Hepatitis B virus DNA and hepatitis B surface antigen levels in chronic hepatitis B

Despite universal vaccination, chronic hepatitis B (CHB) continues to be a major health burden worldwide, with an estimated 350–400 million people infected with the virus. Over the past decade, rapid progress has been made with regards to antiviral therapy for CHB, from conventional interferon to pegylated interferon, and with the earliest oral agent lamivudine to the current, more potent drugs such as entecavir and tenofovir. There have also been new developments in the diagnostic and monitoring tools for CHB. Qualitative hepatitis B surface antigen (HBsAg) testing has been used to diagnose patients infected with CHB. More recently, quantitative HBsAg titers have been used to predict treatment outcome when measured at baseline or early into treatment. The progress on the use of hepatitis B virus (HBV) DNA levels has been more rapid. Serum HBV DNA levels have been shown to be important in the natural history of CHB infection, with higher levels being significantly associated with the development of cirrhosis and hepatocellular carcinoma. For patients receiving antiviral therapy, the baseline and early on-treatment HBV DNA levels are important in determining treatment outcomes. Monitoring of HBV DNA levels during therapy will allow for early detection of drug resistance. The end-of-treatment and post-treatment HBV DNA levels have been demonstrated to be important indicators of treatment success and relapse, respectively. With newer and more powerful antiviral agents, and with the development of quantitative assays that are highly sensitive, further studies are needed to optimize the use of these tools and agents in the modern management of CHB.     

Entecavir is a potent anti-HBV drug superior to lamivudine: experience from clinical trials in China

Infection with the hepatitis B virus (HBV) can result in chronic hepatitis B (CHB) in many patients. Patients with CHB require regular screening and monitoring to facilitate disease surveillance and to determine if/when treatment is indicated. The current goal of CHB treatment is sustained viral suppression with the aim of reducing or preventing hepatic injury and disease progression. Effective anti-HBV therapy is now available that can suppress, but not eradicate, HBV replication. Among the currently licensed and approved anti-HBV nucleos(t)ides, entecavir demonstrates a potent anti-HBV activity and a low rate of emergence of drug resistance, with good safety and tolerability profiles. These excellent pharmacological characteristics were assessed both in large international clinical trials and in separate studies in China. This article presents results from Phase II and Phase III trials involving 876 Chinese patients with CHB. The results of these studies suggest that entecavir should be recommended as a first-line choice among the currently available anti-HBV nucleos(t)ides.     

Postexposure Prophylactic Effect of Hepatitis B Virus (HBV)-Active Antiretroviral Therapy against HBV Infection

Retrospective study indicates that hepatitis B virus (HBV)-active nucleoside (nucleotide) analogues (NAs) used for antiretroviral therapy reduce the incidence of acute HBV infections in human immunodeficiency virus (HIV)-infected patients. Learning from HIV postexposure prophylaxis (PEP), we explored the possibility of using NAs in PEP following HBV exposure, if preexposure prophylaxis is feasible clinically. Using freshly isolated primary human hepatocytes cultured in vitro, we analyzed the effect of HBV-active tenofovir and lamivudine in primary HBV infection and also the effect of treatment with these NAs after HBV infection. HBV-active NAs applied from 24 h before inoculation could not prevent the secretion of hepatitis B surface antigen into the culture medium, and cessation of the NAs after inoculation allowed the cells to establish an apparent HBV infection. In contrast, hepatitis B immune globulin was able to prevent HBV infection completely. NA treatment before infection, however, can control the spread of HBV infection, as detected by immunohistochemistry. Practically, starting NA treatment within 2 days of primary HBV infection inhibited viral spread effectively, as well as preexposure treatment. We demonstrated that preexposure NA treatment was not able to prevent the acquisition of HBV infection but prevented viral spread by suppressing the production of mature progeny HBV virions. The effect of postexposure treatment within 2 days was similar to the effect of preexposure treatment, suggesting the possibility of HBV PEP using HBV-active NAs in HIV- and HBV-susceptible high-risk groups.     

