-year data showed benefit favouring lamivudine (LAM) vs. untreated controls for Child-Turcotte-Pugh (CTP) score improvement by ≥2 (OR: 117 (15 921), P ≤ 0.0001) and transplant-free survival (OR: 3.2 (1.2, 9), P = 0.022). Adefovir (ADV) led to undetectable HBV DNA at 1-year in 41% compared to 83% with LAM and 80% with entecavir (ETV). Overall, 1-year transplant-free survival rates varied from 78% with LAM to 95% and 94% with Tenofovir (TDF) and Telbivudine (TBV), respectively. The 1-year incidence of drug resistant HBV was 0% with ADV, ETV and TDF and 11% with LAM although TBV was associated with a 29% incidence at 2 years. Drug-related adverse events were infrequently reported.. All the oral anti-viral agents were associated with improved virological, biochemical and clinical parameters at 1-year. However, the efficacy of lamivudine and telbivudine is limited by drug resistance, and adefovir is limited by its potency and slower onset of action. Additional studies of tenofovir and entecavir are needed to determine the optimal agent(s) for treatment naïve patients and in those with drug-resistant decompensated HBV cirrhosis.

Topics: Adenine; Administration, Oral; Adult; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Time Factors; Treatment Outcome; Viral Load

There are five approved drugs for the treatment of chronic hepatitis B(lamivudine, adefovir dipivoxil [ADV], entecavir [ETV], as well as pegylated and standard interferon) in Japan. In this paper, the reported data of new four drugs(tenofovir disoproxil fumarate [TDF], telbivudine, emtricitabine [FTC], clevudine) were described. TDF demonstrated potent antiviral efficacy in naive patients. Moreover, TDF is efficacious in lamivudine- or ADV-refractory patients. TDF monotherapy and the combination of FTC and TDF had similar efficacy in patients with incomplete viral suppression after therapy with ADV; response was not influenced by the presence of baseline lamivudine- or ADV-associated mutations.

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Deoxycytidine; Emtricitabine; Hepatitis B, Chronic; Humans; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

HBeAg seropositivity is a marker for active viral replication. In the natural history of chronic hepatitis B infection, HBeAg marks the first two of the four phases, namely the immune tolerant phase and the immune clearance phase, and is associated with highly replicative activity of the hepatitis B virus (HBV). Most HBV consensus reports and guidelines recommend antiviral therapy if the immune clearance phase is prolonged and if there is evidence of significant necroinflammation and fibrosis. Two main types of antiviral agents have been approved for treating patients in the immune clearance phase: interferon and nucleos(t)ide analogues (NUCs). The endpoints of therapy are viral suppression with HBeAg seroconversion, undetectable serum HBV DNA, normalization of serum alanine transaminase and improvement in the histological necroinflammatory and fibrosis scores. The ultimate goal of therapy is to obtain clinical benefit for the patient by reducing complications including hepatocellular carcinoma (HCC). The choice between interferon-based immune modulators or NUCs that target the HBV DNA polymerase must be carefully weighed on an individual basis. Therapy with NUCs is often preferred by doctors and patients because it is easy to administer, with predictable efficacy and minimal side-effects. In specific patient subgroups such as those with decompensated disease, poor predictors of response or lack of response to interferon-based therapy and/or significant comorbidities that cannot tolerate interferon-induced side effects, NUCs therapy is the obvious choice. Entecavir and tenofovir are the treatments of choice because their efficacy and safety profile are better than lamivudine, adefovir and telbivudine. More importantly, there is a minimal risk of drug resistance during long-term therapy with these agents.

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide. According to World Health Organization estimates, more than 300 million people are chronically infected and exposed to the risk of developing severe complications including cirrhosis and hepatocellular carcinoma (HCC). Major progress in the treatment of chronic hepatitis B (CHB) has been made during the last decade with the development of antivirals that inhibit viral polymerase activity. Antiviral drug resistance is an important factor in determining the success of long-term therapy for CHB. The development of resistance to nucleoside analogues (NUCs) has been associated with exacerbations of liver disease. Sequential therapy increases the risk of the emergence of multidrug resistance. The selection of a potent antiviral with a high barrier to resistance as a first-line therapy provides the best chance of achieving long-term treatment goals and should be used whenever possible. This has led to a significant decrease in drug resistance in countries where this strategy is affordable. However, the barrier to resistance of a given antiviral agent is influenced by the genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, the drug mechanisms of action and cross resistance. Furthermore, because of specific viral kinetics, prolonged treatment with NUCs does not result in the clearance of the viral genome from the infected liver. It is therefore important to continue research to identify new viral and immune targets and develop novel antiviral strategies for controlling viral replication as well as preventing drug resistance and its complications in the long term.

Topics: Adenine; Antiviral Agents; Capsid; Clinical Protocols; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Virus Internalization; Virus Replication

Treatment of chronic hepatitis B is still challenging. Lots of parameters are needed to be considered before and during the therapy. There are several possible endpoints and their durability is very much variable. Patients with HBeAg-positive and HBeAg-negative hepatitis B need treatment. Two different strategies are available. Interferon-based therapy is a limited treatment, which might result in a sustained immune response in about one third of the patients, leading to an induced remission, sometimes years after the end of the treatment. According to the other strategy a continuous, indefinite oral nucleoside/nucleotide analogue (NA) treatment is administered to maintain a remission. However, relapse is rather frequent after the cessation of this therapy. During the long-term NA treatment drug resistance can lead to the loss of antiviral effect. Three first-line drugs are recommended, pegylated interferon alfa-2a, entecavir and tenofovir. If there is no contraindication to interferon, it is worth trying to achieve immune control and an induced remission. In patients, who do not respond to interferon, a sequential NA therapy is indicated.

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Nucleotides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

It is estimated there are 350-400 million people worldwide chronically infected with HBV. Many of these are women and of reproductive age. As such, they may face therapeutic decisions regarding antiviral therapy and the implication this may have on future or current pregnancies. This article reviews the data of all antivirals licensed for use against hepatitis B infection regarding teratogenicity, carcinogenicity, clinical experience during pregnancy, placental transfer and excretion in breast milk.

Topics: Adenine; Antiviral Agents; Breast Feeding; Female; Guanine; Hepatitis B; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.

Topics: Acyclovir; Adenine; Amantadine; Antiviral Agents; Comorbidity; Drug Therapy, Combination; Foscarnet; Ganciclovir; Guanine; Hepatitis; Hepatitis B, Chronic; Hepatitis C; Herpesviridae Infections; HIV Infections; Humans; Influenza, Human; Interferons; Lamivudine; Nucleosides; Oligopeptides; Organophosphonates; Oseltamivir; Proline; Protease Inhibitors; Pyrimidinones; Ribavirin; Telbivudine; Thymidine; Valacyclovir; Valganciclovir; Valine; Virus Replication; Zanamivir

Long-term therapy with oral nucleoside/nucleotide analogues (NAs) is a favoured approach to the treatment of patients with chronic hepatitis B (CHB); however, all oral agents currently approved for the treatment of such patients are associated with some risk for drug resistance. This can lead to a rebound in HBV levels and, eventually, progressive liver disease. Combination therapy is one strategy that has the potential for enhanced antiviral effects and diminished or delayed resistance. The disadvantages of combination therapy include increased cost, the potential for drug interactions and increased toxicity. Additional therapeutic efficacy from combination therapy has not been demonstrated in clinical trials of HBV, and this approach might be less relevant now that potent NAs with excellent drug resistance profiles are available. However, it might be possible to identify subsets of patients (for example, those with extremely high viraemia or low baseline alanine aminotransferase levels) who derive added benefit from combination therapy. This review examines efficacy and resistance data for new low resistance oral NAs and clinical experience to date with de novo combination therapy in patients with CHB. The application of combination therapy in select populations of patients with CHB is also discussed.

Topics: Adenine; Administration, Oral; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Chronic infection with hepatitis B virus (HBV) is a major global health problem and an important cause of morbidity and mortality from sequelae of liver cirrhosis and hepatocellular carcinoma. In the past decades, better understanding of the natural history and immunopathogenesis of chronic HBV infection and of the development of many powerful antiviral agents has allowed us to improve therapeutic efficacy. Among these agents, nucleos(t)ide analogs are important and potent viral suppressors. However, when administered alone, they are not able to permanently eradicate HBV, and long-term maintenance therapy is required for therapeutic efficacy. Additionally, prolonged treatment is frequently associated with the emergence of drug-resistant HBV mutants. Before an 'ideal' drug(s), or drug combination, with optimal antiviral efficacy and negligible rates of drug resistance becomes available, the on-treatment monitoring approach using serum HBV DNA level as a predictor for therapeutic efficacy and drug resistance is useful. However, most countries in the Asia-Pacific region have low income economies, insufficient medical care systems, and low awareness of the disease among the general population and government officers. The easy approach of the road-map concept using an affordable drug to treat chronic HBV infection is more important in this region. There is already evidence that the long-term outcomes of chronic HBV infection can be improved under well-managed antiviral therapy. Profound and long-lasting suppression of HBV replication, either maintained on-therapy or sustained after stopping therapy, has been identified as the key determinant for achieving the goals of therapy, for reducing liver damage, and for preventing development of cirrhosis and/ or hepatocellular carcinoma.

Topics: Adenine; Antiviral Agents; Asia; Biomarkers; DNA, Viral; Drug Monitoring; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Time Factors; Treatment Outcome; Viral Load; Virus Replication

Successful treatment of chronic hepatitis B (CHB) often requires long-term oral nucleoside/nucleotide agents which can be associated with viral resistance, patient non-compliance and adverse effects. Telbivudine is one of the more potent options available, with a 6.5- to 6.6-log copies/ml hepatitis B DNA reduction at 12 weeks in an early viral kinetic study, a potency comparable to entecavir. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B.. The efficacy and safety profile of telbivudine in compensated and decompensated CHB patients compared to other agents are discussed. Viral resistance, characteristic adverse effects including elevation in creatine kinase and peripheral neuropathy in telbivudine treatment are reviewed. Infrequent but significant adverse effects of other nucleoside/nucleotide analogs are highlighted.. Readers are provided the latest update on the clinical profile of long-term use of telbivudine.. Long-term telbivudine treatment offers effective viral suppression to CHB patients with certain baseline characteristics and on-treatment virologic response. Creatine kinase elevation is not a good predictor of muscle-related adverse effects with nucleoside/nucleotide analogs. But significant myopathy and neuropathy have been reported in a small number of patients receiving telbivudine.

Topics: Adult; Antiviral Agents; Biomarkers; Creatine Kinase; Double-Blind Method; Drug Resistance, Viral; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Isoenzymes; Male; Multicenter Studies as Topic; Muscular Diseases; Nucleosides; Peripheral Nervous System Diseases; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine

Hepatitis B virus (HBV) is a significant hepatocarcinogen. HBV replication is a major cause for the development of hepatocellular carcinoma (HCC). Past studies have documented that lamivudine (LAM) therapy deterred progression to cirrhosis and HCC. This risk reduction is attributed to effective viral suppression. There is a need for as many effective anti-HBV drugs as possible.. Telbivudine, the fourth FDA-approved oral antiviral drug, is highly potent for viral suppression for HBV. It is more potent than LAM and adefovir; its therapeutic response is superior to that of LAM in both HBeAg-positive and -negative patients, and it produces higher HBeAg seroconversion in patients with baseline ALT > or = 2 times normal. Telbivudine has a resistance rate lower than that of LAM and higher than that of entecavir or tenofovir.. There is a specific group of patients who are likely to achieve good therapeutic response with telbivudine.. Patients with low baseline HBV DNA combined with negative HBV DNA at week 24 obtain good therapeutic results with telbivudine. Therefore, selecting patients who meet the above conditions is important.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome

Chronic viral hepatitis B remains a global public health concern. Currently, several drugs, such as lamivudine and telbivudine, are recommended for treatment of patients with chronic hepatitis B. However, there are no conclusive results on the comparison of the efficacy of lamivudine (LAM) and telbivudine (LdT) in the treatment of chronic hepatitis B.. To evaluate the comparison of the efficacy of LAM and LdT in the treatment of chronic hepatitis B by a systematic review and meta-analysis of clinical trials, we searched PUBMED (from 1990 to April 2010), Web of Science (from 1990 to April 2010), EMBASE (from 1990 to April 2010), CNKI (National Knowledge Infrastructure) (from 1990 to April 2010), VIP database (from 1990 to April 2010), WANFANG database (from 1990 to April 2010), the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Review. At the end of one-year treatment, LdT was better than LAM at the biochemical response, virological response, HBeAg loss, therapeutic response, while less than at the viral breakthrough and viral resistance, but there was no significant difference in the HBeAg seroconversion and HBsAg response. LdT was better than LAM at the HBeAg seroconversion with prolonged treatment to two years.. In summary, LdT was superior in inhibiting HBV replication and preventing drug resistance as compared to LAM for CHB patients. But LdT may cause more nonspecific adverse events and can lead to more CK elevation than LAM. It is thus recommended that the LdT could be used as an option for patients but adverse events, for example CK elevation, must be monitored.

Topics: Antiviral Agents; Clinical Trials as Topic; Databases, Factual; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

Telbivudine (Sebivo®; Tyzeka®) is a synthetic nucleoside analogue that inhibits replication of hepatitis B virus (HBV). It is used in the treatment of adults with chronic hepatitis B (CHB) with evidence of viral replication and persistently elevated serum ALT and/or AST levels, and/or histological evidence of active disease. Telbivudine is a potent antiviral that provides effective and sustained viral suppression in patients with compensated CHB. In clinical trials, treatment outcomes were improved significantly more with telbivudine 600 mg once daily than with lamivudine 100 mg or adefovir 10 mg once daily, and telbivudine-treated patients had significantly less viral resistance than lamivudine-treated patients. Increasing rates of hepatitis B e antigen (HBeAg) seroconversion were achieved in HBeAg-positive patients during periods of up to 4 years continuous telbivudine treatment, and seroconversion was durable in most patients throughout a 2-year, off-treatment follow-up, indicating the potential for a finite treatment period in this group of patients. Telbivudine is associated with a medium genetic barrier to resistance and, as patients with undetectable HBV DNA levels have significantly improved outcomes, it is recommended that HBV DNA levels are monitored at week 24 (and 6 monthly thereafter), with the addition of a nucleoside/nucleotide analogue without cross resistance (such as adefovir dipivoxil) if viraemia is present to reduce the risk of resistance (Roadmap concept). Telbivudine was generally well tolerated in clinical trials for periods of up to 4 years, and has a similar tolerability profile to that of lamivudine. A minority of telbivudine-treated patients experience creatinine kinase elevation, usually transient, and myopathy occurs rarely. In modelled cost effectiveness studies in several Asian countries, treatment with telbivudine Roadmap was cost effective in HBeAg-positive patients. Thus, telbivudine provides a valuable treatment option in CHB, particularly when administered using the Roadmap concept in HbeAg-positive patients.

Topics: Antiviral Agents; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Antiviral therapy is aimed to persistently suppress hepatitis B virus (HBV) to prevent liver complications and improve survival and long-term administration of nucleos(t)ide analogues represents an attractive treatment strategy. Five oral analogues are available, and all inhibit viral replication in most patients during the first year of therapy. By converse, long-term monotherapy is associated to high rates of resistance with lamivudine, and intermediate rates with Adefovir and Telbivudine. Third-generation analogues such as Entecavir and Tenofovir may efficiently inhibits viral replication in most patient for many years as they couple potency and high genetic barrier. In patients developing drug-resistance, specific rescue protocols based upon 'early add-on' have been developed to rapidly and efficiently control viral replication. In cirrhotics, long-term effective analog-based therapy prevented clinical decompensation for many years, but not liver cancer development. Long-term administration of NUCs, either as a monotherapy or as a sequential combination, inhibits HBV replication in most HBeAg-negative patients for at least 5 years, preventing clinical decompensation in cirrhotics.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Virus Replication

The treatment of chronic hepatitis B virus (HBV) infection has been revolutionized in the past decade by the increased availability of effective antiviral agents. Telbivudine is an L-nucleoside that is structurally related to lamivudine and has recently been approved for use in patients with chronic HBV infection. Telbivudine is highly selective for HBV DNA and inhibits viral DNA synthesis with no effect on human DNA or other viruses. This article reviews the pharmacology, pharmacokinetics, therapeutic efficacy and safety of telbivudine, and discusses its place in the current armamentarium against HBV.. Relevant publications were identified from searches of Medline and PubMed between 2000 and 2008, using the search terms "hepatitis B/HBV," "telbivudine/LdT," "beta-L-thymidine," "pharmacokinetics," "safety," "adverse events," and "resistance." The reference lists of retrieved articles were searched for relevant studies.. Phase 3 clinical studies demonstrate that telbivudine is superior to lamivudine over a 2-year period in hepatitis B e-antigen (HBeAg)-positive and HBeAg-negative patients. Telbivudine was associated with a statistically significantly greater reduction in HBV DNA, greater proportion of alanine aminotransferase normalization, and greater histological response than lamivudine. Furthermore, telbivudine use resulted in fewer cases of treatment failure and less virological resistance than lamivudine. However, after 2 years of therapy, telbivudine resistance was appreciable (25%) and considerably higher than that seen with other new antivirals such as tenofovir and entecavir. Overall, telbivudine was found to be safe, although grade 3 or 4 adverse events, including elevations in creatine kinase, were more commonly found in patients receiving telbivudine than lamivudine. Telbivudine is not active against lamivudine-resistant HBV.. Telbivudine is a new antiviral agent joining the armamentarium against HBV. It is superior to lamivudine in terms of therapeutic response and resistance profile. However, concerns about resistance with long-term use, along with inferior cost-effective analyses, have relegated telbivudine to a second-line agent in the management of chronic HBV infection.

Topics: Alanine Transaminase; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; DNA, Viral; Drug Evaluation, Preclinical; Drug Interactions; Drug Resistance, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Safety; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

Chronic hepatitis B is a serious health problem worldwide with a substantial minority of patients experiencing premature death due to end-stage liver disease and/or hepatocellular carcinoma. Antiviral therapy may help prevent complications of chronic hepatitis B, and seven agents are currently approved in many countries. Of these agents, five are nucleos(t)ide analogs that all have a risk of antiviral drug resistance with long-term use. Efforts have been made in the recent years to prevent or to reduce the risk of viral resistance in patients treated with oral nucleos(t)ides as the majority of these patients will require therapy for 3-5 years or longer. One approach is to identify patients who would most likely develop antiviral resistance on long-term therapy using predictors obtainable early in the course of treatment, when intervention with new or additional therapy can be instituted. The most important predictors of treatment outcomes are serum HBV DNA levels at baseline and during the first 6 months of therapy. The purpose of this synopsis is to review the recent literature regarding the importance of serum HBV DNA levels in association with treatment outcomes in chronic hepatitis B, particularly the association of complete viral suppression early in the course of oral therapy with long-term treatment outcomes, particularly the incidence of antiviral drug resistance.

