Chronic Hepatitis B Finite Treatment: Similar and Different Concerns With New Drug Classes.

Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

Impact of Share 35 liver transplantation allocation in Australia and New Zealand.

Patients with high model for end-stage liver disease (MELD) scores waiting for liver transplantation in Australia and New Zealand (ANZ) have had limited access to deceased donor livers and therefore binational sharing of livers, for patients with a MELD score ≥35 was introduced in February 2016. Waiting list mortality, post-transplant outcomes and intention-to-treat survival were compared between patients whose MELD score reached 35 on the waiting list between October 2013 and April 2015 (Pre-Share 35 group, n = 23) and patients who were Share 35 listed between February 2016 and May 2022 (Share 35 group, n = 112). There was significantly reduced waiting list mortality in share 35 listed patients in comparison to the pre-Share 35 group (11.7% vs. 52.2%, OR .120 95% CI .044-.328, P < .001). Post-transplant patient and graft survival were not significantly different between the groups (5-year patient survival 82% vs. 84%, P = .991, 5-year graft survival 82% vs. 76%, P = .543). Intention-to-treat survival was superior in the Share 35 group (HR .302, 95% CI .149-.614, P < .001). Introduction of Share 35 in ANZ resulted in a 78% risk reduction in waiting list mortality, equivalent post-transplant survival and an improvement in intention-to-treat survival.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.

Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials.

BACKGROUND & AIMS: Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts. METHODS: We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection. RESULTS: In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion. CONCLUSIONS: VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188. IMPACT AND IMPLICATIONS: A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.

Atopy and allergy following solid organ transplantation: A 15-year experience.

AIM: There are increasing reports of atopy/allergy following solid organ transplantation, especially paediatric liver transplantation (LT) with minimal New Zealand (NZ) data. We describe the prevalence of transplant-acquired atopy and allergy (TAA) in NZ paediatric liver transplant recipients, compared to paediatric kidney and adult liver transplants. METHODS: TAA focussed health questionnaires were sent to patients selected from the NZ transplant registry (transplanted between January 2003 and December 2017). Demographic and clinical data were also obtained from electronic health records and follow-up phone calls. RESULTS: A total of 232 patients (62% male) participated (111 adult liver, 82 paediatric liver, 39 paediatric kidney transplant recipients). Tacrolimus was primary immunosuppression for all LT patients; with combined tacrolimus, mycophenolate and corticosteroids for kidney transplants. The number of patients who developed TAA was significantly higher (P < 0.001) in the paediatric LT group (36/82, 44%) compared to adult liver (12/111, 11%) and paediatric kidney transplants (4/39, 10%). Eczema was most common (73%), then IgE-mediated food allergy (FA, 33%), allergic rhinitis (19%) and asthma (17%). Six paediatric LT recipients developed eosinophilic oesophagitis (EoE). Egg was the most common allergen in the IgE-mediated FA group. TAAs were severe enough to warrant a switch from tacrolimus to another agent in seven paediatric LT patients. For paediatric LT patients, female gender and younger age at transplant were risk factors for developing TAA. CONCLUSIONS: TAA is common in paediatric liver transplant recipients, with female gender and younger age at transplant being risk factors identified. This highlights the need for detailed atopic and allergy history to be incorporated in all pre-transplant assessments.

How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?

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.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection.

OBJECTIVES: We investigated JNJ-64530440 (a hepatitis B virus capsid assembly modulator) safety, antiviral activity and pharmacokinetics in patients with chronic hepatitis B (CHB) (Phase 1b, NCT03439488). METHODS: Twenty treatment-naive, HBeAg-positive or -negative CHB patients were randomized 4|:|1 to JNJ-64530440 750 mg once or twice daily, or placebo for 28 days. RESULTS: All patients (mean age 43.8 years; 85% male; 70% White; 20% HBeAg positive) completed dosing/28 day follow-up. Mild-to-moderate treatment-emergent adverse events occurred in 3/4 (placebo), 6/8 (once-daily) and 4/8 (twice-daily) patients; mostly fatigue, increased alanine aminotransferase, decreased neutrophil count, and headache. Hepatitis B virus (HBV) DNA was substantially reduced; mean (range) changes from baseline at day 29 were: -3.2 (-2.4 to -3.9) (once-daily) and -3.3 (-2.6 to -4.1) (twice-daily) log10 IU/mL; placebo 0.1 (0.7 to -0.6) log10 IU/mL. HBV DNA levels were below the lower limit of quantification (LLOQ) in 5/8 (once-daily) and 3/8 (twice-daily) patients. For patients with detectable baseline HBV RNA, mean (SE) changes versus baseline in HBV RNA at day 29 were: -2.65 (0.81) (once-daily) and -2.94 (0.33) (twice-daily) log10 copies/mL. HBV RNA levels were 'target not detected' in 4/6 (once-daily) and 3/7 (twice-daily) patients. JNJ-64530440 pharmacokinetics in CHB patients were comparable with those in healthy volunteers. CONCLUSIONS: JNJ-64530440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved potent antiviral activity in CHB patients.

