Publications by authors named "Anuj Gaggar"

77 Publications

Hepatitis B virus genome diversity in adolescents: Tenofovir disoproxil fumarate treatment effect and HBeAg serocon version.

J Viral Hepat 2021 May 18. Epub 2021 May 18.

Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon Cedex, France.

More systematic analysis of hepatitis B virus (HBV) genome diversity, linked with tenofovir disoproxil fumarate (TDF) treatment and HBeAg seroconversion, are needed. GS-US-174-0115 was a double-blind, placebo-controlled, Phase 3, 192-week clinical trial that evaluated TDF in adolescents with chronic hepatitis B (CHB). HBV full-genome deep sequencing was performed using Illumina MiSeq at baseline (BL; n = 85), Week 8 (W8; n = 80), Week 72 (W72; PBO only, n = 42), and treatment-free follow-up (TDF only, n = 25). The viral diversity was calculated using Shannon entropy and population nucleotide diversity with a 2% variant cutoff. Our data showed (i) a higher viral diversity in the X region at baseline than the core/polymerase/surface regions, (ii) higher core/surface viral diversity at baseline for patients with seroconversion, (iii) an expected reduction in viral diversity after 8 weeks of TDF treatment, and (iv) a drop in viral diversity at W72 for patients receiving placebo with a seroconversion (n = 7). The higher viral diversity in X was associated with higher baseline alanine aminotransferase (ALT) levels (p < .001). Patients with greater reduction of diversity at W8 of TDF treatment had higher baseline ALT levels. For placebo patients who seroconverted, the drop in viral diversity at W72 (p = .04) coincided with reduction of serum HBV DNA (average change from baseline = -4.10 log10 copies/ml) and unique combinations of variants were enriched in a patient's viral population post seroconversion. The basal core promoter (BCP) variants, A1762T and G1764A, and the pC variant, G1896A, were most often enriched at or after seroconversion.
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http://dx.doi.org/10.1111/jvh.13547DOI Listing
May 2021

Antiviral kinetics of tenofovir alafenamide and tenofovir disoproxil fumarate over 24 weeks in women of childbearing potential with chronic HBV.

PLoS One 2021 13;16(5):e0251552. Epub 2021 May 13.

New Zealand Liver Transplant Unit, Auckland Clinical Studies, Auckland, New Zealand.

Background/purpose: Use of tenofovir disoproxil fumarate (TDF) improves patient outcomes in preventing mother-to-child transmission (pMTCT) of the hepatitis B virus (HBV) in mothers with chronic HBV and high viral loads. Given the lack of data for tenofovir alafenamide (TAF) in pMTCT, rates of early viral suppression with TAF and TDF were evaluated in women of childbearing potential (WOCBP) participating in 2 randomized, double-blind, Phase 3 studies in chronic HBV.

Methods: In a patient subset meeting WOCBP criteria and with baseline HBV DNA >200,000 IU/mL, rates of viral suppression with TAF or TDF in achieving the target of HBV DNA <200,000 IU/mL at weeks 12 and 24 were assessed. Multivariate logistic regression was used to identify factors predictive of failure to suppress HBV DNA to the target level.

Results: In 275 of 1298 (21%) patients meeting WOCBP criteria with high viral load, 93% and 96% had HBV DNA <200,000 IU/mL at weeks 12 and 24, respectively. Results for TAF (n = 194) vs TDF (n = 81) treatment were similar at weeks 12 and 24 (94% vs. 90% and 97% vs. 93%), respectively. High baseline HBV DNA level, genotype D infection, and prior interferon (week 24 only) were predictive of failure to achieve the target level. Both treatments were well tolerated with TAF showing less impact on renal and bone parameters.

Conclusions: In WOCBP with high VL, no differences were found between TAF and TDF in reducing HBV DNA to levels associated with lower transmission risk. These data support ongoing studies of TAF for pMTCT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118264PMC
May 2021

Safety, pharmacokinetics, and pharmacodynamics of the oral TLR8 agonist selgantolimod in chronic hepatitis B.

Hepatology 2021 Mar 11. Epub 2021 Mar 11.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background & Aims: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 (TLR8) may induce antiviral immunity and drive functional cure. Selgantolimod, a novel TLR8 agonist, was evaluated in CHB patients who were virally suppressed on oral antiviral treatment (OAV) or viremic not on OAV.

Approach & Results: In this Phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once-weekly. Virally suppressed patients received either 1.5 mg (for two weeks) or 3 mg (for two weeks or four weeks). Viremic patients received 3 mg for two weeks. The primary endpoint was safety as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from 6 sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%) and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple-dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, that are important for the expansion and activity of multiple T- cell subsets and innate immunity.

Conclusion: Selgantolimod was safe and well-tolerated in virally suppressed and viremic CHB patients and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
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http://dx.doi.org/10.1002/hep.31795DOI Listing
March 2021

Long-Term Patient-Centered Outcomes in Cirrhotic Patients With Chronic Hepatitis C After Achieving Sustained Virologic Response.

Clin Gastroenterol Hepatol 2021 Jan 22. Epub 2021 Jan 22.

