Hepatitis B Prevalence and Risk Factors in Foreign-Born Asians and Pacific Islanders at a Federally Qualified Health Center in Hawai'i, 2015-2020.

The objective of this study was to estimate the prevalence of chronic hepatitis B infection in foreign-born Asians and Pacific Islanders at Kalihi-Palama Health Center in Honolulu, Hawai'i, and to assess the association between both chronic and resolved hepatitis B infection and risk factors such as household exposure to hepatitis B virus and geographic location of birthplace. The study involved cross-sectional data from 997 participants who accessed medical services at Kalihi-Palama Health Center between September 2015 and July 2020. The prevalence of chronic hepatitis B was 10.7%. On multivariable logistic regression analysis, the adjusted prevalence odds ratio of chronic hepatitis B infection was 3.3 times greater (95% confidence interval: 1.1, 9.2) for those who reported household contact with a person with hepatitis B infection than those who reported no such contact. No association was found with place of birth in this study population. Age was a significant predictor of chronic hepatitis B, with participants between 35-44 years of age having the highest prevalence. Age was also a significant predictor of resolved hepatitis B infection, with participants 65 years of age or older having the highest prevalence. These findings emphasize the need for targeted screening and appropriate follow-up-including vaccination or treatment-in this at-risk population.

Prevalence of drug-drug interactions with pangenotypic direct-acting antivirals for hepatitis C and real-world care management in the United States: a retrospective observational study.

BACKGROUND: Direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) have varying potentials for drug-drug interactions (DDIs). OBJECTIVES: To (1) identify prevalence of potential DDI with glecaprevir-pibrentasvir (GLE-PIB) and sofosbuvir-velpatasvir (SOF-VEL) and (2) describe health care provider actions in response to pharmacist recommendations based on potential interactions with GLE-PIB or SOF-VEL, using 2 complementary data sources. METHODS: Possible interacting drugs were identified among adult patients in a United States electronic medical record database covering 21 health care organizations and 26 million patients in 2018. DDIs were categorized as potential weak interaction (Level 1), potential interaction (Level 2), or contraindicated (Level 3). Real-world recommendations and resultant actions regarding DDIs with GLE-PIB and SOF-VEL were obtained from a specialty pharmacy database. Categorical variable comparisons were done via chi-square analysis with subsequent z-tests of column proportions. RESULTS: DDI prevalence was higher for patients prescribed GLE-PIB (317/769 [41%]) compared with those prescribed SOF-VEL (170/633 [27%]), and the prevalence of a Level 3 (contraindicated) interaction was higher with GLE-PIB than SOF-VEL (61/769 [8%] vs 2/633 [< 1%]). Across all DDI levels, analgesics (139/317 [44%]), proton-pump inhibitors (129/317 [41%]), and lipid-lowering agents (59/317 [19%]) were the top drug classes for the GLE-PIB group with potential for DDI. For SOF-VEL prescribed patients, the top drug classes were proton-pump inhibitors (83/170 [49%]), histamine-2 blockers (42/170[25%]), and lipid-lowering agents (42/170 [25%]). In real-world care management, the overall prevalence of pharmacist recommendations regarding DDIs was significantly lower for SOF-VEL (28/419 [7%]) relative to GLE-PIB (151/1,216 [12%]). Recommended guidance from pharmacists was not followed for 39% (69/179) of patients, 36% (54/151) for GLE-PIB, and 54% (15/28) for SOF-VEL. CONCLUSIONS: The potential for DDIs with pangenotypic HCV DAAs is frequent and may be more frequent with GLE-PIB than SOF-VEL. Physician responses to pharmacist alerts regarding potential interaction can be highly variable, even in cases of contraindication. DISCLOSURES: Funding for this study was provided by Gilead Sciences, Inc. Trio Health Analytics received funding from Gilead Sciences, Inc., to conduct research for this study. Tsai consults for and has received grants and honoraria from Gilead, AbbVie, Merck, and Bristol Myers Squibb; he has also received lecture fees from Gilead and AbbVie. Curry consults for Trio Health Analytics and Gilead and has also consulted for and received grants from Mallinckrodt. Flamm consults for and has received lecture fees from Gilead and AbbVie; he has also received grants from Gilead and AbbVie. Milligan and Wick are employed by Trio Health Analytics and have received research support from Gilead, Merck, and AbbVie. Younossi has received grants from Gilead, Intercept, Bristol Myers Squibb, GlaxoSmithKline, and Novo Nordisk. Afdhal is a paid consultant/advisory board member for Gilead, Echosens, Ligand, Shionogi, and Trio Health; owns stock in Spring-Bank and Allurion and has stock options in SpringBank; receives royalty income from UpToDate; and is on the board of directors for the nonprofit Liver Institute for Education and Research. Data from this study were presented at the American Association for the Study of Liver Disease (AASLD) Liver Meeting 2019; November 8-12, 2019; Boston, MA, and the European Association for Study of the Liver (EASL) International Liver Congress 2020; August 27-29, 2020; virtual.