Nucleos(t)ide analogues for preventing HBV reactivation in immunosuppressed patients with hematological malignancies: a network meta-analysis

Background: We aimed to evaluate the efficacy of five oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of hepatitis B virus (HBV) reactivation and HBV-related complications in chronic hepatitis B virus (CHB) infected patients with hematological malignancies receiving chemotherapy or hematopoietic stem cell transplantation (HSCT) by network meta-analysis.

Methods: The search identified 28 articles involving 5 different prophylactic regimens covering 1478 participants.

Results: Among five prophylactic regimes, tenofovir (predicted probability, 90%), was the most effective intervention followed by entecavir (88%) in preventing HBV reactivation. There was no significant difference between tenofovir and entecavir for preventing HBV reactivation. With regards to other outcomes, tenofovir and telbivudine was not included to evaluate due to lack of relevant studies. Entecavir was the most effective intervention in reducing the risk of HBV related hepatitis (100%), HBV related death (61%) and all other causes of hepatitis (98%).

Conclusion: Tenofovir and entecavir might be the most potent regimes in prevention of HBV reactivation for CHB infected patients with hematological malignancies undergoing chemotherapy or HSCT.     

Special considerations and treatment of patients with HBV-HIV coinfection

Coinfection with HIV and hepatitis B virus (HBV) substantially alters the natural course of HBV infection as well as its management. Therapy for HBV infection in HIV-coinfected patients requires several factors to be taken into consideration, such as whether the antiviral activity of a particular agent is specific for HBV (that is, adefovir, entecavir, telbivudine and pegylated interferon) or for both viruses (that is, lamivudine, emtricitabine and tenofovir), whether the chosen drug has the potential for inducing drug resistance and cross-resistance, and whether use of the agent is associated with hepatotoxicity. For coinfected patients who do not require therapy for their HIV infection, clinicians should avoid prescribing monotherapy with agents that have activity against HIV (that is, tenofovir, entecavir, emtricitabine or lamivudine) so as not to compromise future HIV care. This review discusses the current status of treatment of hepatitis B in the setting of HIV infection. It describes emerging therapeutic strategies and addresses challenges in the treatment of coinfection.     

New approaches to optimize treatment responses in chronic hepatitis B

Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are seven approved agents including two forms of interferon (conventional and pegylated), and five oral nucleoside/nucleotide analogues (lamivudine, adefovir, entecavir, telbivudine and tenofovir disoproxil fumarate). The availability of these multiple treatment options has led to expansion of treatment indications. However, the need for a long duration of treatment with some therapies, the high costs of HBV medications, the side effects associated with some treatments and the risks of drug resistance during long-term use of oral antiviral medications necessitate the careful assessment of the risk-benefit ratio prior to initiating treatment, and the evaluation of better strategies to optimize response once treatment is initiated. In this article, we review the current approaches to optimize treatment response to nucleoside/nucleotide analogue- and interferon-based therapies for chronic hepatitis B.     

Entecavir for the long-term treatment of chronic hepatitis B

Hepatitis B virus is a major cause of chronic liver disease worldwide and is associated with an increased risk of hepatocellular carcinoma, progressive hepatic fibrosis and end-stage liver disease. Suppression of HBV replication is recognized as the primary on-treatment goal of antiviral therapy, as reduction of serum HBV DNA to low or undetectable levels is highly likely to have a positive impact on long-term clinical outcomes in HBV-associated chronic liver disease. Entecavir is an oral nucleoside analogue that effectively inhibits HBV polymerase, resulting in rapid viral suppression. Long-term data on patients receiving entecavir for chronic hepatitis B have demonstrated high potency, a low incidence of antiviral drug resistance and good tolerability, making entecavir an ideal first-line agent for the treatment of chronic hepatitis B.     

Telbivudine: a new option for the treatment of chronic hepatitis B

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-α_2b, pegylated interferon-α_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.     

Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients

Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement -- with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.     

Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients

Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement – with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.     

Antiviral treatment for chronic hepatitis B: Safety,effectiveness, and prognosis

The goal of chronic hepatitis B (CHB) therapy is to improve the patient prognosis through the sustained inhibition of viral replication. However, due to the uncertainty and potentially unlimited duration of the treatment course, nucleus(t)ide analogue (NA) resistance and safety, financial costs and patient compliance, different endpoints of antiviral treatment have been proposed in CHB prevention and treatment guidelines. Different treatment endpoints are closely associated with the safety of drug withdrawal and improvements in prognosis. Antiviral treatment suppresses HBV DNA replication, drug withdrawal leads to relapse, and long-term treatment causes drug safety and resistance issues. Although hepatitis B e antigen seroconversion based on HBV DNA inhibition is considered as “a satisfactory endpoint”, drug withdrawal still leads to high relapse rates. Hepatitis B surface antigen (HBsAg) clearance is the “ideal endpoint” in terms of the safety of drug withdrawal and improvements in prognosis. However, the HBsAg clearance rate is low using the conventional single drug treatment and fixed course regimens. Recently, the application of an “optimized antiviral treatment strategy” has improved the HBsAg clearance rate, and make an “ideal endpoint” possible. This article reviews the different antiviral treatment endpoints in terms of the safety of drug withdrawal, improvements in prognosis and relevant advances.     

南通地区乙型肝炎病毒P区耐药突变与基因型及其临床意义

目的 探讨南通地区乙型肝炎病毒P区耐药基因突变特征与基因型,为临床合理用药提供科学依据。方法 选择158例经核苷(酸)类似物治疗至少2年以上慢性乙型肝炎(CHB)患者和30例未接受过核苷(酸)类似物治疗的CHB患者作为研究对象,采用PCR产物直接测序法检测HBV P区耐药基因和基因型,同时观察三种主要突变模式与ALT和HBV DNA水平的关系。结果 158例CHB患者检出B基因型42例(26.58%),C基因型116例(73.42%)。131例发生P区不同位点突变,突变率为82.91%。共检出11个HBV突变位点,主要突变位点是M204I,L180M,M204V,A181V和A181T,耐药频率依次为41.14%,37.34%,22.15%,11.39%和10.13%,11个突变位点有21种突变模式。拉米夫定(LAM)耐药相关突变中以L180M和M204V合并出现为主,其次以M204I单独出现; 阿德福韦酯(ADV)耐药相关突变中以A181V为主; 恩替卡韦(ETV)耐药率较低。结论 南通地区HBV基因型以B和C型为主,C型为优势基因型; 耐药突变主要集中在拉米夫定和阿德福韦酯耐药相关的突变位点,而恩替卡韦耐药率较低。多位点耐药突变检测有助于及时发现病毒耐药,更好地指导临床治疗。     

One-year entecavir or lamivudine therapy results in reduction of hepatitis B virus intrahepatic covalently closed circular DNA levels

Entecavir and lamivudine are potent nucleoside analogues that can suppress hepatitis B virus (HBV) replication. However, the effects of these two antiviral agents on intrahepatic total HBV DNA and covalently closed circular DNA (cccDNA) are not known. In this study, we aimed to assess the effect of 48 weeks of entecavir/lamivudine therapy on intrahepatic total HBV DNA and cccDNA levels. Forty chronic hepatitis B patients, participating in two Phase III entecavir trials at our centre, were randomized to receive 48 weeks of either 0.5 mg once daily of entecavir (n = 21) or 100 mg once daily of lamivudine (n = 19). Their serological, virological and biochemical responses, as well as intrahepatic HBV DNA levels were monitored. There was no significant difference between entecavir and lamivudine therapy in terms of post-treatment serological, virological and biochemical responses. Both nucleoside analogues reduced serum viral load, intrahepatic total HBV DNA, and cccDNA by about 4.8 logs, 2 logs, and 1 log respectively. An increase in the proportion of intrahepatic HBV DNA in the form of cccDNA was seen after 48 weeks of therapy. In conclusion, both entecavir and lamivudine can successfully reduce intrahepatic HBV DNA and cccDNA. CccDNA becomes the dominant form of HBV DNA during viral suppression and is possibly responsible for viral rebound after short-term antiviral therapy.     