Center for Outcomes Research in Liver Disease, Washington, District of Columbia.

Background & Aims: Achieving sustained virologic response (SVR) among patients with hepatitis C virus (HCV) leads to patient reported outcome (PRO) improvement. We aimed to assess the long-term post-SVR PRO trends in HCV patients with cirrhosis.

Methods: Patients with HCV and cirrhosis treated in clinical trials with direct acting antiviral agents (DAAs) who achieved SVR-12 were prospectively enrolled in a long-term registry (clinicaltrials.gov #NCT02292706). PROs were collected every 24 weeks using the Short Form-36v2 (SF-36), CLDQ-HCV, and WPAI-HCV.

Results: Pre-treatment baseline data were available for 854 cirrhotic patients who achieved SVR after DAAs. Of these, 730 had compensated (CC) and 124 had decompensated cirrhosis (DCC) before treatment- patients with DCC reported severe impairment in their PROs in comparison to CC patients (by mean -5% to -16% of a PRO range size; p < .05 for 16 out of 20 studied PROs]. After achieving SVR and registry enrollment, significant PRO improvements were noted from pre-treatment levels in 11/20 domains for those with DCC (+4% to +21%) and 19/20 PRO domains in patients with CC (+3% to +17%). Patients with baseline DCC had higher rates of hepatocellular carcinoma and mortality (P < .05). In patients with CC, the PRO gains persisted up to 168 weeks (3.5 years) of registry follow-up. In patients with DCC, the improvements lasted for at least 96 weeks but a declining trend after year 2.

Conclusions: Patients with HCV cirrhosis experience severe PRO impairment at baseline with sustainable improvement after SVR. Though those with DCC experience improvement, there is a decline after 2 years.
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http://dx.doi.org/10.1016/j.cgh.2021.01.026DOI Listing
January 2021

PNPLA3 polymorphisms are associated with raised alanine aminotransferase levels in hepatitis C virus genotype 3.

Arab J Gastroenterol 2020 Dec 16;21(4):267-272. Epub 2020 Oct 16.

Laboratory of Molecular Immunology, Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, Delhi, India. Electronic address:

Background And Study Aims: Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver diseases. This study aimed to determine the association between polymorphisms in interleukin 28B (IL28B), PNPLA3, toll-like receptor 7 (TLR7), nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and retinoic inducible gene-I (RIG-I) and HCV genotype and clinical presentation in an Indian population.

Patients And Methods: A total of 500 patients with chronic HCV were enrolled in 19 centres across India. Genomic DNA was extracted from whole blood samples, and single nucleotide polymorphisms (SNPs) for IL28B, PNPLA3, TLR7, NOD2 and RIG-I genes were genotyped by real-time PCR using a TaqManSNP genotyping assay.

Results: The mean age of the patients was 45 + 13 years, and the most common genotype observed was HCV genotype 3 (54%), followed by genotype 1 (24%). Although the allelic frequencies of TLR7, NOD2 and RIG-I were in significant disequilibrium in HCV patients compared with those in controls, the PNPLA3 polymorphism correlated significantly with higher viral load and alanine aminotransferase (ALT) levels in genotype 3 patients. Patients with PNPLA3 CG/GG genotypes, along with IL28B genotype CC, had higher levels of ALT than those with other genotypes.

Conclusion: These results indicate that PNPLA3 polymorphisms are associated with higher ALT levels in HCV genotype 3 patients in India and can help in identifying people who are at greater risk of developing HCV-associated liver diseases.
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http://dx.doi.org/10.1016/j.ajg.2020.09.002DOI Listing
December 2020

Complex genetic encoding of the hepatitis B virus on-drug persistence.

Sci Rep 2020 09 23;10(1):15574. Epub 2020 Sep 23.

Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA, 30329, USA.

Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.
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http://dx.doi.org/10.1038/s41598-020-72467-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511938PMC
September 2020

Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study.

Lancet Microbe 2020 Sep 27;1(5):e200-e208. Epub 2020 Jul 27.

Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Magee-Womens Research Institute, Pittsburgh, PA, USA.

Background: Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women.

Methods: This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir-sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir-sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25-26, 29-30, and 33-34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir-sofosbuvir area under the concentration-time curve of the dosing interval (AUC) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov, NCT02683005.

Findings: From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUC ledipasvir 89·3% [90% CI 68·7-116·1]; sofosbuvir 91·1% [78·0-106·3]).

Interpretation: Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women.

Funding: National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.
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http://dx.doi.org/10.1016/S2666-5247(20)30062-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491553PMC
September 2020

DNA Methylation and Immune Cell Markers Demonstrate Evidence of Accelerated Aging in Patients with Chronic HBV or HCV, with or without HIV Co-Infection.

Clin Infect Dis 2020 Sep 11. Epub 2020 Sep 11.

Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.

Background: Several chronic diseases have been shown to accelerate biological aging. We investigated age acceleration and the association between peripheral blood DNAm and immune cell markers in patients chronically infected with the hepatitis B virus (HBV) or the hepatitis C virus (HCV) with and without human immunodeficiency virus (HIV) co-infection.