Turning the Tide on Hepatitis C Virus-Related Liver Transplantation: The Return on Investment in Hepatitis C Virus Treatment in Australia and New Zealand.

Introduction of universal access to direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) in Australia and New Zealand on March 1st , 2016, has had a major impact on the number of people with chronic HCV infection, but the impact on liver transplantation rates is unknown. We conducted a retrospective registry study including all adult liver transplantations from the Australia and New Zealand Liver and Intestinal Liver Transplant Registry (ANZLITR) data set. Interrupted time series analysis determined the impact of DAAs in 2016 on the number of HCV liver transplantations per year. Cox regression analysis was used to determine the impact of DAAs on post-liver transplantation survival. Between January 1, 1990, and December 31, 2019 5318 adult liver transplantations were performed, and 29% (1531) were for HCV infection. Prior to the introduction of DAAs, there was a mean increase of 3.5 adult liver transplantations performed for HCV per annum, but between 2016 and 2019 there was a mean decrease of 7.9 adult liver transplantations per annum (P < 0.001). Similarly, the proportion of liver transplantations performed for HCV increased from 9% (1990) to 33% in 2016 and then fell to 23% in 2019 (P < 0.001). The number and proportion of patients with HCV added to the liver transplantation waiting list also fell in 2016 (P < 0.001) when compared with other indications. The introduction of DAAs was associated with a 31% reduction in death after liver transplantation, adjusted for age at transplant and hepatocellular carcinoma (HCC; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.48-0.99; P = 0.047). The number of adult liver transplantations performed for HCV-related liver cirrhosis and HCC has reduced since the introduction of universal access to DAAs in 2016 in Australia and New Zealand.

Analysis of Hepatitis B Virus Haplotype Diversity Detects Striking Sequence Conservation Across Genotypes and Chronic Disease Phase.

BACKGROUND AND AIMS: We conducted haplotype analysis of complete hepatitis B virus (HBV) genomes following deep sequencing from 368 patients across multiple phases of chronic hepatitis B (CHB) infection from four major genotypes (A-D), analyzing 4,110 haplotypes to identify viral variants associated with treatment outcome and disease progression. APPROACH AND RESULTS: Between 18.2% and 41.8% of nucleotides and between 5.9% and 34.3% of amino acids were 100% conserved in all genotypes and phases examined, depending on the region analyzed. Hepatitis B e antigen (HBeAg) loss by week 192 was associated with different haplotype populations at baseline. Haplotype populations differed across the HBV genome and CHB history, this being most pronounced in the precore/core gene. Mean number of haplotypes (frequency) per patient was higher in immune-active, HBeAg-positive chronic hepatitis phase 2 (11.8) and HBeAg-negative chronic hepatitis phase 4 (16.2) compared to subjects in the "immune-tolerant," HBeAg-positive chronic infection phase 1 (4.3, P< 0.0001). Haplotype frequency was lowest in genotype B (6.2, P< 0.0001) compared to the other genotypes (A = 11.8, C = 11.8, D = 13.6). Haplotype genetic diversity increased over the course of CHB history, being lowest in phase 1, increasing in phase 2, and highest in phase 4 in all genotypes except genotype C. HBeAg loss by week 192 of tenofovir therapy was associated with different haplotype populations at baseline. CONCLUSIONS: Despite a degree of HBV haplotype diversity and heterogeneity across the phases of CHB natural history, highly conserved sequences in key genes and regulatory regions were identified in multiple HBV genotypes that should be further investigated as targets for antiviral therapies and predictors of treatment response.

