Hepatitis B Virus Management Research Articles

Hepatitis B Awareness and Education: A Failing Grade

Hepatitis B Awareness and Education: A Failing Grade

Preventing Hepatitis B reactivation in immunosuppressed patients: Is it time to revisit the guidelines?

Hepatitis B virus (HBV) infection remains a serious global health concern. Approximately one third of the world's population has evidence of previous HBV infection, and 350 million people are chronic HBV carriers.1 In the United States, the rate of new HBV infections has declined by approximately 82% since 1991, when a national strategy to eliminate HBV infection was implemented.2 The greatest decline has been among those born since 1991, when universal vaccination of children was first recommended.2 Despite these improvements, HBV remains prevalent in the United States; 800,000 to 1.4 million individuals are estimated to be chronic carriers.2 Although intravenous drug users and homosexual men are at high risk for chronic HBV, most cases in the United States are in those emigrating from high prevalence areas (e.g. Asia or Africa), where early life horizontal and vertical transmission is common.3 Reactivation of HBV in immunosuppressed individuals has been well-documented in the literature for several decades. Reactivation can occur either at the cessation of therapy when immune reconstitution occurs, or with prolonged immunosuppression that can result in an accelerated course of HBV infection.4-6 Most cases occur in individuals with cancer undergoing chemotherapy, where reactivation among HBV positive patients is common (e.g. >50% in some lymphoma series) and sometimes fatal.7-18 In rheumatology, HBV reactivation has been reported with a number of disease modifying anti-rheumatic drugs (DMARDs), although the lack of large studies makes it hard to ascertain the exact risk for most drugs. However, it is increasingly apparent that newer biologic therapies, such as TNF-α inhibitors and rituximab, may pose a significant risk of HBV reactivation. Therefore, it is especially timely to take stock of how rheumatologists approach HBV in clinical practice. In this issue of Arthritis Care & Research, Stine et al. report the results of a national survey of rheumatologists regarding screening for and management of HBV infection in patients initiating immunosuppressive therapies. Although only 15% of the over 1000 rheumatologists approached completed the survey, the authors' findings are nonetheless interesting and provide a useful starting place for evaluating rheumatologists' awareness of HBV and their practice patterns regarding screening and management. The study highlights areas of significant practice variation among rheumatologists, especially pertaining to screening (e.g. who is screened and which laboratory tests are used for screening), prophylaxis against reactivation, and monitoring intervals for HBV laboratories in chronic carriers receiving immunosuppressive therapies. This observed variation in physician practice patterns likely reflects a number of factors, including the lack of a strong evidence-base in some of these areas, heterogeneity among patient populations, and the absence of clear and specific guidelines regarding HBV screening and management in patients with rheumatic disease. The study also highlights several areas where quality improvement efforts should be targeted.

Hepatitis B therapies and antiviral resistance detection and management

Hepatitis B virus (HBV) infection is an important health problem and a major cause of chronic hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Durable viral suppression has been documented to lower the risk of hepatocellular carcinoma and disease progression. Treatment of chronic HBV infection remains a major clinical challenge because long-term use with approved oral antiviral agents is associated with drug resistance. Antiviral resistance can result in poor clinical outcomes; therefore first-line therapy with the most potent agent(s) is recommended to lower the risk. Early detection of resistance is paramount to possibly reduce the risk of liver-related morbidity and mortality. It is important that clinicians monitor for therapeutic efficacy and resistance, so as to optimize the management of chronic HBV.

