Randomized, double-blind, placebo-controlled trials of ursodeoxycholic acid (UDCA) in patients with primary biliary cirrhosis (PBC) have not demonstrated improvement in survival during the ...placebo-controlled phases of these trials. Analyses purporting to demonstrate a survival advantage of UDCA are largely dependent on data obtained after the placebo phases were terminated, and placebo-treated patients were offered open-label UDCA. After completion of our 2-yr placebo-controlled trial of UDCA in which we observed no survival benefit for UDCA, we provided the patients with open-label UDCA to see if delay in providing UDCA for 2 yr had any effect on subsequent liver transplantation or death without liver transplantation.
In our previously reported 2-yr placebo-controlled trial, 151 patients with PBC were randomized to receive either UDCA (n = 77) or placebo (n = 74). The number of patients who progressed to liver transplantation or death without transplantation were similar in both the groups, 12 (16%) in the UDCA-treated and 11 (15%) in placebo-treated patients. All the patients were then offered open-label UDCA, with 61 original UDCA and 56 original placebo-treated patients now taking UDCA in an extended open-label phase of the trial.
No significant differences were observed in the number of patients who underwent liver transplantation or died without liver transplantation in the open-label phase of the trial. Moreover, no difference in the time to these endpoints was seen over the period of observation of as long as 6 yr from the time of initial randomization.
Results of open-label extensions of previous conducted placebo-controlled trials of UDCA in PBC leave uncertain whether UDCA impacts significantly on liver transplantation and death without liver transplantation in patients with PBC.
The aim of this study was to assess the validity of categorization of chronic hepatitis B viral infection into stages or phases based upon measures of disease activity and viral load, assuming these ...phenotypes will be useful for prognostication and determining the need for antiviral therapy. We assessed the phenotype of hepatitis B of 1,390 adult participants enrolled in the Hepatitis B Research Network Cohort Study, using a computer algorithm. Only 4% were immune tolerant, while 35% had chronic hepatitis B (18% e antigen positive and 17% e antigen negative) while 23% were inactive carriers. Strikingly, 38% of participants did not fit clearly into any one of these groups and were considered indeterminant. The largest subset of indeterminants had elevated serum aminotransferases with low levels of HBV DNA (less than 10,000 iu/mL). Subsequent determination of hepatitis B phenotype on the next available laboratory tests showed that 64% remained indeterminant. These findings call into question the validity of conventional staging of hepatitis B, in large part because of the substantial proportion of patients who do not fit readily into one of the usual stages or phases. Further studies are needed of the indeterminant category of chronic hepatitis B viral infection, including assessments of whether patients in this group are perhaps in transition to another phase or if they are a distinct phenotype with a need to assess liver disease severity and need for antiviral therapy. (ClinicalTrials.gov identifier NCT01263587).
Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the ...rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co‐infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24 weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24–48 weeks. HBeAg loss was defined as first HBeAg‐negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg‐negative values ≥24 weeks apart. During a median follow‐up of 1.8 years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8–13.3) per 100 person‐years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre‐core mutations versus wild type. Additionally, during follow‐up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies.
Abstract
Broadcast meteorologists play an essential role in communicating severe weather information from the National Weather Service to the public. Because of their importance, researchers ...incorporated broadcast meteorologists in the development of probabilistic hazard information (PHI) in NOAA’s Hazardous Weather Testbed. As part of Forecasting a Continuum of Environmental Threats (FACETs), PHI is meant to bring additional context to severe weather warnings through the inclusion of probability information. Since this information represents a shift in the current paradigm of solely deterministic NWS warnings, understanding end user needs is paramount to create usable and accessible products that result in their intended outcome to serve the public. This paper outlines the establishment of “K-Probabilistic Hazard Information Television” (KPHI-TV), a research infrastructure under the Hazardous Weather Testbed created to study broadcast meteorologists and PHI. A description of the design of KPHI-TV and methods used by researchers are presented, including displaced real-time cases and semistructured interviews. Researchers completed an analysis of the 2018 experiment, using a quantitative analysis of television coverage decisions with PHI, and a thematic analysis of semistructured interviews. Results indicate that no clear probabilistic decision thresholds for PHI emerged among the participants. Other themes arose, including the relationship between PHI and the warning polygon, and communication challenges. Overall, broadcast participants preferred a system that includes PHI over the warning polygon alone, but raised other concerns, suggesting iterative research in the design and implementation of PHI should continue.
Significance Statement
Broadcast meteorologists are the primary source of severe weather warning information for the U.S. public. As a result, researchers at NOAA’s National Severe Storms Laboratory and the Cooperative Institute for Mesoscale Meteorological Studies developed a mock television studio to allow broadcast meteorologists to use and communicate experimental products “on air” as part of the research-and-development process. Feedback provided by broadcasters is incorporated into products through an iterative process. Since 2016, 18 broadcasters have tested probabilistic hazard information at the warning time scale (0–1 h) for severe wind and hail, tornadoes, and lightning.