An Updated Assessment of Chronic Hepatitis B Prevalence Among Foreign-Born Persons Living in the United States.

BACKGROUND AND AIMS: Although prevalence of chronic hepatitis B (CHB) in the USA includes 0.42 million (range, 0.28-0.67) U.S.-born persons, foreign-born (FB) persons contribute a substantially larger number to the burden of CHB in the USA. Over the past decade, patterns of U.S. immigration have changed and many countries have implemented HBV prevention programs. This study aims to estimate the number of FB persons with CHB in the USA by country of origin, updating our 2011 study. APPROACH AND RESULTS: We performed systematic searches for articles published in 2009-2019 reporting HBsAg seroprevalence in emigrants and in-country populations of 117 countries. Data meeting inclusion criteria were combined with data from our 2011 study to calculate pooled prevalence estimates for 99 countries using meta-analyses (total 2,800 surveys involving 112 million subjects). Combining country-specific CHB rate estimates with the number of FB in the USA in 2018, by country of origin from the U.S. Census Bureau, we estimate that the number of FB with CHB in the USA in 2018 was 1.47 million (95% CI, 1.21-1.73), substantially higher than previously reported. The weighted average CHB prevalence for all FB in the USA in 2018 was 3.07%. Approximately 59% of FB with CHB in the USA in 2018 emigrated from Asia, 19% from the Americas, and 15% from Africa. Subgroup analyses found that for many countries, CHB rates are higher in males than females and have declined over the past three decades, but no consistent pattern is observed between emigrant and in-country rates. CONCLUSIONS: Including FB and U.S.-born persons, the total prevalence of CHB in the USA may be as high as 2.4 million.

Changes in gastrointestinal microbial communities influence HIV-specific CD8+ T-cell responsiveness to immune checkpoint blockade.

OBJECTIVES: The aim of this study was to examine the relationship between gut microbial communities in HIV-infected individuals on suppressive antiretroviral therapy (cART), and the peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo immune checkpoint blockade (ICB). DESIGN: Thirty-four HIV-seropositive, 10 HIV-seronegative and 12 HIV-seropositive receiving faecal microbiota transplant (FMT) participants were included. Gut microbial communities, peripheral and gut associated negative checkpoint receptors (NCRs) and peripheral effector functions were assessed. METHODS: Bacterial 16s rRNA sequencing for gut microbiome study and flow-based assays for peripheral and gut NCR and their cognate ligand expression, including peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo anti-PD-L1 and anti-TIGIT ICB were performed. RESULTS: Fusobacteria abundance was significantly higher in HIV-infected donors compared to uninfected controls. In HIV-infected participants receiving Fusobacteria-free FMT, Fusobacteria persisted up to 24 weeks in stool post FMT. PD-1 TIGIT and their ligands were expanded in mucosal vs. peripheral T cells and dendritic cells, respectively. PD-L1 and TIGIT blockade significantly increased the magnitude of peripheral anti-HIV-Gag-specific CD8 T-cell responses. Higher gut Fusobacteria abundance was associated with lower magnitude of peripheral IFN-γ+ HIV-Gag-specific CD8 T-cell responses following ICB. CONCLUSION: The gut colonization of Fusobacteria in HIV infection is persistent and may influence anti-HIV T-cell immunity to PD-1 or TIGIT blockade. Strategies modulating Fusobacteria colonization may elicit a favourable mucosal immune landscape to enhance the efficacy of ICB for HIV cure.