A Significant Proportion of Patients With Chronic Hepatitis B Who are Candidates for Antiviral Treatment are Untreated

Between 350 and 400 million people worldwide have chronic hepatitis B virus (HBV) infection, and in Italy this figure is 1% to 2% in the general population. In clinical practice, however, it is not known how many patients chronically infected by HBV and eligible for antiviral therapy are not treated. To characterize the clinical picture of untreated HBV patients, and to assess whether current experts' recommendations for treatment are actually applied. We evaluated 362 patients chronically infected by HBV alone who were followed for at least 1 year at tertiary referral centers in Liguria region, Italy. Patients' data were evaluated on the basis of the Panel of Experts algorithm for the management of HBV [ie, HBV DNA levels > or =20,000 IU/mL in hepatitis B e antigen (HBeAg)-positive patients, HBV DNA levels > or =2000 IU/mL in HBeAg-negative patients, and evidence of biochemical and/or histologic activity of disease in both groups]. One-hundred and sixteen viremic chronic hepatitis B disease patients were not on antiviral therapy (33 HBeAg positive, 83 HBeAg negative). Serum HBV DNA was > or =20,000 IU/mL and > or =2000 IU/mL in 32 HBeAg-positive and 54 HBeAg-negative patients, respectively, and disease was present in 59 of these 86 patients. Treatment was not indicated in 10 of 59 patients, and had been planned in 8 (4 HBeAg positive), thus 84% potential treatment candidates (41 of 49 patients) were not treated. Evaluation of a large series of patients chronically infected by HBV alone identified a significant proportion of patients who are actually untreated despite being potential candidates for antiviral therapy.

Management of HBV, HCV, and HDV coinfection

Worldwide, chronic hepatitis B virus (HBV) infection is the most common cause of chronic liver disease. Concurrent hepatitis C (HCV) or hepatitis D (HDV) infection is common because of their shared routes of transmission. Studies show that concurrent HBV/HCV or HBV/HDV infections may be associated with a fulminant course of acute hepatitis, more severe forms of chronic liver disease, and higher risk for development of hepatocellular carcinoma. Virologic markers in HBV patients coinfected with HCV or HDV are dynamic and have different patterns. The replication of one virus may dominate the other and antiviral therapeutic strategies should target the dominant virus. Standard interferon-α or pegylated interferon is usually the treatment of choice for HBV/HCV and HBV/HDV coinfection. Adding ribavirin or lamivudine may benefit HBV patients coinfected with HCV but is ineffective against HDV. Treatment guidelines have not been established for chronic HBV coinfection with either HCV or HDV; therefore, management decisions usually depend on the clinical experience of the treating physician and the sparse data available regarding treatment options.

New approaches in the management of chronic hepatitis B: role of tenofovir.

In the field of HIV management, tenofovir disoproxil fumarate (TDF) plays a pivotal role and has been demonstrated to be a safe and well-tolerated antiviral agent. Recent data showed the efficacy of TDF in the treatment of chronically hepatitis B virus (HBV)-infected patients. TDF was superior to adefovir dipivoxil (ADV) in both nucleos(t)ide-naïve HBeAg-positive and HBeAg-negative HBV patients, and appeared to be one of the most potent antiviral agents so far. In addition, several reports showed that TDF was also effective in the nucleos(t)ide-experienced population, although conflicting results have been presented concerning patients with genotypic resistance to ADV. TDF seems to have a good resistance profile as well. The rtA194T mutation in association with lamivudine resistance may confer resistance to TDF, although both in vivo and in vitro studies regarding this mutation demonstrate conflicting results. As treatment with TDF may be associated with nephrotoxicity, all TDF-treated patients should be monitored for renal function at baseline and periodically thereafter. While the relative roles of interferon vs nucleos(t)ide analogues (NA) as initial anti-HBV therapy remains unclear, TDF will probably become one of the key factors in HBV management both as first-choice NA for nucleos(t)ide-naïve patients and as rescue therapy for nucleos(t)ide-experienced patients.

