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We investigated associations between hepatitis B virus (HBV) genome-length haplotype number (HN) at baseline in subjects with HBeAg-positive chronic hepatitis B (CHB), and the likelihood of achieving functional cure during direct-acting antiviral therapy METHOD: We analysed 86 HBeAg-positive baseline samples from patients with HBV genotypes A and D who were enrolled in a Phase II trial of tenofovir disoproxil fumarate (TDF) to determine if HN was a biomarker of HBsAg loss during therapy. Findings were validated using baseline samples from 181 patients with HBV genotypes A and D from an independent clinical trial utilising TDF or tenofovir alafenamide therapy in HBeAg-positive CHB.In the HBeAg-positive test cohort, patients with genotypes A or D and ≤2 haplotypes had a minimum of 21-fold higher likelihood of achieving HBsAg loss on TDF. Baseline HN (p 0.0001) was a stronger predictor of HBsAg loss on therapy than HBsAg titre (p = 0.03), HBeAg titre (p = 0.0002), or the presence of HBV basal core promoter (A1762T, p = 0.0379 and G1764A, p = 0.0176) or G1896A precore mutations (p = 0.0218). This finding was validated in the independent validation cohort. HN was statistically higher in patients with HBV genotypes B or C infection compared to genotypes A and D.Baseline HN ≤2 predicts which patients with HBV genotypes A or D will more likely progress to functional cure on current direct-acting antiviral therapy, with greater accuracy than current biomarkers including baseline HBsAg and HBeAg titre.

Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available. journal article review 2023 Jan 11 2023 01 11 imported

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.

Background & Aims Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking. Methods REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early. Results The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4–89.0) in the short arm and 86/95, 90.5% (95% CI 82.7–95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8–95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0–99.7; difference -8.3%, p = 0.025). Conclusions In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy. Lay summary In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection. ClinicalTrials.gov Identifier NCT02625909 .

Background JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947). Methods Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients). Results Thirty non-Japanese ( n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants ( n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4–9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate. Conclusion JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.

To ascertain the feasibility and outcomes of point-of-care testing for hepatitis C virus (HCV) antibodies in people with risk factors screened in community pharmacies.Ten pharmacies in the Waitematā District Health Board piloted point-of-care antibody HCV screening with consenting participants. Individuals with a positive HCV antibody result had a confirmatory HCV RNA test performed at a local laboratory, with pharmacist follow-up to discuss the result. RNA positive individuals were referred to their general practitioner for further follow-up including antiviral therapy. Number of tests, number of positives and number treated were collected. Pharmacists completed a survey about their experiences.Of 192 participants, seven (3.6%) had positive tests on screening, four of whom had a positive RNA assay and received HCV medication, and one of whom had a positive RNA assay but has not yet received treatment. Two had negative RNA results. Pharmacist feedback was very positive with most wishing to continue the point-of-care testing service. Most wanted to be able to treat HCV in order to improve linkage to care.Pharmacy point-of-care testing with immediate results and pharmacist follow-up of positive results can aid diagnosis of HCV in at-risk populations and help treatment uptake.

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Regular surveillance for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B viral (HBV) infection and hepatitis C (HCV) cirrhosis improves survival by earlier detection of the cancer at an earlier stage when curative intervention may still be possible. We compared patient characteristics, surveillance history and outcomes in patients presenting with advanced HCC secondary to HBV and HCV.In this retrospective study, clinical databases and notes were reviewed in all cases of advanced HCC related to HBV or HCV referred to the tertiary HCC service in Auckland, New Zealand between 1 January 2003 and 31 December 2017.Over the 15-year period, 368 patients were referred with advanced HCC secondary to HBV (HBV-HCC) and 278 secondary to HCV (HCV-HCC), representing over 50% of all cases of HCC cases secondary to viral hepatitis. Of these 646 patients with advanced HCC, 75% of patients were not receiving guideline-recommended surveillance. More patients with advanced HBV-HCC were diagnosed with HCC prior to the diagnosis of HBV, compared to patients with advanced HCV-HCC (40% vs 28%, p0.01). Fewer patients with previously diagnosed HBV infection were undergoing HCC surveillance than patients with previously diagnosed HCV infection (26% vs 42%, p0.01). Late diagnosed patients had the worst outcomes, with 88% receiving palliative care and surviving on average only seven months (HBV five months vs HCV eight months, p=0.05).Survival in New Zealanders with hepatocellular carcinoma remains poor because the cancer is incurable in most patients at the time of detection. Because most cases are secondary to chronic hepatitis B and C infections, improved screening and linkage to antiviral therapy and HCC surveillance should improve outcomes.