Methods: Age acceleration was measured as the difference between epigenetic age (Horvath clock) and chronological age. The immune marker model of age acceleration was developed using Elastic Net regression to select both the immune markers and their associated weights in the final linear model.

Results: Patients with chronic HBV (n=51) had a significantly higher median epigenetic age compared to chronological age (age accelerated) (p < 0.001). In patients with chronic HCV infection (n=63), age acceleration was associated with liver fibrosis as assessed by histology (p < 0.05), or presence of HIV co-infection (p < 0.05), but not HCV mono-infection. Age acceleration defined by immune markers was concordant with age acceleration by DNA methylation (correlation coefficient=0.59 in HBV; p=0.0025). One-year treatment of HBV patients with nucleoside therapy was associated with a modest reduction in age acceleration as measured using the immune marker model (-0.65 years, p=0.018).

Conclusion: Our findings suggest that patients with chronic viral hepatitis have accelerated epigenetic aging and that immune markers defines biological age and has the potential to assess the effects of therapeutic intervention on age acceleration.
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http://dx.doi.org/10.1093/cid/ciaa1371DOI Listing
September 2020

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

Aliment Pharmacol Ther 2020 10 4;52(8):1399-1406. Epub 2020 Sep 4.

Rotterdam, The Netherlands.

Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment.

Aim: To study rates and determinants of clinically significant liver inflammation.

Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2).

Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis.

Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.
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http://dx.doi.org/10.1111/apt.16067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540526PMC
October 2020

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

JAMA 2020 09;324(11):1048-1057

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.

Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.

Design, Setting, And Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.

Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.

Main Outcomes And Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.

Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.

Conclusions And Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.

Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.
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http://dx.doi.org/10.1001/jama.2020.16349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442954PMC
September 2020

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

Hepatology 2021 May;73(5):1652-1670

Division of Molecular Research and Development, Victorian Infectious Diseases, Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne Healthy, University of Melbourne, Melbourne, VIC, Australia.

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.
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http://dx.doi.org/10.1002/hep.31516DOI Listing
May 2021

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

J Hepatol 2020 12 21;73(6):1368-1378. Epub 2020 Jul 21.

Department of Infectious Diseases, First Hospital of Shanxi Medical University, Taiyuan, China.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.

Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).

Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%.

Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.

Lay Summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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http://dx.doi.org/10.1016/j.jhep.2020.07.025DOI Listing
December 2020

Safety, pharmacokinetics and pharmacodynamics of selgantolimod, an oral Toll-like receptor 8 agonist: a Phase Ia study in healthy subjects.

Antivir Ther 2020 ;25(3):171-180

Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA.

Background: Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selgantolimod in healthy volunteers.

Methods: Of 71 subjects enrolled, 59 received a single dose of selgantolimod (0.5, 1.5, 3 or 5 mg) or placebo, and 12 were evaluated for food effect. Safety, PK and PD activity by induction of cytokines, chemokines and acute phase proteins were assessed. PK/PD analyses were conducted.

Results: Single doses of 0.5-5 mg were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most were Grade 1 in severity. Selgantolimod displayed rapid absorption and dose-proportional PK and PD activity. Food had minimal effect on PK but resulted in diminished PD activity. In PK/PD analyses, near-saturation of induction for most evaluated biomarkers occurred at the 5-mg dose.

Conclusions: Single doses of up to 5 mg selgantolimod were safe and induced dose-dependent PD responses. These data support evaluation of selgantolimod in combination with other agents in future clinical studies of CHB. Australian New Zealand Clinical Trials Registration: ACTRN12616001646437.
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http://dx.doi.org/10.3851/IMP3363DOI Listing
January 2020

Twelve weeks of ledipasvir/sofosbuvir all-oral regimen for patients with chronic hepatitis C genotype 2 infection: Integrated analysis of three clinical trials.

Hepatol Res 2020 Oct 11;50(10):1109-1117. Epub 2020 Aug 11.

First Department of Internal Medicine, Gastroenterology and Hepatology, University of Yamanashi, Yamanashi, Japan.

Aim: The combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for the treatment of various hepatitis C virus (HCV) genotypes across many countries. This article presents an integrated analysis of three prospective phase II/III trials in the Asia-Pacific region to evaluate the efficacy and safety of 12 weeks of LDV/SOF in HCV genotype 2 patients without cirrhosis or with compensated cirrhosis.

Methods: A total of 200 patients were included in the integrated analysis. The primary end-point was the rate of sustained virologic response for 12 weeks after the end of therapy (SVR12), analyzed by fibrosis stage, treatment history, HCV genotype subtype, and presence of baseline resistance-associated substitutions (RAS). Safety was evaluated by adverse events and laboratory abnormalities.

Results: Twelve weeks of treatment with LDV/SOF was associated with high SVR12 rates (overall 98%) in patients with genotype 2 HCV, irrespective of fibrosis stage, treatment history, genotype 2 subtype, and presence of baseline non-structural protein 5A resistance-associated substitution (NS5A RAS), and LDV/SOF was well tolerated.

