Modelling jurisdictional disparities in the cascade of care for chronic hepatitis B in Australia: impact of treatment uptake on mortality.

OBJECTIVE: Investigate the cascade of care for chronic hepatitis B (CHB) and estimate impacts of increasing treatment uptake on attributable burden, according to jurisdiction. METHODS: A mathematical model of CHB in Australia was utilised, combined with notifiable disease and Medicare data. We estimated the proportion with CHB who were diagnosed, engaged in care and receiving treatment in each state/territory, and projected future mortality. RESULTS: The highest uptake of all measures was in New South Wales, however, the largest increase over time occurred in Northern Territory. No jurisdiction is due to meet 2022 targets of treatment uptake or mortality reduction. Previously declining mortality is predicted to plateau or increase in all jurisdictions except Northern Territory. The largest gap in the cascade of care was most commonly diagnosed individuals not engaged in care; however, in Victoria and Tasmania it was lack of diagnosis. CONCLUSIONS: Measures of the cascade of care varied substantially between jurisdictions; while all require improvements to reduce mortality, the specific gaps vary, as do potential impacts. IMPLICATIONS FOR PUBLIC HEALTH: Improving the cascade of care for CHB will require jurisdictionally tailored approaches. If improvements are not made, more deaths will occur due to CHB in most states and territories.

The role of explanatory models of chronic hepatitis B on illness experience: a qualitative study of Vietnamese participants in Australia.

ABSTRACTObjective: This study utilises Kleinman's theory of explanatory models of health and illness to explore the experience of chronic hepatitis B (CHB) among Vietnamese people living in Australia. It examines how these explanatory models are formed and shaped by the broader community, and the extent to which this influences understandings and responses to CHB.Design: This study is based on semi-structured interviews with 22 Vietnamese people with CHB in Melbourne, Australia. The individual interviews ranged from 30 minutes to 1.5 hours in length, and were electronically recorded, translated where necessary and transcribed verbatim. Transcripts were thematically coded using NVivo 10, with coding themes guided by categories identified in Kleinman's explanatory models framework.Results: Fundamental to most participants' narratives was the profound impact of cultural, social and economic environments on their understandings and responses to CHB. Regardless of socio-demographic background, most participants juxtaposed biomedical elements of CHB with their own existing humoral-based health belief system. In the context of a chronic asymptomatic condition that, for the most part, does not require pharmaceutical treatment, a humoral-based health belief system provided a familiar conceptual framework from which participants could immediately respond and take control of their infection. This was observed through changes in diet and lifestyle, and the use of traditional herbal medicine in an attempt to 'cure' or halt the progression of their infection.Conclusions: By speaking to people living with CHB directly, it became clear that there is a disjuncture between what is commonly assumed by the biomedical model of CHB and what is understood by individuals with the infection. The public health burden of CHB will continue unless the healthcare system, including public health policies, deliver a hepatitis B model of care that is responsive to the needs and expectations of priority populations.

Severe Guillain-Barré syndrome associated with chronic hepatitis B: A case report and literature review.

RATIONALE: Guillain-Barré syndrome (GBS) is a postinfectious autoimmune peripheral neuropathy characterized by acute paralysis of the limbs. Clinically, extrahepatic manifestations of neurologic involvement in chronic hepatitis B (CHB) are uncommon. Little attention has been paid to the relationship between GBS and CHB viral infection. PATIENT CONCERNS: We presented a severe case of a 34-year-old man with general fatigue, anorexia, jaundice, numbness, and even muscle atrophy in the limbs, and respiratory failure during an acute exacerbation of CHB. DIAGNOSES: Serological liver enzymes test confirmed an acute exacerbation of CHB. Nerve conduction studies revealed the features of acute motor and sensory axonal neuropathy combined with acute inflammatory demyelinating polyneuropathy, and cerebrospinal fluid analysis showed albuminocytologic dissociation. Clinical manifestations and the test results were consistent with a diagnosis of severe CHB-related GBS. INTERVENTIONS: He was treated with mechanical ventilation, 2 courses of intravenous immunoglobulin, antichronic hepatitis B drugs therapy supplemented by hepatoprotection, acupuncture and rehabilitation. OUTCOMES: After 29 days of hospitalization, his neurological condition improved. At a 6-month follow-up visit, he was able to walk with the support of another person. LESSONS: The acute exacerbation of CHB may be a potential predisposing factor for the onset of GBS. This case is a reminder to clinicians that during the acute exacerbation of CHB, patients with neurological symptoms in the limbs should be considered for potential CHB-related GBS.