A case of HIV co‐infected with hepatitis B virus precore/core deletion mutant treated by entecavir

We report a case of a HIV and hepatitis B virus (HBV)-co-infected patient to whom entecavir (ETV) was administered initially before the notification regarding the potential mutagenesis effect on HIV against the nucleoside analog. Since initial evaluations indicated the advanced stage of chronic hepatitis B and preserved numbers of peripheral CD4+ lymphocytes without the manifestation of immunodeficiency, priority was given to the management of HBV. We started HBV therapy with ETV at a dose of 0.5 mg daily without using any HIV drugs. The viral loads of both HBV and HIV-1 decreased gradually during the 5 months following the initial administration of ETV. HBV was well controlled by the gradual replacement of ETV with highly-active antiretroviral therapy against HIV with a regimen including atazanavir, emtricitabine, and tenofovir. HBV was genotyped as A2 with the quasispecies pool consisting of the -1G precore/core deletion mutant strain.

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon α2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier “Asian-Pacific consensus statement on the management of chronic hepatitis B” was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.

Dynamics of lamivudine‐resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapy

Adefovir dipivoxil has been used alone or together with lamivudine to suppress lamivudine-resistant hepatitis B virus (HBV). However, the dynamics of HBV populations under different selection pressures and their impact on treatment outcome are poorly understood. Pyrosequencing was applied to quantify longitudinally the evolution of wild type and lamivudine/adefovir-resistant HBV. Eight patients, with lamivudine-resistant HBV, were randomized to receive adefovir monotherapy or adefovir/lamivudine combination therapy for a median of 79 and 71 weeks, respectively. Pyrosequencing proved highly sensitive with a lower limit of quantitation of minor HBV populations of 2% irrespective of viraemia levels. Adefovir/lamivudine treatment resulted in greater viraemia reduction than adefovir monotherapy. During combination therapy, lamivudine-resistant HBV populations (codons 180 and 204) remained dominant (>90%) and no adefovir-resistance developed. During adefovir monotherapy, reversion to wild-type HBV was detected in two patients with one patient accumulating rapidly adefovir-resistant HBV along with increased viraemia. In conclusion, the dynamics of drug-resistant HBV strains vary under different selection pressures which have a significant impact on the success of rescue therapy, as well as for the selection of new mutations. The use of techniques such as Pyrosequencing provides an evidence-based approach for successful management of drug-resistant HBV.

Building Partnerships with Traditional Chinese Medicine Practitioners to Increase Hepatitis B Awareness and Prevention

The annual Hepatitis B Prevention and Education Symposium aims to develop partnerships between non-Western and Western health care providers to prevent chronic hepatitis B virus (HBV) infection and death from liver cancer among Asians and Pacific Islanders (APIs). Each year from 2004 through 2007, we partnered with professional, academic, and community-based organizations to organize an educational symposium for Traditional Chinese Medicine practitioners and acupuncturists in California. Participants completed pre- and postsymposium surveys assessing knowledge about HBV and liver cancer. The symposia were held in San Francisco, Los Angeles, and Stanford, California. Over 1000 participants attended the four symposia combined; most were born in Asia. Symposium activities included educational lectures and games, presentation of a physician's guide to HBV management, and case studies. Chi-square tests were used to compare the proportion of correct responses to each knowledge-based question, as well as the total number of correct responses, before and after the symposium. Knowledge about HBV and liver cancer was low prior to the symposium. The proportion of correct responses to the most commonly mistaken questions increased significantly at the conclusion of each symposium. The total number of correct responses rose from below 60% to above 75% each year. Similar educational symposia targeting health care providers who serve API patients can improve HBV and liver cancer awareness and prevention throughout the API community.

Management of hepatitis B in liver transplant recipients

Advances in hepatitis B virus (HBV) antiviral prophylaxis have dramatically improved graft and patient survival for patients undergoing liver transplantation for hepatitis B related end-stage liver disease. In particular, the availability of hepatitis B immune globulin (HBIg) in combination with nucleos(t)ide analogues such as lamivudine and adefovir, have transformed outcomes. The availability of newer antivirals such as adefovir, tenofovir and entecavir either as monotherapy or in combination offer an increasing number of antiviral options. Despite these advances, significant challenges remain. Factors that affect the efficacy of anti-viral therapy include detectable HBV viraemia at the time of transplant and emergence of HBV mutants (especially in patients with prior exposure to lamivudine). HBV prophylaxis protocols are expensive especially with use of high-dose HBIg and newer nucleos(t)ide analogues. This review summarizes current HBV prophylaxis protocols and management of recurrent disease post-transplantation. There is an increasing need for individualization of therapy based on prior drug exposures, level of HBV DNA at time of transplantation and type of prophylaxis used.

