Oral antivirals for chronic hepatitis B

Four oral antiviral agents have been approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B: lamivudine, adefovir, entecavir, and telbivudine. This article reviews the durability of response, dose regimen, predictors of response, safety, and problems with resistance of these four agents and of promising agents currently in phase III clinical trials for the treatment of patients who have hepatitis B e antigen-positive and -negative chronic hepatitis B.     

Newer antiviral agents and therapeutic approaches for chronic hepatitis b

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.     

Management of chronic hepatitis B in treatment-experienced patients

Current monotherapy with interferon (IFN), lamivudine, or adefovir remains unsatisfactory for most patients with chronic hepatitis B infection. Prolonged treatment with lamivudine monotherapy is needed in most patients with chronic hepatitis B infection and leads to an increased risk of developing lamivudine resistance. Recent data suggest that lamivudine resistance occasionally can result in serious clinical sequelae. On the other hand, conventional IFN treatment is ineffective in up to 70% of chronic hepatitis B patients. Adefovir resistance, although less frequent than lamivudine resistance,also has been identified. With the introduction of new nucleoside/nucleotide analogs such as entacavir, clevudine, LFd4C,tenofovir, and immunomodulatory agents such as pegylated IFN, new treatment options, either alone or in combination, are being investigated to increase the response rate in treatment-na?ve and treatment-experienced chronic hepatitis B patients.     

DNA-guided hepatitis B treatment： Viral load is insufficient with few exceptions

In DNA-guided hepatitis B treatment, viral load is insufficient, and requires other viral markers for treatment of hepatitis B patients as in patients with acute exacerbation of chronic hepatitis B, end-stage renal disease on dialysis, human immunodeficiency virus co-infected patients. There are exceptions to this rule： a residual level hepatitis B virus （HBV） DNA at 24 wk predicts beneficial outcome and reduced resistance at i year. The genotypic viral resistance to antiviral agents and occult HBV infection can be determined by HBV-DNA levels.     

Current treatment of chronic HBV infection: A European perspective

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.     

Tratamiento actual de la hepatitis B: ¿dónde encajan los nuevos análogos de los núcleos(t)idos?

One of the most important advances made in the treatment of chronic hepatitis B infection has been the development of nucleos(t)ide analogues. The first antiviral agents used had limited efficacy due to the high resistance rate. However, in the last few years, new agents (tenofovir, entecavir) have been developed with greater antiviral potency and a lower resistance rate. Consequently, these agents are considered to be the treatment of choice in the most recent clinical guidelines. Nevertheless, interferon may still play an important role in the treatment of hepatitis B in selected patients. Moreover, in some contexts, such as renal insufficiency, pregnancy or immunosuppression, the role of the new oral antiviral agents has not been precisely defined.The present review analyzes these aspects, as well as some of the particular features of the management of patients treated with nucleos(t)ide analogues.     

Therapeutic Options for Chronic Hepatitis B: Considerations and Controversies

Five agents are currently approved for the treatment of chronic hepatitis B infection. This article will discuss the three agents for which the most extensive data are available; interferon (IFN), lamivudine, and adefovir, while the following article by Dr. Jules Dienstag will discuss the recently marketed agents, entecavir and peginterferon alfa-2a. The advantages of IFN are its finite duration of therapy (4–6 months), lack of emergence of resistance, and durability of response. On the negative side, response to IFN is less durable in patients with HBeAg-negative chronic hepatitis B virus (HBV). Also, use of IFN is limited by adverse effects and the mode of administration (daily to thrice-weekly subcutaneous injection). Lamivudine and adefovir are orally administered and have good tolerability and safety. Even in patients who experience a marked decrease in serum HBV DNA and loss of HBeAg, oral therapy needs to be continued for at least 6 months, to avoid the risk of reappearance of HBeAg and viremia. Rates of HBeAg seroconversion to anti-HBe-positivity increase with duration of lamivudine or adefovir therapy. The likelihood of development of resistance to lamivudine and associated viral breakthrough limits its long-term use. In patients with HBeAg-negative chronic hepatitis B, long-term therapy is usually required, as off-treatment relapse is common. The emergence of resistance to adefovir is delayed and infrequent, hence adefovir may be preferred in patients requiring long-term therapy.     

Current treatment of hepatitis B infection: where do the new nucleos(t)ide analogues fit in?

One of the most important advances made in the treatment of chronic hepatitis B infection has been the development of nucleos(t)ide analogues. The first antiviral agents used had limited efficacy due to the high resistance rate. However, in the last few years, new agents (tenofovir, entecavir) have been developed with greater antiviral potency and a lower resistance rate. Consequently, these agents are considered to be the treatment of choice in the most recent clinical guidelines. Nevertheless, interferon may still play an important role in the treatment of hepatitis B in selected patients. Moreover, in some contexts, such as renal insufficiency, pregnancy or immunosuppression, the role of the new oral antiviral agents has not been precisely defined. The present review analyzes these aspects, as well as some of the particular features of the management of patients treated with nucleos(t)ide analogues.     