Use of complementary and alternative medicine in patients with chronic viral hepatitis in Turkey.

INTRODUCTION: The global use of complementary and alternative medicine (CAM) is growing. The purpose of this study was to determine the prevalence of CAM use in patients in Turkey with CVH, the types of therapy, and patients' sociodemographic characteristics. METHODS: The study was designed as a questionnaire-based, cross-sectional analysis. An infectious diseases outpatient follow-up questionnaire was administered to patients at face-to-face interviews. The data obtained were analyzed using SPSS 17 software. RESULTS: This study included 588 patients, of whom 27% used CAM. No differences in sociodemographic characteristics were determined between patients using CAM and those not using it. Herbal methods were used by 63.6% of patients and cupping techniques by 25.4%. Education level was significantly correlated with herbal methods (p = 0.043). CAM use also increased in line with disease duration (p < 0.05). No difference in CAM use was determined between CHB patients using oral antiviral therapy and those not using it (p = 0.162). CONCLUSION: CAM use, particularly herbal products, is prevalent among Turkish adults with CVH. In case of use of herbal products in chronic viral hepatitis patients, toxicity and liver failure may develop as a result of herbal product-drug interactions. Physicians in the field of hepatology should, therefore, be aware of potential toxicity of CAM, especially in patients with chronic hepatitis liver diseases.

Barriers to chronic Hepatitis B treatment and care in Ghana: A qualitative study with people with Hepatitis B and healthcare providers.

BACKGROUND: Hepatitis B viral (HBV) infection remains an important public health concern particularly in Africa. Between 1990 and 2013, Hepatitis B mortality increased by 63%. In recent times, effective antiviral agents against HBV such as Nucleos(t)ide analogs (NAs) are available. These drugs are capable of suppressing HBV replication, preventing progression of chronic Hepatitis B to cirrhosis, and reducing the risk of hepatocellular carcinoma and liver-related death. Notwithstanding, these treatments are underused despite their effectiveness in managing Hepatitis B. This study sought to explore barriers to treatment and care for people with Hepatitis B (PWHB) in Ghana, paying particular attention to beliefs about aetiology that can act as a barrier to care for PWHB. METHODS: We used an exploratory qualitative design with a purposive sampling technique. Face-to-face interviews were conducted for 18 persons with Hepatitis B (PWHB) and 15 healthcare providers (HCP; physicians, nurses, and midwives). In addition, four focus group discussions (FGD) with a composition of eight HCPs in each group were done. Participants were recruited from one tertiary and one regional hospital in Ghana. Data were processed using QSR Nvivo version 10.0 and analysed using the procedure of inductive thematic analysis. Participants were recruited from one tertiary and one regional hospital in Ghana. RESULTS: Three main cultural beliefs regarding the aetiology of chronic Hepatitis B that act as barriers to care and treatment were identified. These were: (1) the belief that chronic Hepatitis B is a punishment from the gods to those who touch dead bodies without permission from their landlords, (2) the belief that bewitchment contributes to chronic Hepatitis B, and (3) the belief that chronic Hepatitis B is caused by spiritual poison. Furthermore, individual level barriers were identified. These were the absence of chronic Hepatitis B signs and symptoms, perceived efficacy of traditional herbal medicine, and PWHB's perception that formal care does not meet their expectations. Health system-related barriers included high cost of hospital-based care and inadequate Hepatitis B education for patients from HCPs. CONCLUSION: Given that high cost of hospital based care was considered an important barrier to engagement in care for PWHB, we recommend including the required Hepatitis B laboratory investigations such as viral load, and the recommended treatment in the National Health Insurance Scheme (NHIS). Also, we recommend increasing health care providers and PWHB Hepatitis B knowledge and capacity in a culturally sensitive fashion, discuss with patients (1) myths about aetiology and the lack of efficacy of traditional herbal medicines, and (2) patients' expectations of care and the need to monitor even in the absence of symptoms.

Acupuncture for chronic hepatitis B.