Conclusions: Twelve weeks of treatment with LDV/SOF provides a highly effective and safe treatment for patients with genotype 2 HCV, including those with advanced fibrosis. As a ribavirin-free and protease inhibitor-free regimen with minimal on-treatment monitoring requirements, LDV/SOF can potentially play a crucial role in achieving the WHO's goal of HCV elimination.
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http://dx.doi.org/10.1111/hepr.13546DOI Listing
October 2020

Developing a sensitive HBV genotyping assay for HBV DNA suppressed patients using both DNA and RNA sequencing.

J Med Virol 2020 Jul 1. Epub 2020 Jul 1.

Gilead Sciences, Inc., Foster City, California.

Hepatitis B virus (HBV) genotypes impact treatment outcomes and disease progression. The current genotyping methods have limitations in patients with low HBV viral load. In this study, a more sensitive assay has been developed for determining the HBV genotype in HBV DNA suppressed patients. Fifty-five serum samples from 55 chronic hepatitis B patients (HBeAg-, n = 20; HBeAg+, n = 35) across genotypes A to H with long-term nucleos(t)ide analogs (NAs) treatment were collected. All samples had HBV DNA less than 29 IU/mL. Total nucleic acid (viral DNA and RNA) was extracted and a 341 bp amplicon located at HBV S gene overlapping with reverse transcriptase domain of polymerase (pol/RT) was amplified via real time (RT)-nested polymerase chain reaction (PCR) followed by population sequencing. HBV genotype was determined by phylogenetic analysis. The assay successfully amplified HBV S/RT gene from 53 of 55 (96.4%) patient serum samples. Phylogenetic analysis demonstrated that the genotypes of all the 53 PCR positive samples matched the historical genotypes as determined by INNO-LiPA or RT sequence from the corresponding baseline samples. This assay was able to accurately determine HBV genotype irrespective of baseline genotype, HBeAg status, or duration of viral suppression. The ability to determine genotype in virally suppressed patients may facilitate the evaluation of novel treatment agents for HBV in this patient population.
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http://dx.doi.org/10.1002/jmv.26249DOI Listing
July 2020

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

N Engl J Med 2020 11 27;383(19):1827-1837. Epub 2020 May 27.

From the Swedish Center for Research and Innovation, Swedish Medical Center, and the University of Washington, Seattle (J.D.G.), and Providence Regional Medical Center, Everett (G.D.) - both in Washington; the National Center for Infectious Diseases, Lee Kong Chian School of Medicine, Tan Tock Seng Hospital, Singapore (D.C.B.L.); the Chinese University of Hong Kong-Prince of Wales Hospital, Hong Kong (D.S.H.); New York-Presbyterian Hospital and Weill Cornell Medicine, New York (K.M. Marks); Malattie Infettive Fondazione IRCCS Policlinico San Matteo, Pavia-Università di Pavia, Pavia (R.B.), and Università di Milano, Department of Biomedical and Clinical Sciences, L. Sacco Infectious Diseases Unit, ASST Fatebenefratelli Sacco, Milan (M.G.) - both in Italy; Hospital Universitario La Paz, IdiPAZ, Madrid (R.M.), and Barcelona Institute for Global Health (ISGlobal) Hospital Clínic-Universitat de Barcelona, Barcelona (J.M.); Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany (C.D.S.); Seoul Medical Center, Seoul, South Korea (M.-Y.A.); ID Care, Hillsborough, and Robert Wood Johnson University Hospital Somerset, Somerville - both in New Jersey (R.G.N.); Kaohsiung Veterans General Hospital, Taiwan (Y.-S.C.); Gilead Sciences, Foster City (D.S., R.H.H., A.O.O., H.C., C.B., X.W., A.G., D.M.B.), Kaiser Permanente, Los Angeles (W.J.T.), and Stanford University, Palo Alto (A.S.) - all in California; University of Chicago, Chicago (K.M. Mullane); Brigham and Women's Hospital and Harvard Medical School, Boston (F.M.M.); and Miriam Hospital, Warren Alpert Medical School of Brown University, Providence, RI (K.T.T.).

Background: Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).

Methods: We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.

Results: In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).

Conclusions: In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).
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http://dx.doi.org/10.1056/NEJMoa2015301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377062PMC
November 2020

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

J Viral Hepat 2020 10 17;27(10):1061-1070. Epub 2020 Jun 17.

St Vincent's Hospital, Melbourne, Victoria, Australia.

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 log IU/mL, median HBsAg 4.8 log  IU/mL, median HBeAg 3.6 log  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.
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http://dx.doi.org/10.1111/jvh.13318DOI Listing
October 2020

hbsag levels can be used to rule out cirrhosis in hbeag positive chronic hepatitis b: results from the sonic-b study.

J Infect Dis 2020 Apr 21. Epub 2020 Apr 21.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background & Aims: Serum HBsAg levels correlate with the duration of chronic HBV infection and may predict the extent of hepatic fibrosis.

Methods: We analysed data from the SONIC-B database, which contains data from 8 global randomized trials and two large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored and clinically relevant cut-offs were identified to rule out cirrhosis.

Results: The dataset included 2779 patients; 1866 HBeAg-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (Odds Ratio [OR] 0.419, P<0.001) and cirrhosis (OR 0.435, p<0.001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype specific HBsAg cut-offs had excellent NPVs (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cut-offs was comparable among patients in whom cirrhosis could not be ruled out with FIB-4.