Sofosbuvir/velpatasvir for 12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection.

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.

Molecular Phylogenetics of Hepatitis D Virus in New Zealand and the Implications for Pacific Island Countries.

Hepatitis delta virus (HDV) is considered a satellite virus that requires hepatitis B virus surface antigen for infectivity. HDV is endemic in some Pacific Island (PI) countries, including Kiribati and Nauru, with a unique genotype 1, "Pacific clade." The aims of this study were to determine the HDV genotypes in New Zealand and investigate the link of strains to other PI countries and the rest of the world through phylogenetics. Sequencing and phylogenetic analyses were performed on 16 HDV-positive serum samples from 14 individuals collected between 2009 and 2014 at Auckland Hospital. Thirteen of 14 strains were confirmed as genotype 1 and 1 was genotype 5. Eleven of the 13 genotype 1 strains clustered with the Pacific clade. These were isolated from subjects born in Samoa, Kiribati, Tuvalu, and Niue. Another genotype 1 strain isolated from a Maori health-care worker clustered most closely with a European strain. There was an African genotype 1 and genotype 5 from African-born subjects with HIV coinfection. This study supports the probable transmission of HDV Pacific clade around the PI from Micronesia to Polynesia. The data also confirm the need to screen hepatitis B surface antigen-positive individuals for HDV.

Simplified monitoring for hepatitis C virus treatment with glecaprevir plus pibrentasvir, a randomised non-inferiority trial.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy for HCV has high efficacy and limited toxicity. We hypothesised that the efficacy of glecaprevir-pibrentasvir for chronic HCV with a simplified treatment monitoring schedule would be non-inferior to a standard treatment monitoring schedule. METHODS: In this open-label multicentre phase IIIb trial, treatment-naïve adults with chronic HCV without cirrhosis were randomly assigned (2:1) to receive glecaprevir-pibrentasvir 300 mg-120 mg daily for 8 weeks administered with a simplified or standard monitoring strategy. Clinic visits occurred at baseline and post-treatment week 12 in the simplified arm, and at baseline, week 4, week 8, and post-treatment week 12 in the standard arm. Study nurse phone contact occurred at week 4 and week 8 in both arms. Participants requiring adherence support were not eligible, including those reporting recent injecting drug use. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12), with a non-inferiority margin of 6%. RESULTS: Overall, 380 participants (60% male, 47% genotype 1, 32% genotype 3) with chronic HCV were randomised and treated with glecaprevir-pibrentasvir in the simplified (n = 253) and standard (n = 127) arms. In the intention-to-treat population, SVR12 was 92% (95% CI 89%-95%) in the simplified and 95% (95% CI 92%-99%) in the standard arm (difference between arms -3.2%; 95% CI -8.2% to 1.8%) and did not reach non-inferiority. In the per-protocol population, SVR12 was 97% (95% CI 96%-99%) in the simplified and 98% (95% CI 96%-100%) in the standard arm. No treatment-related serious adverse events were reported. CONCLUSIONS: In patients with chronic HCV infection without cirrhosis, treatment with glecaprevir-pibrentasvir was safe and effective. In comparison to standard monitoring, a simplified monitoring schedule did not achieve non-inferiority. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03117569. LAY SUMMARY: Direct-acting antiviral (DAA) therapy for hepatitis C is highly effective and well tolerated. The SMART-C randomised trial evaluated an 8-week regimen of glecaprevir-pibrentasvir for hepatitis C treatment, using a simplified monitoring schedule that included no pathology tests or clinic visits during treatment. This simplified strategy produced a high cure rate (92%), but this was not equivalent to the standard monitoring schedule cure rate (95%).

HBV variants are common in the 'immune-tolerant' phase of chronic hepatitis B.