BACKGROUND: Chronic hepatitis B is a liver disease associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming to reduce the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, as well as to improve health-related quality of life. Acupuncture is being used to decrease discomfort and improve immune function in people with chronic hepatitis B. However, the benefits and harms of acupuncture still need to be established in a rigorous way. OBJECTIVES: To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. SEARCH METHODS: We undertook electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry (ChiCTR) for ongoing or unpublished trials until 1 March 2019. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B as defined by the trialists or according to guidelines. We allowed co-interventions when the co-interventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: Review authors in pairs individually retrieved data from reports and through correspondence with investigators. Primary outcomes were all-cause mortality, proportion of participants with one or more serious adverse events, and health-related quality of life. Secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered not to be serious. We presented the pooled results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risks of bias using risk of bias domains with predefined definitions. We put more weight on the estimate closest to zero effect when results with fixed-effect and random-effects models differed. We evaluated the certainty of evidence using GRADE. MAIN RESULTS: We included eight randomised clinical trials with 555 randomised participants. All included trials compared acupuncture versus no intervention. These trials assessed heterogeneous acupuncture interventions. All trials used heterogeneous co-interventions applied equally in the compared groups. Seven trials included participants with chronic hepatitis B, and one trial included participants with chronic hepatitis B with comorbid tuberculosis. All trials were assessed at overall high risk of bias, and the certainty of evidence for all outcomes was very low due to high risk of bias for each outcome, imprecision of results (the confidence intervals were wide), and publication bias (small sample size of the trials, and all trials were conducted in China). Additionally, 79 trials lacked the necessary methodological information to ensure their inclusion in our review.None of the included trials aim to assess all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. We are uncertain whether acupuncture, compared with no intervention, has an effect regarding adverse events considered not to be serious (RR 0.67, 95% CI 0.43 to 1.06; I² = 0%; 3 trials; 203 participants; very low-certainty evidence) or detectable hepatitis B e-antigen (HBeAg) (RR 0.64, 95% CI 0.11 to 3.68; I² = 98%; 2 trials; 158 participants; very low-certainty evidence). Acupuncture showed a reduction in detectable hepatitis B virus (HBV) DNA (a non-validated surrogate outcome; RR 0.45, 95% CI 0.27 to 0.74; 1 trial, 58 participants; very low-certainty evidence). We are uncertain whether acupuncture has an effect regarding the remaining separately reported adverse events considered not to be serious.Three of the eight included trials received academic funding from government or hospital. None of the remaining five trials reported information on funding. AUTHORS' CONCLUSIONS: The clinical effects of acupuncture for chronic hepatitis B remain unknown. The included trials lacked data on all-cause mortality, health-related quality of life, serious adverse events, hepatitis-B related mortality, and hepatitis-B related morbidity. The vast number of excluded trials lacked clear descriptions of their design and conduct. Whether acupuncture influences adverse events considered not to be serious is uncertain. It remains unclear if acupuncture affects HBeAg, and if it is associated with reduction in detectable HBV DNA. Based on available data from only one or two small trials on adverse events considered not to be serious and on the surrogate outcomes HBeAg and HBV DNA, the certainty of evidence is very low. In view of the wide usage of acupuncture, any conclusion that one might try to draw in the future should be based on data on patient and clinically relevant outcomes, assessed in large, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding.

Prevalence and predictors of complementary and alternative medicine modalities in patients with chronic hepatitis B.

BACKGROUND & AIMS: The use of complementary and alternative medicine (CAM) in patients with chronic hepatitis B (CHB) can interact with antiviral treatment or influence health-seeking behaviour. We aimed to study the use of individual CAM modalities in CHB and explore determinants of use, particularly migration-related, socio-economic and clinical factors. METHODS: A total of 436 CHB outpatients who attended the Toronto Centre for Liver Disease in 2015-2016 were included in this cross-sectional study. Using the comprehensive I-CAM questionnaire and health records, data were collected on socio-demographic and clinical variables and on usage of 16 CAM modalities in the last year. RESULTS: Sixty percent of patients were male, 74% were Asian and 46% were using antiviral treatment. Three-hundred and nine (71%) patients used CAM. Vitamin/mineral preparations (45% of patients) were most commonly used. Overall CAM use and the specific use of potentially injurious CAM, such as green tea extract (9.2%) and St. John's wort (0.2%), were not associated with liver disease severity. Female sex, family history of CHB, lower serum HBV DNA, and higher socio-economic status were independently associated with bio-holistic CAM use, the clinically most-relevant CAM group (P < 0.05); ethnicity, antiviral therapy use and liver disease severity were not. CONCLUSIONS: CAM use among CHB patients was extensive, especially use of vitamin and mineral preparations, but without direct influence on liver disease severity. Bio-holistic CAM use appeared to be associated with socio-economic status rather than with ethnicity or liver disease severity. Despite the rare use of hepatotoxins, physicians should actively inquire about it.