Conclusions: HBV genotype specific HBsAg cut-offs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C and D and can be an adjunct to FIB-4 to reduce the need for further testing.
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http://dx.doi.org/10.1093/infdis/jiaa192DOI Listing
April 2020

Longitudinal analysis of serum microRNAs as predictors of cirrhosis regression during treatment of hepatitis B virus infection.

Liver Int 2020 07 2;40(7):1693-1700. Epub 2020 May 2.

Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.

Background And Aims: Most patients with cirrhosis induced by chronic HBV infection experience fibrosis regression after long-term antiviral treatment, while some remain cirrhotic. Fibrosis regression is associated with lower odds of developing hepatic decompensation and hepatocellular carcinoma, but mechanisms impacting differential fibrosis regression between individuals are unclear. We asked whether soluble molecules, including serum microRNAs, could serve as biomarkers of fibrosis regression.

Methods: We analysed cryopreserved sera from clinical trials in which cirrhotic HBV-infected patients (baseline Ishak fibrosis score of 5-6) received 240 weeks of nucleotide analogue treatment. Liver biopsies at week 240 in these trials showed 71/96 patients (74%) had fibrosis regression (Ishak ≤ 4) while 25/96 (26%) remained cirrhotic (Ishak 5-6). We quantified inflammatory markers (CXCL10, soluble CD163) and miRNAs (n = 179) from serum at baseline, week 48 and week 240 of treatment in a sub-cohort of patients with (n = 14) or without (n = 14) fibrosis regression.

Results: CXCL10, sCD163 and miRNAs previously associated with HBV replication and inflammation decreased during treatment but did not differ based on fibrosis regression. Two miRNAs (miR-421 and miR-454-3p) had lower baseline expression in patients with subsequent fibrosis regression. In all, 27 miRNAs differed at week 240 and had higher expression in patients with fibrosis regression (eg miR-199a-3p, miR-423-3p, miR-142-3p, miR-let-7d-5p). Several miRNAs (miR-141-3p, let-7d-5p) that correlated with regression have previously been implicated in the pathophysiology of non-alcoholic steatohepatitis.

Conclusions: In cirrhotic patients with chronic HBV infection treated with antiviral therapy, serum miRNAs have differential expression based on fibrosis regression, suggesting potential utility as biomarkers.
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http://dx.doi.org/10.1111/liv.14474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681260PMC
July 2020

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

N Engl J Med 2020 06 10;382(24):2327-2336. Epub 2020 Apr 10.

From Cedars-Sinai Medical Center, Los Angeles (J.G.), El Camino Hospital, Mountain View (D.S., D. Chelliah), Sutter Santa Rosa Regional Hospital, Santa Rosa (G.G.), Regional Medical Center (A.S., J.R.) and Good Samaritan Hospital (S.M.), San Jose, John Muir Health, Walnut Creek (J.B.), UC Davis Health, Sacramento (S.H.C.), NorthBay Medical Center, Fairfield (S.I.), and Gilead Sciences, Foster City (A.O.O., A.D., Y.Z., L.Z., A. Chokkalingam, E.E., L. Telep, L. Timbs, I.H., S.S., H.C., S.K.T., L.W., P.D., R.M., A.G., R.P.M., D.M.B.) - all in California; the National Center for Global Health and Medicine, Tokyo (N.O.), Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu City (R.O.), Hiratsuka City Hospital, Hiratsuka (K.Y.), Yokohama City University Hospital, Yokohama (H.K.), Gunma University Hospital, Gunma (T.M.), and Tosei General Hospital, Seto (Y.M.) - all in Japan; Providence Regional Medical Center Everett, Everett (G.D.), and University of Washington Medical Center-Northwest (M.L.G.) and Virginia Mason Medical Center (S. Chihara), Seattle - all in Washington; Fondazione IRCCS Policlinico San Matteo, Pavia (E.A.), IRCCS, San Raffaele Scientific Institute (A. Castagna) and Azienda Socio Sanitaria Territoriale Spedali (ASST) Santi Paolo e Carlo, Department of Health Services, University of Milan (A.D.M.), Milan, National Institute for Infectious Diseases, IRCCS, L. Spallanzani, Rome (E.N.), Università degli Study of Brescia, ASST Civili di Brescia, Brescia (E.Q.-R.), San Gerardo Hospital, ASST Monza, University of Milan-Bicocca, Monza (G.L.), and Azienda Unite Sanitarie Locali-IRCCS, Reggio Emilia (M.M.) - all in Italy; Universitätsklinikum Düsseldorf, Düsseldorf, Germany (T. Feldt); Université de Paris, Infection, Antimicrobiens, Modélisation, Evolution (IAME), INSERM, and Assistance Publique-Hôpitaux de Paris, Department of Infectious Diseases, Bichat Hospital, Paris (F.-X.L.), Centre Hospitalier Régional et Universitaire de Brest-La Cavale Blanche, Brest (E.L.), and Division of Infectious Diseases and Tropical Medicine, University Hospital of Bordeaux, Bordeaux (D.N.) - all in France; St. Alexius Medical Center, Hoffman Estates, IL (S.A.); Mackenzie Health, Richmond Hill, ON, Canada (D. Chen); Columbia University Irving Medical Center, New York (J.C.); Hospital Universitario La Paz-Carlos III, Instituto de Investigación Hospital Universitario La Paz, Madrid (M.M.-R.); Bernhoven Hospital, Uden, the Netherlands (E.V.); Kaiser Franz Josef Hospital, Vienna (A.Z.); the U.S. Public Health Service Commissioned Corps, Washington, DC (R.C.); and Miriam Hospital, Providence, RI (T. Flanigan).