Nucleos(t)ide analogues (NUC) treatment prevents progression of liver fibrosis in subjects with chronic hepatitis B (CHB). However, risk of hepatocellular carcinoma (HCC) persists despite viral suppression. Specific HBV variants have been associated with adverse outcomes, including HCC; however, the frequency of these variants during the seemingly benign immunotolerant (IT) phase is unknown. Next-generation sequencing and detailed virological characterization on a cohort of treatment-naïve IT subjects were performed to determine the frequency of clinically relevant viral variants. Samples from 97 subjects (genotype B/C 55%/45%, median HBV-DNA 8.5 log10 IU/mL, median HBsAg 4.8 log10  IU/mL, median HBeAg 3.6 log10  PEIU/mL) were analysed. Despite subjects being in the IT phase, clinically relevant HBV variants were common at baseline, particularly in the basal core promoter (BCP, overlaps the hepatitis B X (HBx) gene), precore and PreS regions. BCP/HBx variants were independently associated with lower baseline HBeAg, HBsAg and HBV-DNA titres. Precore variants were independently associated with higher baseline ALT. Increased viral diversity was associated with increased age and lower HBV-DNA, HBsAg and HBeAg levels. Low-level (<5%) drug resistance-associated amino acid substitutions in the HBV reverse transcriptase were detected in 9 (9%) subjects at pre-treatment but were not associated with reduced antiviral activity. Future studies should evaluate whether the detection of HBV variant during IT CHB is predictive of progression to immune clearance and poor prognosis, and whether early initiation of antiviral therapy during IT CHB to prevent the selection of HBV variants is clinically beneficial.

Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-ß1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP). METHODS: Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-ß1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS). RESULTS: Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-ß1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2). CONCLUSIONS: Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-ß1 levels (vs no response) correlated with longer survival. TRIAL REGISTRATION NUMBER: NCT01246986 at ClinicalTrials.gov.

Patient-reported outcomes in patients chronic viral hepatitis without cirrhosis: The impact of hepatitis B and C viral replication.

BACKGROUND & AIM: Chronic infections with hepatitis B or C (HBV and HCV) are associated with adverse clinical outcomes and patient-reported outcomes (PROs). The aim is to compare PRO scores in patients with chronic HBV and HCV without advanced liver disease before and after suppression/clearance of their infection. METHODS: Patients with HCV and HBV infection prior to initiation of antiviral treatment and after viral suppression/eradication completed PRO questionnaires. RESULTS: We included 132 patients with HBV and 132 matched patients with HCV. Baseline PRO scores were significantly higher in patients with HBV in the domains of Physical Functioning, Role Physical, Bodily Pain, Social Functioning, and Role Emotional of SF-36, SF-6D utility, Emotional and Fatigue domains of CLDQ, Presenteeism and total Work Productivity Impairment of WPAI:SHP in comparison to patients with HCV by 5.8%-13.2% of a PRO score range (all P < 0.05). After viral suppression (HBV DNA < 20 IU/mL after 48 weeks of treatment for HBV) or eradication (SVR-12 for HCV), only Physical Functioning and Role Physical scores remained higher in HBV by 6.7%-9.9%, while other PRO scores became similar between HBV and HCV groups (P > 0.05). The most prominent improvement of PROs in HCV was noted in Vitality, Emotional, Fatigue and Worry domains. In addition, General Health, Worry and Work Productivity scores were the most improved in HBV. CONCLUSIONS: Prior to treatment, PRO scores were lower in patients with HCV in comparison to HBV. After successful treatment, both groups of patients experienced improvement in some PRO domains confirming the positive impact of treatment.

Aiming for the elimination of viral hepatitis in Australia, New Zealand, and the Pacific Islands and Territories: Where are we now and barriers to meeting World Health Organization targets by 2030.

Viral hepatitis affects more than 320 million people globally, leading to significant morbidity and mortality due to liver failure and hepatocellular carcinoma (HCC). More than 248 million people (3.2% globally) are chronically infected with hepatitis B virus (HBV), and an estimated 80 million people (1.1% globally) are chronically infected with hepatitis C virus (HCV). In 2015, more than 700 000 deaths were directly attributable to HBV, and nearly 500 000 deaths were attributable to HCV infection; 2-5% of HBV-infected people develop HCC per annum irrespective of the presence of cirrhosis, whereas 1-5% HCV-infected people with advanced fibrosis develop HCC per annum. The rapidly escalating global mortality related to HBV and HCV related viral hepatitis to be the 7th leading cause of death worldwide in 2013, from 10th leading cause in 1990. Australia, New Zealand, and Pacific Island Countries and Territories fall within the World Health Organization Western Pacific Region, which has a high prevalence of viral hepatitis and related morbidity, particularly HBV. Remarkably, in this region, HBV-related mortality is greater than for tuberculosis, HIV infection, and malaria combined. The region provides a unique contrast in viral hepatitis prevalence, health system resources, and approaches taken to achieve World Health Organization global elimination targets for HBV and HCV infection. This review highlights the latest evidence in viral hepatitis epidemiology and explores the health resources available to combat viral hepatitis, focusing on the major challenges and critical needs to achieve elimination in Australia, New Zealand, and Pacific Island Countries and Territories.