Maternal knowledge of the risk of vertical transmission and offspring acquisition of hepatitis B.

INTRODUCTION AND OBJECTIVES: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B. MATERIALS AND METHODS: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed. RESULTS: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02). CONCLUSIONS: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5-15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.

Effectiveness of 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve, Compensated Cirrhotic Patients with Chronic Hepatitis C Infection.

INTRODUCTION: Glecaprevir/pibrentasvir (G/P) was approved on 26 September 2019 by the US Food and Drug Administration for 8-week duration in treatment-naïve (TN) hepatitis C virus (HCV)-infected patients with compensated cirrhosis (CC). Evidence from the EXPEDITION-8 study demonstrated that 8 weeks of G/P achieved a 98% intent-to-treat (ITT) sustained virologic response rate 12 weeks post treatment (SVR12) in 343 TN/CC patients. The aim of this study is to demonstrate the first US real-world effectiveness of G/P 8-week treatment in genotype 1-6 TN/CC HCV patients. METHODS: Data from 73 TN/CC patients who initiated 8 weeks of G/P treatment between August 2017 and November 2018 were collected electronically from providers and specialty pharmacies of the Trio Health network and analyzed. Cirrhosis was determined by FIB-4 > 5.2 or was physician reported. The primary outcome was Per Protocol (PP) SVR12. RESULTS: The majority (60%) of patients were male, with (mean values): age 59 years, body mass index (BMI) of 30, aspartate aminotransferase (AST) 105, and alanine aminotransferase (ALT) 101 IU/ml. HCV genotypes (GT) were: GT1 81% (59/73), GT2 10% (7/73), GT3 5% (4/73), GT4 3% (2/73), and GT6 1% (1/73). Eight percent (6/73) of patients had concurrent proton pump inhibitor (PPI) use, and 15% (11/72) had a baseline viral load > 6 MM IU/ml. Zero patients discontinued, two patients were reported as lost to follow-up, and there was one virologic failure. PP sustained virologic response at 12 weeks (SVR12) rate was 99% (70/71), and the intent-to-treat (ITT) SVR12 rate was 96% (70/73). CONCLUSIONS: Early real-world experience indicates high effectiveness of the 8-week G/P regimen in a diverse treatment-naïve, compensated cirrhotic US population.

Changing demographics among populations prescribed HCV treatment, 2013-2017.

OBJECTIVES: We analyzed the demographics and disease characteristics of patients prescribed treatment for chronic hepatitis C virus (HCV) infection from 2013 through 2017, a time frame that encompasses the expansion of available direct-acting antiviral inhibitors. STUDY DESIGN: Retrospective analysis. METHODS: Using a proprietary disease-management program, data for 19,944 patients receiving HCV treatment were collected from providers and specialty pharmacies. Six-month time periods accounting for introductions of novel treatments were established as follows: December 2013 to May 2014 (n = 1438), simeprevir and sofosbuvir; October 2014 to March 2015 (n = 2242), ledipasvir/sofosbuvir and ombitasvir/paritaprevir/ritonavir plus dasabuvir; October 2015 to March 2016 (n = 5514), daclatasvir; July 2016 to December 2016 (n = 5562), elbasvir/grazoprevir and sofosbuvir/velpatasvir; and July 2017 to December 2017 (n = 5188), sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Changes over time were evaluated for statistical significance. RESULTS: In the 2013-2014 time period, 44% of patients receiving prescriptions for HCV treatment were treatment-experienced and 45% had cirrhosis. By 2017, only 14% were treatment-experienced (P <.001) and 21% had cirrhosis (P <.001). The percentage of patients with HCV genotype 1 increased from 69% to 87% from 2013-2014 to 2014-2015 (P <.001) but subsequently decreased to 74% in 2017 (P <.001). The percentage of patients receiving HCV prescriptions in an academic setting declined from 61% in 2013-2014 to 13% in 2017 (P <.001). CONCLUSIONS: In the United States, since the introduction of interferon-free HCV regimens, the patient population prescribed treatment has changed, becoming predominantly treatment-naïve, without cirrhosis, and treated in nonacademic centers.