Topics: Adenine; Administration, Oral; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Time Factors; Treatment Outcome

Studies published to date regarding on-treatment outcome prediction during chronic hepatitis B therapy were reviewed. Studies have shown that initial virological responses in terms of week 24 serum hepatitis B virus (HBV) DNA levels are associated with therapeutic outcomes of 1-year pegylated interferon-alpha and entecavir therapy, and weeks 52 or 104 of lamivudine and telbuvudine therapy. HBV DNA levels at week 48 are also associated with long-term adefovir therapy outcomes. Conceptual on-treatment adjustment and strategies have been proposed; however, this approach seems only necessary during therapy with nucleos(t)ide analogues with substantial risk of drug resistance. In addition, studies are needed to decide whether switching to or adding on a second drug, and with which drug, is the most cost-effective strategy.

Topics: Adenine; Antiviral Agents; Cost-Benefit Analysis; DNA, Viral; Drug Resistance, Multiple, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Medication Adherence; Nucleosides; Organophosphonates; Polyethylene Glycols; Prognosis; Pyrimidinones; Recombinant Proteins; Telbivudine; Thymidine; Time Factors; Treatment Outcome

Chronic hepatitis B is a worldwide health problem. Research interests have focused on the development of potent and safe antiviral agents with low resistance rates. Among these, telbivudine is an oral nucleoside analogue with specific activity against hepatitis B virus DNA polymerase. Various prospective, randomized clinical trials have demonstrated the potent efficacy of telbivudine in suppressing viral replication and achieving hepatitis B e antigen seroconversion. Telbivudine was also proved to be superior to lamivudine and adefovir dipivoxil. This article provides an overview of the pharmacokinetics, clinical efficacies, resistance profile and safety of telbivudine. A comparison of telbivudine with other oral antiviral agents is also highlighted.

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleic Acid Synthesis Inhibitors; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Virus Replication

The development of clevudine as a treatment for hepatitis B was terminated recently because of case reports of myopathy. In each case, the onset of symptoms occurred between 8 and 13 months after the initiation of treatment. Electromyography and muscle biopsy confirmed the presence of myonecrosis. One report also found evidence of mitochondrial toxicity. The delayed onset and the finding of mitochondrial damage are reminiscent of fialuridine toxicity. Telbivudine has also been reported to be associated with myopathy and neuropathy, particularly when used in combination with pegylated interferon. These findings serve as a sober reminder of the lack of data on long-term safety of nucleos(t)ide analogs for hepatitis B, the importance of balancing benefits versus risks before initiating treatment, and the need for more stringent post-marketing surveillance for drug toxicities.

Topics: Animals; Antiviral Agents; Arabinofuranosyluracil; Creatine Kinase; Drug Discovery; Early Termination of Clinical Trials; Hepatitis B, Chronic; Humans; Lamivudine; Mitochondrial Myopathies; Muscular Diseases; Nervous System Diseases; Nucleosides; Nucleotides; Pyrimidinones; Republic of Korea; Telbivudine; Thymidine

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of telbivudine for the treatment of chronic hepatitis B (CHB) in adults based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from one randomised controlled trial (RCT) (GLOBE) of reasonable methodological quality comparing telbivudine with lamivudine. One other RCT that appeared to meet the inclusion criteria was excluded from the submission. For the primary outcome of therapeutic response telbivudine was statistically superior to lamivudine at weeks 52 and 104 for hepatitis B e antigen (HBeAg)-positive patients, and at week 104 for HBeAg-negative patients. There were statistically significant differences in favour of telbivudine for some secondary outcomes at 2 years including hepatitis B virus (HBV) DNA reduction, HBV DNA non-detectability and alanine aminotransferase normalisation though not for HBeAg-positive patients. In HBeAg-positive patients there was no significant difference between treatment groups for HBeAg loss or seroconversion at any time point. The incidence of adverse events was similar between treatments. Two RCTs comparing entecavir with lamivudine were included in the indirect comparison; however, this was poorly conducted and the results should be treated with caution. The manufacturer developed two economic models to determine the cost-effectiveness of telbivudine. Evidence on the efficacy of telbivudine and lamivudine was taken from the GLOBE trial; efficacy of adefovir was based on assumption. There was a lack of critical assessment and assurance of the quality of the data used to populate the models. The manufacturer concluded that telbivudine is a cost-effective option compared with lamivudine using evidence from the viral load model [HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 19,087 pounds/49,003 pounds, mean quality-adjusted life-year (QALY) gain 1.30/4.67, incremental cost-effectiveness ratio (ICER) 14,665 pounds/10,497 pounds per QALY]. Resubmitted results after a request for clarification by the ERG gave less favourable ICERs (HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 23,983 pounds/41,910 pounds, mean QALY gain 1.56/2.07, ICER 15,377 pounds/20,256 pounds per QALY). The manufacturer conclude

Topics: Adult; Antiviral Agents; Cost-Benefit Analysis; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Chronic hepatitis B is a serious disease both worldwide and in the United States. There are two types of drugs available to treat chronic hepatitis B virus (HBV) infection: interferons that boost the immune system, and antiviral or nucleoside analogues that are designed to interfere with HBV DNA to prevent its replication. This review focuses on nucleoside antivirals, namely lamivudine, entecavir and telbivudine, which are widely prescribed for patients with the disease, particularly lamivudine. Additionally, current Food and Drug Administration-approved nucleoside antivirals for hepatitis B will be briefly highlighted. Comparisons are performed based on previous clinical trials from primary sources. Treatments with entecavir and telbivudine are compared with lamivudine treatment in regard to pharmacotherapy, resistance and cost-effectiveness. Outcomes varied depending on each trial, but the main findings were more favorable for entecavir and telbivudine treatments than for lamivudine treatment. It was concluded that entecavir treatment is associated with better outcomes than lamivudine in the three aspects studied. Similarly, telbivudine showed more improvements than lamivudine in all three areas. Concomitant pharmacotherapy, especially in lamivudine-refractory patients, demonstrated significant improvement in the management of chronic hepatitis B. Furthermore, the availability of hepatitis B vaccines should enable us to prevent the occurrence of the disease.

Topics: Antiviral Agents; Cost-Benefit Analysis; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Substantial progress has been made in the treatment of chronic hepatitis B during the past decade. Nucleos(t)ide analogues are now widely used due to their convenience, less side effects, and considerable response rates. However, development of antiviral resistance is a major problem being considered as the most important factor for the treatment failure. Viral breakthrough associated with selection of antiviral-resistant hepatitis B virus (HBV) is usually followed by biochemical breakthrough, clinical deterioration, and even progressive liver failure. Therefore, appropriate management of antiviral resistance is critical for improving treatment outcomes. Strategies for the management of antiviral-resistant chronic HBV infection are described herein considering recently published guidelines. Lamivudine/telbivudine resistance can be managed by adding adefovir. Switching to adefovir or entecavir is also a viable option. However, careful follow-up of viral load is mandatory to detect any primary or secondary treatment failure in case of sequential monotherapy. Interferon or peg-interferon therapy can also be considered in case of young patients with compensated liver disease. For adefovir resistance, lamivudine can be added, but adding or switching to entecavir is a more reasonable option. Likewise, adding or switching to adefovir can be considered for entecavir resistance. Adding or switching to tenofovir needs to be considered upon availability. Experiences for clevudine resistance are still lacking, and need to be studied further upon the isolation of clinically resistant strains. To avoid emergence of resistant mutations, antiviral therapy should be initiated after careful balance of risk and benefit, and the most potent antiviral agent with the lowest resistance rate should be selected.

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Drug Resistance, Multiple, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Mutation; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

Chronic hepatitis B is a worldwide health problem. Research interests have focused on the development of potent and safe antiviral agents with low resistance rates. Telbivudine is a nucleoside analogue that has been approved for treatment of chronic hepatitis B.. This review article concentrates on the pharmacokinetics and therapeutic efficacy of telbivudine. The resistance and safety profiles are also addressed.. Relevant publications were identified from searches of MEDLINE (1996-June 2007), the Cochrane Library and BIOSIS (1993-June 2007). Search items included, but were not limited to, telbivudine, pharmacokinetics, hepatitis B, resistance and adverse events.. Clinical trials demonstrated telbivudine to be a safe and potent antiviral agent for treatment of chronic hepatitis B. Telbivudine has superior efficacy compared to lamivudine and adefovir.

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Viral; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine

Treatment of chronic hepatitis B with oral nucleos(t)ide analogs is evolving rapidly with newer compounds gaining approval. Recently, the US FDA and European Medicines Agency (EMEA) have approved telbivudine, a potent anti-hepatitis B virus (HBV)-specific agent with a hitherto excellent safety profile. This review focuses on the efficacy of this agent in chronic hepatitis B compared with lamivudine, evaluated clinically in Phase II and a large Phase III study. Monitoring of the virologic response under treatment with sensitive HBV-DNA assays has been applied, aiming at increasing efficacy and reducing HBV resistance. The results are critically presented and the evolving concept of effective long-term telbivudine and other nucleos(t)ide analog therapy, predicted by the extent of suppression of HBV replication at week 24, are analyzed and discussed.

Topics: Drug Resistance, Viral; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-alpha, pegylated interferon-alpha (PEG-IFNalpha), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNalpha has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNalpha is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNalpha and PEG-IFNalpha are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNalpha induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNalpha and PEG-IFNalpha is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNalpha and PEG-IFNalpha are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNalpha could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Genotype; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Multicenter Studies as Topic; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Randomized Controlled Trials as Topic; Recombinant Proteins; Telbivudine; Thymidine; Treatment Outcome

At least 4 nucleos(t)ide analogs have been approved for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, entecavir, and telbivudine. The introduction of these drugs has radically changed the treatment of this disease. The advantages of these drugs are their oral administration, excellent tolerability and efficacy in all types of chronic hepatitis B (compensated and decompensated disease). The limitations are the need for prolonged treatments, which hampers adherence and can cause selection of HBV strains resistant to distinct drugs. The resistance rate differs for each of the drugs. Nucleotide analogs such as adefovir and tenofovir are useful in patients resistant to nucleoside analogs such as lamivudine, entecavir and telbivudine and vice versa. In cases of resistance to one of these drugs, combined treatment is advised.

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Genotype; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Multicenter Studies as Topic; Nucleosides; Organophosphonates; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Treatment Outcome; Virus Replication

Chronic hepatitis B is still a major public health problem, aggravated by the growing phenomenon of immigration from areas with a high prevalence of infection with this virus. In the last few years, marked progress has been achieved in diagnostic methods, knowledge of the natural history of the disease and in therapeutic options, including liver transplantation, which has improved survival in these patients. These advances have been accompanied by an increase in the complexity of decision making. Six treatments have currently been approved for hepatitis B, including two interferon formulations--standard and pegylated--and four neucleos(t)ide analogs, lamivudine, adefovir, entecavir and telbivudine, as well as two further drugs that are used in patients coinfected with HIV, tenofovir and emtricitabine. However, none of the current treatments is able to eradicate the virus and consequently prolonged treatments are often required with the consequent risk of generating resistance. For this reason, as well as the heterogeneity of the natural history of the disease, there is a lack of consensus on the indications for treatment and the parameters in which treatment should be based, the most suitable drug or drug combination, and the criteria to be used to continue, modify or suspend treatment. Therefore, despite the enormous progress made, numerous questions remain that make the clinical management of these patients a major challenge.

Topics: Adenine; Antiviral Agents; Biopsy; Combined Modality Therapy; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Female; Genotype; Guanine; Hepatitis B Antibodies; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Liver; Liver Transplantation; Male; Nucleosides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Virus Replication

Studies in the past decades have shown that active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression, and thus sustained viral suppression is of paramount importance in the management of chronic HBV infection. The nucleos(t)ide analogues lamivudine, adefovir, entecavir, telbivudine and tenofovir are potent inhibitors of HBV polymerase/reverse transcriptase activity and are highly effective in the suppression of HBV replication, but rarely eliminate the virus. Long-term therapy is usually required to achieve sustained hepatitis B e antigen seroconversion, HBV DNA suppression, ALT normalization and fibrosis reversal. Maintained long-term therapy has been demonstrated to significantly lower the rate of hepatic decompensation and development of cirrhosis or hepatocellular carcinoma. However, drug resistance is a serious risk on prolonged nucleos(t)ide analogue therapy, and this poses a critical challenge. Prevention and proper management of drug resistance are crucial to ensure long-term success.

Topics: Adenine; Adenine Nucleotides; Alanine Transaminase; Carcinoma, Hepatocellular; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Organophosphonates; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

The practising clinician is currently faced with a number of effective treatment options for chronic hepatitis B, including two formulations of interferon (standard IFN and pegylated IFN) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir). Treatment strategies can be divided into those aiming for sustained response after discontinuation of therapy and those that need to be maintained by prolonged antiviral therapy. Sustained response is particularly achieved with interferon-based therapy, while treatment-maintained response can be achieved with long-term nucleos(t)ide analogue therapy in the majority of patients. Of currently available drugs for the treatment of chronic hepatitis B, PEG-IFN seems to result in the highest rate of off-treatment sustained response after a 1-year course of therapy. Sustained transition to the immune-control phase (inactive HBsAg carrier state) can be achieved in 30-35% of HBeAg-positive patients and 20-25% of HBeAg-negative patients. Loss of HBsAg has been observed in 11% of both HBeAg-positive and HBeAg-negative patients after 3-4 years. Since hepatitis B virus (HBV) genotype is an important predictor of response to PEG-IFN, determination of HBV genotype is essential in patients in whom sustained off-treatment response is pursued. Aiming for sustained response is of particular interest because many HBV-infected patients are in need of antiviral therapy at a young age and may otherwise require indefinite antiviral therapy.

Topics: Adenine; Antiviral Agents; DNA, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Practice Guidelines as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

The ultimate goal of treatment for chronic hepatitis B (CHB) is to prevent hepatocellular carcinoma (HCC). During the last decade, great strides have been made in the treatment of hepatitis B virus (HBV) infections. Six highly effective anti-HBV agents are currently available and more agents are on the horizon. Prospective and retrospective studies of large numbers of CHB patients with advanced liver disease, including cirrhosis, have demonstrated that the treatment with lamivudine not only delays the disease progression but also reduces the incidence of HCC. In a large prospective study of 3,653 HBV carriers in Taiwan, 164 persons developed HCC in a 12-year follow-up period; an extensive analysis of their condition led to the conclusion that the most important risk factor for HCC is an increased serum level of HBV DNA >10,000 copies/mL regardless of the HBeAg status, alanine aminotransferase levels or presence of cirrhosis. The incidence of HCC correlated with serum HBV DNA level at entry in a dose-response relationship. These pivotal studies re-emphasize the need for an active anti-HBV therapy for CHB patients with viral replication as the ultimate prevention and/or delay for the development of HCC.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Liver Neoplasms; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Topics: Adenine; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Time Factors; Treatment Outcome

Topics: Adolescent; Adult; Aged; Antiviral Agents; Biomarkers, Pharmacological; Biotransformation; Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Female; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Muscular Diseases; Nucleosides; Phosphorylation; Prodrugs; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine; Virus Replication

The long-term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma.. To review the current treatment of chronic hepatitis B, with a focus on diagnosis and management of resistance and active management of suboptimal responses.. A systematic review of the literature, with a focus on recent guidelines, was undertaken.. Among the six drugs licensed for the treatment of chronic hepatitis B in the US, the preferred agents in 2008 will include entecavir, peginterferon alfa-2a, possibly telbivudine, and tenofovir following licensure. When using an oral agent, a major focus of management is on the selection of a drug with high potency and low rate of resistance, and active on-treatment management to optimize therapy. Preventing the sequelae of antiviral drug resistance and appropriate management when resistance is initially detected are also the major focus of current management. The addition of an antiviral agent that is not cross-resistant is critical to restore suppression of viral replication.. Newer agents and modified treatment strategies, especially using combination therapy, hold promise to optimize the management of patients with chronic hepatitis B by achieving the high potency and the lowest rate of resistance.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; Deoxycytidine; Drug Resistance, Viral; Emtricitabine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Virus Replication

The ultimate goal in managing patients with chronic hepatitis B (CHB) is to improve long-term outcomes by decreasing deaths and liver transplantation procedures due to hepatitis B virus (HBV)-related cirrhosis and hepatocellular carcinoma. Active intervention and vaccination of individuals susceptible to HBV infection are key steps to decrease the risk of this global public health problem. Large studies have demonstrated that long-term outcomes of CHB are tied to serum levels of HBV DNA. New oral treatments, characterized by potent antiviral effects, good tolerability, improved histology, stable seroconversion, and minimal resistance, are available. Long-term data with oral medications have shown decreased rates of liver cancer development, liver disease reversal, and progression to liver failure. Pegylated interferon trials have demonstrated modest rates of hepatitis B e antigen seroconversion and improved histology after treatment. This paper describes ways to improve outcomes of CHB using vaccines, interferon, lamivudine, adefovir, and newer agents.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B Vaccines; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Telbivudine; Thymidine; Treatment Outcome; Viral Load

Chronic hepatitis B virus (HBV) infection affects > 350 million individuals worldwide. Chronic hepatitis B is associated with complications of end-stage liver disease, including cirrhosis and hepatocellular carcinoma. HBV replication is the best predictor of liver disease progression to cancer, and antiviral therapy may diminish or halt this unfavorable outcome. Six drugs have been approved for the treatment of chronic hepatitis B: interferon-alpha(2b), pegylated interferon-alpha(2a), lamivudine, adefovir, entecavir and telbivudine. Most agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy; therefore, new agents and treatment strategies are needed. Telbivudine is the latest approved anti-HBV agent; it is an orally administered nucleoside analog that selectively inhibits HBV replication. It has demonstrated potent activity against HBV in Phase III clinical studies, with good tolerance, lack of mitochondrial toxicity and no dose-limiting side effects.

