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Chronic hepatitis B (CHB) remains an important health issue in Taiwan. The major candidates for antiviral therapy are HBeAg-positive and -negative CHB patients, and individuals with compensated or decompensated cirrhosis. Lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF) are the currently available nucleos(t)ide analogues (NA). Entecavir and TDF are recommended as the first-line agents for long-term use. The therapeutic endpoints recommended by the Asian Pacific Association for the Study of the Liver treatment guidelines have been adopted for clinical practice. Only a small number of patients qualify for short-term NA therapy; the majority of patients need long-term treatment. Current therapeutic endpoints confer off-therapy durability in approximately 50 % of patients. Patients with cirrhosis should receive long-term NA therapy. The use of serum HBsAg level as a guide for cessation of NA therapy requires further investigation.

The introduction of the new DAAs Entecavir and Tenofovir have had a major impact on liver transplant for hepatitis B virus (HBV) infection. These agents have been shown to rescue patients with decompensated HBV in a manner similar to Lamivudine but without the same concern about resistance. The use of these agents post liver transplant with HBIG reduce HBV recurrence to

The treatment of chronic hepatitis B has been transformed with the advent of nucleos(t)ide analogues. With this came the recognition of viral resistance which was defined as rebound of viral HBV DNA >1 log from nadir associated with genotypic mutations of viral resistance. Resistance was associated with loss of efficacy, with the clinical consequences of viral relapse, reactivation of chronic hepatitis B, increased risk of hepatitis B flares, liver decompensation, and increased mortality especially in cirrhotic patients. Resistance rates varied between different nucleos(t)ide analogues and were generally classified as low or high genetic barrier to resistance. Different pathways to development of viral resistance were recognized, with therapeutic options for rescue therapy determined by such pathways. The two high genetic barrier drugs, entecavir and tenofovir showed remarkably low or absence of viral resistance in treatment naive patients over 5 years or longer of therapy. However in treatment-experienced patients, particularly those with viral resistance, results were less optimal. For entecavir, prior lamivudine resistance conferred an entecavir resistance rate of 43 % over 5 years while with tenofovir, although resistance did not seem apparent, patients with prior adefovir resistance had suboptimal responses to tenofovir therapy. In cases of multiresistant hepatitis B virus defined as resistance to at least two nucleos(t)ide analogues in the same viral strain, rescue with a combination of tenofovir and entecavir appeared highly efficacious. Consequently, the optimistic view that these new drugs lead to absence of resistance needs to be tempered by the larger burden of drug experienced and drug resistant patients compared to treatment naive patients. Furthermore, it is unclear whether resistance may be a concern with high genetic barrier drugs after one or two decades of therapy. In time, it is possible that with the increasing use of high genetic barrier drugs, viral resistance will be a lesser problem, but unlikely to disappear completely.

Long-term administration of oral anti-hepatitis B virus (HBV) nucleoside or nucleotide analogues therapy (NUC) is the first-line treatment option for most patients with chronic hepatitis B infection. Although NUC rapidly inhibits HBV replication in most patients, in the long term, this therapeutic regimen is challenged by the emergence of drug-resistant mutant virions, ultimately leading to treatment failure and liver disease progression. Indeed, viral resistance occurs most frequently in patients exposed to first-generation NUC (e.g., lamivudine), whereas second-generation regimens (e.g., adefovir and telbivudine) are definitively safer but still at risk of developing resistance. Third-generation NUCs (e.g., entecavir and tenofovir) are considered safe and unlikely to cause genetic resistance. Drug-resistant strains can be identified by close monitoring of serum levels of HBV DNA before they can attenuate the antiviral response, and can be rescued by a specific “add-on” strategy with a non–cross-resistant drug, to ensure complete long-lasting suppression of HBV. Entecavir and tenofovir are the recommended first-line options in naive patients to minimize the risk of drug resistance. Tenofovir is the recommended rescue therapy in most patients who fail to respond to nucleoside analogues.

Acute infection with the hepatitis B virus resolves in 95% of adults with no need for specific medical therapy. However, a few cases present as severe hepatitis or acute liver failure, which may require orthotopic liver transplantation or cause death. Under these circumstances, medical therapy that can improve the clinical outcome and improve spontaneous survival would be highly useful; yet, published data regarding the utility of antiviral therapy in acute hepatitis B is quite limited. In this paper, the efficacy and safety of oral nucleoside and nucleotide analogues in the treatment of acute hepatitis B are reviewed, and guidelines for treatment of these acute cases are revisited.

Chronic hepatitis B virus (HBV) infection remains a major cause of liver disease and hepatocellular carcinoma worldwide. Although less prevalent in the United States than in other areas of the world, HBV infection results in a significant disease burden in many American immigrant communities. Seven treatments are approved by the US Food and Drug Administration for the treatment of chronic HBV infection: interferon-α (standard interferon-α2b or pegylated interferon-α2a), and the nucleos(t)ide analogues lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. There is preliminary evidence that the disease burden from HBV infection may be diminishing in the United States, reflecting not only HBV vaccine progress but also more than a decade of antiviral therapy.