Background: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.

Methods: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.

Results: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

Conclusions: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).
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http://dx.doi.org/10.1056/NEJMoa2007016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169476PMC
June 2020

Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection.

J Clin Invest 2020 06;130(6):3205-3220

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.

In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we studied the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon (IFN) signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV superinfection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic IFN response. Using blood samples of coinfected patients, IFN-stimulated gene products including C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic IFN response following HCV clearance and identify serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV-coinfected persons.
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http://dx.doi.org/10.1172/JCI135616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259999PMC
June 2020

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study.

Lancet Gastroenterol Hepatol 2020 05 20;5(5):441-453. Epub 2020 Feb 20.

The Chinese University of Hong Kong, China.

Background: Treatment with tenofovir disoproxil fumarate has been associated with renal toxicity or reductions in bone mineral density, or both, in some patients with chronic hepatitis B virus (HBV) infection. Tenofovir alafenamide is a tenofovir prodrug with high intrahepatic concentrations of active drug and reduced systemic tenofovir exposures compared with tenofovir disoproxil fumarate. In patients with chronic HBV, tenofovir alafenamide has shown efficacy non-inferior to that of tenofovir disoproxil fumarate with improved renal and bone safety. With this non-inferiority study, we aimed to evaluate the efficacy and safety of tenofovir alafenamide in patients with HBV infection switching from tenofovir disoproxil fumarate who are virally suppressed.

Methods: Patients with chronic HBV infection who had been receiving tenofovir disoproxil fumarate for 48 weeks or more and who had HBV DNA less than the lower limit of quantification (LLOQ) for at least 12 weeks were recruited to this randomised, multicentre, double-blind, phase 3 non-inferiority study. Patients were randomly assigned in a 1:1 ratio to receive tenofovir alafenamide 25 mg once a day or to continue tenofovir disoproxil fumarate 300 mg once a day. The primary efficacy endpoint was loss of virological control, defined as the proportion of patients who received at least one dose of study drug who had HBV DNA of at least 20 IU/mL at week 48 by the modified US Food and Drug Administration (FDA) snapshot algorithm. Key safety endpoints were changes in hip and spine bone mineral density, estimated creatinine clearance by Cockcroft-Gault, and markers of bone turnover and renal tubular function. The study was powered for non-inferiority in efficacy of tenofovir alafenamide versus tenofovir disoproxil fumarate with a 4% margin. Investigators and patients were unaware of treatment allocation and on-treatment results. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02979613.

Findings: Participants in this study were enrolled between Dec 29, 2016, and Oct 20, 2017. 541 patients were screened and 490 patients were randomly assigned to switch to tenofovir alafenamide or to stay on tenofovir disoproxil fumarate. Two patients assigned to receive tenofovir alafenamide did not receive treatment; thus the full analysis set for efficacy and safety analyses consisted of 243 patients in the tenofovir alafenamide group and 245 in the tenofovir disoproxil fumarate group. At week 48, one patient from each treatment group (both <1%) had HBV DNA of at least 20 IU/mL (difference in proportion 0·0%, 95% CI -1·9 to 2·0), thereby showing non-inferior efficacy of tenofovir alafenamide to tenofovir disoproxil fumarate. Patients who received tenofovir alafenamide had significantly increased bone mineral density at hip (mean change 0·66% [SD 2·08] vs -0·51% [SD 1·91]; difference in least square means 1·17% [95% CI 0·80 to 1·54; p<0·0001]) and at spine (mean change 1·74% [3·46] vs -0·11% [3·13]; difference in least square means 1·85% [1·24 to 2·46; p<0·0001]), creatinine clearance by Cockcroft-Gault relative to tenofovir disoproxil fumarate (median change 0·94 mL/min [IQR -4·47 to 6·24] vs -2·74 mL/min [-7·89 to 1·88]; p <0·0001), and improved markers of bone turnover and tubular function at week 48. The most common treatment-emergent adverse events were upper respiratory tract infection (18 [7%] of 243 patients in the tenofovir alafenamide group and 16 [7%] of 245 patients in the tenofovir disoproxil fumarate group) and nasopharyngitis (13 [5%] of 243 patients in the tenofovir alafenamide group and 12 [5%] of 245 patients in the tenofovir disoproxil fumarate group). The incidence of grade 3 and above adverse events and serious adverse events was low and similar between groups. No viral resistance was observed in patients who qualified for viral sequencing.