Immunomodulatory Effects of Combination Therapy with Bushen Formula plus Entecavir for Chronic Hepatitis B Patients.

AIM: To compare the clinical efficacy of the combination therapy with Bushen formula (BSF) plus entecavir (ETV) in naïve chronic hepatitis B (CHB) patients and that in CHB patients with partial virological response to ETV and explore the relevant immunoregulatory mechanism. MATERIALS AND METHODS: Two hundred and twenty CHB patients were enrolled in the historical prospective cohort study. Patients were categorized into a treatment group (T-Group: combination therapy with BSF plus ETV) and a control group (C-Group: ETV). Patients in T-Group and C-Group were grouped into T1/C1 (treatment-naïve patients) and T2/C2 (patients with partial virological response to ETV). Biochemical assessment, viral load quantitation, and HBV markers were tested. Chinese medicine symptom complex score was evaluated and recorded as well. In addition, peripheral blood mononuclear cells were separated from blood samples in 56 patients and 11 healthy donors. The frequencies of Th1, Treg, and dendritic cells (DCs) and expression levels of PD-1/PD-L1 were examined by flow cytometry. RESULTS: In treatment-naïve CHB patients, complete viral suppression rates in HBeAg(-) patients were higher than those in HBeAg(+) patients in both T and C groups. In patients with partial virological response to ETV, the rate of HBsAg decline ≥ 20% in HBeAg(+) patients of T2-Group was higher than that in HBeAg(+) patients of C2-Group. A significant reduction of Chinese medicine symptom complex score was only observed in T-Group. The study of mechanism showed that, compared with healthy controls, Th1 and DC frequencies were decreased in all CHB patients, while Treg frequency was increased only in treatment-naïve patients. In addition, compared with healthy controls, PD-1 expression levels on Th1 and Treg were increased in all patients and PD-L1 expression levels on DCs were increased only in treatment-naïve patients. In treatment-naïve patients, the combination therapy with BSF plus ETV increased Th1 and DC frequencies and decreased Treg frequency, which was correlated with HBsAg decline. In addition, in patients with partial virological response to ETV, the combination therapy downregulated PD-L1 levels on DCs and the frequency of Treg, which was related with HBsAg decline. CONCLUSIONS: In patients with partial virological response to ETV, HBeAg(+) patients tend to achieve ideal effects after the combination therapy with BSF plus ETV, which may correlate with the decrease of Treg frequency and the downregulation of PD-L1 levels on DCs.

Influence of autoleukocyte vaccination on activity level of tumor necrosis factor alpha in patients with chronic hepatitis B.

OBJECTIVE: Introduction: data about influence of intradermal vaccination with native autoleukocytes on activity level of pro-inflammatory cytokine tumor necrosis factor alpha in patients with chronic hepatitis B have been presented in the article. The aim: Based on positive results, obtained from autoleukocyte immunization in patients with psoriasis [14], the aim of our research was to use and study such therapy for reducing the synthesis of pro-inflammatory cytokine TNF-α in patients with chronic hepatitis B (chronic hepatitis B). PATIENTS AND METHODS: Materials and methods: Patients with chronic hepatitis B with high level of tumor necrosis factor alpha (≥30pg/ml) were vaccinated with native autoleukocytes (23); simultaneously, the same procedure was performed to patients (11) with low level of this cytokine (5pg/ml). Leukocytes were isolated from heparinized peripheral venous blood of a patient with hepatitis B by centrifuging plasma, obtained after blood precipitation for 140-160 minutes at temperature 370 С. The suspension was resuspended in 1-1.5 ml of a patient's blood serum and injected into the skin of the back in the dose 0.1 ml. RESULTS: Results: in 30 days after immunization, reduction of tumor necrosis factor alpha was observed in all patients with its high level (100%), in 65.25% of individuals - to 5 pg/ml; in some patients, who had low or average level of pro-inflammatory cytokine, the level individually increased (41.67%). CONCLUSION: Conclusions: The elaborated method of influence on activity of tumor necrosis factor alpha in patients with chronic hepatitis B is effective and worth implementing into clinical practice.

