Interferon alpha induces a stronger antiviral effect than interferon lambda in HBV/HDV infected humanized mice.

Recent studies indicate that treatment of chronic hepatitis D virus (HDV) with either pegylated interferon (IFN)λ or pegylated IFNα monotherapy leads to a dramatic decline in HDV RNA. Herein, we investigated the innate antiviral efficacy of IFNλ and IFNα in humanized mice that lack an adaptive immune response. Humanized mice were either co-infected with hepatitis B virus (HBV) and HDV simultaneously, or HDV infection was performed subsequent to HBV infection (i.e., superinfected). After steady viral replication was achieved, mice received either IFNλ (n = 6) or IFNα (n = 7) for 12 (or 13) weeks. Pretreatment median levels of serum HBV DNA (8.8 [IQR:0.2] log IU/ml), HDV RNA (9.8 [0.5] log IU/ml), HBsAg (4.0 [0.4] log IU/ml) and human albumin, hAlb (6.9 [0.1] log ng/mL) were similar between mice treated with IFNα or IFNλ and between those coinfected versus superinfected. Compared to mice treated with IFNλ, mice treated with IFNα had a significantly greater decline in HBV, HDV, and HBsAg levels. In conclusion, IFNα induces stronger inhibition of HBV and HDV than IFNλ in humanized mice that lack an adaptive immune response. Further studies are needed to assess the respective role of the combined innate-and adaptive-immune systems in the treatment of HBV and HDV with IFNα and IFNλ.

Estimating the prevalence of hepatitis delta virus infection among adults in the United States: A meta-analysis.

BACKGROUND AND AIMS: Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of U.S. HDV prevalence. We aim to provide an updated assessment of HDV prevalence in the U.S. using a comprehensive literature review and meta-analysis approach. METHODS: A comprehensive literature review of articles reporting HBsAg seroprevalence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of foreign-born (FB) persons in the U.S. in 2022 from U.S. Census Bureau to estimate total numbers of FB with CHB and HDV, respectively. These estimates were further combined with updated estimates of U.S.-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. RESULTS: In 2022, we estimated 1.971 million (M) (95% CI 1.547-2.508) persons with CHB; 1.547 M (95% CI 1.264-1.831) were FB and 0.424 M (95% CI: 0.282-0.678) were U.S.-born. The weighted average HDV prevalence among FB persons in the U.S. was 4.20% (64 938 [95% CI 33055-97 392] persons), among whom 45% emigrated from Asia, 25% from Africa, and 14% from Europe. When combined with updated estimates of U.S.-born persons with HDV, we estimate 75 005 (95% CI: 42187-108 393) persons with HDV in the U.S. CONCLUSIONS: Including both FB and U.S.-born persons, we estimated that 1.971 M and 75 005 persons were living with CHB and HDV, respectively, in the U.S. in 2022.

An updated assessment of hepatitis delta prevalence among adults in Canada: A meta-analysis.

Foreign-born (FB) persons represent a large proportion of adults with chronic hepatitis B (CHB) in Canada due to higher prevalence rates in countries of birth for FB persons. Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of Canada HDV prevalence. We aim to provide an assessment of CHB and HDV prevalence in Canada using a comprehensive literature review and meta-analysis. A comprehensive literature review of articles reporting HBsAg seroprevalence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of FB persons in Canada in 2021 from Statistics Canada to estimate total numbers of FB with CHB and HDV, respectively. These estimates were combined with estimates of Canada-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. In 2021, we estimated 0.550 million (M) (95% CI 0.488-0.615) persons with CHB; 0.344 M (95% CI 0.288-0.401) were FB and 0.206 M (95% CI: 0.200-0.214) were Canada-born. The weighted average HDV prevalence among FB persons in Canada was 5.19% (17,848 [95% CI 9611-26,052] persons), among whom 50% emigrated from Asia and 31% from Africa. When combined with estimates of Canada-born persons with HDV, we estimate 35,059 (95% CI: 18,744-52,083) persons with HDV in Canada. In conclusion, we estimate 0.550 M and 35,059 persons living with CHB and HDV, respectively, in Canada in 2021.

Do healthcare providers consider the social determinants of health? Results from a nationwide cross-sectional study in the United States.

BACKGROUND: While the social determinants of health (SDOH) have a greater impact on individual health outcomes than the healthcare services a person receives, healthcare providers face barriers to addressing these factors in clinical settings. Previous studies have shown that providers often lack the necessary knowledge and resources to adequately screen for and otherwise assist patients with unmet social needs. This study explores the perceptions and behaviors related to SDOH among healthcare providers in the United States (US). METHODS: This cross-sectional study analyzed data from a 22-item online survey using Reaction Data's research platform of healthcare professionals in the US. Survey items included demographic questions as well as Likert scale questions about healthcare providers' perceptions and behaviors related to SDOH. Descriptive statistics were calculated, and further analyses were conducted using t-tests and analysis of variance. RESULTS: A total of 563 respondents completed the survey, with the majority being male (72.6%), White (81%), and located in urban areas (82.2%). In terms of perceptions, most providers agreed or strongly agreed that SDOH affect the health outcomes of all patients (68.5%), while only 24.1% agreed or strongly agreed that their healthcare setting was set up to address SDOH. In terms of behavior, fewer than half currently screened for SDOH (48.6%) or addressed (42.7%) SDOH in other ways. Most providers (55.7%) wanted additional resources to focus on SDOH. Statistical analyses showed significant differences by gender, with females being more likely than males to prioritize SDOH, and by specialty, with psychiatrists, pediatricians, and family/general medicine practitioners being more likely to prioritize SDOH. CONCLUSION: Most healthcare providers understand the connection between unmet social needs and their patients' health, but they also feel limited in their ability to address these issues. Ongoing efforts to improve medical education and shift the healthcare system to allow for payment and delivery of more holistic care that considers SDOH will likely provide new opportunities for healthcare providers. In addition to what they can do at the institutional and patient levels, providers have the potential to advocate for policy and system changes at the societal level that can better address the root causes of social issues.