Management of hepatitis B and C in special population

Chronic viral hepatitis is one of the leading causes of cirrhosis worldwide. Chronic hepatitis B is more common in the Asia-Pacific region due to the larger population and lower screening availability. Hepatitis C predominates in the west due to injection drug abuse. The discovery of (oral) direct-acting antiviral agents (DAAs) has changed the landscape of chronic hepatitis C (CHC) management. Nucleos(t)ide analogs (NUCs) have also changed the approach to the treatment of chronic hepatitis B (CHB). Oral NUCs and DAAs have excellent efficacy and patient acceptance as well as a lower risk of resistance. However, certain populations have no robust data and safety and efficacy of such oral drugs is still evolving. In this review, we provide an overview of the management of CHB and CHC in special populations, such as those with chronic kidney disease, pregnant women, healthcare workers, and those undergoing chemo- or immunosuppressive therapy.     

Antiviral Therapy: Analysis of Long-term Efficacy and Safety

Despite the adoption of universal vaccination in many countries, chronic hepatitis B virus (HBV) infection continues to be a global problem. Morbidity and mortality from this infection, although possibly declining, remains significant. Fortunately, our treatment armamentarium has expanded exponentially in the past decade. Newer antiviral agents are not only effective against HBV infection, but they also confer a lower risk for virologic resistance than the first-generation oral nucleoside, lamivudine. In this article, the long-term efficacy and safety of available antiviral therapy in the treatment of chronic hepatitis B are reviewed, and differences in drug potencies, side-effect profiles, and risks of development of virologic resistance are discussed to provide guidance for optimal choices for long-term antiviral therapy.     

Dual therapy for chronic hepatitis B virus

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: early viral suppression and long‐term outcomes of therapy with oral nucleos(t)ides

Summary. 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.     

Monitoring and treatment strategy for chronic hepatitis B and antiviral resistant hepatitis B]

Clinical management of chronic hepatitis B is rapidly evolving after the recent development of new antiviral drugs. These agents have been shown to be effective in improving virological, biochemical, and histological features in high proportion of the patients with chronic hepatitis B. However, these drugs can not eliminate hepatitis B virus (HBV) directly. It can only suppress HBV replication. Furthermore, the emergence of drug resistant HBV has become problematic according to the long-term use of oral antiviral drugs. Therefore, physicians should be careful in selecting whom to treat, when to start treatment, how long to treat, how to monitor patients before, during and after the treatment, which drug to choose, and how to manage patients with drug resistance. This review will focus on the monitoring and treatment strategy for chronic hepatitis B and drug resistant hepatitis B, quoting some clinical data of recently introduced or promising future drugs.     

Telbivudine： A new treatment for chronic hepatitis B

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.     

Treatment of chronic hepatitis B with the combination of pegylated interferon with lamivudine

Several agents are currently approved for the treatment of chronic hepatitis B: interferon alpha (IFN), pegylated interferon-α (PEG IFN), lamivudine, adefovir, and entecavir. Each agent has inherent limitations. IFN is effective in a minority of patients and has frequent side effects that limit its tolerability. Large randomized controlled trials have demonstrated the efficacy of PEG IFN in the treatment of chronic hepatitis B. The efficacy of lamivudine is limited by the emergence of drug-resistant hepatitis B virus (HBV) mutants, restricting its utility as a long-term therapy. Adefovir is well tolerated and is associated with low incidence of resistance, but its antiviral effect is not optimal. Entecavir has a high antiviral effect and is well tolerated. However, its long term efficacy and resistance profile are not yet determined. Lamivudine, adefovir and entecavir have the advantages of oral administration and excellent safety profiles. However, theyinduce a sustained response after withdrawal of therapy in only a minority of patients, and therefore, the treatment needs to be indefinitely administered in most patients. IFNs have two mechanisms of action: (i) direct antiviral effect by inhibiting synthesis of viral DNA and by activating antiviral enzymes; and (ii) exaggeration of the cellular immune response against hepatocytes infected with HBV. PEG IFN, administered for 48 weeks, gives an overall sustained response rate of approximately 30%. Two large randomized controlled trials have conducted to registration of PEG IFN-α-2a in the treatment of chronic hepatitis B.     

