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.

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.

Real-world Experience with Sofosbuvir-based Regimens for Chronic Hepatitis C, Including Patients with Factors Previously Associated with Inferior Treatment Response.

The introduction of sofosbuvir, a direct acting antiviral, has revolutionized the treatment of chronic hepatitis C virus (HCV). Phase 3 clinical trials have demonstrated the efficacy, simplicity, and tolerability of sofosbuvir-based regimens and report high rates of sustained virological response (SVR) rates. The purpose of this study was to assess whether clinical trial findings translate into a real-world setting, particularly with treatment of chronic HCV in our diverse, multiethnic population of Hawai'i. Retrospective analysis was performed for 113 patients with genotype 1-6 HCV infection being treated at the Queen's Liver Center between January 2014 and March 2015. SVR rates for our cohort were slightly lower than the rates published by the clinical trials. Data analysis also suggested that most baseline characteristics previously associated with inferior response might not be as significant for sofosbuvir-based regimens; in our cohort, male gender was the only factor significantly related to increased risk of virologic relapse. Pacific Islanders also had higher rate of relapse compared to other ethnic groups, but the small number of patients treated in this subgroup make it difficult to validate this finding. While newer all-oral treatment regimens have been introduced since this study, we highlight the importance of comparing real-world versus clinical trial results for new treatments, and provide data analyses for treatment of chronic HCV in Hawai'i.

Trial and error: investigational drug induced liver injury, a case series report.

This is a case report series of four patients who exhibited signs and symptoms of acute liver dysfunction during participation in a Phase I trial of a novel non-steroidal anti-inflammatory drug (NSAID) designed to inhibit microsomal prostaglandin synthase 1 (MPGES1). Within one month of trial initiation, all four patients presented with epigastric pain, fatigue, nausea, and increasing liver function tests (LFTs). Two out of four patients required hospitalization, underwent liver biopsies, and were treated with N-acetylcysteine. The remaining two patients were managed as outpatients. Liver biopsies were consistent with drug induced liver injury (DILI). Within three months of stopping the investigational drug, symptoms subsided and LFTs normalized in all patients. This case report series signifies the importance of NSAIDs and novel drug agents in general as potentially hepatotoxic substances, the need for a high level of suspicion of DILI when considering possible etiologies of acute liver failure, and the need for prompt withdrawal of the causative agent in management of patients presenting with DILI.

New triple therapy for chronic hepatitis C: real life clinical experience in a community setting.

Recent advances in treatment of chronic hepatitis C virus have improved significantly due to the introduction of two new protease inhibitors-telaprevir and boceprevir. In combination with the previous standard of care, peginterferon and ribavirin, telaprevir and boceprevir have demonstrated improved sustained virologic response rates for HCV genotype 1 patients by approximately 30%. The purpose of this study was to assess the validity of large clinical trial data with respect to efficacy and side effects in a community setting in Honolulu, Hawai'i. This retrospective study was performed by reviewing the charts of 59 chronic HCV patients who were started on triple therapy from July 1, 2011 to July 7, 2012. Sustained virologic response was attained by 73% of patients treated with telaprevir and 46% of patients treated with boceprevir respectively. Our clinical experience with telaprevir demonstrates that SVR rates are compatible with published literature values. Rates of SVR in our cohort were also similar to those reported in cirrhotic patients - about 50%. Due to small number of patients treated with a boceprevir-based regimen, it is difficult to compare our experience with pivotal trial experience. The side effect profiles for the two protease inhibitors were similar to the literature values except for more rectal irritation and a higher incidence and severity of anemia on telaprevir therapy in the clinical setting. While not intended to be conclusive, our study demonstrates that clinical trial data are largely compatible with the outcomes obtained in our community setting.

Seroepidemiology of hepatitis B virus infection: analysis of mass screening in Hawaii.

BACKGROUND: Although hepatitis B seroprevalence has been studied extensively in California and New York, detailed information for other high-risk areas in the United States is lacking. To study current prevalence and risk for hepatitis B virus (HBV) infection in Hawaii, we analyzed cross-sectional data from Hawaii residents screened between July 2003 and April 2006. METHODS: We retrospectively reviewed the screening records of 3,989 participants recruited at health fairs and clinics. Prevalence and risk factors for HBV infection were estimated using univariate and multivariate logistic regression models. RESULTS: Total prevalence of hepatitis B surface antigen (HBsAg) was 3.6%. Gender, age, and ethnicity were independently associated with HBsAg seropositivity. In a multivariate logistic regression model, males were at increased risk for HBsAg compared with females (odds ratio [OR] = 1.53, 95% confidence interval [CI]: 1.09-2.16) and persons aged 70 years or older were less likely to test positive than those younger than 30 (OR = 0.25, 95% CI: 0.11-0.61). In addition, multivariate ORs of HBsAg seropositivity were 3.24 (95% CI: 1.04-10.09), 4.13 (95% CI: 1.66-10.29), and 7.47 (95% CI: 2.52-22.11) for Vietnamese, Chinese, and Pacific Islanders, respectively, compared with Whites. CONCLUSIONS: This study furthers current knowledge of HBV epidemiology in areas with large populations of high-risk immigrants and demonstrates the relevance of screening programs for hepatitis B.