Topics: Animals; Antiviral Agents; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

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-alpha 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.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

Telbivudine, the unmodified L-enantiomer of the naturally occurring nucleoside D-thymidine, is a potent synthetic nucleoside analogue. It acts as a hepatitis B virus (HBV) polymerase inhibitor and preferentially inhibits HBV second strand (DNA-dependent) compared with first strand (RNA-dependent) DNA synthesis. More telbivudine than lamivudine recipients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and similar proportions of telbivudine or lamivudine recipients with HBeAg-negative disease achieved a therapeutic response at 52 weeks in the large 2-year GLOBE trial. In a phase III trial in Chinese patients, greater reductions in serum HBV DNA occurred with telbivudine than lamivudine at 52 weeks. Reductions in serum HBV DNA at 24 weeks were greater with telbivudine than adefovir in the 1-year switching trial. A lower residual viral load at 52 weeks was seen in patients who received telbivudine or who switched from adefovir to telbivudine at 24 weeks than in patients receiving adefovir. In the 1-year lamivudine switching trial in patients with serum HBV DNA levels >3 log10 copies/mL despite having received prior treatment with lamivudine for a mean of [almost equal or equal to]7 months, those randomised to telbivudine therapy achieved greater reductions in serum HBV DNA levels at 24 weeks than patients randomised to continue lamivudine therapy. Telbivudine was generally well tolerated and most adverse events were of mild or moderate severity. The incidence of severe ALT flares with telbivudine was half that seen with lamivudine at both 52 and 104 weeks in the GLOBE trial.

Topics: Antiviral Agents; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleic Acid Synthesis Inhibitors; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

The hepatitis B virus (HBV) has a complex natural history and causes a wide spectrum of disease. Choices of therapy depend on a number of factors predictive of treatment response, clinical circumstances and stage of disease, and the likelihood and consequences of resistance to treatment. Telbivudine (beta-L-2'deoxythymidine) is a thymidine analogue that belongs to a new class of beta-L-configuration nucleoside analogues with specific activity against hepadnavirus. Phase III studies of telbivudine versus lamivudine in hepatitis B e antigen (HBeAg) and anti-HBe have been completed. In HBeAg-positive patients, HBV DNA was not detectable by polymerase chain reaction (PCR) assay in 56% of the HBeAg-positive patients receiving telbivudine after two years of treatment. In HBeAg-negative patients, at two years, HBV DNA was undetectable by PCR in 82% of HBeAg-negative patients (versus 52% of lamivudine recipients). Patients who were PCR-negative after 24 weeks were less likely to develop resistance. HBeAg seroconversion rates were also greatest in patients whose HBV DNA was undetectable at 24 weeks. These results are promising and could be used to devise a strategy to utilize combination therapy or to adjust therapy if an inadequate early viral response is observed. However, resistance is a potential shortcoming of the use of single agents for the treatment of HBV.

Topics: Antiviral Agents; Clinical Trials as Topic; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Virus Replication

Hepatitis B virus (HBV)viral load is closely related to necroinflammation and the outcome of chronic hepatitis B. The available treatment options to reduce viral load, and hence improve outcome, are either based on IFN or on nucleoside/nucleotide analogue antiviral agents, which inhibit HBVDNA replication. Use of IFN alfa or pegylated IFN alfa-2a for periods longer than 48 weeks is limited by their side-effects. The antiviral agents have much more acceptable side-effect profiles, and lamivudine, the first antiviral to become available, was widely used until it became apparent that it carries a high potential for resistance to emerge, which rapidly negates its benefit. A new antiviral agent, telbivudine, has been approved in the USA and Europe and appears to be very rapid and potent against HBV, with an excellent safety profile.

Topics: Alanine Transaminase; Antiviral Agents; DNA, Viral; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine; Viral Load

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15%-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade merits to the advent of nucleoside/nucleotide analogues and the use of pegylated interferons. Approved drugs for chronic hepatitis B treatment include: standard interferon-alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. Unfortunately, these agents are not effective in all patients and are associated with distinct side effects. Interferons have numerous side effects and nucleoside or nucleotide analogues, which are well tolerated, need to be used for prolonged periods, even indefinitely. However, prolonged treatment with nucleoside or nucleotide analogues is associated with a high rate of resistance. Telbivudine is a novel, orally administered nucleoside analogue for use in the treatment of chronic hepatitis B. In contrast to other nucleoside analogues, Telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine has demonstrated potent activity against hepatitis B with a significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment. Telbivudine has been generally well tolerated, with a low adverse effect profile, and at its effective dose, no dose-limiting toxicity has been observed. Telbivudine is one of the most potent antiviral agents for chronic hepatitis B virus and was approved by the FDA in late 2006.

Topics: Antiviral Agents; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Hepatitis B, Chronic; Humans; India; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

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.. 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.. 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.. 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.. 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.

Topics: Alanine Transaminase; Antiviral Agents; Clinical Trials as Topic; DNA, Viral; Drug Interactions; Drug Resistance, Viral; Hepatitis B, Chronic; Humans; Molecular Structure; Nucleosides; Pyrimidinones; Salvage Therapy; Telbivudine; Thymidine

Topics: Adenine; Drug Resistance, Viral; Drug Therapy, Combination; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine

To review available literature on the pharmacology, pharmacokinetics, dosing and administration, efficacy, and safety of the antiviral nucleoside analog telbivudine.. Information was obtained from searching MEDLINE (1966-December 2005), International Pharmaceutical Abstracts (1970-December 2005), and the Cochrane Database of Systematic Reviews (4th quarter 2005) using the search words telbivudine, L-dT, L-deoxythymidine, L-nucleosides, and nucleosides. Abstracts from the Annual Meeting of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver were also searched, including bibliographies from the identified articles.. Data from double-blind, placebo-controlled clinical trials and unpublished information were extracted.. Telbivudine is a novel, orally administered nucleoside analog under development for use in the treatment of chronic hepatitis B. In contrast to other nucleoside analogs, telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine demonstrated potent activity against hepatitis B with significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment. Telbivudine has been generally well tolerated, with low adverse effect profile, and at its effective dose, no dose-limiting toxicity has been observed.. Telbivudine is a novel oral nucleoside analog effective in the treatment of chronic hepatitis B infection.

Topics: Animals; Antiviral Agents; Clinical Trials as Topic; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Although preventable by vaccination, hepatitis B infection is common, affecting more than 350 million individuals worldwide. Chronic hepatitis B infection is associated with the complications of chronic liver disease including cirrhosis and hepatocellular carcinoma. Current agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy and a demand for new agents and strategies continues. This review focuses on telbivudine, a novel agent in the fight against hepatitis B.

Topics: Antiviral Agents; Clinical Trials, Phase II as Topic; DNA, Viral; Drug Resistance, Viral; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Viral Core Proteins

Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Telbivudine, beta-L-2'-deoxythymidine (LdT), is a new beta-L-nucleoside analogue with potent inhibitory activity against the hepatitis B virus. In in vitro studies and animal models, telbivudine has demonstrated potent and specific antiviral activity against hepatitis B. Additionally, in preclinical animal toxicology studies, telbivudine showed no adverse side effects or adverse effects on mitochondrial function. The promising results of the early in vitro and animal telbivudine studies prompted the development and initiation of Phase I and II human clinical trials. The Phase I clinical study demonstrated that end-of-treatment virological response rates were better for telbivudine recipients at multiple dosing levels as compared with placebo patients. The subsequent Phase IIb human clinical study demonstrated superior antiviral efficacy of telbivudine, significantly better ALT normalisation and better hepatitis B e-antigen loss as compared with lamivudine. Telbivudine was well tolerated with no identified safety issues. Virological breakthrough with telbivudine was significantly lower than with lamivudine.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine

Telbivudine, the prototype member of beta-L-2 -deoxynucleosides, has proven to be safe in in vitro animal and human studies. Telbivudine given for 4 weeks resulted in an 8-log reduction of woodchuck hepatitis virus DNA, and a 3.8-log reduction of hepatitis B virus DNA in human. After 52 weeks of telbivudine treatment there was an approximate 6-log reduction of hepatitis B virus DNA levels, hepatitis B virus DNA became undetectable by PCR assay in 61% of patients. Its antiviral efficacy is significantly better than lamivudine. The probability of tyrosine-methionine-aspartate-aspartate mutations at 52 weeks of telbivudine therapy is low, although still occurring in 4.5% of patients. After 96 weeks of therapy, the proportion of patients with undetectable hepatitis B virus DNA by PCR assay increased to 71%, but genotypic resistance also increased to 18.2%, with only 4.5% showing alanine aminotransferase flares. Telbivudine is probably one of the most potent antiviral agents for hepatitis B virus that will become available in the near future.

Topics: Antiviral Agents; DNA, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Molecular Structure; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Currently approved treatments for chronic hepatitis B are limited by low rates of sustained response, side effects, or drug resistance. Thus, new treatments that have more potent antiviral effects, less toxicity, and minimal or no risk of resistance are needed. This article will focus on new antiviral agents that are being evaluated in clinical trials.

Topics: Adenine; Animals; Antiviral Agents; Arabinofuranosyluracil; Deoxycytidine; Drug Resistance, Viral; Emtricitabine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Organophosphorus Compounds; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Treatment Outcome

Interleukin-21 (IL-21) stimulates T cell and B cell responses and plays a role in control of chronic viral infections. The role of IL-21 in chronic hepatitis B virus (HBV) infection is not understood.. Serum IL-21 levels were measured by enzyme immunoassay in 75 HBeAg-positive chronic hepatitis B (CHB) patients undergoing telbivudine treatment. The findings were validated in 103 patients from a separate clinical trial of telbivudine. A complete response to telbivudine was defined as having both HBeAg seroconversion and serum HBV-DNA level <300 copies/ml by treatment week 52. The proportions of T-cells producing IL-21 and/or expressing programmed death 1 (PD-1) in peripheral blood mononuclear cells were assessed longitudinally during treatment by intracellular cytokine staining and flow cytometry.. Median serum IL-21 levels at treatment week 12 were significantly higher in patients who did achieve vs. patients who did not achieve a complete response in both the initial (128.4 vs. 69.2 pg/ml, p=0.003) and the validation (142.2 vs. 89.9 pg/ml, p=0.004) trials. Serum levels of IL-21 (p=0.005) or HBV-DNA (p=0.003) levels at treatment week 12 independently predicted HBeAg seroconversion in the first year of treatment. The decrease in PD-1 expression on CD4(+) and CD8(+) T cells during the first 12 weeks on telbivudine treatment was not correlated with changes in IL-21 concentrations.. Serum IL-21 levels may be a biomarker for HBeAg seroconversion, and may contribute to individualization of antiviral therapy in HBeAg-positive CHB. IL-21 may also have a role in immunotherapy for CHB.

Topics: Adult; Alanine Transaminase; Antiviral Agents; Biomarkers; Disease Progression; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interleukins; Male; Nucleosides; Pyrimidinones; Reproducibility of Results; Sensitivity and Specificity; Severity of Illness Index; Telbivudine; Thymidine; Treatment Outcome

Chronic hepatitis B is characterized by an impaired immune response to hepatitis B virus (HBV). Telbivudine treatment has significantly improved the clinical outcome of chronic HBV infection. However, the underlying mechanism behind the antiviral response of patients treated with nucleoside analogs remains unclear. To gather more evidence about the mechanism responsible for the weak immune response, in this study we analyzed the effects on HBV viral load of treatment with the nucleoside analogue telbivudine and the percentage of Tregs, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, and related cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum of 28 patients with chronic hepatitis B were collected at baseline, and 3 mo and 6 mo after therapy was begun. In parallel with the decline in viral load and serum ALT normalization, we found a decline in circulating CD4(+)CD25(high) Tregs, PD-L1 on CD4(+) T cells, and IL-9 production. The expression of PD-1 on CD4(+) T cells and the production of IFN-γ did not increase during therapy. Our findings suggest that the antiviral effect of the nucleoside analogs may be attributable not only to their direct effect on virus suppression, but also to their immunoregulatory capabilities.

Topics: Adult; Antiviral Agents; B7-H1 Antigen; CD4-Positive T-Lymphocytes; Cytokines; Down-Regulation; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interleukin-2 Receptor alpha Subunit; Interleukin-9; Lymphocyte Count; Male; Nucleosides; Pyrimidinones; T-Lymphocytes, Regulatory; Telbivudine; Thymidine; Treatment Outcome; Viral Load; Virus Replication

Telbivudine reduces hepatitis B virus (HBV) DNA and normalizes levels of alanine aminotransferase (ALT) in patients with chronic hepatitis B (CHB). We investigated its use in preventing vertical transmission.. We performed an open-label, prospective study of 88 hepatitis B (HB) e antigen (HBeAg)-positive pregnant women with CHB, levels of HBV DNA >6 log(10) copies/mL, and increased levels of ALT. Women were given telbivudine (n = 53) starting in the 2nd or 3rd trimester, or no treatment (controls, n = 35) and followed until postpartum week (PPW) 28. All infants received standard immunoprophylaxis after birth.. At 28 weeks, none of the infants whose mothers received telbivudine had immunoprophylaxis failure, whereas 8.6% of the infants of control mothers did (P = .029). There were no differences between groups in mothers' adverse events or infants' congenital deformities, gestational age, height, and weight, or Apgar scores. At postpartum week 28, significantly more telbivudine-treated mothers had levels of HBV DNA <500 copies/mL, normalized levels of ALT, and hepatitis B e antigen seroconversion compared with controls (58% vs none, P < .001; 92% vs 71%; P = .008; and 15% vs none; P < .001, respectively) but none had loss of hepatitis B surface antigen. Telbivudine-treated mothers had no virologic breakthrough (HBV DNA >1 log(10) increase from <500 copies/mL) or discontinuations from adverse events. After delivery, 13/52 patients discontinued telbivudine due to preference. There were no episodes of severe hepatitis (levels of ALT >10 times the upper limit of normal) in either group during 28 weeks of postpartum observation.. Women with CHB given telbivudine during the second or third trimester of pregnancy have reduced rates of perinatal transmission. Telbivudine produced no adverse events in mothers or infants by 28 weeks.

Topics: Adult; Antiviral Agents; Case-Control Studies; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Incidence; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Pyrimidinones; Telbivudine; Thymidine

To study the influences of warming kidney prescription on antiviral therapeutic efficacy and creatine kinase (CK) level in telbivudine-treated HBeAg-positive chronic hepatitis B patients with kidney yang deficiency syndrome. Ninety-six cases were enrolled and randomly divided into two groups (n=48 each): warming kidney prescription treatment or control. Both groups were treated for 52 weeks with telbivudine monotherapy, but the treatment group received additional treatment with the warming kidney prescription. Traditional Chinese medicine (TCM) syndrome score, biochemical response, virological response, serological response, CK level, and adverse reactions were recorded for each group in order to perform comparative analysis of the warming kidney prescription's effects. A total of 84 patients, including 43 cases in the treatment group, completed the study. The warming kidney prescription led to significantly improved total clinical syndrome efficacy, TCM syndrome score, biochemical response, virological response, and HBeAg serological responses, as evidenced by changes for each parameter observed in the treatment group versus the control group (respectively, 88.37% vs. 63.41%, 4.97+/-1.88 vs. 10.13+/-3.72, 95.35% vs. 75.61%, 81.40% vs. 56.10%, 48.84% vs. 26.83% (all, P less than 0.05)). No patient in either group experienced primary treatment failure. Seven cases, all from the control group, experienced virological breakthrough. Elevated CK was observed in both the treatment and control groups, but significantly more patients in the control group experienced this adverse reaction (respectively, 73.17% vs. 44.19%; P less than 0.01). The warming kidney prescription can increase telbivudine antiviral therapeutic efficacy and decrease the telbivudine-induced increase in creatine kinase in HbeAg-positive chronic hepatitis B patients with kidney yang deficiency syndrome.

Topics: Adult; Antiviral Agents; Creatine Kinase; Female; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Phytotherapy; Pyrimidinones; Telbivudine; Thymidine

There is no standard management of chronic hepatitis B (CHB) patients with suboptimal response to nucleoside/nucleotide analogues (NAs). This study aimed to evaluate two different NA combination therapies in patients with suboptimal response to adefovir (ADV).. In this study, 72 CHB patients with suboptimal response to ADV were assessed, with 37 patients receiving lamivudine plus ADV (group A) and 35 patients receiving telbivudine plus ADV (group B).. Baseline characteristics between two groups were similar. At month 12, rates of biochemical response (BR) and virological response (VR) were similar between groups A and B (17/19 versus 18/20 for BR, [P=0.269] and 30/37 versus 31/35 for VR [P=0.377]), and cumulative rates of serological response were greater in group B than in group A (10/26 versus 2/28 in hepatitis B e antigen [HBeAg] loss [P=0.006] and 7/26 versus 1/28 in HBeAg/hepatitis B e antibody seroconversion [P=0.022]). After 12-month treatment, 8.1% (3/37) of patients in group A and 5.7% (2/35) of patients in group B had VR; among patients in group A, two had rtM204V/I and rtL180M and one had rtN236T, whereas the two patients in group B had rtM204I+rtL180M.. Both combination therapies led to a significant decrease in HBV DNA. HBeAg serological outcomes were higher with telbivudine plus ADV combination therapy.