The hepatitis C virus (HCV) envelope glycoprotein-2 inhibits the interferon (IFN)–induced, double-stranded RNA-activated protein kinase (PKR) via the PKR eukaryotic initiation factor-2α ...phosphorylation homology domain (PePHD). The present study examined the genetic variability of the PePHD in patients receiving IFN therapy. The PePHD from 12 HCV genotype 1 (HCV-1)—infected patients receiving daily IFN therapy was amplified by reverse-transcriptase polymerase chain reaction and analyzed by direct and clonal sequencing. The PePHD was highly conserved in 38 HCV GenBank isolates. There was no difference in pretreatment PePHD sequences isolated from IFN responders versus nonresponders. The major PePHD quasi-species variant did not change after 6 weeks of daily IFN therapy, and in 1 patient the major quasi-species variant did not change during 9 months of observation. Sequencing of 25 pretreatment PePHD clones from 3 patients confirmed that there was extremely low sequence variability surrounding the PePHD. The PePHD is highly conserved in HCV-1—infected IFN responders and nonresponders and does not appear to evolve in response to IFN therapy.
Background: In chronic hepatitis B (CHB) viral infection, e antigen positivity (HBeAg+) is associated with high levels of viral replication and infectivity. Furthermore, HBeAg‐positive CHB is ...associated with a liver disease spectrum ranging from none to severe. Aim: To assess whether the level of circulating HBeAg is associated with different clinical presentations of HBeAg‐positive CHB. Methods: A cross‐sectional analysis was conducted among HBV mono‐infected participants enrolled in Hepatitis B Research Network (HBRN) cohorts to explore clinical and virological associations with quantitative HBeAg (qHBeAg). Results: Among 763 HBeAg+ participants (56% female; 85% Asian; median age 26 years), multivariable median regression modelling significantly associated qHBeAg with liver injury (inverse qHBeAg association with ALT p<.001 and APRI p<.001), and with both race and age (p=0.01). Among Asians, qHBeAg was inversely related to age; a relationship less clear among Blacks and Whites. Among Asians also, median qHBeAg levels were higher among those infected with HBV genotype C versus B (p<0.001), suggesting causal virologic differences. Across all races, median qHBeAg was higher in women (p=.01). Independent of sex, age, race and HBV genotype, qHBeAg was higher in participants with predominant wild‐type versus basal core promoter and/or precore ‘stop’ viral variants (p<0.001). Conclusion: Lower qHBeAg was observed among HBRN participants with the greatest degree of liver injury independent of demographics and HBV genotype. These data support longitudinal studies to examine the role of qHBeAg in modulating the host immune response and predicting the outcomes of chronic HBV infection.
Diabetes is associated with liver disease progression and increased hepatocellular carcinoma risk, but factors associated with diabetes in patients with chronic hepatitis B virus (HBV) infection in ...North America are unknown. We aimed to determine factors predictive of diabetes and impaired fasting glucose (IFG) in a large HBV‐infected multiethnic cohort. Adults with chronic HBV not receiving antiviral therapy were enrolled from 21 centers in North America. Diabetes was defined by history/medication use or fasting glucose ≥126 mg/dL and IFG as fasting glucose 100‐125 mg/dL. Of 882 patients included, 47.2% were female, 71.3% Asian, 83.7% foreign born, median age was 44 years, and median body mass index BMI 24.3 kg/m2. In this cohort, 26.0% were hepatitis B envelope antigen (HBeAg) positive, 43.9% had HBV DNA ≥20,000 IU/mL, and 26.7% alanine aminotransferase (ALT) ≥2× upper limit of normal (≥40 U/L women, ≥60 U/L men). Overall, 12.5% had diabetes and 7.8% IFG. The combined prevalence of diabetes or IFG was highest among blacks (36.7%) and those either born in the United States/Canada or foreign born with migration >20 years ago (25.5%). Obesity (odds ratio OR: 2.13), hyperlipidemia (OR, 4.13), hypertension (OR, 3.67), high ALT level (OR, 1.86), and family history of diabetes (OR, 3.43) were associated with diabetes. Factors associated with IFG were obesity (OR, 4.13) and hypertension (OR, 3.27), but also HBeAg positivity (OR, 0.39). Recent migration was negatively associated with diabetes among non‐Asians (OR, 0.30). Conclusions: Diabetes is more prevalent in HBV‐infected North American adults than the general population and is associated with known metabolic risk factors and liver damage, as determined by ALT levels. Among the foreign born, longer duration of North America residence predicted diabetes risk in non‐Asians. These results highlight the opportunities for interventions to prevent diabetes especially among at‐risk ethnic groups with HBV. (Hepatology 2015;62:1364–1374)
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