Management of antiviral resistance in patients with chronic hepatitis B

A meeting of physicians and scientists involved in the management of chronic hepatitis B (CHB) was held to review current scientific data regarding antiviral resistance in hepatitis B virus (HBV) infection. The goals of the meeting were to describe current treatments for CHB, discuss emerging issues in HBV drug resistance and to delineate patient monitoring, including markers for resistance, during administration of antiviral therapy. The aim of this review article is to provide treating physicians with a framework for the management of CHB in the context of antiviral resistance. Definitions of primary and secondary antiviral treatment failure can be used to aid monitoring and early diagnosis of drug resistance before disease progression occurs as a consequence of viral breakthrough. Primary antiviral treatment failure is defined as failure of a drug to reduce HBV DNA levels by > or = 1 x log10 IU/ml within 3 months following initiation of therapy, and secondary antiviral treatment failure as a rebound of HBV replication of > or = 1 x log10 IU/ml from nadir in patients with an initial antiviral treatment effect (> or = 1 x log10 IU/ml decrease in serum HBV DNA). Confirmation of antiviral drug failure can be established by sequencing the HBV DNA polymerase and identifying specific genetic markers of antiviral drug resistance. In addition to virological assays, HBV resistance can be assessed from a clinical perspective including increased serum alanine aminotransferase levels and the development of systemic symptoms or signs of liver failure. Potential strategies to prevent the emergence of resistance and how to manage drug-resistant HBV once it emerges are discussed.     

乙型肝炎病毒基因型耐药检测和临床因素分析

目的探讨乙型肝炎病毒(HBV)耐药的相关因素和临床意义。方法回顾性分析该院2011~2013年的153例慢性乙型肝炎(CHB)患者的临床资料,对已知4种核苷(酸)类似物拉米夫定、阿德福韦酯、恩替卡韦和替比夫定的8个病毒耐药位点使用双脱氧末端终止法(Sanger法)直接测序,检测耐药;统计分析病毒基因型耐药的相关临床因素,分析预后与耐药的相关性。结果 CHB患者共有47例(29.8%)出现了病毒基因型耐药,常见的变异位点为204M-I(18例)、204M-V(8例)、181A-T(10例)、181A-V(5例)、180L-M(14例)。有家族史、HBeAg阳性,既往使用核苷(酸)类似物、基线丙氨酸氨基转移酶(ALT)≥5倍患者病毒耐药比例显著增加,发生率分别为38.8%,34.8%,34.6%和50.0%。COX多因素回归还发现HBV-DNA基因型耐药增加进展为肝硬化的风险,OR值为4.704(95%CI:1.199~18.454)。结论 Sanger法直接测序是HBV-DNA基因型耐药的可靠方法。有乙型肝炎家族史、HBeAg阳性以及使用过核苷(酸)类似物、基线ALT≥5倍患者中病毒耐药比例显著增加;HBV-DNA基因型耐药还增加进展为肝硬化的风险。     