Topics: Adenine; Adult; Biomarkers; DNA, Viral; Drug Therapy, Combination; Female; Genotype; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Nucleosides; Organophosphonates; Prospective Studies; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Young Adult

Patients with decompensated cirrhosis owing to chronic hepatitis B viral (HBV) infection have a high morbidity/mortality rate, and the treatment remains a challenge. We studied the safety and efficacy of telbivudine and lamivudine in such patients. This noninferiority, double-blind trial randomized 232 treatment-naive patients with decompensated HBV (1:1) in 80 academic hospitals to receive once-daily telbivudine 600 mg or lamivudine 100 mg for 104 weeks. Primary composite endpoint was proportion of patients with HBV DNA <10 000 copies/mL, normal alanine aminotransferase (ALT) and Child-Turcotte-Pugh score improvement/stabilization at week 52. Response rates using a post hoc modified endpoint (HBV DNA <300 copies/mL [57 IU/mL] and ALT normalization) in intent-to-treat analysis (missing = failure) were 56.3%vs 38.0% after 76 weeks (P = 0.018) and 45.6%vs 32.9% after 104 weeks (P = 0.093) for telbivudine vs lamivudine. Telbivudine treatment was an independent predictive factor for HBV DNA <300 copies/mL and ALT normalization (P = 0.037). Response rates with protocol-defined composite endpoint in intent-to-treat analysis (M = F) were 56.2 vs 54.0% (noninferiority not achieved) and 39.1%vs 36.4% (noninferiority achieved) in telbivudine and lamivudine groups at 52 and 104 weeks. Telbivudine treatment was associated with a significant improvement in glomerular filtration rate compared to lamivudine treatment and was also associated with a trend for improvement in survival (87%vs 79%). No cases of lactic acidosis were reported. Telbivudine compared to lamivudine was associated with a higher rate of patients with both viral suppression and ALT normalization, a trend towards a higher rate of survival and significant improvement in glomerular filtration.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Double-Blind Method; Female; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Failure; Male; Middle Aged; Multicenter Studies as Topic; Nucleosides; Prospective Studies; Pyrimidinones; Severity of Illness Index; Telbivudine; Thymidine; Treatment Outcome; Young Adult

Telbivudine showed greater antiviral suppression than lamivudine in phase II and III clinical trials.. The present phase IIIb, randomized, double-blind, multicentre global trial assessed the antiviral efficacy and safety of telbivudine switch in chronic hepatitis B (CHB) patients who exhibited persistent viraemia under lamivudine therapy.. HBeAg-positive and HBeAg-negative adult patients (N=246) with persistent viraemia [hepatitis B virus (HBV) DNA>3 log(10) copies/ml] under lamivudine treatment for 12-52 weeks were randomized (1:1) to continue lamivudine 100 mg/day or switch to telbivudine 600 mg/day for 1 year. Primary endpoint was the reduction in serum HBV DNA levels from baseline at Week 24.. The mean reduction in serum HBV DNA levels from baseline with telbivudine was significantly higher than lamivudine at Week 24 (-1.9 ± 0.18 vs. -0.9 ± 0.27 log(10) copies/ml; P<0.001) and maintained through 1 year. The rate of treatment failure was significantly lower (P<0.001) for patients who switched to telbivudine (5%) compared with those who continued lamivudine (20%) after 52 weeks of treatment. In the telbivudine group, treatment failure occurred in only five patients with >24 weeks of prior lamivudine treatment, all associated with pre-existent lamivudine-resistant mutations. Genotypic resistance rates were higher in patients continuing lamivudine compared with those who switched to telbivudine with <24 weeks of lamivudine exposure. Both treatments were well tolerated with similar safety profiles.. Early (≤ 24 weeks) switch to telbivudine improves virological outcomes in CHB patients with persistent viral replication under lamivudine treatment.

Topics: Adult; Antiviral Agents; Biomarkers; Chi-Square Distribution; DNA, Viral; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; Drug Substitution; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome; Viral Load; Virus Replication

An increased CD8(+) T cell response to hepatitis B virus (HBV) peptides occurs between 12 and 24 weeks after starting antiviral therapy for chronic hepatitis B. It is not known whether these cells have antiviral function. The aim of this study was to determine whether clonal expansions of CD8(+) T cells at these time points predict the virological response to therapy. Peripheral blood CD8(+) T cells were obtained from 20 patients treated with lamivudine or telbivudine for chronic hepatitis B at baseline, 12 weeks, and 24 weeks. The CDR3 spectratype of each T cell receptor (TCR) β chain variable region (Vβ) gene family was analyzed, and the changes in the numbers of Vβ families with clonal expansions were compared in subjects with (n = 12) and without (n = 8) a virological response (52 week HBV DNA < 300 copies/ml). The number of CD8(+) TCR Vβ families with clonal expansions at 12 weeks relative to baseline (median [10th to 90th percentile], +2.5 [0 to +7] versus +1 [0 to +2], P = 0.03) and at 24 weeks relative to 12 weeks (+1 [0 to +2] versus -1 [-3 to +4], P = 0.006) was higher in subjects with a virological response versus subjects without a virological response, as were interleukin-2 (IL-2) but not IL-21 mRNA levels in peripheral blood mononuclear cells. The duration of new expansions at 12 weeks was higher (P < 0.0001) in responders. Increased numbers of CD8(+) T cell expansions after antiviral therapy are associated with a virological response to treatment. These CD8(+) T cells are a potential target for a therapeutic vaccine for chronic hepatitis B.

Topics: Adult; Antiviral Agents; CD8-Positive T-Lymphocytes; Complementarity Determining Regions; Double-Blind Method; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Lymphocyte Activation; Male; Nucleosides; Polymerase Chain Reaction; Pyrimidinones; Receptors, Antigen, T-Cell, alpha-beta; Telbivudine; Thymidine; Treatment Outcome; Young Adult

In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB).. To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial.. Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years.. Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial.. Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; Biomarkers; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Female; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome; Viral Load; Young Adult

To investigate the efficacy of Telbivudine and Entecavir for therapy of HBeAg positive chronic hepatitis B for 52 weeks.. In this random and control study, the efficacy of Telbivudine and Entecavir treatments were compared in 180 patients with HBeAg positive chronic hepatitis B.The patients were randomly assigned to a daily 600 mg Telbivudine treatment group or daily 0.5 mg Entecavir group for 52 weeks.. At week 52, HBV DNA undetectable rate was better in the Entecavir-treated group than in the Telbivudine-treated group, but didn't reach statistical significance. The viral breakthrough rates were significantly lower in the Entecavir-treated group than in the Telbivudine-treated group (x2 = 4.09, P <0.05). The clearance and seroconversion of HBeAg and the mean reductions of HBeAg from baseline at week 52 were significantly greater in the telbivudine-treated group than in the entecavir-treated group (x(2) clearance = 4.63, x(2) seroconversion = 4.80, (t-mean) reductions = 2.02; P < 0.05). The HBeAg seroconversion rates were not associated with both baseline ALT and baseline HBV DNA in both groups (P more than 0.05). In Telbivudine-treated group, the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 1 log at week 12 and the HBeAg baseline were independent factors correlated to HBeAg seroconversion rates at week 52 by Binary Logistic analysis, and also in entecavir-treated group the HBeAg decline is more than 2 log at week 24, HBeAg decline is more than 2 log at week 36 and the HBeAg decline is more than 2 log at week 12 were independent factors correlated to HBeAg seroconversion rates at week 52.. Significant difference of HBeAg seroconversion rates at week 52 existed between Telbivudine-treated group and Entecavir-treated group. Entecavir is significantly superior to Telbivudine with less resistance to nucleosides. HBeAg decline is more than 2 log at week 24 is the best predicting factor for HBeAg seroconversion at week 52.

Topics: Adolescent; Adult; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Young Adult

In the Asia-Pacific region, perinatal transmission of the hepatitis B virus (HBV) is the primary cause of chronic hepatitis B infection. Despite the use of HBIG and HBV vaccination, HBV perinatal transmission (PT) occurs in 10-30% of infants born to highly viremic mothers. We evaluated the efficacy and safety of LTD use during late pregnancy in reducing HBV transmission in highly viremic HBeAg+mothers.. Two hundred and twenty-nine HBeAg+HBV DNA levels>1.0×10(7) copies/ml mothers received telbivudine 600 mg/day from week 20 to 32 of gestation (n=135) or served as untreated controls (n=94). All infants in both arms received 200 IU of HBIg within 12 h postpartum and recombinant HBV vaccine of 20 μg at 0, 1, and 6 months. HBsAg and HBV DNA results of infants at week 28 were used to determine perinatal transmission rate. All telbivudine treated subjects were registered in the Antiretroviral Pregnancy Registry.. Telbivudine treatment was associated with a marked reduction in serum HBV DNA and hepatitis B e antigen (HBeAg) levels and normalization of elevated ALT levels before delivery. A striking decline of HBV DNA levels started from treatment onset to week 4, and sustained in a low level since week 12. Forty-four (33%) of the 135 telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction-undetectable viremia (DNA<500 copies/ml) at delivery. Seven months after delivery, the incidence of perinatal transmission was lower in the infants that completed follow-up born to the telbivudine-treated mothers than to the controls (0% vs. 8%; p=0.002). HBV DNA levels were only detectable in HBsAg+infants. No significant differences in anti-HBs levels were observed during postnatal follow-up. No serious adverse events were noted in the telbivudine-treated mothers or their infants.. Telbivudine used during pregnancy in CHB HBeAg+highly viremic mothers can safely reduce perinatal HBV transmission. Telbivudine was well-tolerated with no safety concerns in the telbivudine-treated mothers or their infants on short term follow up. These data support the use of telbivudine in this special population.

Topics: Adult; Antiviral Agents; DNA, Viral; Female; Hepatitis B Antibodies; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B Vaccines; Hepatitis B, Chronic; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Young Adult

Topics: Adult; Antiviral Agents; Female; Hepatitis B, Chronic; Humans; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Young Adult

We characterized the early viral kinetic profiles of telbivudine and entecavir and the effects of these potent nucleoside analogs on hepatitis B virus (HBV) DNA and alanine aminotransferase levels in adults with hepatitis B e antigen-positive compensated chronic hepatitis B. Forty-four patients were enrolled in this open-label, parallel-group, multicenter study and randomized to receive telbivudine or entecavir for 12 weeks. Reductions in hepatitis B virus DNA and alanine aminotransferase levels from baseline to weeks 2, 4, 8, and 12 were assessed. Viral kinetic parameters, including viral clearance per day, loss of infected cells per day, and efficiency of inhibition of viral production, were estimated by using a biphasic mathematical model. Statistical analyses were limited to descriptive analyses. The 2 treatment groups achieved similar reductions in HBV DNA and alanine aminotransferase levels. Mean reductions in levels of hepatitis B virus DNA at week 12 were 6.6 +/- 1.6 and 6.5 +/- 1.5 log(10) copies/ml for the telbivudine- and entecavir-treated patients, respectively. There were no significant differences between groups in values for mean viral clearance per day, mean loss of infected cells per day, or efficiency of blocking viral production. The safety profiles for both medications were favorable. During the first 12 weeks of treatment, telbivudine and entecavir demonstrated similar antiviral potencies, resulting in a rapid and profound suppression of serum hepatitis B virus DNA and reduction of alanine aminotransferase levels. No differences in the effects of these 2 agents on early viral kinetics were observed. Both medications were well tolerated.

Topics: Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Kinetics; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

Because drug-resistant strains of hepatitis B virus (HBV) have developed, and because serum HBV-DNA levels may rebound in patients who receive treatment with nucleoside/nucleotide analogues for up to 2 years, there remains a largely unmet clinical need for agents to induce potent virologic suppression in the initial stage of the disease course of HBV infection.. The aim of this work was to compare the early antiviral effectiveness of telbivudine and entecavir in the treatment of patients with hepatitis B e antigen (HBeAg)-positive HBV.. In this parallel-group, open-label trial, adult Chinese patients with previously untreated HBeAg-positive HBV (HBV-DNA concentration: >or=6 log(10) copies/mL; alanine aminotransferase [ALT] level: >or=2 times the upper limit of normal) were randomized to receive telbivudine 600 mg or entecavir 0.5 mg daily for 24 weeks. Blood samples were collected at the baseline and at 12 and 24 weeks after the treatment. The primary end point was the mean reduction from baseline in serum HBV-DNA concentration at week 24. Secondary end points included mean reduction from baseline in serum HBV-DNA concentration at week 12, the absence of serum HBV-DNA, absence of serum HBeAg, HBeAg seroconversion at week 24, the normalization of serum ALT at week 24, and occurrence of adverse events through week 24.. A total of 131 patients were enrolled in the study: 91 men and 40 women, with a mean (SD) age of 32.5 (8.9) years. All patients were ethnic Han Chinese. The baseline demographic characteristics and serum HBV-DNA concentrations in the 2 treatment groups were well matched. Sixty-five patients were randomized to receive telbivudine and 66 to receive entecavir. The mean reductions from baseline in serum HBV-DNA were 4.99 and 4.69 log(10) copies/mL at week 12, respectively, and 6.00 and 5.80 log(10) copies/mL at week 24 (both time points, P = NS between groups). At week 12, HBV-DNA was undetectable in 43.1% (28/65) of the telbivudine group and 34.8% (23/66) of the entecavir group (P = NS); at week 24, it was undetectable in 67.7% (44/65) of the telbivudine group and 57.6% (38/66) of the entecavir group (P = NS). At week 12, HBeAg absence and seroconversion rates were significantly greater in the telbivudine group than the entecavir group (absence: 20.0% [13/65] vs 3.0% [2/66], respectively [P = 0.002]; seroconversion: 13.8% [9/65] vs 3.0% [2/66] [P = 0.030]). However, at week 24, HBeAg absence and seroconversion rates were comparable between the telbivudine and entecavir groups (absence: 36.9% [24/65] vs 28.8% [19/66] [P = NS]; seroconversion: 24.6% [16/65] vs 13.6% [9/66] [P = NS]). In addition, the normalization of ALT levels was observed in 78.5% (51/65) and 74.2% (49/66) of patients treated with telbivudine and entecavir, respectively, at week 24 (P = NS). The adverse events were upper respiratory tract infection (12.3% of telbivudine patients vs 9.1% of entecavir patients), fatigue (6.2% vs 7.6%), diarrhea (1.5% vs 3.0%), and coughing (0% vs 1.5%), most of which were mild to moderate. Elevated creatinine phosphokinase was noted in 8 telbivudine-treated patients (12.3%). There were no statistically significant differences in rates of adverse events between groups except for creatinine phosphokinase.. In this study of ethnic Han Chinese adults with previously untreated HBeAg-positive HBV infection, there were no statistically significant differences in effectiveness or tolerability between telbivudine 600 mg and entecavir 0.5 mg at the end of 24 weeks of treatment. ChiCTR.org identifier: ChiCTR-TRC-00000341.

Topics: Adult; Antiviral Agents; China; DNA, Viral; Female; Guanine; Hepatitis B; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

To analyze antiviral effects of telbivudine in patients with chronic hepatitis B.. 72 chronic hepatitis B patients without prior history of antiviral therapy were treated with telbivudine 600mg once daily.. At week 4, 37.5% of the patients achieved undetectable HBV DNA, and 33.3% achieved ALT normalization. At week 108, 87.5% of the patients achieved undetectable HBV DNA, and 91.7% achieved ALT normalization. HBeAg seroconversion occurred in 23.9% of the 46 HBeAg positive patients. The rates of undetectable HBV DNA and HBeAg seroconversion at week 108 in the patients with HBV DNA < 3 log(10) copies/ml at week 12 were significant higher than those in patients with HBV DNA >or= 3 log(10) copies/ml. The rate of undetectable HBV DNA at week 108 in the patients with HBV DNA < 3 log(10) copies/ml at week 24 was significantly higher than that in patients with HBV DNA >or= 3 log(10) copies/ml, and the rate of antiviral resistance rate at week 108 in the patients with HBV DNA < 3 log(10) copies/ml at week 24 was significantly lower than that in patients with HBV DNA >or= 3 log(10) copies/ml. Antiviral therapy could significantly improve Child-Pugh score in patients with liver cirrhosis.. Telbivudine treatment results in suppression of HBV and high HBeAg seroconversion, and improvement of Child-Pugh score in the patients with liver cirrhosis.

Topics: Adult; Antiviral Agents; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

To evaluate the efficacy and safety of telbivudine (LDT) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who have high baseline alanine aminotransferase (ALT) levels between 10 and 20 times the upper limit of normal.. Forty HBeAg-positive CHB patients with high baseline ALT levels between 10 and 20 times the upper limit of normal were enrolled and received LDT monotherapy for 52 wk. Another forty patients with baseline ALT levels between 2 and 10 times the upper limit of normal were included as controls. We compared the virological, biochemical, serological and side effect profiles between the two groups at 52 wk.. By week 52, the mean decrease in hepatitis B virus (HBV) DNA level compared with baseline was 7.03 log(10) copies/mL in the high baseline ALT group and 6.17 log(10) copies/mL in the control group, respectively (P < 0.05). The proportion of patients in whom serum HBV DNA levels were undetectable by polymerase chain reaction assay was 72.5% in the high baseline ALT group and 60% in the control group, respectively (P < 0.05). In addition, 45.0% of patients in the high baseline ALT group and 27.5% of controls became HBeAg-negative, and 37.5% of those in the high baseline group and 22.5% of controls, respectively, had HBeAg seroconversion (P < 0.05) at week 52. Moreover, in the high baseline group, 4 out of 40 patients (10%) became hepatitis B surface antigen (HBsAg)-negative and 3 (7.5%) of them seroconverted (became HBsAg-positive). Only 1 patient in the control group became HBsAg-negative, but had no seroconversion. The ALT normalization rate, viral breakthrough, genotypic resistance to LDT, and elevations in creatine kinase levels were similar in the two groups over the 52 wk.. High baseline ALT level is a strong predictor for optimal results during LDT treatment.

Topics: Alanine Transaminase; Antiviral Agents; DNA, Viral; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Young Adult

To investigate the efficacy of antiviral treatment on patients with acute-on-chronic hepatitis B liver failure with low viral load.. 352 patients with acute-on-chronic hepatitis B liver failure including 175 cases of low HBV viral load and 177 cases of high HBV viral load were enrolled into this study. The patients were divided into the antiviral group which received antiviral therapy (Lamivudine, Entecavir or Telbivudine) plus routine supportive therapy and the control group which received supportive therapy only. The clinical features and the 24-week short-term efficacy of antiviral therapy were assessed.. At week 24,total survival rate in antiviral group was higher than that in control group (P = 0.010). The survival rate of patients with low viral load in the antiviral group was higher than that in the control group (P = 0.001). But there was no significant difference between the antiviral group and the control group with high viral load (P = 0.856). But in the antiviral group, there was no significant difference in survival rate between the patients with high HBV viral load and those with low viral load (P = 0.755).. Antiviral therapy can significantly improve survival rate of patients of acute-on-chronic hepatitis B liver failure with low viral load. Liver failure;

Topics: Adult; Antiviral Agents; End Stage Liver Disease; Female; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Liver Failure, Acute; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Viral Load

The GLOBE trial has compared the efficacy and safety of telbivudine versus lamivudine treatment over 2 years in patients with chronic hepatitis B.. Hepatitis B e antigen (HBeAg)-positive (n = 921) and HBeAg-negative (n = 446) patients received telbivudine or lamivudine once daily for 104 weeks. The primary outcome, assessed in the intent-to-treat population, was therapeutic response (hepatitis B virus DNA <5 log(10) copies/mL and either HBeAg loss or normalization of alanine aminotransferase [ALT] level).. The therapeutic response to telbivudine was superior to that of lamivudine in HBeAg-positive (63% vs 48%; P < .001) and HBeAg-negative (78% vs 66%; P = .007) patients. HBeAg-positive patients given telbivudine also had better outcomes compared with lamivudine in terms of nondetectable viremia (< 300 copies/mL) at 55.6% versus 38.5% (P < .001), HBeAg loss at 35.2% versus 29.2% (P = .056), and viral resistance at 25.1% versus 39.5% (P < .001). Hepatitis B e antigen seroconversion was 29.6% versus 24.7% (P = .095) in all patients and 36% versus 27% (P = .022) in patients with baseline ALT level > or = 2 times normal. Telbivudine-treated HBeAg-negative patients showed higher rates of nondetectable viremia compared with lamivudine at 82.0% versus 56.7% (P < .001) and less resistance at 10.8% versus 25.9% (P < .001). Adverse events occurred with similar frequency, whereas grade 3/4 increases in creatine kinase levels were more common in patients given telbivudine (12.9% vs 4.1%, P < .001). Multivariate logistic regression analyses identified telbivudine treatment, among other variables, as an independent predictor of better week 104 outcomes.. Telbivudine is superior to lamivudine in treating patients with chronic hepatitis B over a 2-year period.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Double-Blind Method; Female; Global Health; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Longitudinal Studies; Male; Middle Aged; Nucleosides; Prospective Studies; Pyrimidinones; Regression Analysis; Telbivudine; Thymidine; Treatment Outcome; Virus Replication; Young Adult

To study the therapeutic efficacy of 48-week telbivudine treatment on cirrhosis resulting from chronic hepatitis B.. 80 patients were equally divided into two groups, and treated with telbivudine 600 mg or lamivudine 100mg once daily for 48 weeks, respectively. The changes of virological and biochemical markers, PTA, Child-Pugh score, and viral resistance were observed at the different time points after antiviral treatment.. The mean of serum HBV DNA level in telbivudine group before treatment was (6.52+/-1.33) log10 copies/ml, and the mean reduction of serum HBV DNA was (2.09+/-1.30), (2.83+/-1.22), (3.23+/-1.27), (3.42+/-1.32), (3.65+/-1.30), (3.67+/-1.43) log10 copies/ml at 2, 4, 8, 12, 24, 48 weeks, respectively. The proportion of patients with serum HBV DNA undetectable was 92.5% (37/40) at 24, 48 weeks. At week 24 and 48, the rates of HBeAg/anti-HBe seroconversion were 30.0% (6/20), 35.0% (7/20), respectively. ALT, AST, albumin, total bilirubin, PTA, and Child-Pugh score were improved (P less than 0.05). Mutation of YMDD observed in telbivudine group was 5.0%. The mean reduction of serum HBV-DNA and the proportion of patients with undetectable serum HBV-DNA were greater in telbivudine group than in lamivudine group (P less than 0.05).. Telbivudine can rapidly and effectively inhibit the replication of HBV in patients with cirrhosis resulting from chronic hepatitis B, and the resistance mutation rate was low. In addition, telbivudine treatment can improve the liver function.

