pyrimidinones and adefovir

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

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

The combination of antiretroviral (ARV) therapies introduced at the end of the 1990s profoundly changed the natural history of human immunodeficiency virus (HIV) infection. Liver diseases are one of the three primary causes of 'non-AIDS-related' death in people living with HIV for three reasons: the high prevalence of hepatotropic viral co-infections, the hepatotoxicity of ARV drugs and new emerging liver diseases, including nodular regenerative hyperplasia and hepatitis E virus infection. The impact of HIV infection on the natural history of hepatitis C virus (HCV) or hepatitis B virus (HBV)/HIV co-infection has markedly changed in the past few decades with the progress made in ARV treatment and the improved definition of therapeutic strategies for HCV or HBV. Initially, HIV had a negative impact on hepatotropic infections. Today, HIV does not appear to significantly modify the natural history of HCV and HBV infection. This is associated with fair immune restoration, viral suppression associated with analogues having dual activity against HBV and HIV and with the increasing efficacy of antiviral treatments against HCV. A significant decline is expected in the morbidity and mortality associated with chronic liver infection in co-infected patients. Nevertheless, today, there are three major issues: (i) improving preventive measures including vaccination and risk reduction; (ii) screening patients infected with HBV or HCV and evaluating the impact of chronic infection on the liver and finally; (iii) early screening of hepatocellular carcinoma whose occurrence is higher and that evolves more rapidly in co-infected than in mono-infected patients.

Topics: Adenine; Antiviral Agents; Deoxycytidine; Disease Progression; Drug Therapy, Combination; Emtricitabine; Guanine; Hepatitis B; Hepatitis C; Hepatitis Viruses; HIV Infections; Humans; Interferon-alpha; Lamivudine; Nucleosides; Organophosphonates; 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

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

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. 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

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

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

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

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

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

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

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

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

Hepatitis B is a DNA virus affecting hundreds of millions of individuals worldwide. As the clinical sequelae of cirrhosis and hepatocellular cancer are increasingly recognized to be related to viral levels, the impetus increases to offer treatment to those previously not treated. With the development of more robust antivirals with reasonable safety profiles, long-term treatment is becoming more common. The oral nucleos(t)ide analogs have become the preferred first-line therapies for most genotypes of hepatitis B. Five are now available, all with different potencies and resistance profiles. Long-term data spanning several years are now available for most compounds in this arena. This article focuses on the common natural variants and those secondary to nucleos(t)ide therapy, as well as diagnostic methods to detect resistance.

Topics: Adenine; Antiviral Agents; Drug Resistance, Viral; Genetic Testing; Genotype; Guanine; Hepatitis B; Humans; Lamivudine; Nucleosides; Organophosphonates; Phenotype; Pyrimidinones; Telbivudine; Tenofovir; Thymidine

To reduce the incidence of drug resistance and to maintain viral suppression, patients chronically infected with HBV might require combination therapy using two or more drugs with different resistance profiles. We investigated the activity of clevudine (CLV) in combination with other nucleoside/nucleotide analogues to determine if these combinations were compatible in vitro.. Using the HepAD38 cell line, which expresses wild-type HBV, and a real-time PCR assay, we tested the anti-HBV activity of CLV in combination with entecavir, lamivudine, adefovir, tenofovir and telbivudine (TBV). We evaluated the uptake and phosphorylation of CLV in the presence of TBV, using HepAD38 cells and primary hepatocytes to determine the effect of TBV on the phosphorylation of CLV and vice versa. Phosphorylation of TBV and CLV to their corresponding monophosphate by deoxycytidine kinase, thymidine kinase-1 and thymidine kinase-2, and the phosphorylation of TBV monophosphate and CLV monophosphate by thymidylate kinase was evaluated and compared.. When CLV was combined with entecavir, lamivudine, adefovir or tenofovir, a synergistic antiviral effect was observed; however, the combination of CLV and TBV gave an antagonistic antiviral response. The results of in vitro metabolism and enzyme studies suggest that the antagonism observed with the CLV/TBV combination involves competition for uptake and phosphorylation.. The results of our studies demonstrate that combination treatments can provide enhanced antiviral activity and, when used in conjunction with appropriate metabolic investigations, provide a rational basis for the design and development of combination regimens for treating chronic HBV infection.