Tenofovir therapy for lamivudine resistance following liver transplantation

BACKGROUND: Resistant hepatitis B virus (HBV) strains develop in 30% of liver transplant recipients treated with lamivudine within 2 years from the time of transplantation. OBJECTIVE: To assess safety and outcomes of tenofovir salvage therapy for patients with lamivudine resistance in a retrospective cohort of liver-transplanted patients. METHODS: Medical records were retrospectively evaluated for patients who received tenofovir. Data collected included demographics, HBV serologic information prior to and during tenofovir therapy, drug-related complications, and creatinine clearance. Criteria for lamivudine resistance included elevation of liver chemistries along with reappearance of hepatitis B surface antigen, hepatitis Be antigen, and/or HBV DNA. RESULTS: Sixteen patients showed resistance to lamivudine at 10-85 months (median 26) following liver transplantation. Tenofovir 300 mg/day orally was added in 8 patients 1-66 months after the development of viral lamivudine resistance and continued for 14-26 months (median 19.3). All 8 patients experienced HBV DNA viral suppression, with 7 currently nondetectable. No adverse events were reported, and creatinine clearance was not impaired. CONCLUSIONS: Our results suggest that tenofovir safely and markedly decreases replication of lamivudine-resistant HBV variants after liver transplantation and is another potential option for the treatment of HBV lamivudine resistance.     

Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus

Tenofovir is an acyclic nucleotide analog with activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Tenofovir disoproxil fumarate (tenofovir DF), a bis-alkoxyester prodrug of tenofovir, is approved for the treatment of HIV and is currently being developed to treat chronic hepatitis B. In this report, we further characterize the in vitro activity of tenofovir against HBV as well as its metabolism in hepatic cells. We show that tenofovir is efficiently phosphorylated to tenofovir diphosphate (TFV-DP) in both HepG2 cells and primary human hepatocytes. TFV-DP has a long intracellular half-life (95 h) and is a potent and competitive inhibitor of HBV polymerase (Ki = 0.18 microM). Tenofovir has a 50% effective concentration of 1.1 microM against HBV in cell-based assays, and potency is improved > 50-fold by the addition of bis-isoproxil progroups. Tenofovir has previously demonstrated full activity against lamivudine-resistant HBV in vitro and clinically. Here we show that the major adefovir resistance mutation, rtN236T, confers three- to fourfold-reduced susceptibility to tenofovir in cell culture; the clinical significance of this susceptibility shift has not yet been determined. The rtA194T HBV polymerase mutation recently identified in tenofovir DF-treated HIV/HBV-coinfected patients did not confer in vitro resistance to tenofovir as a single mutation or in a lamivudine-resistant viral background. Overall, the antiviral and metabolic profile of tenofovir supports its development for the treatment of chronic hepatitis B.     

替诺福韦和恩替卡韦治疗乙型肝炎肝硬化的疗效对比

目的对比长期应用替诺福韦和恩替卡韦治疗乙肝肝硬化的临床疗效。方法回顾性分析2012年7月~2015年8月在我院治疗的未进行肝移植的120例乙肝肝硬化患者,其中62例接受替诺福韦抗病毒治疗,58例接受恩替卡韦治疗。替诺福韦治疗组平均随访时间20个月（7~42）,恩替卡韦治疗组平均随访时间21个月（7~44）,收集患者的临床和实验室数据,对比两种药物的治疗效果。结果平均随访1年时,替诺福韦治疗组92%的患者HBV DNA水平低于20 U/mL,57.3%的患者丙氨酸氨基转移酶恢复正常范围;恩替卡韦治疗组90.6%的患者HBV DNA水平低于20 U/mL,56.5%的患者丙氨酸氨基转移酶恢复正常范围,两组间无显著统计学差异（P > 0.05）。末次随访阶段,替诺福韦治疗组31%的患者表现为Child-Turcotte-Pugh评分的改善且65%的患者保持稳定;恩替卡韦治疗组29.2%的患者表现为Child-Turcotte-Pugh评分的改善且63.2%的患者保持稳定,两组间无显著统计学差异（P > 0.05）。3年累计肝失代偿率、肝癌发生率和肝硬化发生率在替诺福韦治疗组分别为3.1%、1.9%和2.1%;恩替卡韦治疗组分别为2.9%、2.2%和2.4%,两组间无显著统计学差异（P > 0.05）。结论替诺福韦和恩替卡韦在乙肝肝硬化的长期治疗中均能获得良好的临床疗效,提高患者生活质量。