Topics: Adult; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

In the GLOBE trial, telbivudine treatment was identified as a significant, independent predictor of better outcomes at 2 years. We analyzed all telbivudine recipients in this trial to determine the predictors of optimal outcomes.. The intent-to-treat population comprised 458 HBeAg-positive and 222 HBeAg-negative telbivudine-treated patients. Multivariate logistic regression analyses were employed to evaluate baseline and/or early on-treatment variables.. Baseline HBV DNA<9 log(10)copies/mL, or ALT levels > or = 2x above normal were strong pretreatment predictors for HBeAg-positive, but not for HBeAg-negative patients. However, non-detectable serum HBV DNA at treatment week 24 (TW24) was the strongest predictor for better outcomes for both groups. A combination of pretreatment characteristics plus TW24 response identified subgroups with the best outcomes: (1) HBeAg-positive patients with baseline HBV DNA<9 log(10)copies/mL, ALT > or = 2x above normal and non-detectable HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 89%, HBeAg seroconversion in 52%, telbivudine resistance in 1.8%; and (2) HBeAg-negative patients with baseline HBV DNA<7 log(10)copies/mL and non-detectable serum HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 91%, telbivudine resistance in 2.3%.. During telbivudine treatment, non-detectable serum HBV DNA at treatment week 24 is the strongest predictor for optimal outcomes at 2 years.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

To investigate the efficacy of telbivudine on intrauterine hepatitis B virus (HBV) infection during the last stage of pregnancy.. 61 pregnant chronic hepatitis B (CHB) patients were enrolled and 31 patients were treated by telbivudine 600 mg once daily, 30 patients in the control group were not received antiviral treatment. Maternal HBV DNA level and the HBsAg positive rate in newborns were investigated.. The levels of serum HBV DNA in patients treated with Telbivudine were significantly reduced (t = 19.09, P less than 0.01). Compared with the control group, serum HBV DNA levels were significantly lower in telbivudine treated patients than those in the control group before parturition (t = 23.64, P less than 0.01). The infection rate of 7-month newborns were 0 and 13.33% (4/30), in telbivudine group and control group, respectively (x2 = 4.29, probability value less than 0.05).. Telbivudine treatment can block intrauterine infection in pregnant chronic hepatitis B patients.

Topics: Administration, Oral; Antiviral Agents; DNA, Viral; Female; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

To evaluate the efficacy and safety of telbivudine (LDT) versus entecavir treatments in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.. Eighty HBeAg-positive compensated CHB patients with HBV DNA more than 6 log10 copies/ml and serum ALT 2 x ULN were divided into two groups: a telbivudine treatment group, and a entecavir treatment group. HBV DNA, ALT and HBeAg were surveyed at baseline and at 12 and 24 weeks. The efficacy and safety of the two nucleoside analogues were assessed at 12 and 24 weeks.. Undetectable serum HBV DNA levels of the telbivudine group (50% and 80%) were similar to those of the entecavir B group (50% and 70%) according to the polymerase-chain-reaction assay at week 12 and 24. There were no significant differences in the normalization of alanine aminotransferase levels between the two groups at week 12 and 24 (52.5% vs 60.0%, 77.5% vs 75.0%). The mean reductions in serum HBV DNA from the baseline levels at week 12 and 24 were similar between the two groups [5.27 vs.5.36, 6.49 vs.6.18 log (on a base-10 scale) copies per milliliter]. More patients in the telbivudine group had HBeAg seroconversion at week 12 than those in the entecavir group (20.0% vs 5.0%, P = 0.043); however, there was no significant difference between the two groups at week 24 (27.5% vs 17.5%). No adverse reactions were found in either group.. There was no significant difference in HBV DNA undetectable rates and the ALT normalization rates between the two groups in a short-term therapy (24 weeks), but the telbivudine group had a higher rate in HBeAg seroconversion than that in the entecavir group at week 12.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Viral Load; Young Adult

Chronic hepatitis B and its life-threatening sequelae are highly prevalent in China. There is a need for effective new therapies to suppress hepatitis B virus (HBV) replication and ameliorate liver disease. In this study, we compared the efficacy of telbivudine, a nucleoside analogue, with lamivudine in Chinese patients. In this phase III, double-blind, multicenter trial conducted in China, 332 patients with compensated hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B were randomly assigned to treatment with 600 mg of telbivudine or 100 mg of lamivudine daily for 104 weeks. The primary efficacy endpoint was reduction in serum HBV DNA levels at week 52 of treatment. Secondary endpoints included clearance of HBV DNA to undetectable levels, HBeAg loss and seroconversion, therapeutic response, and alanine aminotransferase (ALT) normalization. Viral resistance and safety were assessed. At week 52, among 290 HBeAg-positive patients, mean reductions of serum HBV DNA were significantly greater in telbivudine recipients than lamivudine recipients (6.3 log(10) versus 5.5 log(10), P < 0.001), and HBV DNA was polymerase chain reaction-negative in significantly more telbivudine recipients than lamivudine recipients (67% versus 38%, P < 0.001). ALT normalization (87% versus 75%, P = 0.007), therapeutic response (85% versus 62%, P = 0.001), and HBeAg loss (31% versus 20%, P = 0.047) were also significantly more common in the telbivudine group. Treatment effects showed similar patterns in the smaller HBeAg-negative group (n = 42). Viral resistance in telbivudine recipients was approximately half that observed with lamivudine; however, this difference was not statistically significant. Clinical adverse events were similar in the two treatment groups.. In Chinese patients with chronic hepatitis B, telbivudine treatment for 52 weeks provided greater antiviral and clinical efficacy than lamivudine, with less resistance.

Topics: Adolescent; Adult; Antiviral Agents; China; DNA, Viral; Double-Blind Method; Female; Genotype; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

To investigate the possibilities of an association between the degrees of HBV suppression with nucleoside treatments at week 24 and week 52 in hepatitis B patients and to find a useful predictor for treatment efficacy.. In this phase III, double-blind, multicenter trial, we compared the efficacy of telbivudine treatment with lamivudine treatment in 332 Chinese compensated chronic hepatitis B patients. The patients were randomly assigned to a daily 600 mg telbivudine treatment group or daily 100 mg lamivudine group for 24 weeks. They were then categorized into 4 groups according to their serum HBV DNA levels (copies/ml) at week 24: a PCR-undetectable group (< 300 copies/ml); a QL- < 10(3) copies/ml group; a 10(3)-<10(4) copies/ml group; and a > or = 10(4) copies/ml group. The treatments were continued as they previously had been for another 28 weeks and the patients serum HBV DNA levels were examined again.. At week 52, mean reductions of serum HBV DNA were significantly greater in the telbivudine-treated patients than in the lamivudine-treated group (6.2 log10 vs 5.4 log10, t = 3.6, P < 0.01). Viral resistance was twice as common in lamivudine-treated patients compared to those receiving telbivudine. Telbivudine was well-tolerated with an adverse event profile similar to that of lamivudine. The lower the HBV DNA level achieved at week 24, the higher HBV DNA non-detectable by PCR. ALT normalization and HBeAg seroconversion achieved at week 52, and viral resistance at week 48 decreased parallel to the degree of HBV DNA inhibition.. HBV DNA PCR-undetectable at week 24 in nucleoside-treated hepatitis B patients suggests a better efficacy at week 52 and lower viral resistance at week 48. The degree of suppression of HBV at week 24 may be used as a predictor of 1-year outcome.

Topics: Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Double-Blind Method; Female; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Young Adult

The efficacy of nucleoside and nucleotide analogues for hepatitis B has been linked to the magnitude and durability of hepatitis B virus (HBV) suppression.. To compare the antiviral efficacy of telbivudine and adefovir dipivoxil, and the effects of switching from adefovir to telbivudine, in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B.. Randomized, controlled, open-label trial.. 16 outpatient clinics.. 135 treatment-naive, HBeAg-positive adults with chronic hepatitis B.. Patients were randomly assigned in a 1:1:1 ratio to 52 weeks of telbivudine (group A) or adefovir (group B), or 24 weeks of adefovir and then telbivudine for the remaining 28 weeks (group C). One hundred thirty-one patients completed 52 weeks of treatment.. The primary efficacy comparison was serum HBV DNA reduction at week 24, with a secondary comparison at week 52.. At week 24, mean HBV DNA reduction was greater in group A than in pooled groups B and C (-6.30 vs. -4.97 log10 copies/mL; difference, -1.33 log10 copies/mL [95% CI, -1.99 to -0.66 log(10) copies/mL]; P < 0.001), and more patients in group A were polymerase chain reaction-negative (39% vs. 12%; odds ratio, 4.46 [CI, 1.86 to 10.72]; P = 0.001). At week 52, the mean residual HBV DNA level was lower in group A and group C than in group B (3.01 log10 copies/mL [group A] and 3.02 log10 copies/mL [group C] vs. 4.00 log10 copies/mL [group B]; difference, -0.99 log10 copies/mL [CI, -1.67 to -0.32 log10 copies/mL] and -0.98 log10 copies/mL [CI, -1.64 to -0.32 log10 copies/mL]; P = 0.004). Adverse events were similar across groups; the most common were upper respiratory symptoms, headache, back pain, and diarrhea.. The trial was open-label and was not of sufficient size or duration to compare clinical outcomes and long-term efficacy.. Telbivudine demonstrated greater and more consistent HBV DNA suppression than adefovir after 24 weeks of treatment. After 52 weeks, HBV DNA suppression was greater in patients who had received continuous telbivudine or were switched to telbivudine after 24 weeks than in those who received continuous adefovir.

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; Biomarkers; DNA, Viral; Drug Therapy, Combination; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine; Viral Load

Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B.. In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses.. At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine.. Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov].).

Topics: Adolescent; Adult; Aged; Antiviral Agents; DNA, Viral; Double-Blind Method; Drug Resistance, Viral; Female; Genotype; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Telbivudine is an L-nucleoside analogue with potent antiviral activity against hepatitis B virus (HBV). Clinical trials have shown that telbivudine is more potent than lamivudine for suppressing virus.. A total 101 Korean patients among 1,367 patients who participated in the phase III GLOBE trial were randomized in this study. All 101 HBeAg positive or HBeAg negative patients were assigned to treatment with 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy endpoint (the "therapeutic response") was defined as suppression of the serum HBV DNA to less than 5 log10 copies/mL coupled with either normalization of the serum alanine aminotransferase level or loss of HBeAg. The secondary endpoints included the histologic response, serum HBV DNA reduction, serum alanine aminotransferase normalization and HBeAg loss for the HBeAg positive patients. This analysis includes the data collected at 52 weeks of treatment.. Fifty four of 101 patients were assigned to telbivudine treatment and 47 patients were assigned to lamivudine treatment. At week 52, significantly more patients who were treated with telbivudine than those treated with lamivudine had a therapeutic response (83% vs 62%, respectively, P=0.017), their mean serum HBV DNA levels were more reduced (6.6 vs 5.6 log10 copies/mL, respectively, P=0.027), and they more often achieved PCR-undetectable levels of serum HBV DNA (74% vs 34%, P<0.0001). No virologic resistance to telbivudine was detected (0% vs 18%, respectively, P=0.001). Telbivudine was well tolerated and it had a safety profile comparable to lamivudine.. Patients treated with telbivudine achieved earlier and more profound viral suppression than those treated with lamivudine.

Topics: Adolescent; Adult; Alanine Transaminase; Antiviral Agents; Drug Resistance, Viral; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Korea; Lamivudine; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.

Topics: Administration, Oral; Adult; Antiviral Agents; Area Under Curve; Asian People; China; Cohort Studies; DNA, Viral; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Half-Life; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome

A previous 4-week trial of telbivudine in patients with chronic hepatitis B indicated marked antiviral effects with good tolerability, leading to the present 1-year phase 2b trial.. This randomized, double-blind, multicenter trial evaluated the efficacy and safety of telbivudine 400 or 600 mg/day and telbivudine 400 or 600 mg/day plus lamivudine 100 mg/day (Comb400 and Comb600) compared with lamivudine 100 mg/day in hepatitis B e antigen (HBeAg)-positive adults with compensated chronic hepatitis B.. A total of 104 patients were randomized 1:1:1:1:1 among the 5 groups. Median reductions in serum hepatitis B virus (HBV) DNA levels at week 52 (log(10) copies/mL) were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, 6.05. At week 52, telbivudine monotherapy showed a significantly greater mean reduction in HBV DNA levels (6.01 vs 4.57 log(10) copies/mL; P < .05), clearance of polymerase chain reaction-detectable HBV DNA (61% vs 32%; P < .05), and normalization of alanine aminotransferase levels (86% vs 63%; P < .05) compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion (31% vs 22%) and less viral breakthrough (4.5% vs 15.8%) (P = NS for both). Combination treatment was not better than telbivudine alone. All treatments were well tolerated. In exploratory scientific analyses, clinical efficacy at 1 year appeared related to reduction in HBV DNA levels in the first 6 months of treatment.. Patients with chronic hepatitis B treated with telbivudine exhibited significantly greater virologic and biochemical responses compared with lamivudine. Results with the combination regimens were similar to those obtained with telbivudine alone. These data support the ongoing phase 3 evaluation of telbivudine for treatment of patients with chronic hepatitis B.

Topics: Adolescent; Adult; Age Factors; Aged; DNA, Viral; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Liver Function Tests; Long-Term Care; Male; Maximum Tolerated Dose; Middle Aged; Nucleosides; Pyrimidinones; Reference Values; Risk Assessment; Severity of Illness Index; Sex Factors; Telbivudine; Thymidine; Treatment Outcome

Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against hepatitis B virus (HBV) in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity, and pharmacokinetics were assessed in 43 adults with hepatitis B e antigen-positive chronic hepatitis B. This placebo-controlled dose-escalation trial investigated 6 telbivudine daily dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks' follow-up. Serum HBV DNA levels were monitored via quantitative polymerase chain reaction. The results indicate that telbivudine was well tolerated at all dosing levels, with no dose-related or treatment-related clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were dose-proportional within the studied dose range. Marked dose-related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800 mg/d cohort, the mean HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a 99.98% reduction in serum viral load. Correspondingly, posttreatment return of viral load was slowest in the high-dose groups. Viral dynamic analyses suggested a high degree of efficiency of inhibition of HBV replication by telbivudine and helped refine selection of the optimal dose. In conclusion, these results support expanded clinical studies of this new agent for the treatment of hepatitis B.

Topics: Adult; Aged; DNA, Viral; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

iNKT cells are relatively abundant in the liver, which suggests that they may play important roles in the clearance of invading foreign pathogens such as hepatitis B virus. In this study, we investigated the frequencies, functions and PD-1 expression of peripheral iNKT cells from HBeAg-positive chronic hepatitis B (CHB) patients during antiviral treatment with Telbivudine. Results demonstrated that as compared with the healthy donors, the peripheral iNKT cells from these patients existed at lower frequencies, displayed impaired capabilities to produce IFN-γ and expressed higher PD-1. Antiviral treatment with Telbivudine significantly increased IFN-γ production by iNKT cells, which may be associated with the decreased PD-1 expression as manifested by blocking experiments. Our study suggested that iNKT cells played an important role in the chronicity of HBV infection and antiviral therapy with Telbivudine could restore at least in part the impaired host immune response in the HBeAg-positive CHB patients.

Topics: Adult; Antiviral Agents; Female; Gene Expression Profiling; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Immunologic Factors; Interferon-gamma; Male; Middle Aged; Natural Killer T-Cells; Nucleosides; Programmed Cell Death 1 Receptor; Pyrimidinones; Telbivudine; Thymidine

To evaluate the efficacy of telbivudine and entecavir in chronic hepatitis B (CHB) patients over a 1 year period.. Ninety-seven telbivudine-naive and 98 entecavir-naive CHB patients who had been treated for at least 1 year were enrolled. Serial serum hepatitis B virus (HBV) DNA levels were checked at baseline and at weeks 24 and 48 after treatment.. Entecavir and telbivudine groups had similar baseline HBV DNA levels (5.9 ± 1.7 versus 6.0 ± 1.5 log copies/mL, P=0.529). The undetectable rate of HBV DNA after 1 year of treatment was significantly higher in the entecavir group than the telbivudine group (94.9% versus 82.0%, P=0.009). Resistance developed in 6.7% of the telbivudine-naive patients after 1 year compared with none of the entecavir-naive patients (P=0.009). However, there was a significant difference between the telbivudine and entecavir groups in hepatitis B e antigen (HBeAg) seroconversion 24 weeks after treatment (40% versus 12.5%, P=0.007). Multiple logistic regression analysis revealed that baseline alanine aminotransferase (ALT) >200 IU/L (P=0.008) was independently associated with HBeAg seroconversion. Applying the roadmap concept with ALT >2× upper limit of normal at baseline, telbivudine and entecavir had favourable outcomes in PCR negativity, ALT normalization, HBeAg seroconversion and resistance.. In real-world clinical practice, telbivudine resulted in higher rates of HBeAg seroconversion and drug resistance at week 48 compared with entecavir. A combination with baseline ALT plus 24 week HBV DNA levels led to the lowest rates of resistance in HBeAg-positive telbivudine-naive patients and had the highest probability of HBeAg seroconversion in both entecavir- and telbivudine-naive patients.