Characterization and assessment of HBV chronically infected patients: Identification of those eligible for treatment in the South West region of Cameroon.

BACKGROUND: The management of patients with chronic hepatitis B infection is quite complex because it requires an in-depth knowledge of the natural history of the disease. This study was aimed at characterizing HBV infected patients in order to determine the phase of the infection and identify the proportion eligible for treatment using 3 different guidelines. METHODS: HBV chronically infected patients (negative for HIV and HCV) were enrolled and the following tests were done for them: ALT, AST, HBV viral load, HBV serologic panel and Full blood count. APRI score was calculated for all patients. These patients were classified into immunotolerant, immune clearance, immune control and immune escape phases of the infection. The WHO and the 2018 AASLD criteria was also used to identify those who need treatment. Patients were clinically examined for signs and symptoms. Questionnaire was administered to all participants to ascertain their treatment status. Statistical analysis was done using SPSS version 21. RESULTS: A total of 283 participants (101 females and 182 males) with a mean age of 31.3±8.5 were enrolled. Fifty-two (18.4%) were eligible for treatment (Immune clearance and immune escape phases) and they recorded a significantly higher mean APRI score (0.71±0.51) as compared to those in the immune control and immune tolerant phase (0.43±0.20). Based on WHO and AASLD criteria, 12(4.2%) and 15 (5.3%) were eligible for treatment respectively and these were all subsets of the 52 cases mentioned above. Six (2.1%) and 29 (10.2%) of those identified under the immune control phase were on tenofovir and traditional medication respectively. CONCLUSION: Considering treatment for patients in the immune clearance and immune escape phases of the infection can be a reliable strategy to implement in our setting as this may probably tie with considerations from other treatment guidelines. Fifty-two (18.4%) patients were eligible for treatment and none of them were among the 2.1% of patients put on Tenofovir based treatment. This calls for the need for more trained health experts to periodically assess patients, implement an adequate treatment guideline and place the right patients on treatment in Cameroon.

Therapeutic effects of targeted nursing interventions combined with auricular-plaster therapy on anxiety level and life quality of Hepatitis B patients.

Mood disorders are common problems in patients with chronic hepatitis B virus (HBV) infection, most clinical treatment focus on anti-viral and anti-fibrosis rather than taking care of mood disorders. In the past decades, we have developed a Chinese medicine treatment method together with nursing intervention, which shows a positive treatment effect on patients. 158 cases of hepatitis B patients were randomly divided into one control group (78 cases), and one observation group (80 cases). The patients in control group received hepatology nursing, liver protecting and transaminase lowering medicine, and ear acupoint bean pressing treatment. In addition to the nursing and treatment as the control group, the patients in observation group were given targeted nursing interventions, including psychological intervention, emotional intervention, cognitive intervention, and systematic family and community support intervention. The anxiety level and sleep quality of patients in both groups were compared. The improvement of hepatic indexes was checked and life qualities in both groups were also compared. Compared to the control group, the patients in the observation group provided have statistically significant mprovement on anxiety control, sleep quality, and hepatic indexes changes (P<0.05). The observation group also showed remarkably better life quality scores (GQLI-64) than the control group (P<0.01). This research confirmed that targeted nursing intervention coupled with ear acupoint bean pressing showed effective improvement on the anxiety control and sleep quality of chronic hepatic B patients, and demonstrated better hepatic index recovery. Patients in the observation group also have higher life quality scores than the control group.

A meta-analysis of the antiviral activity of the HBV-specific immunotherapeutic TG1050 confirms its value over a wide range of HBsAg levels in a persistent HBV pre-clinical model.