Interpretation: These findings suggest that tenofovir alafenamide can be substituted for tenofovir disoproxil fumarate in patients with HBV infection for improved safety without a loss of efficacy.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2468-1253(19)30421-2DOI Listing
May 2020

Durability of Hepatitis B Surface Antigen Loss With Nucleotide Analogue and Peginterferon Therapy in Patients With Chronic Hepatitis B.

Hepatol Commun 2020 Jan 10;4(1):8-20. Epub 2019 Oct 10.

Hôpital Beaujon Université de Paris Diderot Clichy France.

In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg-IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti-HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg-IFN-containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative-qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile [Q]1, Q3, 46, 135) weeks follow-up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti-HBs seroconversion was observed during follow-up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti-HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off-treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). HBsAg loss after NUC or Peg-IFN-containing regimens was durable in 82% of patients with CHB. Anti-HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.
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http://dx.doi.org/10.1002/hep4.1436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939500PMC
January 2020

Liver safety assessment in clinical trials of new agents for chronic hepatitis B.

J Viral Hepat 2020 02 11;27(2):96-109. Epub 2019 Dec 11.

Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.

Investigational agents that reduce or eliminate covalently closed circular DNA (cccDNA) or enhance host immunity against hepatitis B virus (HBV)-infected hepatocytes are intended to induce a durable off-treatment clearance of hepatitis B surface antigen (HBsAg) (referred to as functional cure). The aim of this paper was to highlight challenges in interpreting liver safety data in clinical trials of these agents when given alone or in combination regimens. The incidence, grading and management of spontaneous serum ALT flares in untreated chronic HBV patients are reviewed along with a summary of serum ALT flares observed during the registration trials for peginterferon and nucleos(t)ide reverse transcriptase inhibitors. Recommendations regarding the detection, management and interpretation of liver safety biomarker data in future clinical trials as well as suggested inclusion and exclusion criteria for phase 1/2 vs phase 3 studies are provided. Criteria to help classify liver safety signals as being due to the intended therapeutic response, emergence of drug-resistant HBV virions, or idiosyncratic drug-induced liver injury are provided along with a review of the role of an expert hepatic adjudication panel in assessing a compound's hepatotoxicity profile. Finally, an algorithmic approach to the differential diagnosis and recommended medical evaluation and management of individual clinical trial patients that develop a liver safety signal is provided along with the rationale to collect and test research blood samples for future mechanistic studies.
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http://dx.doi.org/10.1111/jvh.13223DOI Listing
February 2020

Patients With Nonalcoholic Steatohepatitis Experience Severe Impairment of Health-Related Quality of Life.

Am J Gastroenterol 2019 10;114(10):1636-1641

Center for Outcomes Research in Liver Disease, Washington, DC, USA.

Introduction: Although there is substantial evidence suggesting poor health-related quality of life (HRQL) in patients with chronic hepatitis C (CHC), similar data in nonalcoholic steatohepatitis (NASH) have not been fully assessed. The aim is to compare HRQL scores in patients with CHC to those with NASH.

Methods: Matched patients with advanced fibrosis (bridging fibrosis and compensated cirrhosis) due to CHC and NASH completed Short Form-36 (SF-36) questionnaire, Chronic Liver Disease Questionnaire (CLDQ), and Work Productivity and Activity Instrument questionnaire.

Results: We included 1,338 patients with NASH with advanced fibrosis (mean age 57.2 years, 47% men, 55% cirrhosis) and 1,338 matched patients with CHC. Patients with CHC and NASH had similar rates of employment and psychiatric disorders (P > 0.05). As expected, patients with NASH had higher body mass index (mean 33.7 vs 27.6) and more type 2 diabetes (74% vs 16%) (all P < 0.01). Patients with NASH had significantly lower HRQL scores related to physical health: Physical Functioning, Bodily Pain, General Health, Vitality, Physical Summary of SF-36, and Fatigue of CLDQ (P < 0.02). By contrast, patients with CHC had a lower Mental Health score of SF-36 and Emotional score of CLDQ and reported greater impairment in daily activities as measured by the Work Productivity and Activity Instrument questionnaire (P < 0.002). In multivariate analysis, after adjustment for demographic parameters, cirrhosis, and history of psychiatric disorders, having NASH was associated with lower physical HRQL scores and higher mental health-related scores (P < 0.05).

Discussion: Patients with NASH and advanced fibrosis have more impairment of their physical health-related scores than patients with CHC with advanced fibrosis. These data should dispel the misconception that NASH is an asymptomatic disease with little negative impact on patients' well-being.
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http://dx.doi.org/10.14309/ajg.0000000000000375DOI Listing
October 2019

Predicting HBsAg clearance in genotype A chronic hepatitis B using HBsAg epitope profiling: A biomarker for functional cure.

Liver Int 2019 11 21;39(11):2066-2076. Epub 2019 Aug 21.

Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, Victoria, Australia.

Background And Aim: Functional cure is the major goal of chronic hepatitis B (CHB) therapy though few biomarkers predict this outcome. HBsAg epitope occupancy can be influenced by therapeutic and immune pressure. The aim of this study was to map the HBsAg epitope profiles during long-term nucleos(t)ide analogue therapy in patients with genotype A CHB, in the context of HBsAg loss (SL)/seroconversion.