Earlier diagnosis of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) increases treatment options and survival. The aim of this study is to evaluate which factors are associated with late presentation of HBV-related HCC.This is a retrospective review of all cases of HBV-related HCC diagnosed with late-stage/incurable HCC in New Zealand between 2003 and 2017. Cases were defined as patients with a positive hepatitis B surface antigen (HBsAg), and advanced (not amenable to potentially curable treatments) HCC at initial diagnosis. Patients were categorised into four groups according to potential reasons for late presentation: no previous diagnosis of HBV infection (Group A); known HBV diagnosis but not receiving HCC surveillance (Group B); known HBV diagnosis and receiving suboptimal HCC surveillance (Group C); and known HBV diagnosis and receiving optimised HCC surveillance (Group D).A total of 368 patients were reviewed. The average age at death was 59 years, and the majority of patients were Māori (39%), Pacific (34%) or Asian (20%). The incidence of patients presenting with HBV-related advanced HCC increased from 4.5 cases to 6.3 cases per million people over the review period. Of the cases, 40% were categorised into Group A, 26% into Group B, 12% into Group C and 23% in Group D. Overall, the median survival was 138 days, and this did not change during the study period. Patients receiving optimised surveillance (Group D) survived longer (mean 469 days) than patients in Group A (90 days), Group B (145 days) or Group C (152 days) (p0.05). Patients in Group D were more likely to be treated with transarterial chemoembolisation than patients in other groups (40% vs 15%, p0.05).This study has highlighted the need for improved rates of HBV diagnosis, better follow-up of those infected and the importance of optimal HCC surveillance. In New Zealand, HBV-related HCC disproportionately affects minority ethnic groups, and given the increasing incidence, provides a potential domain to reduce health inequities.

Hepatitis C (HCV), hepatitis B (HBV), alcohol-related liver disease (ALD), and non-alcohol-related fatty liver disease (NAFLD) are leading indications for adult liver transplantation in Australia and New Zealand. However, these diseases are potentially preventable through effective primary and/or secondary prevention strategies. This study evaluates the relative contribution of potentially preventable liver diseases to liver transplant numbers in Australia and New Zealand over time.Prospectively recorded clinical, demographic, and outcome data were collected from the Australian and New Zealand Liver Transplant Registry for all primary adult liver transplants performed in Australia and New Zealand from 1 January 1985 until 31 December 2012. Potentially preventable liver disease was defined as HBV, HCV, NAFLD, ALD, and HCC. The etiology of liver disease leading to liver transplantation and the proportion of preventable liver disease-related liver transplantation was compared between Era 1 (1985-1993), Era 2 (1994-2003), and Era 3 (2004-2012).Overall, 1252 of 3266 adult primary liver transplants (38.3%) were performed for potentially preventable liver disease. There was a significant increase in the proportion of liver transplants because of preventable liver disease from 21.2% (93 of 439) in Era 1, to 49.8% (623 of 1252) in Era 2 and 63.5% (1000 of 1575) in Era 3 (P 0.0001). Over time, there was a significant increase in HCV (P 0.0001), ALD (P = 0.002), and NAFLD (P 0.0001) as a primary indication for adult liver transplant, whereas HBV has significantly decreased from Era 1 to Era 3 as an indication for transplant (P 0.0001). The number of transplants performed for HCC also increased across Eras (P 0.0001), with 84% due to underlying potentially preventable liver disease.Since 2004, the majority of primary adult liver transplants within Australia and New Zealand have been because of potentially preventable liver diseases and the prevalence of these diseases has increased over time. This finding represents an opportunity for clinicians to make a significant impact on the overall burden of advanced liver disease in Australia and New Zealand by improving primary and secondary prevention measures.

Liver transplantation (LT) is established treatment for adults and children with acute or chronic liver failure, however there are insufficient donor organs to meet demand and 14% of New Zealand patients have died waiting or were de-listed due to deterioration whilst on the waiting list. Live donor liver transplantation (LDLT) offers an alternative graft source that enables timely transplantation, but also carries the risk of morbidity and mortality for the donor.To report the initial experience with LDLT in New Zealand.Review of donor and recipient outcomes for the first 20 cases.129 potential live liver donors were assessed for 68 recipients. Donors were evaluated according to a multi-step protocol including independent donor advocacy. Twenty LDLT were performed on 7 adults and 13 paediatric recipients using 5 right lobe, 2 extended left lobe, 2 left lobe, and 11 left lateral section grafts. Five donors (25%) experienced postoperative complications, none of which were life-threatening. Four recipients had acute liver failure and 16 had chronic liver disease including one retransplant. There was a high rate of recipient biliary complications (40%) but graft and recipient survival is 100% to date.LDLT has been successfully introduced in New Zealand with good donor and recipient outcomes.