Pre-clinical models mimicking persistent hepatitis B virus (HBV) expression are seldom, do not capture all features of a human chronic infection and due to their complexity, are subject to variability. We report a meta-analysis of seven experiments performed with TG1050, an HBV-targeted immunotherapeutic, 1 in an HBV-persistent mouse model based on the transduction of mice by an adeno-associated virus coding for an infectious HBV genome (AAV-HBV). To mimic the clinical diversity seen in HBV chronically infected patients, AAV-HBV transduced mice displaying variable HBsAg levels were treated with TG1050. Overall mean percentages of responder mice, displaying decrease in important clinical parameters i.e. HBV-DNA (viremia) and HBsAg levels, were 52% and 51% in TG1050 treated mice, compared with 8% and 22%, respectively, in untreated mice. No significant impact of HBsAg level at baseline on response to TG1050 treatment was found. TG1050-treated mice displayed a significant shorter Time to Response (decline in viral parameters) with an Hazard Ratio (HR) of 8.3 for viremia and 2.6 for serum HBsAg. The mean predicted decrease for TG1050-treated mice was 0.5 log for viremia and 0.8 log for HBsAg, at the end of mice follow-up, compared to no decrease for viremia and 0.3 log HBsAg decrease for untreated mice. For mice receiving TG1050, a higher decline of circulating viremia and serum HBsAg level over time was detected by interaction term meta-analysis with a significant treatment effect (p = 0.002 and p<0.001 respectively). This meta-analysis confirms the therapeutic value of TG1050, capable of exerting potent antiviral effects in an HBV-persistent model mimicking clinical situations.

Mapping progress in chronic hepatitis B: geographic variation in prevalence, diagnosis, monitoring and treatment, 2013-15.

OBJECTIVE: To measure progress towards Australia's National Hepatitis B Strategy 2014-17 targets, and assess geographic variation in disease burden and access to care for those living with chronic hepatitis B (CHB). METHODS: Data were generated from routinely collected sources, including risk-group prevalence and population data, infectious diseases notifications, Medicare records, and immunisation registry data, and assessed nationally and according to geographic area for 2013-15. RESULTS: CHB prevalence in 2015 was 239,167 (1.0%), with 62% of those affected having been diagnosed (target 80%). Treatment uptake was 6.1% (target 15%), and only 15.3% of people with CHB received guideline-based care. CHB prevalence ranged within Australia's 31 Primary Health Networks (PHNs) from 1.77% (NT) to 0.56% (Grampians & Barwon South West VIC). No PHN reached the 15% treatment target, with uptake highest in South Western Sydney (13.7%). Immunisation coverage reached the 95% target in three PHNs. CONCLUSIONS: The CHB burden in Australia is significant and highly geographically focused, with notable disparities in access to care across Australia. Implications for public health: Efforts to improve progress toward National Strategy targets should focus on priority areas where the prevalence of CHB is substantial but access to treatment and care remains low.

Immunoregulatory functions of immune complexes in vaccine and therapy.

Clinical and experimental preparations of IgG/soluble antigen complexes, as well as those formed following antibody therapy in vivo, are multifaceted immune regulators. These immune complexes (ICs) have been tested in humans and animal models, mostly in forms of experimental or clinical vaccination, for at least a century. With intensified research on Fcγ receptor-mediated immune modulation, as well as with immune complex-directed antigen processing, presentation, and inflammatory responses, there are renewed interests of using ICs in vaccines and immunotherapies. Currently, IC-based immune therapy has been broadly experimented in HBV and HIV viral infection control and antitumor treatments. However, mechanistic insights of IC-based treatments are relatively recent subjects of study; strong efforts are needed to establish links to connect laboratory findings with clinical practices. This review covers the history, mechanisms, and in vivo outcomes of this safe and effective therapeutic tool, with a clear aim to bridge laboratory findings with evolving clinical applications.

Current status of immunomodulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: Search for the "magic bullet" to kill cccDNA.

Chronic hepatitis B (CHB) is currently treated with IFN-α and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus-specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis".

Addressing viral hepatitis in the opiate substitution setting: an integrated nursing model of care.