Methods: We evaluated 25 genotype A CHB patients in the GS-US-174-0103 trial of HBeAg-positive CHB patients treated with tenofovir or adefovir for 4 years, 14 who achieved SL whilst 11 had no change. We epitope mapped the major domains of HBsAg to identify those patients with HBsAg clearance profile (CP) (loss of binding at both loops 1 and 2 epitopes of the 'a' determinant) vs non-clearance profile (no change in epitope recognition, or loss of epitope binding at one loop only), correlating this to on-treatment HBsAg responses. Complexed anti-HBs was also measured.

Results: Analysis of the HBsAg epitope profiles of the 25 patients at baseline identified no predictive correlation with SL. In contrast, analysis at week 48 and end of study (week 192) or prior to SL identified significant predictive associations between development of HBsAg CPs and outcome of functional cure. The detection of a CP also correlated with the development of an alanine aminotransferase flare and detection of anti-HBs complexed with HBsAg.

Conclusion: The detection of HBsAg CPs by epitope mapping represents a novel viral biomarker, reflecting an emerging anti-HBs selection pressure prior to functional cure.
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http://dx.doi.org/10.1111/liv.14207DOI Listing
November 2019

Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection.

Clin Gastroenterol Hepatol 2020 02 31;18(2):468-476.e11. Epub 2019 Jul 31.

Center for Outcomes Research in Liver Disease, Washington, District of Columbia.

Background & Aims: Patients with hepatitis C virus (HCV) infections who achieve a sustained virologic response (SVR) to treatment have improved patient-reported outcomes (PROs). We compared post-treatment PRO scores between patients with chronic HCV infection who did and did not achieve an SVR to treatment.

Methods: Patients who completed treatment in clinical trials were enrolled in 2 registries, depending on the treatment outcome (NCT01457755, NCT01457768), from 2016 to 2017 in 17 countries in North America, Europe, and the Asia-Pacific region. PRO scores (scale, 0-100) were collected at pretreatment (baseline); the last day of treatment; the post-treatment week 12 follow-up visit (in patients with SVR only); the registry baseline; and on registry weeks 12, 24, 36, 48, and 96 (the non-SVR registry) or every 24 weeks until week 96 (SVR registry), using the Short Form-36 (SF-36) instrument.

Results: Our analysis included 4234 patients with an SVR and 242 without an SVR from whom pretreatment PRO data were available (mean age, 54 ± 10 y; 63% male; 65% enrolled in the United States; 17% with cirrhosis; 12% with human immunodeficiency virus co-infection). Upon registry enrollment, patients with an SVR had significant increases in all PRO scores compared with pretreatment baseline levels (all P < .05). Patients without an SVR had mean reductions of 9.2 points or less in PRO scores while followed up on the registry (P < .05 for 4-8 of 8 PRO domains measured by the SF-36). In contrast, patients with an SVR had sustained increases in PRO scores (mean increase, ≤7.0 points) while on the registry. In multivariate analysis, achieving an SVR was associated independently with superior scores in all SF-36 domains at all registry time points (β, +4.8 to +15.9 points, all P ≤ .01).

Conclusions: In a follow-up analysis of participants in clinical trials, we found that those with an SVR to treatment for HCV infection had significant increases in well-being, based on PRO scores. Patients without an SVR had decreasing PRO scores over the follow-up period.
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http://dx.doi.org/10.1016/j.cgh.2019.07.047DOI Listing
February 2020

Genomic modeling of hepatitis B virus integration frequency in the human genome.

PLoS One 2019 29;14(7):e0220376. Epub 2019 Jul 29.

Gilead Sciences Inc., Foster City, CA, United States of America.

Hepatitis B infection is a world-wide public health burden causing serious liver complications. Previous studies suggest that hepatitis B integration into the human genome plays a crucial role in triggering oncogenic process and may also constitutively produce viral antigens. Despite the progress in HBV biology and sequencing technology, our fundamental understanding of how many hepatocytes in the liver actually carry viral integrations is still lacking. Herein we provide evidence that the HBV virus integrates with a lower-bound frequency of 0.84 per diploid genome in hepatitis B positive hepatocellular cancer patients. Moreover, we calculate that integrated viral DNA generates ~80% of the HBsAg transcripts in these patients. These results underscore the need to re-evaluate the clinical end-point and treatment strategies for chronic hepatitis B patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663024PMC
March 2020

Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients.

Sci Rep 2019 07 19;9(1):10529. Epub 2019 Jul 19.

Kings College Hospital, London, UK.

Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients' clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient's HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.
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http://dx.doi.org/10.1038/s41598-019-46609-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642195PMC
July 2019

Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study.

J Hepatol 2019 11 12;71(5):900-907. Epub 2019 Jul 12.

School of Biological Sciences, and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.

Background & Aims: To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV.

Methods: In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24.

Results: There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24.

Conclusions: In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient.

Lay Summary: Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.
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http://dx.doi.org/10.1016/j.jhep.2019.06.028DOI Listing
November 2019