Topics: Adult; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome; Viral Load

Topics: Antiviral Agents; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interleukins; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Dysfunction of dendritic cells (DCs) is considered one of the factors for chronic hepatitis B virus (HBV) infection. However the reason for impairment of DCs remains elusive. The aim of this study was to investigate the effect of telbivudine on number and function of DCs in patients with chronic hepatitis B (CHB). After 6 months of telbivudine treatment, the number of plasmacytoid DCs (pDCs) increased significantly, nearly to levels observed in normal controls. However the capacity of pDCs to produce interferon α (IFN-α) was not enhanced during treatment. Accordingly, monocyte-derived DCs (MoDCs) exhibited a markedly enhanced expression of HLA-DR, decreased expression of PD-L1, and increased capacity to produce interleukin (IL)-12. These findings suggest that the improved function of peripheral myeloid DCs (mDCs) with telbivudine therapy in CHB patients may be associated with up-regulated expression of HLA-DR and down-regulated expression of PD-L1.

Topics: Adult; Antigens, CD; Antiviral Agents; B7-H1 Antigen; Cells, Cultured; Dendritic Cells; Down-Regulation; Gene Expression; Hepatitis B Antigens; Hepatitis B, Chronic; HLA-DR Antigens; Humans; Interferon-alpha; Interleukin-12; Male; Monocytes; Myeloid Cells; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Up-Regulation; Virus Replication

CD4⁺ T cells serve as master regulators of the adaptive immune response to HBV. However, CD4⁺ T-cell subsets are heterogeneous, and it remains unknown how the antiviral agents affect the different CD4⁺ T cell subtypes. To this end, the expressions of signature transcription factors and cytokines of CD4⁺ T-cell subtypes were examined in hepatitis B patients before and after treatment with telbivudine. Results showed that, upon the rapid HBV copy decrease induced by telbivudine treatment, the frequencies and related cytokines of Th17 and Treg cells were dramatically decreased, while those for Th2 cells were dramatically increased. No obvious changes were observed in Th1 cell frequencies; although, IFN-γ expression was upregulated in response to telbivudine treatment, suggesting another cell source of IFN-γ in CHB patients. Statistical analyses indicated that Th17 and Tr1 (a Treg subtype) cells were the most sensitive subpopulations of the peripheral blood CD4⁺ T cells to telbivudine treatment over 52 weeks. Thus, Th17 and Tr1 cells may represent a suitable and effective predictor of responsiveness during telbivudine therapy. These findings not only improve our understanding of hepatitis pathogenesis but also can aid in future development of appropriate therapeutic strategies to control viral hepatitis.

Topics: Adult; Antiviral Agents; Case-Control Studies; CD4-Positive T-Lymphocytes; Cytokines; Female; Hepatitis B, Chronic; Humans; Immune System; Interferon-gamma; Leukocytes, Mononuclear; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Th17 Cells; Thymidine; Time Factors

Treatment choice for chronic HBV infection is a continuously evolving issue, with a wide range of options. We aimed to evaluate the current practice of HBV therapies in the real world in Southern Italy.. A prospective study enrolling over a six month period (February-July 2010) all consecutive HBsAg positive subjects, never previously treated, referred to 16 liver units in two Southern Italy regions (Calabria and Sicily).. Out of 247 subjects evaluated, 116 (46.9%) had HBV-DNA undetectable or lower than 2000 UI/ml. There were 108 (43.7%) inactive carriers, 103 (41.7%) chronic hepatitis, and 36 (14.6%) liver cirrhosis. Antiviral treatment was planned in 94 (38.0%) patients (26 cases with Interferon or Pegylated Interferon and 68 with nucleos(t)ides analogues). As many as 49.5% of subjects with chronic hepatitis did not receive antiviral treatment.. The majority of chronic HBsAg carrier referring centres for evaluation were not considered suitable for antiviral treatment. Nucleos(t)ides analogues are the preferred first choice for therapy. A long-lasting period of observation may be needed to make appropriate therapeutic decisions in several cases.

Topics: Adenine; Adult; Age Factors; Aged; Aged, 80 and over; Antiviral Agents; Female; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-alpha; Italy; Lamivudine; Male; Middle Aged; Nucleosides; Organophosphonates; Polyethylene Glycols; Practice Patterns, Physicians'; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Young Adult

The significance of early HBV DNA suppression during telbivudine treatment in predicting long-term outcomes needs further investigation.. We determined the cumulative rates of HBeAg seroconversion, ALT normalization, HBV DNA suppression (<12IU/ml) and telbivudine resistant mutations (using the highly sensitive line probe assay) for 117 treatment-native chronic hepatitis B (CHB) patients (61.5% HBeAg-positive) on telbivudine for 3years. The significance of serum HBV DNA at week 12 and 24 was compared.. The median age and duration of follow-up were 39years and 24.2months, respectively. 117, 105, 69, and 43 patients had been followed up for at least 6months and 1, 2, and 3years, respectively. The cumulative rates of HBeAg seroconversion, ALT normalization, HBV DNA undetectability were 46.8%, 80.5%, and 51.2%, respectively, at 3years. There was an incremental increase in virologic breakthroughs to 39.5% by year 3. The cumulative rate of telbivudine resistant mutations was 4.8%, 17.6%, and 34.0% for year 1, 2, and 3, respectively. Week 12 HBV DNA of <200IU/ml was predictive of a higher chance of HBV DNA undetectability (p=0.022) and lower chance of resistance (p=0.001) by year 3. Undetectable HBV DNA at week 24 was predictive of viral suppression at year 2 (p<0.001) but not at year 3 (p=0.241).. Continuous telbivudine resulted in improved biochemical and virologic outcomes, although there was an incremental increase in cumulative rate of resistance up to year 3. Week 12 HBV DNA of <200IU/ml was predictive of favorable long-term outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Mutation; Nucleosides; Predictive Value of Tests; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome; Viral Load; Young Adult

Current agents used in the treatment of chronic hepatitis B (CHB) can be classified into interferons-α (IFN-α: standard or pegylated) and nucleos(t)ide analogues (NUCs). NUCs are now used in most CHB patients for several reasons. They can be given to all CHB patients, even those with contraindications to IFN-α. NUCs are more convenient to use (one oral tablet daily) than IFN-α (subcutaneous injections) and are well tolerated with a good safety profile, while IFN-α has frequent and potentially severe side effects and worsens the patient's quality of life. All NUCs are potent anti-hepatitis B virus agents (all but adefovir are more potent than IFN-α) with entecavir(ETV) and tenofovir offering the highest potency and most importantly minimal to negligible risk of resistance during long-term monotherapy [corrected]. Prolongation of entecavir or tenofovir monotherapy maintains and slightly increases the initially high virological remission rates (67-76% of HBeAg-positive and 90-93% of HBeAg-negative patients) and this is expected to result in improved long-term outcomes. The need for long-term, perhaps indefinite, treatment is the main limitation of NUCs and the finite duration (48 weeks) the main advantage of IFN-α. However, only a minority of IFN-α-treated patients achieve durable sustained off-treatment responses (HBeAg-positive: 30-35%, HBeAg-negative: 20-25%), while NUCs may be safely discontinued in HBeAg-positive patients with stable HBeAg seroconversion. Because there will always be concerns for safety and family planning issues with long-term therapy, NUCs should be used judiciously and should not be prescribed in young CHB patients with mild liver disease.

Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine; Time Factors; Treatment Outcome

Hepatitis B surface antigen (HBsAg) clearance during chronic hepatitis B (CHB) infection is associated with improved long-term clinical outcome, so is considered an important therapeutic goal in CHB. Studies have shown that serum HBsAg quantification during, and at end of, treatment may predict long-term HBsAg loss.. Performance comparison of the qualitative Elecsys HBsAg II assay using a quantitative research protocol and an established quantitative HBsAg assay.. A dilution algorithm was developed for the Elecsys HBsAg II assay to allow quantification of HBsAg levels; this was used to measure HBsAg levels in a range of samples including sera from patients infected with different HBV genotypes, HBV mutants, and longitudinal samples from patients undergoing antiviral treatment. Results were compared with those from the quantitative Architect HBsAg assay.. There was significant overall correlation between Elecsys and Architect assays (correlation coefficient [r]=0.97; p<0.001). HBsAg levels measured with both assays correlated well in all phases of infection (r=0.80-0.96), across all genotypes tested (HBV genotype A, r=0.89; HBV genotype D, r=0.97), and in samples with lamivudine-resistant mutations (r=0.94). Bland-Altman analysis showed only minor discordance between assays in different phases of chronic HBV-infection (3.8-5.1%). This strong correlation was also present for sera with lower HBsAg concentrations. On-treatment HBsAg levels were similar when measured with either assay.. Using a simple dilution algorithm, the quantitative Elecsys HBsAg II assay reliably determined serum HBsAg levels in a wide range of samples, and showed very high correlation with the Architect HBsAg assay.

Topics: Clinical Laboratory Techniques; Drug Resistance, Viral; Genotype; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunoassay; Lamivudine; Longitudinal Studies; Mutation; Nucleosides; Pyrimidinones; Reagent Kits, Diagnostic; Telbivudine; Thymidine

The study investigated the hepatitis B virus (HBV) genotypic resistance profile in 1803 nucleos(t)ide analogue (NA)-experienced Chinese patients with chronic HBV infection. Serum HBV DNA was extracted, and the reverse transcriptase region was analysed by a high-sensitive direct PCR sequencing and verified by clonal sequencing if necessary. Drug-resistant mutations were detected in 560 of the 1803 patients, including 214 of 490 patients who received lamivudine (LAM), 35 of 428 patients who received adefovir (ADV), five of 18 patients who received telbivudine and 306 of 794 patients who received various sequential/combined NA therapies. ADV-resistant mutations were detected in 36 of 381 patients who received LAM and then switched-to ADV in contrast to one of 82 patients who received ADV add-on LAM. Entecavir (ETV)-resistant mutations were detected not only in LAM- and ETV-treated patients but also in LAM-treated ETV-naïve patients. Double mutations rtM204I and rtL180M were detected more frequently in genotype C than in genotype B virus, and patients infected with this mutant had higher alanine transaminase levels than those infected with mutant containing the rtM204I substitution alone. Multidrug-resistant HBV strains were identified in eight patients, including two novel strains with mutational patterns rtL180M + A181V + S202G + M204V + N236T and rtL180M + S202G + M204V + N236T. The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China.

Topics: Adenine; Adult; Amino Acid Substitution; Antiviral Agents; China; DNA, Viral; Drug Resistance, Viral; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Nucleosides; Organophosphonates; Pyrimidinones; RNA-Directed DNA Polymerase; Sequence Analysis, DNA; Telbivudine; Thymidine; Viral Proteins

Topics: Antiviral Agents; Biomarkers; DNA, Viral; Drug Resistance, Viral; Drug Substitution; Endemic Diseases; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Time Factors; Treatment Outcome; Viral Load

Over the past decade, advances in the antiviral therapy in patients with chronic hepatitis B have enabled the sustained suppression of hepatitis B viral replication and the prevention of progressive liver disease. Hepatitis B surface antigen (HBsAg) has been used to diagnose patients with hepatitis B virus infection. Recently, test for quantitative HBsAg titers are available and on-treatment HBsAg quantitations are used to predict treatment outcome. Serum HBV DNA levels have been shown to predict natural course of chronic hepatitis B infection. The HBV DNA levels have been reported to be positively correlated with the development of cirrhosis, hepatocellular carcinoma and related death. The baseline and on-treatment levels of HBV DNA are important factors for predicting treatment outcomes. In this article, we will discuss the role of HBV DNA and HBsAg quantitation during antiviral therapy.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

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.

Topics: Adult; Alanine Transaminase; Antiviral Agents; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Cytokines; DNA, Viral; Enzyme-Linked Immunospot Assay; Female; Hepatitis B Core Antigens; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunity, Cellular; Liver; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome

Serum alanine aminotransferase (ALT) increase is a well-known phenomenon during interferon treatment for chronic hepatitis B. However, little is known about these increases during nucleoside/nucleotide treatment and the effects on long-term clinical outcomes.. A total of 170 treatment-naive hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogue for at least 2 years and followed up for 1 more year post-treatment. Clinical characteristics were detected and analysed at baseline and at every 3-month interval.. Two patterns of ALT increase, virus- and host-induced, were detected. Virus-induced increases were characterized by a rapid increase in serum ALT and HBV DNA typically after 2 years of treatment, and were more common than host-induced ALT increases (15.9% versus 6.5%; P<0.05) with a median ALT increase of 5.7-fold the upper limit of normal (ULN). Host-induced ALT increases were characterized by moderately increased ALT (median 2.5-fold ULN) with a slow decrease in HBV DNA that occurred mainly in the first year of treatment (63.6%). Most importantly, host-induced increases were associated with favourable long-term treatment outcomes in HBV DNA undetectable rate (82% versus 0%), HBeAg seroconversion (82% versus 7%) and histological improvement. Moreover, interferon-γ-expressing T-helper cells were increased in patients with host-induced ALT increases.. Two patterns of ALT increases may occur during nucleoside/nucleotide analogue treatment. Host induced ALT increases, accompanied by decreased HBV DNA, lead to better long-term clinical outcomes.

Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Guanine; Hepacivirus; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferon-gamma; Lamivudine; Male; Middle Aged; Nucleosides; Organophosphonates; Predictive Value of Tests; Pyrimidinones; T-Lymphocytes; Telbivudine; Thymidine; Treatment Outcome; Up-Regulation; Young Adult

Topics: Female; Hepatitis B, Chronic; Humans; Infectious Disease Transmission, Vertical; Male; Nucleosides; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Telbivudine; Thymidine

HIV-HBV-coinfected individuals who need to be treated only for their HBV infection have limited therapeutic options, since most approved anti-HBV agents have a risk of selecting for drug-resistant HIV mutants. In vivo data are inconclusive as to whether telbivudine (LdT) may exert antiviral effects against HIV. Thus, we investigated in further detail the antiviral activity and the biochemical properties of LdT against HIV-1.. To investigate the activity of LdT against HIV-1 in humans we analysed viral dynamics and genotypic and phenotypic resistance development in two HIV-HBV-coinfected individuals with no prior antiviral exposure. To investigate the activity of LdT against HIV-1 in vitro, LdT susceptibility for HIV-1 wild-type strains as well as drug-resistant strains was determined. Furthermore, we studied whether the 5'-triphosphate form of LdT (LdT-TP) can act as a substrate for wild-type HIV-1 RT.. In the two patients studied, LdT treatment did not result in a significant decline of HIV-1 RNA load nor in selection of genotypic or phenotypic resistance in HIV-1 RT. In vitro virological analyses demonstrated that LdT had no activity (50% effective concentration >100 μM) against wild type HIV and drug-resistant variants. Biochemical analyses demonstrated that LdT-TP is not incorporated by wild-type HIV-1 RT.. Based on the in vivo and in vitro evidence obtained in this study, we conclude that LdT has no anti-HIV-1 activity and is currently the only selective anti-HBV agent among the five FDA-approved nucleoside/nucleotide analogues for treatment of HBV infections in HIV-infected individuals.

Topics: Adult; Antiviral Agents; CD4 Lymphocyte Count; Cell Line; Coinfection; DNA, Viral; Drug Resistance, Viral; Genotype; HEK293 Cells; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nucleosides; Phenotype; Pyrimidinones; RNA, Viral; Telbivudine; Thymidine; Viral Load

With the extensive use of telbivudine, more and more studies reported its association with creatine kinase (CK) elevations and myopathy. However, clinical features of these adverse effects were poorly understood. The aim of the present study was to investigate the clinical features and risk factors of CK elevations and myopathy associated with telbivudine. The serum CK levels of 200 patients who were treated with telbivudine for chronic hepatitis B (CHB) between January 2007 and July 2010 were monitored and analysed along with clinical manifestations. The 3-year cumulative incidence of CK elevations and myopathy was 84.3% and 5%, respectively. CK elevations occurred more frequently in men than in women, and patients aged ≤45 years and with negative HBeAg had higher incidence of CK elevations. There was no difference in CK elevations among patients with different HBV DNA levels. Male, younger age and HBeAg negativity were independent predictors of CK elevations by multivariate Cox regression analysis. There was no association between the occurrence of myopathy and variables including age, sex, HBeAg and HBV DNA. No risk factors of myopathy were identified. CK elevations usually occurred 21 months after starting treatment, and most patients resolved spontaneously without interruption of telbivudine therapy except three patients who had to switch to other agents. In conclusion, CK elevations are common adverse reactions associated with telbivudine therapy, while myopathy is rare. Male, younger age and HBeAg negativity might be risk factors of CK elevations.

Topics: Adolescent; Adult; Age Distribution; Aged; Antiviral Agents; Creatine Kinase; Female; Hepatitis B, Chronic; Humans; Incidence; Male; Middle Aged; Muscular Diseases; Nucleosides; Pyrimidinones; Risk Factors; Sex Distribution; Telbivudine; Thymidine; Young Adult

Topics: Adenine; Antiviral Agents; Arabinofuranosyluracil; Deoxycytidine; Emtricitabine; Hepatitis B, Chronic; Humans; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

Invariant NKT (iNKT) cells are involved in the pathogenesis of various infectious diseases. However, their role in hepatitis B virus (HBV) infection is not fully understood, especially in human species. In this study, 35 chronic hepatitis B (CHB) patients, 25 inactive carriers (IC) and 36 healthy controls (HC) were enrolled and the proportions of circulating iNKT cells in fresh isolated peripheral blood mononuclear cells (PBMC) were detected by flow cytometry. A longitudinal analysis was also conducted in 19 CHB patients who received antiviral therapy with telbivudine. Thereafter, the immune functions of iNKT cells were evaluated by cytokine secretion and a two-chamber technique. The median frequency of circulating iNKT cells in CHB patients (0.13%) was lower than that in HC (0.24%, P = 0.01) and IC (0.19%, P = 0.02), and increased significantly during antiviral therapy with telbivudine (P = 0.0176). The expressions of CC chemokine receptor 5 (CCR5) and CCR6 were dramatically higher on iNKT cells (82.83%±9.87%, 67.67%±16.83% respectively) than on conventional T cells (30.5%±5.65%, 14.02%±5.92%, both P<0.001) in CHB patients. Furthermore, iNKT cells could migrate toward the CC chemokine ligand 5. Patients with a high ratio (≥1.0) of CD4-/CD4+ iNKT cells at baseline had a higher rate (58.33%) of HBeAg seroconversion than those with a low ratio (<1.0, 0%, P = 0.0174). In conclusion, there is a low frequency of peripheral iNKT cells in CHB patients, which increases to normal levels with viral control. The ratio of CD4-/CD4+ iNKT cells at baseline may be a useful predictor for HBeAg seroconversion in CHB patients on telbivudine therapy.