Despite the availability of effective therapies for hepatitis C virus (HCV) and B virus (HBV), only a minority of infected patients receive treatment. In the general population, morbidity and mortality associated with chronic HCV is now successfully being addressed through the use of antiviral therapy. In Australia, an estimated 41% to 68% of people who inject drugs (PWID) are HCV positive, and between 28% and 59% of users are estimated to have been exposed to HBV. Although current treatment guidelines suggest that active drug use should not preclude people from HCV treatment, uptake of therapy thus far has been low. Patient, physician, social, and logistical-related barriers contribute to the low uptake of HCV treatment among PWID. Traditional means of managing HCV infection­referral to secondary or tertiary health centers­historically has a poor track record in increasing therapy uptake among this population. The same is true for people with chronic HBV who inject drugs. Close to 50,000 Australians receive opioid substitution therapy (OST) through a range of services, including public and private clinics, thus this setting is an ideal target for identifying and treating people at risk for and already infected with HBV and HCV. Over the last 11 years, a nursing model of care initiated by a teaching hospital in Sydney, Australia that integrates viral hepatitis screening, assessment, and treatment into the OST setting has enhanced access to services among the marginalized injecting drug use population.

Chronic hepatitis B: role of anti-platelet therapy in inflammation control.

Platelets play a known role in the maintenance of vascular homeostasis, but these cells are emerging as important cellular mediators of acute and chronic inflammatory diseases. Platelets are key elements in the pathogenesis of acute and chronic liver disease associated with hepatitis B virus (HBV) infection by promoting the accumulation of virus-specific CD8(+) T cells and nonspecific inflammatory cells into the liver parenchyma. This review discusses major platelet functions in immune and inflammatory responses, with an emphasis on recent pre-clinical studies that suggest that the inhibition of platelet activation pathways represent an alternative therapeutic strategy with potential use in the reduction of virus-specific T cell-mediated chronic inflammation, liver fibrosis and hepatocellular carcinoma in patients who are chronically infected with HBV.

Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice.

BACKGROUND & AIMS: Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB-110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment. METHODS: For animal study, mice (BALB/c or HBV transgenic) were immunized with mHB-110, and T-cell and antibody responses were evaluated. For clinical study, 27 patients randomly received either ADV alone or ADV in combination with HB-110. Liver function tests, serum HBV DNA levels and the presence of HBeAg/anti-HBe were analysed. T-cell responses were estimated by ELISPOT and FACS analysis. RESULTS: mHB-110 induced higher T-cell and antibody responses than mHB-100 in mice. No adverse effects were observed by HB-110 cotreated with ADV. HBV-specific T-cell responses were induced in a portion of patients in medium to high dose of HB-110. Interestingly, HB-110 exhibited positive effects on ALT normalization and maintenance of HBeAg seroconversion. One patient, who received high dose of HB-110 exhibited HBeAg seroconversion during vaccination, which correlated with vaccine-induced T-cell responses without ALT elevation. CONCLUSIONS: HB-110 was safe and tolerable in CHB patients. In contrast to results in animal models, HB-110 in Korean patients exhibited weaker capability of inducing HBV-specific T-cell responses and HBeAg seroconversion than HB-100 in Caucasian patients. As Asian patients, who are generally infected via vertical transmission, appeared to have higher level of immune tolerance than Caucasian, novel approaches for breaking immune tolerance rather than enhancing immunogenicity may be more urgently demanded to develop effective therapeutic HBV DNA vaccines.

Systemic diseases and biotherapies: understanding, evaluating, and preventing the risk of hepatitis B reactivation.

Hepatitis B virus (HBV) reactivation can occur in chronic carriers of the HBV surface antigen (HBsAg) and constitutes a well-known complication of immunosuppressive therapy. HBV reactivation has also been reported after contact with the HBV. The increasing use of biological agents (TNFα antagonists, rituximab, abatacept, and tocilizumab) to treat systemic diseases has resulted in numerous publications about the risk of HBV reactivation. The relevant scientific societies have issued recommendations designed to prevent HBV reactivation. The main measures consist of screening for markers indicating chronic HBV infection (HBsAg) or HBV infection in the distant past (antibodies to the HBV core antigen) before initiating biological therapies, vaccinating marker-negative patients, and considering close follow-up or antiviral treatment before immunosuppressive treatment initiation or in the event of HBV reactivation. Here, we discuss the pathophysiological mechanisms underlying HBV reactivation during biological treatments, most notably in patients with occult HBV infection or markers for remote HBV infection, whose hepatocyte nuclei may contain a resistance form of HBV DNA known as covalently closed circular DNA (cccDNA). Assessment of the risk of reactivation relies on the HBV status, drugs used, and data from the literature. Finally, we discuss the various recommendations and modalities for HBV vaccination, preemptive treatment, and patient management, according to the level of risk and to the circumstances in which reactivation occurs.