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.

Total Alanine Aminotransferase (ALT) Flares in Pregnant North American Women With Chronic Hepatitis B Infection: Results From a Prospective Observational Study.

INTRODUCTION: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV. METHODS: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy. RESULTS: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation. DISCUSSION: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Entecavir and Peginterferon Alfa-2a in Adults With Hepatitis B e Antigen-Positive Immune-Tolerant Chronic Hepatitis B Virus Infection.

Monotherapy with interferon or nucleoside analog is generally not recommended during the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection. Recognition that high HBV DNA levels are associated with hepatocellular carcinoma has increased interest in treating HBV in the IT phase. Small pediatric studies reported efficacy with combination nucleoside analog and interferon therapy. The aim of this study was to evaluate the safety and efficacy of the combination of entecavir and peginterferon in adults in the IT phase of chronic HBV infection. Hepatitis B e antigen (HBeAg)-positive adults with HBV DNA > 107 IU/mL and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal (ULN) (male: ≤ 45, female: ≤ 30 U/L) received entecavir 0.5 mg daily for 8 weeks followed by the addition of peginterferon alfa-2a 180 µg/week to entecavir for an additional 40 weeks. The primary endpoint was HBeAg loss and HBV DNA ≤ 1,000 IU/mL 48 weeks after end of treatment (EOT). Among 28 participants from 11 sites, the median age was 37.2 (range: 22-61) years, 54% were male, and 96% were Asian. Nearly all were infected with genotype C (64%) or B (32%). Median baseline HBV DNA was 8.2 log10 IU/mL, and ALT was 0.9 times the ULN. Although one (4%) participant cleared HBeAg, none met the primary endpoint of both HBeAg loss AND HBV DNA ≤ 1,000 IU/mL 48 weeks post-EOT. ALT elevations > 5 times the ULN occurred in eight (29%) participants, and none were associated with icterus. Forty-eight weeks posttreatment, HBV DNA rebounded to baseline levels in all participants, including the participant who lost HBeAg, and ALT values returned to near baseline levels in all but four participants. Conclusion: A lead-in strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir therapy for 40 weeks had limited efficacy in adults in the IT phase of chronic HBV infection and cannot be recommended.

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.

PET/CT with 18F Fluorocholine as an Imaging Biomarker for Chronic Liver Disease: A Preliminary Radiopathologic Correspondence Study in Patients with Liver Cancer.

