Hepatitis B cure: From discovery to regulatory approval.
TL;DR: Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval ofnew diagnostic assays used to measure efficacy or to predict response.
About: This article is published in Hepatology.The article was published on 2017-10-01 and is currently open access. It has received 183 citations till now. The article focuses on the topics: Hepatitis B & Hepatitis B virus.
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TL;DR: Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or ten ofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease.
Abstract: Importance More than 240 million individuals worldwide are infected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who are untreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer. Observations Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovir disoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation and fibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk of hepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss with undetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and 1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48 weeks and is not associated with the development of resistance; however, its use is limited by poor tolerability and adverse effects such as bone marrow suppression and exacerbation of existing neuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, and tenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance compared with older agents (lamivudine and adefovir) and should be considered as the first-line treatment. Conclusions and Relevance Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates are low, most patients will require therapy indefinitely.
434 citations
07 Jun 2018
TL;DR: This Primer addresses several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis, prevention and management, including antiviral agents that directly act on viral replication and immunomodulators, such as interferon therapy.
Abstract: Hepatitis B virus (HBV) is a hepatotropic virus that can establish a persistent and chronic infection in humans through immune anergy. Currently, 3.5% of the global population is chronically infected with HBV, although the incidence of HBV infections is decreasing owing to vaccination and, to a lesser extent, the use of antiviral therapy to reduce the viral load of chronically infected individuals. The course of chronic HBV infection typically comprises different clinical phases, each of which potentially lasts for decades. Well-defined and verified serum and liver biopsy diagnostic markers enable the assessment of disease severity, viral replication status, patient risk stratification and treatment decisions. Current therapy includes antiviral agents that directly act on viral replication and immunomodulators, such as interferon therapy. Antiviral agents for HBV include reverse transcriptase inhibitors, which are nucleoside or nucleotide analogues that can profoundly suppress HBV replication but require long-term maintenance therapy. Novel compounds are being actively investigated to achieve the goal of HBV surface antigen seroclearance (functional cure), a serological state that is associated with a higher remission rate (thus, no viral rebound) after treatment cessation and a lower rate of cirrhosis and hepatocellular carcinoma. This Primer addresses several aspects of HBV infection, including epidemiology, immune pathophysiology, diagnosis, prevention and management. Hepatitis B virus is a human hepatotropic DNA virus that can cause a lifelong chronic infection and progressive liver disease. This Primer discusses the epidemiology, mechanisms, diagnosis, prevention and management of chronic hepatitis B virus infection.
425 citations
University of Messina1, Lyon College2, University of Michigan3, University of Cambridge4, University of Pavia5, National Taiwan University6, Hannover Medical School7, University of Hamburg8, University of Parma9, University of Giessen10, University of the Witwatersrand11, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico12, Southern Medical University13, National Institutes of Health14, St. John's University15, University of Paris-Est16, French Institute of Health and Medical Research17, University of Hong Kong18
TL;DR: The objectives of the workshop were to review the existing knowledge on OBI, to identify issues that require further investigation, to highlight both the existing controversial and newly emerging aspects, and ultimately to update the statements previously agreed in 2008.
312 citations
Cites background from "Hepatitis B cure: From discovery to..."
...on achieving functional cure defined as HBsAg clearance in a high proportion of patients after a finite course of therapy.(122) Patients with overt HBV infection who achieve functional cure would...
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Royal Melbourne Hospital1, Scripps Research Institute2, University of Hamburg3, University of Toronto4, Indiana University5, Pennsylvania State University6, University of the Witwatersrand7, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico8, Istituto Italiano di Tecnologia9, Tsinghua University10, National Institutes of Health11, National University of Singapore12, Peking University13, Saint Louis University14, University of Freiburg15, French Institute of Health and Medical Research16
TL;DR: The International Coalition to Eliminate HBV (ICE-HBV) as mentioned in this paper is a coalition of experts dedicated to accelerating the discovery of a cure for chronic hepatitis B. Following extensive consultation with more than 50 scientists from across the globe, as well as key stakeholders including people affected by HBV, they have identified gaps in our current knowledge and new strategies and tools that are required to achieve HBV cure.
280 citations
TL;DR: In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led toHBsAg decline in most patients and sustained HBsAg loss in one patient.
195 citations
References
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TL;DR: This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection, and future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
3,016 citations
TL;DR: Elevated serum HBV DNA level (> or =10,000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.
Abstract: ContextSerum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B.ObjectiveTo evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma.Design, Setting, and ParticipantsProspective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992.Main Outcome MeasureIncidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems.ResultsThere were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41 779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100 000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100 000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P<.001) after adjustment for sex, age, cigarette smoking, alcohol consumption, serostatus for the hepatitis B e antigen (HBeAg), serum alanine aminotransferase level, and liver cirrhosis at study entry. The dose-response relationship was most prominent for participants who were seronegative for HBeAg with normal serum alanine aminotransferase levels and no liver cirrhosis at study entry. Participants with persistent elevation of serum HBV DNA level during follow-up had the highest hepatocellular carcinoma risk.ConclusionElevated serum HBV DNA level (≥10 000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.
2,853 citations
TL;DR: Continuous treatment with lamivudine delays clinical progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma.
Abstract: Background The effectiveness of antiviral therapy in preventing disease progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis is unknown. Methods Patients with chronic hepatitis B who had histologically confirmed cirrhosis or advanced fibrosis were randomly assigned in a 2:1 ratio to receive lamivudine (100 mg per day) or placebo for a maximum of five years. Of 651 patients, 436 were assigned to receive lamivudine and 215 to receive placebo. The primary end point was time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. An independent data and safety monitoring board monitored the progress of the study and performed interim analyses of the data. Results We randomly assigned 651 patients (98 percent Asian and 85 percent male) to receive lamivudine or placebo. The study was terminated after a median duration of treatment of 32.4 months (ra...
2,178 citations
Sindh Institute of Urology and Transplantation1, The Chinese University of Hong Kong2, National Taiwan University3, Memorial Hospital of South Bend4, Ankara University5, Auckland City Hospital6, Aga Khan University7, Capital Medical University8, University of Hong Kong9, Asan Medical Center10, University Health System11, Bangabandhu Sheikh Mujib Medical University12, University of Malaya13, Yonsei University14, Prince of Songkla University15, University of Santo Tomas16, Peking University17, Zhejiang University18
TL;DR: The final clinical practice guidelines and recommendations for the optimal management of chronic HBV infection are presented here, along with the relevant background information.
Abstract: Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.
1,787 citations
TL;DR: Aasld Guidelines for Treatment of Chronic Hepatitis B Norah Terrault;Natalie Bzowej;Kyong-Mi Chang;Jessica Hwang;Maureen Jonas;Hassan Murad; Hepatology
1,596 citations