Topics: Adult; Case-Control Studies; CD4-Positive T-Lymphocytes; Cell Movement; Cytokines; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Natural Killer T-Cells; Nucleosides; Pyrimidinones; Receptors, CCR5; Receptors, CCR6; Telbivudine; Thymidine; Young Adult

Effective management of chronic hepatitis B infection is still very challenging, despite decades of clinical research. Telbivudine is one of the most frequently used antiviral drug at the current stage, but its long-term effectiveness, particularly at off-treatment, is still unclear.. To assess on-treatment HBsAg kinetics in patients treated with telbivudine for 2 years, and predicting sustained virologic response (SR) at 2 years off-treatment.. Serum HBV DNA/HBsAg levels were assessed from 17 HBeAg+ patients treated with telbivudine 600 mg/day for 104 weeks, at baseline, weeks 24, 52 and 104, as well as during off-treatment follow-up.. HBsAg levels <2 log(10)IU/ml at treatment week 104 were highly predictive of SR (i.e., HBV DNA <300 copies/ml, HBeAg seroconversion, ALT normalization) at 2 years off-treatment (positive predictive value [PPV], 93%; negative predictive value [NPV], 100%). HBsAg levels consistently declined from baseline only in patients achieving SR during 2 years off-treatment. At weeks 24 and 52, HBsAg decline rate was a better predictor of off-treatment response than HBV DNA decline rate. HBsAg decline rates of >0.8 and >1 log(10)IU/ml at treatment weeks 24 and 52 were predictive of SR (PPV, 75%; NPV, 86% at week 24; PPV, 75%; NPV, 86% at week 52).. Serum HBsAg levels <2 log(10)IU/ml at treatment week 104 are highly predictive of SR to telbivudine at 2 years off-treatment. HBsAg decline rate at on-treatment weeks 24 and 52 from baseline were also more predictive of SR than HBV DNA decline rate.

Topics: Adolescent; Adult; Antiviral Agents; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Multivariate Analysis; Nucleosides; Predictive Value of Tests; Pyrimidinones; ROC Curve; Statistics, Nonparametric; Telbivudine; Thymidine; Treatment Outcome; Viral Load

Most approved drugs with activity against hepatitis B virus (HBV) have activity against human immunodeficiency virus type 1 (HIV-1), which precludes their use in patients who are coinfected with HBV and HIV-1 and who are not receiving antiretroviral therapy due to the risk of inducing resistance. The activity of telbivudine, a highly selective HBV inhibitor, against temporally and geographically distinct wild-type and multidrug-resistant HIV-1 clinical isolates was evaluated in vitro. No inhibition was observed with up to 600 muM drug, which supports further exploration of telbivudine as a therapeutic option for the treatment of HBV infections in patients coinfected with HIV-1.

Topics: Anti-HIV Agents; Antiviral Agents; Drug Resistance, Viral; Guanine; Hepatitis B virus; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

The roadmap approach is recommended to guide chronic hepatitis B treatment. We evaluated the cost-effectiveness of various treatment strategies in the global market.. Lamivudine and telbivudine were tested in roadmap models with switch-to tenofovir if HBV was detectable at week 24 or add-on tenofovir if resistance developed at year 1. Tenofovir and entecavir were tested as continuous monotherapy. In the reference arm, lamivudine was used with add-on tenofovir if resistance developed at year 1. The primary measure of effectiveness was undetectable HBV DNA at year 2. Cost-effectiveness was measured by incremental cost-effectiveness ratio (ICER) in US dollars against the reference arm.. In the US and Germany, costs of the reference arms were US $14,486 and US $9,998 for hepatitis B e antigen (HBeAg)-positive and US $11,398 and US $7,531 for HBeAg-negative patients, respectively. In HBeAg-positive patients, the lamivudine roadmap was most cost-effective (ICER US $15,260 in the US and US $29,113 in Germany) with comparable effectiveness (75.1%) to other strategies. In HBeAg-negative patients, tenofovir and entecavir monotherapies were most effective (91-96%) and cost-effective (ICER US $31,297-43,387 in the US and US $53,976-59,822 in Germany). In Asia, where telbivudine cost was lower, both telbivudine and lamivudine roadmaps were cost-effective in HBeAg-positive patients. Tenofovir would be most cost-effective in HBeAg-negative patients if its cost equaled that of telbivudine in Asia.. In HBeAg-positive patients, lamivudine roadmap was most cost-effective; in Asia, telbivudine roadmap had comparable cost-effectiveness to lamivudine roadmap because of the relatively low price of telbivudine. In HBeAg-negative patients, entecavir and tenofovir monotherapies were more cost-effective than the roadmap models.

Topics: Adenine; Antiviral Agents; Asia; Cost-Benefit Analysis; Decision Support Techniques; DNA, Viral; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Germany; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Models, Economic; Nucleosides; Organophosphonates; Pyrimidinones; Salvage Therapy; Telbivudine; Tenofovir; Thymidine; Treatment Outcome; United States

The aim of this study was to investigate the economic consequences of nucleoside analog therapy for hepatitis B treatment in China.. A cost-utility analysis of treatments for HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) was conducted using a Markov model, in which patients' yearly transitions between different health states were tracked. Patients were tracked as they moved between the following health states: CHB, HBeAg seroconversion (HBeAg-positive CHB patients can have this special health state), virologic resistance, virologic response, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. The transition parameters were derived either from systematic reviews of the literature or from previous economic studies. Cost and utility data came from studies based on a Chinese CHB cohort. One-way sensitivity analyses as well as second-order Monte Carlo and probabilistic sensitivity analyses were performed.. The entecavir strategy yielded the most quality-adjusted life years (QALYs) for both HBeAg-positive and HBeAg-negative patients when compared with the "no treatment," the lamivudine, the adefovir, and the telbivudine strategies. The risks of complications and mortality also decreased. In the economic analysis, the "no treatment" strategy was the least effective, whereas the entecavir strategy was both the least expensive and the most cost-effective option, followed by telbivudine and lamivudine. The probabilistic sensitivity analysis showed that the entecavir strategy would result in improved cost-effectiveness in >90% of cases at a threshold of $20,000 per QALY. In a one-way sensitivity analysis, the most influential parameters impacting the model's robustness were the utilities of the CHB and virologic response health states.. In China, when treating both HBeAg-positive and HBeAg-negative CHB populations, entecavir is the most cost-effective option when compared with lamivudine, adefovir, and telbivudine.

Topics: Adenine; Antiviral Agents; China; Cost-Benefit Analysis; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Markov Chains; Models, Economic; Models, Statistical; Monte Carlo Method; Nucleosides; Organophosphonates; Pyrimidinones; Quality-Adjusted Life Years; Reverse Transcriptase Inhibitors; Serologic Tests; Telbivudine; Thymidine

We report the case of a patient with non-Hodgkin's lymphoma who, during chemotherapy according to the r-CHOP schedule (rituximab-cyclophosphamide-doxorubicin-vincristine and prednisone), showed a hepatic flare with jaundice. Given the patient's state of asymptomatic carrier of HBsAg, we began a treatment of telbivudine (600 mg/die), resulting in a regression of hepatitis flare and negativization of HBV viraemia.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Cyclophosphamide; Cytomegalovirus; Cytomegalovirus Infections; Doxorubicin; Hepatitis B virus; Hepatitis B, Chronic; Humans; Hyperbilirubinemia; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nucleosides; Prednisone; Pyrimidinones; Rituximab; Telbivudine; Thymidine; Vincristine; Viremia; Virus Activation

Accumulating evidence supports the theory that expression of CD127 on CD8 T cells during the process of antiviral immune response indicates a subset of effect CD8 T cells that successfully develop into fully protective memory. CD8 T cells expression of CD127 may be used as a predictor to evaluate disease status in chronic viral infection. The aim of this study was to investigate the CD127 expression level on different subsets of CD8 T cell and explore the relationship between CD127 expression on CD8 memory T cells and serum hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) levels in patients with chronic hepatitis B (CHB). We also aimed to investigate the CD127 expression pattern on CD8 memory T cells of CHB patients who were treated with Telbivudine.. Twenty HBeAg-positive CHB patients were selected and treated with telbivudine 600 mg/day for 48 weeks. The memory CD8 T cells were characterized by expression of CD45RA and CD27 markers. CD127 expression on the CD8 T-cell surface was measured by four-colour flow cytometry. Our results showed that CD127 expression on memory CD8 T cells was reduced in CHB patients. There was a strong negative correlation between CD127 expression on memory CD8 T cells and serum HBV DNA and HBeAg levels in CHB patients. Moreover, successful antiviral therapy increased CD127 expression on CD8 memory T cells as well as on HBV-specific CD8 T cells in CHB patients.. These results suggest that diminished CD127 expression on CD8 memory T cells of CHB patients is a potential mechanism explaining cellular immune function impairment in CHB infection, and that CD127 expression on CD8 memory T cells is a useful indicator for evaluating the effects of anti-HBV therapy.

Topics: Adult; Antiviral Agents; CD8-Positive T-Lymphocytes; DNA, Viral; Female; Gene Expression Profiling; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunologic Memory; Interleukin-7 Receptor alpha Subunit; Male; Nucleosides; Pyrimidinones; T-Lymphocyte Subsets; Telbivudine; Thymidine

The impact of prolonged direct antiviral therapy on hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B is poorly understood. We quantitatively assessed serum HBsAg levels during 3 years of telbivudine treatment, as well as their relationship with virologic and biochemical characteristics in 162 hepatitis B e antigen-positive patients who maintained undetectable serum hepatitis B virus (HBV) DNA long-term. Telbivudine treatment progressively reduced serum HBsAg levels (mean ± SD) from baseline (3.8 ± 0.6 log₁₀ IU/mL) to treatment week 24 (3.4 ± 0.7 log₁₀ IU/mL), treatment year 1 (3.3 ± 0.8 log₁₀ IU/mL), and treatment year 3 (3.0 ± 1.4 log₁₀ IU/mL) (P <0.0001). In this patient population, HBsAg loss was observed in nine (6%) of 162 patients through year 3. During the first year of treatment, three patterns of HBsAg decline were observed: rapid (≥ 1 log₁₀ IU/mL) in 32 patients, slow (0-1 log₁₀ IU/mL) in 74 patients, and steady levels in 56 patients. These findings were associated with different likelihoods of HBsAg loss during long-term telbivudine therapy. Eight of 32 patients with rapid HBsAg decline versus none of 56 patients with steady HBsAg levels achieved HBsAg loss at year 3 (P = 0.0024). HBV genotype was a significant determinant for HBsAg kinetics, with the fastest decline in genotype A patients. In patients with subsequent HBsAg loss, viral antigens were already undetectable in liver biopsy samples after 1 year of treatment. This was associated with markedly enhanced antiviral T cell reactivity.. In patients who have effective suppression of viral replication during telbivudine treatment, a rapid decline in serum HBsAg levels during the first year may identify those with a greater likelihood of achieving HBsAg clearance.

Topics: Adult; Antiviral Agents; Body Weight; Enzyme-Linked Immunosorbent Assay; Genotype; Hepatitis B Core Antigens; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Humans; Kinetics; Liver; Lymphocyte Activation; Nucleosides; Patient Selection; Pyrimidinones; Racial Groups; T-Lymphocytes; Telbivudine; Thymidine; Time Factors

Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Nucleosides; Peripheral Nervous System Diseases; Pyrimidinones; Rhabdomyolysis; Telbivudine; Thymidine

To study PD-1 and PD-L1 expressions during 24 weeks telbivudine antiviral treatment in patients with chronic hepatitis B (CHB) and to explore the relationship between PD-1 expression and HBeAg/HBeAb seroconversion.. Ten CHB cases with HLA-A2 and HBeAg positive were treated with telbivudine 600 mg/d orally for 24 weeks. Fresh blood samples were collected at week 0, 12 and 24 after treatment. HBV-specific CD8+ T cells were expanded in vitro. Cell culture medium were collected for interferon gamma (IFNgamma) detection. Flow cytometry was used to detect the HLA-A type, PD-1, PD-L1 and HBV specific CD8+ T cells. The expressions of PD-1 and PD-L1, the counts of HBV-specific CD8+ T cells in circulating CD8+ lymphocytes, and IFNgamma concentration in culture medium were evaluated during antiviral treatment.. At week 0, 12 and 24 after telbivudine treatment, 7 of 10 patients were HBV DNA undetectable, 2 were HBeAg seroconversion and 2 were HBeAg lose but anti-HBe negative. The frequency of PD-1-positive PBMCs were 52.1%+/-17.0%, 39.1%+/-18.2% and 23.4%+/-16.3% (week 24 vs week 0, P < 0.01) respectively; PD-L1 positive PBMCs were 45.6%+/-15.4%, 34.6%+/-16.2% and 20.9%+/-9.5% respectively(week 24 vs week 0, P < 0.01; week 24 vs week 12, P < 0.05). The frequency of PD-1-positive CD8+ T cells were 76.2%+/-10.4%, 66.5%+/-15.4% and 49.5%+/-25.3% respectively (week 24 vs week 0, P < 0.01; week 12 vs week 0, P < 0.05; week 24 vs week 12, P < 0.05); HBV-specific CD8 cells were 1.3%+/-0.5%, 1.5%+/-1.0% and 2.2%+/-1.5%; IFNgamma levels in cell culture medium were (91.7+/-82.1) pg/ml, (99.4+/-93.5) pg/ml and (109.5+/-86.6) pg/ml. A remarkable decrease of PD-1 and PD-L1 expressions and increase of HBV-specific CD8+ T cells were observed in patients who had HBeAg/HBeAb seroconversion at week 24.. Direct suppression of HBV replication by telbivudine in CHB patients can decrease PD-1 and PD-L1 expressions and restore HBV-specific CD8+T cells. The relationship between the changes of PD-1 expression and HBeAg/HBeAb seroconversion during antiviral therapy in HBeAg-positive patients need to confirm by future study.

Topics: Adult; Antiviral Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Nucleosides; Programmed Cell Death 1 Receptor; Pyrimidinones; Telbivudine; Thymidine; Young Adult

Topics: Adolescent; Adult; Antiviral Agents; DNA, Viral; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Young Adult

Hepatitis B virus (HBV) genomic variability is responsible for the complexity of the viral quasi-species and its evolution during the course of infection. The persistence of infected cells promotes the selection of drug-resistant strains. The development of nucleoside analogs without cross-resistance has provided a rationale for combination therapy. De novo combination, with low genetic barrier drugs, prevents the emergence of resistance in the short-term for drugs with a low genetic barrier and improves the control of infection. Long-term studies are needed to determine whether de novo combination is beneficial for analogs with a high genetic barrier as well. The add-on strategy is a standard in case of emergence of resistant mutants. This strategy needs to be implemented as early as possible before the virological breakthrough, especially if the viral suppression is sub-optimal. Clinical trials are mandatory in order to assess whether a) de novo combination is better than an early add-on strategy; and b) whether in case of sub-optimal viral suppression, an early add-on strategy is better in the long-term than a switch to a more potent drug with a high genetic barrier.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

As human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are acquired through the same routes of contamination, the prevalence of HBV serological markers found in the HIV-infected population is approximately 7%. Liver-related mortality and morbidity is higher in HIV/HBV co-infected patients than in HBV mono-infected patients. Both viruses must be considered before a treatment decision is made. According to the European consensus conference on the treatment of chronic hepatitis B and C in HIV coinfected patients, treatment is based on whether there is an existing indication of anti- HIV therapy or not. In patients with no indication of anti-HIV therapy, drugs with dual anti-viral activity (lamivudine, entecavir, tenofovir disoproxil fumarate) should not be used due to the risk of developing HIV-resistance. Interferon or adefovir in combination with telbivudine are recommended. In patients with an indication of anti-HIV therapy, a backbone of highly active anti-retroviral therapy should include tenofovir in combination with lamivudine or emtricitabine. The same regimen is recommended in patients who develop lamivudine resistance.