HIV and liver disease forum: Conference proceedings

Liver disease has emerged as one of the major causes of morbidity and mortality among patients infected with the human immunodeficiency virus (HIV), particularly in regions where highly active antiretroviral therapy (ART) is widely available. This dramatic change in disease epidemiology is attributable to a complex interaction between etiologic factors that appear to increase the rate of hepatic fibrosis and accelerate progression to end-stage liver disease. Key factors include ART related hepatoxicity, frequent coinfection with hepatitis B and C, and possibly the direct interaction of HIV virus or soluble protein viral products that interact with hepatocytes and other liver resident cell types. Additionally, there is some evidence that gut permeability is altered during active HIV replication, which affects the complex mix of toxins and growth factors present in the portal circulation. It is critical that hepatologists maintain a strong knowledge base to provide the best possible guidance to HIV-infected patients and their healthcare providers. To this end, the second international forum on HIV and Liver Disease was convened in Jackson Hole, WY in September 2008. The first forum, held two years earlier was previously summarized in Hepatology, and has been widely cited by experts in the field.1 However, the fast moving nature of this critical health issue led to development of a second meeting, supported by grants from three institutes of the National Institutes of Health (NIAID, NIDDK, NIAAA) and by unrestricted grants provided by the pharmaceutical industry. As before, the meeting sought to bring together basic and clinical researchers representing multiple disciplines including hepatology, infectious diseases, epidemiology, virology, and drug development as well as governmental experts in health policy, research and research funding. This document provides a summary of key presentations and highlights the current state of knowledge and future directions this field will take.

799. Expressed Long Hairpin RNA Sequences Inhibit HBV Replication In Vivo without Inducing an Interferon Response

Chronic infection with the hepatitis B virus (HBV) occurs in approximately 6% of the global population and HBV carriers are at an increased risk for cirrhosis and hepatocellular carcinoma. Licensed therapies against HBV are only partially effective and development of improved treatment modalities remains an important medical objective. Exploitation of the RNA interference (RNAi) pathway shows promise as a novel antiviral treatment strategy for the management of HBV. Traditionally short hairpin RNAs (shRNAs) of 21–23 bp in the stem region have been used to induce RNAi- mediated gene silencing and avoid inducing the sequence non-specific interferon response.

Adefovir dipivoxil: review of a novel acyclic nucleoside analogue

Adefovir dipivoxil (ADF) is a novel acyclic nucleoside analogue that has recently been approved for the treatment of chronic hepatitis B virus (HBV). Adefovir was initially assessed at higher doses for the treatment of human immunodeficiency virus (HIV) infection. However, in these studies, nephrotoxicity proved a dose-limiting side effect. Large randomised controlled studies have recently shown that ADF results in histological, virological and biochemical improvement in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic HBV. While the rate of HBeAg seroconversion at 1 year (12%) was lower than both lamivudine and interferon, this increases with prolonged treatment. The clinical improvements occurred without serious side effects or the development of resistance at the dose of 10 mg daily, in treatment trials of up to 2 years, although resistance has now been observed. In addition, the drug is efficacious in HBV/HIV co-infection and hepatitis B-infected liver transplant recipients, particularly in those who have developed lamivudine resistance. ADF can be added as a treatment option to existing treatment options (interferon-alpha and lamivudine) and assumes a role in the ongoing management of chronic HBV. The optimal use of ADF as either a monotherapy or as part of combination therapy requires further assessment.