Purpose To determine the relationship between hepatic uptake at preoperative fluorine 18 (18F) fluorocholine combined positron emission tomography (PET) and computed tomography (CT) and the histopathologic features of chronic liver disease in patients with Child-Pugh class A or B disease who are undergoing hepatic resection for liver cancer. Materials and Methods Forty-eight patients with resectable liver tumors underwent preoperative 18F fluorocholine PET/CT. Mean liver standardized uptake value (SUVmean) measurements were obtained from PET images, while histologic indexes of inflammation and fibrosis were applied to nontumor liver tissue from resection specimens. Effects of histopathologic features on liver SUVmean were examined with analysis of variance. Results Liver SUVmean ranged from 4.3 to 11.6, correlating significantly with Knodell histologic activity index (ρ = -0.81, P < .001) and several clinical indexes of liver disease severity. Liver SUVmean also differed significantly across groups stratified by necroinflammatory severity and Metavir fibrosis stage (P < . 001). The area under the receiver operating characteristic curve for 18F fluorocholine PET/CT detecting Metavir fibrosis stage F1 or higher was 0.89 ± 0.05, with an odds-ratio of 3.03 (95% confidence interval: 1.59, 5.88) and sensitivity and specificity of 82% and 93%, respectively. Conclusion Correlations found in patients undergoing hepatic resection for liver cancer between liver 18F fluorocholine uptake and histopathologic indexes of liver fibrosis and inflammation support the use of 18F fluorocholine PET/CT as a potential imaging biomarker for chronic liver disease. © RSNA, 2018.

Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B.

BACKGROUND & AIMS: Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment. METHODS: In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation. RESULTS: The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41-80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex. CONCLUSIONS: Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed. LAY SUMMARY: In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed. Clinical Trial Number: GS-US-283-1059; NCT 02166047.

Pitfalls in surveillance for hepatocellular carcinoma: How successful is it in the real world?

BACKGROUND/AIMS: Surveillance for hepatocellular carcinoma (HCC) with ultrasound in high-risk populations is generally believed to improve opportunities for treatment. However, tumors are still missed due to various factors. This study explores success versus failure of HCC surveillance. METHODS: This is a retrospective study of 1,125 HCC cases. Categories considered for successful detection were largest tumor ≤3.0 cm, single tumors ≤3.0 cm and ≤2.0 cm, and adherence to Milan criteria. Examined factors were age <60 years, gender, rural residence, body-mass index (BMI), hepatitis infection, smoking, diabetes, hyperlipidemia, cirrhosis, ascites, and Model for End-Stage Liver Disease <10. RESULTS: HCC was found on surveillance in 257 patients with a mean tumor size of 3.17 cm; multiple tumors were seen in 28% of cases, bilateral tumors in 7.4%, and vascular invasion in 3.7%. Surveillance was successful in 61.5% of cases involving a largest tumor ≤3.0 cm, with BMI ≥35 negatively affecting detection (odds ratio [OR] 0.28, P=0.014) and cirrhosis positively affecting detection (OR 2.31, P=0.036). Ultrasound detected 19.1% of single tumors ≤2.0 cm with ascites improving the detection rate (OR 3.89, P=0.001). Finally, adherence to Milan criteria occurred in 75.1% of cases, revealing negative associations with diabetes (OR 0.48, P=0.044 and male gender (OR 0.49, P=0.08). CONCLUSIONS: Although surveillance is recommended for HCC, not all surveillance ultrasound are ideal. Tumor detection can depend on gender, BMI, diabetes, cirrhosis, and ascites and is achieved in 19.1-75% of cases depending on the definition of success. Closer follow-up or additional imaging might be necessary for some patient subgroups.

Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection.

Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus-infected patients who are treatment-naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real-world experience. Using data from real-world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut für Interdisziplinäre Medizin), Burman's Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta-analysis of six additional real-world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow-up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment-eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta-analysis of six additional real-world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98-1.00). CONCLUSION: An 8-week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094-1103).

Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real-world cohort study.