Topics: Adenine; Antiretroviral Therapy, Highly Active; Antiviral Agents; Deoxycytidine; Drug Resistance, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine

Antiviral drug-resistant HBV mutants under a variety of treatment protocols are complex and only partly understood. Here, a population-based cross-sectional study was performed to analyse the profile of resistance mutations in distinct evolutionary pathways refractory to different nucleoside/nucleotide analogues (NAs).. Serum samples of 199 chronic hepatitis B patients undergoing NA treatment from five hospitals in four northern cities of China were obtained between January 2007 and July 2009. The genotypic resistance of HBV in these samples was characterized. The full-length HBV reverse transcriptase region was amplified, sequenced and analysed with particular focus on the following NA-resistant changes: rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250.. Among 199 HBV isolates, 30 (15.08%) and 169 (84.92%) were genotypes B and C, respectively, and 65 (32.66%) harboured NA-resistant mutations. The prevalence of mutations at rtM204 was 34.33% in 134 patients who had received or who had been exposed to lamivudine-based therapy. Five cases of rtN236 mutations were detected exclusively among 75 patients receiving adefovir-dipivoxil-based therapies. A total of 19 cases of multidrug resistance rtA181 mutations were observed in those with lamivudine-, adefovir-dipivoxil- or telbivudine-based treatment (186 cases), but not in those undergoing entecavir treatment (13 cases). Mutations were not found at rtI169, rtT184, rtA194 or rtS202. rtM204 mutations (27 rtM204I, 15 rtM204V and 5 rtM204I/V cases) were detected at the highest frequency among 65 mutants (72.30% [47/65]) and found to display 16 combination mutation patterns, in which rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively (P<0.01).. One-third of the studied population harboured NA-resistant HBV with complicated mutation patterns. Monitoring HBV genotypic resistance mutation markers and patterns is therefore shown to be beneficial for optimizing antiviral therapies and for avoiding clinical deterioration.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; China; Cross-Sectional Studies; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Molecular Typing; Mutation, Missense; Nucleosides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine; Young Adult

Topics: Anti-HIV Agents; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

To investigate the dynamic changes of Th1/Th2 type cytokines in peripheral blood of patients with hepatitis B e antigen-positive chronic hepatitis B treated with telbivudine (LDT).. The levels of IL-2, IL-4, IL-6, IL-10, TNF alpha, IFN gamma in the blood cells of HBeAg positive chronic hepatitis B patients were measured at 0, 4, 8, 12, 24, 48 weeks after LDT treatment by fluorescence activated cell sorting (FACS), the levels and dynamic changes of Th1/Th2 type cytokines in groups of complete response, partial response, non-response, virologic breakthrough were compared.. The levels of Th1 type cytokines in complete response group were higher than those in groups of partial response, non-response and virologic breakthrough, however, the levels of Th2 type cytokines showed an opposite trend compared with Th1 type cytokines. There were no significant differences between each group. In complete response group, the levels of IL-2, TNF alpha and IFN gamma were higher than baseline 12 weeks after LDT treatment (P < 0.05). In partial response group the level of IFN gamma was higher than baseline 24 weeks after LDT treatment (P < 0.05). In non-response group, the levels of IL-6 and IL-10 were higher than baseline at 48 weeks after LDT treatment (P < 0.05). In virologic breakthrough group, the level of IL-4 was higher than baseline 24 weeks after LDT treatment (P < 0.05), while the level of IL-6 was higher than baseline 12 weeks after LDT treatment (P < 0.05).. The balance of Th1/Th2 type cytokines plays an important role in the outcome of patients with hepatitis B e antigen-positive chronic hepatitis B treated with LDT. The immune response of patients with chronic hepatitis B is improved to some extent after LDT therapy.

Topics: Adult; Antiviral Agents; DNA, Viral; Female; Flow Cytometry; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-gamma; Interleukins; Male; Nucleosides; Pyrimidinones; Telbivudine; Th1 Cells; Th2 Cells; Thymidine; Time Factors; Tumor Necrosis Factor-alpha; Young Adult

Topics: Antiviral Agents; Enzyme Inhibitors; Hepacivirus; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunoglobulins; Interferons; Mental Disorders; Nucleosides; Pyrimidinones; Substance-Related Disorders; Telbivudine; Thymidine

Long-term management of some chronic hepatitis B patients might require combination therapy using drugs with distinct resistance profiles to sustain viral suppression and to reduce the resistance-associated failure. Tenofovir disoproxil fumarate (TDF), approved for hepatitis B virus (HBV) and HIV-1 treatment, is active against wildtype HBV and HBV containing YMDD mutations, which confer resistance to emtricitabine (FTC), lamivudine (3TC) and telbivudine (LdT) and contribute to entecavir (ETV) resistance. We therefore evaluated the in vitro anti-HBV activity of tenofovir (TFV), the active parent drug of TDF, combined with FTC, 3TC, ETV, LdT and adefovir (AFV).. The anti-HBV activities of the compounds were tested using the AD38 cell line that expresses wild-type HBV from a tetracycline-controllable promoter. Intracellular HBV DNA levels were quantified using real-time PCR assay and cytotoxicities were assessed with XTT assays. The antiviral data of the drug combinations were evaluated using MacSynergy analyses on the basis of the Bliss independence model as well as isobologram analyses on the basis of the Loewe additivity theory.. All drug combinations tested, FTC+TFV, 3TC+TFV, ETV+TFV, LdT+TFV and AFV+TFV, showed additive antiviral interactions as analysed by MacSynergy. Isobologram analyses revealed that these combination pairs were additive, with the exception of FTC+TFV, which demonstrated slight synergistic activity. No cytotoxic or antagonistic effects were observed with any of the combinations tested.. The combination of TFV with FTC, 3TC, ETV, LdT or AFV had additive to slightly synergistic anti-HBV effects in vitro. These results support the use of TDF as a component in combination regimens with currently available anti-HBV nucleoside analogues.

Topics: Adenine; Antiviral Agents; Cell Line; Cell Survival; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Nucleotides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine

Topics: Antiviral Agents; DNA, Viral; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Topics: Antiviral Agents; Congresses as Topic; DNA, Viral; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Nucleosides; Patient Compliance; Pyrimidinones; Telbivudine; Thymidine

Pretreatment alanine transaminase (ALT) elevation may be used as a predictor for higher hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B patients. However, the role of dynamic changes of on-treatment ALT for seroconversion is unknown. A total of 170 naïve HBeAg-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogues (NA), either lamivudine, adefovir, entecavir, or telbivudine, for at least 2 years and followed up for 1 more year. Clinical characteristics were detected and analysed at baseline and at 3-month intervals. On-treatment ALT predicted HBeAg seroconversion more accurately than baseline ALT. Among the patients with on-treatment ALT 5 x UNL, HBeAg seroconversion was 11.4, 5.4, 24.4 and 65.0% (odds ratio = 1.0, 0.4, 2.5 and 14.4, respectively), respectively. Moreover, two models/types of seroconversion were observed. Type I was characterized by rapidly decreased ALT and HBV DNA during the first 3-month interval, but with high HBeAg reversion rate (50%) after consolidation treatment. Type II was a slow decreased DNA procedure accompanied by significant elevated ALT with less reversion (23%). Receiver operating characteristic curve analysis showed a 1.9-fold increased ALT ratio (present visit ALT: previous visit ALT) accompanied by at least a 0.8 log decreased HBV DNA may be used to classify these two seroconversion types. We conclude that on-treatment elevated ALT levels is a better predictor for seroconversion after NAs treatment, and HBV DNA profiles may help to identify different models of seroconversion.

Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Female; Follow-Up Studies; Guanine; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Nucleosides; Organophosphonates; Prognosis; Pyrimidinones; Retrospective Studies; Telbivudine; Thymidine; Young Adult

To evaluate long-term cost effectiveness of telbivudine and lamivudine for the treatment of CHB.. Cost effectiveness was conducted from social health insurance perspective. A Markov model was established based on disease progression pattern and the data from the 2 years GLOBE clinical trial. The information of annual medical expenditure and quality-of-life assessment for different CHB-related diseases was obtained from literature. Incremental cost per life year or quality-adjusted life year gained was measured.. Compared with lamivudine, the incremental cost for 1 additional QALY gained with telbivudine in treating HBeAg-positive and -negative CHB were 5403 yuan and 28239 yuan in Beijing, as well 4916 yuan and 29618 yuan in Guangzhou, respectively. According to national economic burden of CHB-related diseases, the ICER with telbivudine vs lamivudine were 1282 yuan and 31565 yuan for HBeAg-positive and -negative CHB.. According to WHO recommendation for ICER threshold, telbivudine is cost effective in treating HBeAg-positive and -negative CHB, as compared to lamivudine.

Topics: Adult; Antifungal Agents; China; Cost-Benefit Analysis; DNA, Viral; Drug Costs; Economics, Pharmaceutical; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Insurance, Long-Term Care; Lamivudine; Liver Cirrhosis; Male; Markov Chains; Middle Aged; Models, Economic; Nucleosides; Prescription Drugs; Pyrimidinones; Quality-Adjusted Life Years; Telbivudine; Thymidine

Chronic hepatitis B affects 5-10% of HIV patients in Western countries. Lamivudine should no longer be used as a single anti-HBV agent in HIV-HBV co-infected patients, given its limited antiviral potency and high risk of selection of resistance, which further results in wide cross-resistance to all other nucleoside analogues. Recent reports of transmission of lamivudine-resistant HBV in HIV patients are of especial concern, and large surveillance studies suggest that it may occur in up to 10% of new HBV infections in Western countries. Another worrisome aspect of the selection of lamivudine-resistant HBV is the potential for selection of vaccine escape mutants. Currently, tenofovir must be viewed as the drug of choice in HIV-HBV co-infected patients in whom antiretroviral therapy is advised. Its co-formulation with emtricitabine (Truvada) is particularly convenient for treating both HIV and HBV in co-infected individuals. While pegIFN-alpha monotherapy for 1 year may be considered for HIV-HBV coinfected individuals with good spontaneous HIV control (elevated CD4 cell count, low plasma HIV-RNA), and certain HBV features (genotype A, HBeAg+, low serum HBV-DNA and elevated ALT), it is clear that very few coinfected patients fulfill these criteria. In HBeAg-negative HIV patients, adefovir may be an option but the relatively low antiviral potency of this drug discourages its wide use. Given its potential anti-HIV activity, both entecavir and telbivudine must only be prescribed with antiretroviral agents. Lack of information about potential pharmacodynamic interactions between entecavir and abacavir (both are guanosine analogues) or between telbivudine and zidovudine or stavudine (all are thymidine analogues) further discourages their concomitant use. At this time, most experts agree that early introduction of anti-HBV active HAART is the best strategy for the treatment of chronic hepatitis B in HIV patients, and Truvada must be part of the triple regimen.

Topics: Adenine; Antiviral Agents; Deoxycytidine; DNA, Viral; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B Surface Antigens; Hepatitis B, Chronic; HIV Infections; Humans; Interferon alpha-2; Interferon-alpha; Lamivudine; Liver Cirrhosis; Nucleosides; Organophosphonates; Polyethylene Glycols; Pyrimidinones; Recombinant Proteins; Telbivudine; Tenofovir; Thymidine; Transaminases

Topics: Adenine; AIDS-Related Opportunistic Infections; Algorithms; Anti-HIV Agents; Antiviral Agents; Comorbidity; DNA, Viral; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Function Tests; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine

Telbivudine is a potent inhibitor of hepatitis B virus (HBV) replication without anti-HIV type-1 (HIV-1) activity demonstrated in vitro; however, very few clinical data on HIV-1-infected patients are available at present. Because it represents a therapeutic option in HIV-1-HBV-coinfected patients who do not require antiretroviral therapy, we strictly monitored three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy for chronic hepatitis B.. We performed molecular analysis of HBV DNA and of HIV-1 reverse transcriptase and protease RNA and DNA sequences in three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy.. Despite a transient and deep reduction of HIV-1 RNA, observed in two of the three patients studied, no genotypic resistance mutations were detected on both HIV-1 and HBV viruses.. Telbivudine therapy for 24 weeks showed a potent anti-HBV activity in HIV-1-positive, hepatitis B e antigen-positive patients with high HBV viraemia. No direct anti-HIV-1 activity of telbivudine was demonstrated and no genotypic resistance mutations to anti-HIV-1 drugs was found; however, the transient but deep reduction of HIV RNA, after telbivudine introduction, deserves further investigation and a strict monitoring of HIV-1 viraemia in HIV-1-infected patients on treatment with this drug.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; Hepatitis B, Chronic; HIV Infections; HIV-1; Humans; Male; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine; Treatment Outcome; Virus Replication

Topics: Administration, Oral; Adult; Alanine Transaminase; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interferons; Male; Nucleosides; Pyrimidinones; Retreatment; Telbivudine; Thymidine; Treatment Outcome; Virus Replication

Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

To analyze the clinical features and risk factors of adverse reactions associated with telbivudine.. Clinical data were collected from cases that presented with serious adverse reactions to telbivudine. We analyzed general information and medicine status, clinical features, results of examination, and misdiagnosis.. Out of 105 patients who were treated with telbivudine for hepatitis B in an outpatient department from January, 2007 to January, 2008, five presented with serious adverse drug reactions. Most of these five patients had used other nucleoside analogues in the past. Four were treated with a combination of telbivudine and interferon or another nucleoside analogue, while the other received an increased dose of telbivudine. The main adverse reactions were myalgia and general weakness. This was accompanied by cardiac arrhythmia in one patient, and nervous symptoms in three. Serum creatine kinase was elevated. The rate of misdiagnosis was high.. The adverse reactions were related to telbivudine, but the biological mechanism of the reactions is not yet clear. Combination therapy with interferon or another nucleoside analogue and a high dose may increase the risk of adverse reactions.

Topics: Adult; Arrhythmias, Cardiac; Creatine Kinase; Drug Synergism; Hepatitis B, Chronic; Humans; Interferons; Male; Middle Aged; Muscle Weakness; Neuralgia; Nucleosides; Pyrimidinones; Retrospective Studies; Risk Factors; Telbivudine; Thymidine

Hyperexpression of the programmed death 1 (PD-1) molecule is a hallmark of exhausted T-cells, having a negative impact on T-cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)-positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment-induced viremia reduction and HBeAg seroconversion with respect to PD-1 levels and T-cell reactivity. PD-1 expression was assessed by (1) flow cytometry and (2) quantitative real-time polymerase chain reaction; hepatitis B virus (HBV)-specific CD8+ T-cells were quantitated by pentamer staining; T-cell reactivity to HBV antigens was determined by interferon gamma (IFNgamma) and interleukin 10 (IL-10) enzyme-linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD-1 expression correlated closely with viremia levels. On therapy, PD-1 decreased significantly on total CD8+ T-cells, HBV-specific CD8+ T-cells, and CD3+/CD8- T-cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD-1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD-1 decrease with a 50% reduction in the frequency of PD-1+/CD8+ T-cells, which was not observed in patients remaining HBeAg-positive. The decrease in PD-1 expression was associated with increased frequencies of IFNgamma-producing T-cells and decreased frequencies of IL-10 producing T-cells. At baseline, PD-1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD-1 expression and HBcAg-specific effector phenotypes.. These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD-1 expression and resulting T-cell impairment. Treatment-induced suppression of HBV replication reduces PD-1 expression; however, additional immunotherapeutic interventions are needed for restoration of T-cell functions.

Topics: Adult; Alanine Transaminase; Antigens, CD; Antiviral Agents; Apoptosis Regulatory Proteins; Biopsy; CD8-Positive T-Lymphocytes; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-gamma; Interleukin-10; Lamivudine; Liver; Longitudinal Studies; Male; Middle Aged; Nucleosides; Programmed Cell Death 1 Receptor; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Viral Load; Viremia

Worldwide, 350 million people are infected with chronic hepatitis B. Over the last few years, it has been possible to treat chronic hepatitis B. Treatment very often consists of nucleos(t)ide analogs and in a few cases of pegylated alpha-interferon. In 2007, a new nucleoside analog, Telbivudine, was approved to treat chronic hepatitis B. In phase II and ongoing phase III studies, Telbivudine has proven more effective than the nucleoside analog, Lamivudine, which was very often used up until recently.

Topics: Antiviral Agents; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Thymidine

To investigate the effect of telbivudine on peripheral blood regulatory T cells and its significance in patients with chronic hepatitis B (CHB).. Thirty-six HbeAg positive chronic hepatitis B patients were recruited and received telbivudine treatment for 9 months. Before and during the 3, 6, 9 months of treatment, flow cytometry was used to detect the proportion of peripheral blood Tregs; real-time PCR was used to detect the levels of HBV DNA in the serum. Markers of hepatitis B virus infection were detected by ELISA assay and levels of alanine aminotransferase in the serum were measured.. The proportion of peripheral blood Tregs in patients with CHB was significantly higher than that in healthy controls and decreased over 6 or 9 months of telbivudine treatment to a level comparable to that of the healthy controls. After 3 months of telbivudine treatment, the rate of undetectable HBV DNA in patients whose proportion of peripheral blood Tregs was decreased was higher than those whose Tregs had been reduced, but the difference was not statistically significant (P more than 0.05). Three, 6 or 9 months of telbivudine treatment resulted in HbeAg negativity in 4 (11.1%) patients, 7 (19.4%) patients or 9 (25.0%) patients respectively. In 7 (19.4%) patients who had seroconversion from HBeAg to anti-HBeAg, after 3 or 6 months of telbivudine treatment, their proportion of peripheral blood Tregs had decreased to a level comparable to that of the healthy controls.. Telbivudine treatment reduces HBV replication and the proportion of peripheral blood Tregs. In addition, patients who have their proportion of peripheral blood Tregs decreased quickly at the early phase of telbivudine treatment are prone to have HBeAg to anti-HBeAg seroconversion.

Topics: Adolescent; Adult; Antiviral Agents; Case-Control Studies; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Interleukin-2 Receptor alpha Subunit; Middle Aged; Nucleosides; Pyrimidinones; T-Lymphocytes, Regulatory; Telbivudine; Thymidine; Young Adult

Topics: Antiviral Agents; Asia; Drug Therapy, Combination; Guanine; Hepatitis B, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Function Tests; Nucleosides; Pacific Islands; Practice Guidelines as Topic; Pyrimidinones; Recombinant Proteins; Severity of Illness Index; Telbivudine; Thymidine

Telbivudine does not offer any tangible advantage over existing treatments. It is better to continue to use lamivudine, which is known to prevent clinical complications and has been in use for many years.

Topics: Clinical Trials as Topic; Europe; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; United States

Topics: Adenine; Antiviral Agents; Deoxycytidine; Drug Resistance, Viral; Emtricitabine; Hepatitis B, Chronic; Humans; Interferons; Nucleic Acid Synthesis Inhibitors; Nucleosides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine

Topics: Antiviral Agents; Drug Resistance, Viral; Genotype; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Mutation; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Viral Load

Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.

Topics: Administration, Oral; Animals; Antiviral Agents; Carcinogenicity Tests; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Female; Hepatitis B, Chronic; Humans; Macaca fascicularis; Male; Mice; Mice, Transgenic; Mutagenicity Tests; Nerve Degeneration; Nucleosides; Pregnancy; Pyrimidinones; Rabbits; Rats; Rats, Sprague-Dawley; Reproduction; Safety; Telbivudine; Thymidine

Topics: Antiviral Agents; Clinical Trials as Topic; Drug Resistance, Viral; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Telbivudine; Thymidine

Topics: Antiviral Agents; Enzyme Inhibitors; Guanine; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine

Topics: Antiviral Agents; Dose-Response Relationship, Drug; Drug Resistance, Viral; Hepatitis B, Chronic; Humans; Nucleosides; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine; Treatment Outcome

Topics: Antiviral Agents; Clinical Trials as Topic; DNA, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Nucleosides; Pyrimidinones; Telbivudine; Thymidine; Virus Replication

Topics: Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Nucleosides; Practice Guidelines as Topic; Pyrimidinones; Telbivudine; Thymidine; Virus Replication

Topics: Adenine; Adolescent; Adult; Aged; Antiviral Agents; Biomarkers; DNA, Viral; Drug Therapy, Combination; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Male; Middle Aged; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Thymidine; Viral Load

We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrollment.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Italy; Liver Diseases; Lopinavir; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrimidinones; Ritonavir