Chronic hepatitis B infection remains a relatively common disease in European hepatology and gastroenterology practice. Current treatment guidelines in Europe discuss pegylated interferon-α or nucleoside analogues in treating chronic hepatitis B. The indications and the necessity for treatment are based mainly on the combination of three criteria: serum hepatitis B virus DNA concentrations, serum aminotransferase levels, and histologic grade and stage. The advent of potent nucleoside analogues with low rates of resistance has potentially simplified treatment. The pipeline of new agents to treat hepatitis B remains restricted, and cross-resistance is shared by several nucleosides. Thus, the guidelines emphasize the advantage and necessity of using potent agents with low rates of resistance as optimal therapy to avoid difficult-to-treat, multidrug-resistant hepatitis B.

Suppression of hepatitis B virus DNA is a principal goal in treating chronic hepatitis B because suppression improved liver histology and decreased the risk of developing hepatic complications and hepatocellular carcinoma. For patients who do not qualify for treatment with pegylated interferons, five nucleotide reverse transcriptase inhibitors (NRTIs) are available to treat chronic hepatitis B. These drugs differ significantly in antiviral efficacy and resistance profile, and the clinician should be aware of both factors for rational treatment decisions. A major problem when using NRTIs to treat patients with chronic hepatitis B is the risk of viral resistance, which may result in viral breakthrough and treatment failure. This article summarizes recent findings on clinical implications and treatment recommendations to avoid and manage viral resistance and suboptimal treatment success.

Viral hepatitis, specifically hepatitis B or C, is a worldwide epidemic that causes significant morbidity and mortality, including the development of cirrhosis, hepatocellular carcinoma, and hepatic decompensation. The management and treatment of viral hepatitis and renal failure is clinically challenging because of the potential for an additive increase in morbidity and mortality. This article reviews the current scientific literature designed to assess the prevalence, diagnostic evaluation, and clinical course of viral hepatitis in individuals with renal failure as well as current treatment options.

Chronic hepatitis B virus infection is a leading cause of morbidity and mortality throughout the world. Antiviral therapy should target patients who are at a substantial risk of developing liver disease because the response to treatment is often suboptimal and long-term monotherapy is invariably associated with the development of resistance. Currently, there are six agents approved for the treatment of chronic hepatitis B: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine. The currently available monotherapy regimens have limited efficacy and result in suboptimal responses in many patients with chronic hepatitis B. Various studies have evaluated different combination regimens for the treatment of chronic hepatitis B, but no combined regimen has been proven superior to monotherapy in achieving sustained off-treatment viral suppression. Combination therapy has the advantage of a reduced rate of antiviral drug resistance, but this relative benefit over drugs with a low risk of antiviral drug resistance when used as monotherapy requires further comparative study.

Chronic hepatitis B with negative hepatitis B e antigen (HBeAg) is becoming a more prevalent form of chronic hepatitis B. This change is the result of selection pressure on the virus leading to a precore or double core promoter mutation of hepatitis B virus that either abolishes or downregulates synthesis of HBeAg. De novo acute infection with HBeAg-negative mutant virus rarely leads to chronic infection but usually results in acute hepatitis with a course ranging from benign to fulminant. Chronic HBeAg-negative hepatitis B is thought to evolve from wildtype HBeAg-positive chronic hepatitis B and is associated with a worse natural history than HBeAg-positive disease. Long-term treatment is required to maintain suppression of viral replication when using the oral nucleoside or nucleotide analogues, which have improved management of this condition. However, the need for extended therapy makes strategies to reduce or avoid resistance to antiviral drugs an important consideration.

A new era in the treatment of chronic hepatitis B began approximately a decade ago. Three oral nucleoside or nucleotide analogues—lamivudine, adefovir dipivoxil, and entecavir—are now approved in the United States for the treatment of chronic hepatitis B. Other new oral agents, including telbivudine, clevudine, and emtricitabine, are in various stages of clinical investigation. This article reviews the efficacy and resistance data of these oral antiviral agents, and the preliminary results of combination therapy for chronic hepatitis B.

Treatment protocols for chronic liver disease caused by hepatitis C virus (HCV) and hepatitis B virus have different outcomes among various ethnic groups. Outcome information has been slowed by the limited number of trials aimed at the various ethnic minorities. The current opinion is that there is a vast difference in treatment success with antiviral therapies, especially with African-American men suffering from chronic HCV. This article investigates the up-to-date information in treatment outcomes for the two diseases, and liver transplant survivals.