Economics of chronic hepatitis B and hepatitis C

Although not all patients develop progressive liver disease, chronic hepatitis B and chronic hepatitis C infections cause substantial morbidity and mortality worldwide. To address this need, many new antiviral treatments have become available over the past 10 years. While safety, efficacy, and therapeutic indications have been well established for these agents, the economics of antiviral treatment have become increasingly a focus of discussion for physicians, policymakers, and health payers. In this paper, we will elucidate some economic principles using examples from the treatment of hepatitis B and C. In particular, we will examine the considerations in estimating drug costs, methods for performing economic analyses and lastly summarize published cost-effectiveness analyses for antiviral treatments of chronic hepatitis B and chronic hepatitis C. This review should help clinicians understand economic issues regarding new drugs and answer questions about whether the clinical benefit provided by a medication justifies its expense.     

替诺福韦酯挽救治疗对核苷（酸）类药物耐药的慢性乙型肝炎研究进展

核苷（酸）类似物已广泛应用于慢性乙型肝炎的治疗,其中替诺福韦酯（TDF）具有安全性高和耐药率低的特点,对慢性乙型肝炎（CHB）初治、经治患者,甚至是肝硬化肝功失代偿期患者均具有较强的抗病毒作用,成为经治耐药患者补救治疗的最佳选择。本文综述了TDF在拉米夫定、阿德福韦酯、恩替卡韦治疗慢性乙型肝炎无效或其他核苷（酸）类药物耐药患者中的抗病毒疗效。     

A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.

BACKGROUND AND AIMS: Chronic hepatitis B is an important public health problem worldwide and in the United States. A treatment algorithm for chronic hepatitis B virus (HBV) infection was developed by a panel of US hepatologists based on new developments in the understanding of the virology of HBV, availability of more sensitive molecular diagnostic testing, and advantages and disadvantages of currently approved therapies. METHODS: This algorithm is based on available evidence, but where data are lacking, the panel relied on clinical experience and consensus expert opinion. RESULTS: Serum HBV DNA can be detected at levels as low as 100-1000 copies/mL by using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest level possible. The threshold level of HBV DNA for determination of candidacy for therapy is >/=10(5) copies/mL for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A lower serum HBV DNA threshold is appropriate for patients with HBeAg-negative chronic hepatitis B and those with decompensated cirrhosis, and the panel recommends thresholds of 10(4) copies/mL and 10(3) copies/mL, respectively. CONCLUSIONS: Interferon alfa-2b, lamivudine, and adefovir dipivoxil are all approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost. Studies are under way to explore the safety and efficacy of combination therapy, which may prove to be more effective than monotherapy in suppressing viral replication and may decrease or delay the incidence of drug resistance.     

替诺福韦酯与恩替卡韦对慢性乙型肝炎初治疗患者的疗效

目的评估替诺福韦酯与恩替卡韦在治疗慢性乙型肝炎的疗效。 方法纳入2010年6月至2015年6月入住济南军区总医院的慢性乙型肝炎的初治患者100例,采用随机数字表法分为观察组(替诺福韦酯)50例、对照组(恩替卡韦)50例,随访时间12、24个月,比较二者在HBV-DNA转阴率、HBeAg血清学转换率、丙氨酸转氨酶复常率、耐药率、安全性方面是否存在差异。 结果与治疗前比较,观察组与对照组在随访观察12、24个月后各项指标较前明显改善,但二者在HBV-DNA转阴率(32/50 vs.28/50、46/50 vs.42/50)、HBeAg血清学转换率(4/28 vs.6/30、8/28 vs.12/30)、丙氨酸转氨酶复常率(42/50 vs.40/50、49/50 vs.46/50)、耐药率方面未见明显差异;但长期口服恩替卡韦对肾脏影响高于替诺福韦酯组,差异有统计学意义(P<0.05)。 结论替诺福韦酯与恩替卡韦比较,二者在治疗慢性乙型肝炎效果相当,但长期口服药物安全性方面有优势,因此建议长期治疗慢性乙型肝炎临床运用替诺福韦酯作为首选方案。     

Medical therapy of patients affected by HBeAg-negative chronic hepatitis B

Five agents are currently approved for the treatment of chronic hepatitis B: standard interferon-alpha (IFN-alpha), pegylated interferon-alpha 2a (PEG-IFN-alpha 2a), lamivudine, adefovir and entecavir. Each agent has inherent limitations. IFN and PEG-IFN-alpha 2a are effective in a minority of patients and have frequent side effects that limit their tolerability. The efficacy of lamivudine is limited by the emergence of drug-resistant hepatitis B virus (HBV) mutants, restricting its utility as a long-term therapy. Adefovir is well tolerated and associated with a low incidence of resistance but its antiviral effect is not optimal. Entecavir, which has been recently registered, has a more potent anti-viral effect but its long term efficacy and resistance profile is still not known. These antivirals induce a sustained response after withdrawal of therapy in only a minority of patients and therefore the treatment needs to be indefinitely administered in the majority of patients. After a brief summary of the natural history of chronic hepatitis B in order to understand the indications and the objectives of therapy, this review focuses on treatment of HBeAg-negative chronic hepatitis B with IFN and PEG-IFN-alpha 2a.