Many patients with chronic hepatitis C virus (HCV) are on prolonged proton-pump inhibitor (PPI) therapy and wish to remain on PPI therapy once treatment for HCV starts. A preliminary report recently suggested decrease rates of sustained virological response (SVR) for patients taking concomitant PPI and ledipasvir/sofosbuvir (LDV/SOF). We sought to determine the effect of PPI use on the rate of SVR in a real-world cohort of 1,979 patients with chronic HCV treated with LDV/SOF. We collected clinical data and pharmacy dispensing records on patients taking 8, 12, or 24 weeks of LDV/SOF ± ribavirin (RBV). The primary outcome was sustained virological response at 12 weeks after treatment completion (SVR12) in a per-protocol analysis in order to determine the effect of PPI use adjusted for confounders. Statistical adjustment was performed in propensity-matched analysis. Among treatment completers, SVR12 was achieved in 441 (97.1%) of PPI recipients compared with 1,497 (98.2%) in PPI nonrecipients (P = 0.19). Neither low- nor high-dose PPI was associated with decreased SVR, although patients taking twice-daily PPI achieved a lower SVR12 rate (91.2%; 95% confidence interval [CI], 77.0-97.0; P = 0.046). After propensity matching for PPI use, there were no significant associations between SVR12 and any dose or frequency of PPI use. However, in a sensitivity analysis focusing on patients with cirrhosis, twice-daily PPI use was associated with lower odds ratio for SVR12 (0.11; 95% CI, 0.02-0.59). CONCLUSION: These data from a cohort of real-world patients receiving hepatitis C antibody therapy with LDF/SOF ± RBV support the prescription labeling suggesting that patients take no more than low-dose (20-mg omeprazole equivalents) PPI daily. (Hepatology 2016;64:1893-1899).

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial.

BACKGROUND & AIMS: Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. METHODS: We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naïve and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6-12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29 of 33; 95% confidence interval, 72%-97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28 of 30; 95% CI, 78%-99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%-100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%-100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis. ClinicalTrials.gov ID: NCT02378961.

Comparison of genome-scale DNA methylation profiles in hepatocellular carcinoma by viral status.

Hepatocellular carcinoma (HCC) incidence has steadily increased in the US over the past 30 years. Our understanding of epigenetic regulation in HCC is still limited, especially the impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection on aberrant DNA methylation. We performed genome-wide DNA methylation profiling in 33 fresh frozen tumor samples, including 10 HBV-HCC, 13 HCV-HCC, and 10 non-infected (NIV-HCC) using the Illumina HumanMethylation450 BeadChip. Gene expression profiling was also performed using the Illumina whole-genome DASL HT Assay. Biological influences and gene networks of the differentially-methylated (DM) CpG loci were predicted using the Ingenuity Pathway Analysis. Genome-wide methylation analysis identified 7, 26, and 98 DM loci between HBV-HCC vs. HCV-HCC, HBV-HCC vs. NIV-HCC, and HCV-HCC vs. NIV-HCC, respectively, at P < 5 × 10(-5) for each. Overall, the DM loci were highly enriched for enhancers (48%), promoters (37%), or CpG islands and surrounding regions (37%). Most DM loci were hypermethylated in HCV-HCC compared to HBV-HCC or NIV-HCC. The DM loci were associated with a variety of biological functions including Cell Morphology (HBV-HCC vs. NIV-HCC), Cell Death/ Survival (HBV-HCC vs. NIV-HCC), or Cellular Growth and Proliferation (HCV-HCC vs. NIV-HCC). A subset of the DM loci were correlated (either positively or negatively) with their gene expression or associated with alcohol consumption, BMI, cirrhosis, diabetes, and cigarette smoking. Our findings of differential methylation by viral infection lend insights into the potential effects of viral infection on the epigenetic regulation and further the development and progression of HCC.

Examining the clinical course of genotype 1 chronic hepatitis C patients treated with the cosmos regimen: including patients with advanced liver disease and East Asian ancestry.

