Advances in imaging techniques such as vibration-controlled transient elastography and magnetic resonance elastography have reduced the need for liver biopsy as a means of diagnosing liver disease.
The majority of persons currently treated for chronic hepatitis B require long‐term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune ...modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. 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 of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof‐of‐concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).
Hepatitis B Jeng, Wen-Juei; Papatheodoridis, George V; Lok, Anna S F
The Lancet (British edition),
03/2023, Letnik:
401, Številka:
10381
Journal Article
Recenzirano
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires ...serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
Chronic hepatitis B viral (HBV) infection remains a significant global health problem. Evidence‐based guidelines are needed to help providers determine when treatment should be initiated, which ...medication is most appropriate, and when treatment can safely be stopped. The American Association for the Study of Liver Diseases HBV guideline methodology and writing committees developed a protocol a priori for this systematic review. We searched multiple databases for randomized controlled trials and controlled observational studies that enrolled adults ≥18 years old diagnosed with chronic HBV infection who received antiviral therapy. Data extraction was done by pairs of independent reviewers. We included 73 studies, of which 59 (15 randomized controlled trials and 44 observational studies) reported clinical outcomes. Moderate‐quality evidence supported the effectiveness of antiviral therapy in patients with immune active chronic HBV infection in reducing the risk of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In immune tolerant patients, moderate‐quality evidence supports improved intermediate outcomes with antiviral therapy. Only very low‐quality evidence informed the questions about discontinuing versus continuing antiviral therapy in hepatitis B e antigen‐positive patients who seroconverted from hepatitis B e antigen to hepatitis B e antibody and about the safety of entecavir versus tenofovir. Noncomparative and indirect evidence was available for questions about stopping versus continuing antiviral therapy in hepatitis B e antigen‐negative patients, monotherapy versus adding a second agent in patients with persistent viremia during treatment, and the effectiveness of antivirals in compensated cirrhosis with low‐level viremia. Conclusion: Most of the current literature focuses on the immune active phases of chronic HBV infection; decision‐making in other commonly encountered and challenging clinical settings depends on indirect evidence. (Hepatology 2016;63:284–306)
Perinatal or mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV) remains the major risk factor for chronic HBV infection worldwide. In addition to hepatitis B immune globulin and ...vaccination, oral antiviral therapies in highly viremic mothers can further decrease MTCT of HBV. We conducted a systematic review and meta‐analysis to synthesize the evidence on the efficacy and maternal and fetal safety of antiviral therapy during pregnancy. A protocol was developed by the American Association for the Study of Liver Diseases guideline writing committee. We searched multiple databases for controlled studies that enrolled pregnant women with chronic HBV infection treated with antiviral therapy. Outcomes of interest were reduction of MTCT and adverse outcomes to mothers and newborns. Study selection and data extraction were done by pairs of independent reviewers. We included 26 studies that enrolled 3622 pregnant women. Antiviral therapy reduced MTCT, as defined by infant hepatitis B surface antigen seropositivity (risk ratio = 0.3, 95% confidence interval 0.2‐0.4) or infant HBV DNA seropositivity (risk ratio = 0.3, 95% confidence interval 0.2‐0.5) at 6‐12 months. No significant differences were found in the congenital malformation rate, prematurity rate, and Apgar scores. Compared to control, lamivudine or telbivudine improved maternal HBV DNA suppression at delivery and during 4‐8 weeks' postpartum follow‐up. Tenofovir showed improvement in HBV DNA suppression at delivery. No significant differences were found in postpartum hemorrhage, cesarean section, and elevated creatinine kinase rates. Conclusions: Antiviral therapy improves HBV suppression and reduces MTCT in women with chronic HBV infection with high viral load compared to the use of hepatitis B immunoglobulin and vaccination alone; the use of telbivudine, lamivudine, and tenofovir appears to be safe in pregnancy with no increased adverse maternal or fetal outcome. (Hepatology 2016;63:319–333)
Chronic hepatitis B: Update 2009 Lok, Anna S. F.; McMahon, Brian J.
Hepatology (Baltimore, Md.),
September 2009, Letnik:
50, Številka:
3
Journal Article
Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy-proven ...acute rejection (BPAR) based on an analysis of a more recent national sample of recipients of liver transplants from living and deceased donors.
We analyzed data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete-survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living and deceased donors.
At least 1 BPAR episode occurred in 239 of 890 recipients in A2ALL (26.9%) and 7066 of 45,423 recipients in SRTR (15.6%). In each database, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio HR, 0.57; 95% confidence interval CI, 0.43-0.76; and SRTR HR, 0.78; 95% CI, 0.66-0.91) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each database, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post-BPAR period in patients whose first episode occurred more than 1 year after liver transplantation: HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64-17.45) and 4.41 in SRTR (95% CI, 3.71-5.23); HRs for death were 8.81 in A2ALL (95% CI, 3.37-23.04) and 3.94 in SRTR (95% CI, 3.22-4.83). In analyses of cause-specific mortality, associations were observed for liver-related (graft failure) causes of death but not for other causes.
Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all-cause mortality, and graft failure-related death, regardless of primary liver disease etiology. Living donor liver transplantation from a biologically related donor is associated with decreased risk of rejection.
Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication ...and antigen production (covalently closed circular DNA cccDNA and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.
PDF