Coinfection of hepatitis C virus (HCV)-infected patients with HIV or hepatitis B virus (HBV) is common because of shared modes of transmission. Coinfection with HBV or HIV has been shown to accelerate the course of chronic hepatitis C and facilitate progression to cirrhosis and hepatocellular carcinoma. Currently, the combination of pegylated interferon and ribavirin is the best available treatment in HIV/HCV-coinfected patients. The optimal treatment of HCV in persons with HBV coinfection has not been defined but may include pegylated interferon alpha plus ribavirin initially, followed by oral anti-HBV agents, such as lamivudine or adefovir, or both.

Chronic hepatitis B virus (HBV) infection is the leading cause of cirrhosis and hepatocellular carcinoma. The availability of universal vaccination has made a significant impact in reducing the incidence of these complications. Several developments have been made in the treatment of chronic HBV infection. Three drugs (interferon alpha, lamivudine, and adefovir dipivoxil) are currently approved for use in HBV infection in the United States; these treatments have been shown to reduce morbidity and mortality for some individuals with chronic hepatitis B. However, these therapies are not universally successful and have limited long-term efficacy. In addition, the development of drug-resistant HBV mutants also impacts on the long-term benefit of some of these agents. Several new agents are currently undergoing study and will add to the list of available agents for the treatment of chronic HBV infection. In addition, the role of combination therapy using two or more agents has not been well defined in the management of hepatitis B.

Nucleos(t)ide analogues have revolutionized the treatment of chronic hepatitis B. However, the rapid emergence of drug-resistant strains of the hepatitis B virus poses a new challenge to clinicians and patients. Modern molecular technologies have uncovered the biology of drug resistance and aided the monitoring and treatment of this condition. This article updates the molecular virology of drug resistance in chronic hepatitis B virus infection.

There have been many exciting developments in the treatment of chronic hepatitis B during the past several years. Interferon, adefovir, and lamivudine are currently licensed therapies, and several promising nucleoside analogues that are capable of treating both wild-type and lamivudine-resistant forms of hepatitis B virus are in latestage development. Pegylated interferon has been shown to have greater antiviral activity when compared with conventional interferon. Each of these drugs has advantages and disadvantages. The greatest challenge for the future will reside in how to best use these agents, either alone or in combination, so as to maximize therapeutic benefit.

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis is characterized by persistent or intermittent hepatitis B virus (HBV) replication with a high lifetime incidence of cirrhosis and hepatocellular carcinoma. Antiviral therapy, which aims to suppress viral replication, may be achieved in as many as 70% to 90% of patients treated with 1 year of lamivudine and 51% to 74% of patients treated with 1 year of adefovir dipivoxil (ADV). However, the short-term therapeutic advantage of lamivudine is offset by the high incidence of drug-resistant mutations, which approaches 60% at 48 months. Both lamivudine and ADV have been associated with a high rate of virologic relapse following drug withdrawal and a low rate of hepatitis B surface antigen (HBsAg) clearance. Although interferon alpha is associated with HBsAg loss in up to 10% of treated patients, its side-effect profile precludes its use in patients with advanced liver disease. Thus, selection of antiviral therapy for patients with HBeAg-negative liver disease requires individualization based on disease severity, drug efficacy, and resistance profile.

The outcome of orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver disease depends on the prevention of allograft reinfection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of longterm hepatitis B immunoglobulin (HBIG) administration as a prophylaxis of HBV recurrence and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM) or adefovir, were a major breakthrough in the management of these patients. The results of OLT for HBV infection are similar to those results achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and, thus, decrease the risk of reinfection of the graft. Combination prophylaxis with LAM and HBIG after transplantation is highly effective in reducing the rate of HBV reinfection even in HBV-replicative cirrhotic patients. The optimal HBIG protocol in the LAM and adefovir era has yet to be defined: dosing of HBIG, routes of administration, and the possibility of stopping HBIG.

Interferon (IFN) alpha, lamivudine, and adefovir are the three antiviral therapies currently approved for the treatment of chronic hepatitis B virus (HBV). Initiation of treatment is indicated in patients with abnormal liver enzymes and markers of active viral replication (ie, HBV DNA positive). Hepatitis B early antigen seroconversion rates are higher and treatment duration is shorter with IFN than with lamivudine or adefovir. However, treatment results in frequent side effects and many patients have contraindications to therapy. Lamivudine and adefovir are better tolerated, but have lower seroconversion rates after 12 months of treatment. Resistance develops in 20% of lamivudine patients after 12 months; adefovir resistance has not been identified to date. Individualization of therapy, based on factors such as patient comorbidities, response to prior therapies, and stage of disease (ie, presence of cirrhosis), is recommended. All patients over the age of 40 or with advanced liver disease should be continually screened for hepatocellular carcinoma with serum alphafetoprotein and abdominal imaging every 6 months.

There are three licensed drugs for chronic hepatitis B at the current time: interferon alpha, and the nucleoside analogues, lamivudine and adefovir. The benefits as well as limitations of each of these agents are described in this article. Preliminary studies suggest that the combination of interferon and lamivudine is associated with an enhanced rate of virologic response when compared with either agent alone.