Topics: Adenine; Anti-HIV Agents; Antiviral Agents; Arabinofuranosyluracil; Cell Line; Cells, Cultured; Drug Antagonism; Drug Synergism; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatocytes; Humans; Lamivudine; Microbial Sensitivity Tests; Nucleosides; Nucleotides; Organophosphonates; Pyrimidinones; Reverse Transcriptase Inhibitors; Telbivudine; Tenofovir; Thymidine

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

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

Telbivudine, a nucleoside analog inhibitor of the viral polymerase of hepatitis B virus (HBV), has been approved for the treatment of chronic HBV infection, along with the nucleoside inhibitors lamivudine and entecavir, and the nucleotide inhibitors adefovir and tenofovir. The resistance profiles of these agents were investigated via drug treatment of HepG2 cells stably transfected with wild-type or mutant HBV genomes bearing known resistance mutations. Telbivudine was not active against HBV strains bearing lamivudine mutations L180M/M204V/I but remained active against the M204V single mutant in vitro, potentially explaining the difference in resistance profiles between telbivudine and lamivudine. Against HBV genomes with known telbivudine-resistance mutations, M204I and L80I/M204I, telbivudine, lamivudine and entecavir lost 353- to >1000-fold activity whereas adefovir and tenofovir exhibited no more than 3-5-fold change. Conversely, against HBV cell lines expressing adefovir resistance mutations N236T and A181V, or the A194T mutant associated with resistance to tenofovir, telbivudine remained active as shown by respective fold-changes of 0.5 (N236T) and 1.0 (A181V and A194T). These in vitro results indicate that nucleoside and nucleotide drugs have different cross-resistance profiles. The addition of telbivudine to ongoing adefovir therapy could provide effective antiviral therapy to patients who develop adefovir resistance.

Topics: Adenine; Amino Acid Substitution; Antiviral Agents; Cell Line, Tumor; Drug Resistance, Viral; Gene Products, pol; Hepatitis B virus; Humans; Microbial Sensitivity Tests; Mutation, Missense; Nucleosides; Organophosphonates; Pyrimidinones; Telbivudine; Tenofovir; 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

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

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

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

The new German and American guidelines on hepatitis B show similarities but also some discrepancies. In general, indication for therapy depends more on hepatitis B virus-(HBV-)DNA than alanine aminotransferase (ALT) values. Antivirals are recommended by German guidelines when HBV-DNA exceeds 10,000 copies/ml and ALT is increased more than twice the upper normal limit or when liver biopsy shows significant inflammation and fibrosis. By contrast, American guidelines recommend therapy only when HBV-DNA exceeds 100,000 copies/ml. American guidelines do not recommend lamivudine or telbivudine as initial monotherapy because of risk for resistance, but adefovir or entecavir. By contrast, according to German guidelines monotherapy with lamivudine, telbivudine, adefovir or entecavir may be initiated, if HBV-DNA is < 1 million copies/ml and cirrhosis is absent. Both guidelines recommend to monitor HBV-DNA even in the absence of therapy. Under antiviral therapy HBV-DNA should be measured more often than previously recommended to early identify lack of response and upcoming resistance. When resistance occurs, combination therapy is indicated. Risk for resistance is low as long as viral suppression is effective. In both guidelines liver biopsy should be considered when there are doubts on indication of therapy or selection of antiviral substances. In the presence of severe fibrosis and high HBV-DNA, antiviral substances should have high potency and low risk for resistance.

Topics: Adenine; Alanine Transaminase; Antiviral Agents; Biopsy; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Germany; Guanine; Hepatitis B; Humans; Lamivudine; Liver; Liver Cirrhosis; Nucleosides; Organophosphonates; Practice Guidelines as Topic; Pyrimidinones; Telbivudine; Thymidine; United States