Effects of Treatment of Chronic Hepatitis B Virus Infection on Patient-Reported Outcomes.

BACKGROUND & AIMS: Chronic infection with hepatitis B virus (HBV) causes liver disease and cirrhosis. It is not clear how treatment of chronic HBV infection affects patient-reported outcomes (PROs). We aimed to assess changes in PROs in patients treated for chronic HBV infection. METHODS: We collected and analyzed PRO data from 242 patients with chronic HBV infection (without advanced fibrosis or cirrhosis) enrolled in 2 international phase 2 blinded controlled clinical trials from 2015 through 2017. In these trials, patients were treated with an approved oral antiviral regimen (tenofovir, entecavir, adefovir, lamivudine, or telbivudine) and then randomly assigned to groups given vesatolimod (an oral agonist of Toll-like receptor 7) or placebo. PROs were collected using the Short Form-36, the Chronic Liver Disease Questionnaire, and the Work Productivity and Activity Impairment: Specific Health Problem questionnaires before treatment and during treatment weeks 12, 24, and 48. RESULTS: We did not observe significant differences in PROs between patients receiving vesatolimod vs placebo. At baseline, patients with viral suppression (HBV DNA level, <20 IU/mL) had higher PRO scores (by up to +10.6% of a PRO range size). During treatment, there were significant increases in scores for some domains of the Chronic Liver Disease Questionnaire and in General Health scores of Short Form-36 (increases of up to 4.9%; P < .05). Patients with a decrease of at least 2.7 log10 IU/mL in level of HBV DNA had substantially larger increases in PRO scores (P < .05 for 10 of 22 studied PROs). In multivariate analysis, a reduction in viral load was independently associated with increases in PROs (ß values up to 1.6% per log10 IU/mL decrease; P < .05). CONCLUSIONS: In an analysis of data from phase 2 trials, we associated active treatment of chronic HBV infection with increased PRO scores. These findings support inclusion of PRO end points in assessments of efficacy and safety in clinical trials of treatments for HBV infection.

ALT flares during nucleotide analogue therapy are associated with HBsAg loss in genotype A HBeAg-positive chronic hepatitis B.

BACKGROUND: Alanine aminotransferase (ALT) flares during NA therapy are uncommon but occur. Evaluation of ALT flares during nucleos(t)ide analogue (NA) therapy is important as new immunomodulatory therapies for hepatitis B virus (HBV) are developed. We evaluated the association between ALT flares and HBsAg loss during long-term therapy for genotype A CHB. METHODS: This analysis included genotype A subjects from a phase III study of tenofovir vs adefovir in HBeAg-positive HBV. ALT flare was defined as (i) a rise in ALT >2x ULN from normal ALT levels; or (ii) a rise in ALT >2x baseline ALT level. HBsAg response at week 384 was recorded as one of HBsAg loss vs HBsAg decline (≥1 log10  IU/mL decline) vs non-response. The primary analysis evaluated the association between ALT flare and HBsAg response. RESULTS: 54 subjects were included. 23/54 (43%) subjects experienced an on-treatment ALT flare. 45% achieved an HBsAg reduction ≥1 log10  IU/mL, and of these 67% achieved HBsAg loss at a median of 102 weeks [IQR: 64-156]. Flare was associated with HBsAg decline vs non-response (67% vs 23%, P = .002), and were more common in subjects who achieved HBsAg loss vs non-response (56% vs 23%), P = .049). There was a median delay of 56 weeks [IQR: 40-80] between a flare and HBsAg loss. CONCLUSION: In genotype A subjects undergoing long-term NA therapy, ALT flares predict for HBsAg response. The delay between ALT flare and HBsAg loss has implications for clinical trial design for early phase development of immunomodulatory strategies aiming for HBsAg loss.