Characterization of Hepatitis B Virus Surface Antigen and Polymerase Mutations in Liver Transplant Recipients Pre- and Post-Transplant

We evaluated serum samples from 18 chronic hepatitis B virus (HBV) patients who underwent liver transplantation for the presence of HBV polymerase and S gene mutations and HBV genotype using a new commercially available sequencing assay. All three patients with hepatitis B immune globulin (HBIG) treatment failure followed by nucleoside analogue treatment failure were infected with HBV genotype C; a pre-existing HBV S antigen (HBsAg) mutation (sD144A) was identified in one patient pretransplant, while sG145R mutations emerged in the other two patients post-transplant. These HBsAg mutations persisted for the duration of the study (5-6 years), despite the absence of HBIG administration for a 4-5-year period. Significant viral polymerase mutations (rtL180M and rtM204I/V) also emerged in all of these patients following treatment with lamivudine and/or famciclovir. Four of six patients with HBIG breakthrough without nucleoside analogue treatment failure yielded potentially significant HBsAg mutations post transplant. These data do not support previous reports highlighting the disappearance of HBsAg mutants in liver transplant recipients after discontinuation of HBIG. Determination of HBV genotype, as well as identification of HBV polymerase and S gene mutations in liver transplant candidates may be warranted to optimize HBV management strategies post transplant.

Management of chronic hepatitis B: an overview.

Approximately 400 million individuals worldwide have developed chronic hepatitis B after exposure to the hepatitis B virus (HBV). Up to 40% of these will eventually develop serious hepatic complications. Although widespread immunization, improved blood supply testing, and emphasis on safe sex have significantly decreased new HBV infections, the large reservoir of infected individuals (400 million) remains a serious health problem. At present, only two agents are available for the treatment of chronic hepatitis B: interferon alfa and lamivudine. Both are associated with important limitations of efficacy or safety, or both. These limitations and other problems associated with the evaluation of current and investigational therapies for chronic hepatitis B give rise to several key issues in management of HBV: duration of therapy, goals of therapy, need for standardization of the measurement of clinical responses, and definitions of response to therapy. The last two of these key issues are of particular concern. The lack of similarity in study designs, the use of inconsistent definitions of and criteria for therapeutic response, and the lack of uniformity in assays to detect HBV DNA titers hamper consistent evaluations of treatment. Therefore, there is a need for the scientific community to standardize the measures of performance and methods of analysis and reporting of clinical trials for current and new drugs.

Clinical aspects of hepatitis B virus infection

Adults with a healthy immune system who are exposed to hepatitis B virus (HBV) usually suffer from a mild acute infection. The likelihood of chronicity is only 5%, but climbs as high as 90% in newborns and n the immunocompromised. Acute HBV infection can cause fulminant liver failure (case fatality rate of 80%). People with chronic infection tend to have no symptoms, normal liver enzymes, and normal or almost normal liver histology, making diagnosis difficult. Active viral replication occurs in most people with active liver disease. People with persistent active replication are at higher risk of death from liver disease or hepatocellular carcinoma (HCC) than those with inactive disease. HBV transmission occurs via sexual intercourse or blood or needle contact. In the US, iv drug use is the major risk factor for HBV infection in adults. Prevention of HBV infection is through patient education and vaccination. Some people advocate universal HBV vaccination because it is often difficult to vaccinate high risk populations and to identify risk factors. Universal vaccination is not cost effective in low risk areas, however, e.g., the US and Europe. Treatment for chronic HBV infection is limited. Response to interferon therapy depends on low HBV DNA levels, high transaminase levels, and a history of acute hepatitis. Short- and longterm response rates tend to be low, however ( 40% short term and much lower for longterm). Experimental drugs are thymosin and nucleoside analogues. Standard treatment for patients with end-stage chronic liver disease or fulminant hepatic failure is liver transplantation. High dose immune globulin is the best means to delay and prevent recurrent HBV infection in transplantation patients. Some problems with management of chronic HBV are prevention of HCC and recurrent HBV after transplantation. Variant viruses are mutations of the precore or of a surface gene. HIV/AIDS is often associated with HBV and hepatitis delta virus infection.