BACKGROUND/OBJECTIVES: The COSMOS study was a phase 2a clinical trial that showed high cure rates of genotype 1 chronic hepatitis C (CHC) and a favorable side effect profile using a 12-week regimen of simeprevir + sofosbuvir (SIM + SOF). Given the small number of patients treated with the SIM + SOF regimen in the COSMOS trial, there is uncertainty regarding the efficacy and safety of this combination therapy. We now report our experience with the COSMOS regimen in the multiethnic population of Hawaii, including patients of East Asian ancestry and with decompensated cirrhosis. METHODS: This study is a retrospective review of 138 patients treated with a fixed dose regimen of SIM 150 mg and SOF 400 mg daily at a single referral center. We collected data on demographics, side effects, laboratory studies and sustained virological response (SVR). Statistical analysis was performed with Stata v8.2 software. RESULTS: Baseline characteristics of the 138 patients initiated with SIM + SOF therapy were: 68.8 % cirrhotic (22.1 % of those Child-Pugh Class B), 37 % Asian, 11.6 % Pacific Islander, 63 % male, mean age 61.3 ± 7.8 years, mean BMI 27.8 ± 6.1 kg/m(2), 26.8 % diabetic, 63.8 % genotype 1a, 44.9 % previously treatment experienced. A total of 100 % of patients that completed therapy (n = 137) had undetectable viral loads at end of treatment (EOT). Twelve patients relapsed post-treatment resulting in an overall 12 week SVR (SVR12) rate of 89.1 %. 95 % of decompensated cirrhotic patients achieved SVR12, compared to 85.3 % of compensated cirrhotic patients and 93 % of non-cirrhotic patients. 92 % of Asian patients achieved SVR12 compared to 87.5 % in non-Asian patients. There were no statistically significant differences in SVR12 between treatment naive and treatment experienced patients (86.8 vs 91.9 %). 87.5 % of post-transplant patients achieved SVR12. The main side effects were headache 16.2 %, fatigue 24.2 %, pruritis 14.1 %; none were >grade 2 in severity. There were no differences in side effect profiles of patients with decompensated cirrhosis. Pruritis only was statistically significant between Asians and non-Asians (22 vs 5.7 %). Trends toward improvement in platelet counts and total bilirubin were noted at 12-weeks post treatment, while improvement in albumin in cirrhotic patients reached statistical significance (3.77-4.01 mg/dL, p = 0.0108). CONCLUSIONS: The 12-week fixed dose course of SIM + SOF was well tolerated in a multiethnic population of primarily cirrhotic patients, including those with decompensated disease. This real world trial achieved SVR12 rates comparable to the COSMOS data. Higher incidence of adverse side effects was not observed with an exception of higher rate of pruritis in Asians. The increase in albumin in cirrhotic patients was statistically significant and suggested early improvement in synthetic function following viral eradication. Higher BMI (≥30 kg/m(2)) was the only factor that correlated with post-treatment relapse by multivariate analysis.

Autoimmune Hepatitis in Hawai'i.

Autoimmune Hepatitis (AIH) is a poorly understood disease. There has been a paucity of reports on the epidemiology and clinical course of AIH in multiethnic populations. The aim of this study is to examine the clinical and serologic features of AIH in the multiethnic population of Hawai'i. This was a retrospective, cross-sectional study of a cohort of patients seen between 2010-2013 in a tertiary referral center in Hawai'i. All 32 patients were diagnosed according to International Autoimmune Hepatitis Group (IAIHG) criteria. The mean (SD) age of diagnosis was 49.4 (17.5) years, 75% of patients were female, 72% were Asian, 19% were Caucasian, 6% were Pacific Islander, and 3% were African American. When compared to Caucasians, Asians had lower transaminase levels and international normalized ratio (INR), and were more likely to have anti-nuclear antibody (ANA) seropositivity at presentation. Asians were also older at diagnosis and more likely to achieve complete or partial remission. Patients diagnosed before the age of 40 had higher levels of total bilirubin at presentation compared to those diagnosed after the age of 40. No significant differences were observed between genders. Asian patients with type I AIH present later in life with more favorable laboratory values, and have a superior treatment response compared to Caucasians. Diagnosis before the age of 40 is associated with less favorable laboratory values at diagnosis. Further studies are necessary to validate these findings and determine the reason for the ethnic differences.