To summarise the transplant-related activity of the New Zealand Liver Transplant Unit over the first four years.The records of all patients assessed for liver transplantation between 1 December 1997 and 30 December 2001 were examined. Listing criteria, demographics, waiting time, transplant-hospitalisation details and long-term outcome for those who underwent liver transplantation were recorded.One hundred and eighty six patients over 14 years of age (acute liver failure 28, chronic liver disease 158) were assessed and 150 were listed for liver transplantation. Fifteen died waiting, 13 were de-listed (6 for cancer progression) and 14 remain listed. One hundred and nine liver transplants (including 1 combined heart-liver, 1 sequential liver-bone marrow and 5 re-transplants) were performed on 104 patients (13 acute liver failure, 96 chronic liver failure or hepatocellular carcinoma). The median waiting time was 2 days (range 0 5) for acute liver failure and 62 days (range 0 320) for other patients. Median age at transplant was 50 years (range 14-70); 73 patients (66%) were male; 71 (65%) were European; 13 (12%) Maori; 12 (11%) Pacific Islander; and 8 (7%) Asian. Median duration of surgery was 480 minutes (range 300 720 minutes); red cell transfusion 5 units (0 32); intensive care and total hospital stays were 2 (range 1 17) and 11 days (range 6 91). One transplanted patient died in hospital, 1- and 3-year patient survival was 94% and 87% and corresponding graft survival was 91% and 83%. Ninety three transplanted patients (89%) are alive. Of the 92 patients at least three months post-transplant, 62 (67%) were employed.Liver transplantation is now established in New Zealand as treatment of choice for acute and chronic liver failure and small hepatocellular carcinoma. Excellent outcomes have been attained in those transplanted to date. Reduction in waiting list mortality will require identification of and investment in strategies that will expand the donor organ availability.

This paper describes the design and measured performance of a low-noise L band oscillator based on Agilent's Film Bulk Acoustic Resonator (FBAR) for applications in digital communication systems. This experimental oscillator demonstrated at 1951 MHz with a phase noise of - 115 dBc/Hz at 10KHz from the carrier represents the first example of a low noise Si-Bipolar FBAR oscillator.

Background: TGF-β signaling is associated with HCC progression in moderate to poorly differentiated tumors. LY is a TGF-β receptor I kinase inhibitor currently in clinical testing in glioblastoma (GBM), hepatocellular, and pancreatic cancer. We report here the safety and PK/PD profile of LY in HCC patients. Methods: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib (SF), advanced Child-Pugh A/B7 HCC, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/14 days off (28 days = 1 cycle). Patients received either 160 mg/day or 300 mg/day. PK data were used to build a population PK model for HCC patients. This population PK model guided appropriate sampling and identification of potential demographic covariates. PD analysis included serum alpha-fetoprotein (AFP). AFP response was defined as at least 20% decrease. Results: Among 148 patients enrolled, 137 patients were evaluable for PK. There was dose-proportional increase in exposure (AUC0-∞ = 3.8 mg*h/L for 160 mg and AUC0-∞ = 7.0 mg*h/L for 300 mg dose). There were higher exposures in HCC patients than previously observed for exposures in GBM patients (AUC0-∞ = 2.1 mg*h/L for 160 mg and AUC0-∞ = 3.7 mg*h/L for 300mg dose)1. PK data suggested that total oral clearance (CL/F = 25.4 L/hr) of LY in HCC patients is lower than previously reported clearance in GBM patients (CL/F = 38.4 L/hr). Moderate between-patient variability on exposure was observed in HCC patients similar to GBM patients. LY appears to be fully eliminated at the end of the 14-days-off period of a cycle. Administration of 300 mg/day to patients with HCC may result in higher exposures compared to patients with GBM. These increased exposures did not result in increase of toxicities. Eight patients discontinued treatment due to a possibly drug-related adverse event (AE). LY was well tolerated, most adverse events being grade1-2. Most common grade 3/4 possibly drug-related AEs in patients were: neutropenia (n = 3), anemia (n = 3) and fatigue (n = 2). Thirty-nine percent of 69 patients with HCC who had baseline AFP of >200 ng/mL had AFP response. The median time-to-progression of responders vs. non-responders was 18 vs. 10 weeks (p Rodon AJ., et al. First human dose (FHD) study of the oral transforming growth factor-beta receptor I kinase inhibitor LY2157299 in patients with treatment-refractory malignant glioma. Abstract #3011. 2011 ASCO Annual Meeting, Chicago, IL, USA. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C261. Citation Format: Eric Raymond, Sandrine Faivre, Armondo Santoro, Robin K. Kelley, Robin K. Kelley, Philippe Merle, Ed Gane, Jean-Yves Douillard, Dirk Waldschmidt, Mary Mulcahy, Charlotte Costentin, Beatriz Minguez, Luca Di Lena, Ivelina Gueorguieva, Colin Miles, Ann Cleverly, Michael M. Lahn, Sophie Ameryckx, Karim A. Benhadji, Gianluigi Giannelli. Pharmacokinetics (PK) and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor LY2157299 monohydrate (LY) in hepatocellular carcinoma (HCC) compared to glioma patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C261.

BACKGROUND & AIMS: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy. METHODS: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group). RESULTS: Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6-53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir. CONCLUSIONS: In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.