Providers' Perceptions of the Effectiveness of Electronic Health Records in Identifying Opioid Misuse.

GOAL: This study aimed to understand prescribing providers' perceptions of electronic health record (EHR) effectiveness in enabling them to identify and prevent opioid misuse and addiction. METHODS: We used a cross-sectional survey designed and administered by KLAS Research to examine healthcare providers' perceptions of their experiences with EHR systems. Univariate analysis and mixed-effects logistic regression analysis with organization-level random effects were performed. PRINCIPAL FINDINGS: A total of 17,790 prescribing providers responded to the survey question related to this article's primary outcome about opioid misuse prevention. Overall, 34% of respondents believed EHRs helped prevent opioid misuse and addiction. Advanced practice providers were more likely than attending physicians and trainees to believe EHRs were effective in reducing opioid misuse, as were providers with fewer than 5 years of experience. PRACTICAL APPLICATIONS: Understanding providers' perceptions of EHR effectiveness is critical as the health outcome of reducing opioid misuse depends upon their willingness to adopt and apply new technology to their standardized routines. Healthcare managers can enhance providers' use of EHRs to facilitate the prevention of opioid misuse with ongoing training related to advanced EHR system features.

Reflective structured dialogue as a tool for addressing wicked public health problems.

Introduction: Attempts to address wicked public health problems can benefit from collaborative approaches to problem-solving, such as dialogue through structured conversations, that engage a wide range of stakeholders in deliberate inquiry to build trust and mutual understanding. This study seeks to assess the effects of participation in Reflective Structured Dialogue (RSD) on university students' polarization-related attitudes. Methods: The BYU Campus Conversations project held 27 structured conversations with 139 participants on three divisive public health topics: COVID-19, mental health, and racism. The conversation structure encouraged students to share their personal experiences and learn from others in an environment that promoted vulnerability and confidentiality. Results: Pre- and post-conversation surveys measured participant outcomes and found that participation in conversations was strongly associated with improved attitudes related to openness, tribal identity, and moral disdain. Over 95% of participants reported that they enjoyed taking part in the conversations and that it helped them better understand the experiences of others. Discussion: The results of this project indicate similar conversations could be an effective tool in helping build understanding around divisive public health issues in university and community settings.

HDV RNA assays: Performance characteristics, clinical utility, and challenges.

Coinfection with HBV and HDV results in hepatitis D, the most severe form of chronic viral hepatitis, frequently leading to liver decompensation and HCC. Pegylated interferon alpha, the only treatment option for chronic hepatitis D for many years, has limited efficacy. New treatments are in advanced clinical development, with one recent approval. Diagnosis and antiviral treatment response monitoring are based on detection and quantification of HDV RNA. However, the development of reliable HDV RNA assays is challenged by viral heterogeneity (at least 8 different genotypes and several subgenotypes), intrahost viral diversity, rapid viral evolution, and distinct secondary structure features of HDV RNA. Different RNA extraction methodologies, primer/probe design for nucleic acid tests, lack of automation, and overall dearth of standardization across testing laboratories contribute to substantial variability in performance characteristics of research-based and commercial HDV RNA assays. A World Health Organization (WHO) standard for HDV RNA, available for about 10 years, has been used by many laboratories to determine the limit of detection of their assays and facilitates comparisons of RNA levels across study centers. Here we review challenges for robust pan genotype HDV RNA quantification, discuss particular clinical needs and the importance of reliable HDV RNA quantification in the context of drug development and patient monitoring. We summarize distinct technical features and performance characteristics of available HDV RNA assays. Finally, we provide considerations for the use of HDV RNA assays in the context of drug development and patient monitoring.

Distinct histological patterns in chronic hepatitis D with nucleos(t)ide analogue therapy.

Background: Chronic hepatitis delta virus (HDV) infection leads to a more severe hepatitis than hepatitis B virus (HBV) infection alone. Specific histological staining patterns have been described in HBV mono-infection, however this has not been extensively investigated in HDV co-infection. This study evaluated whether the use of nucleos(t)ide analogs (NAs) for concurrent HBV infection has an impact on the histological appearance of chronic HDV. Methods: Liver biopsies of all patients referred for management of HDV infection were reviewed and hepatitis-specific stains for HBV antigens were evaluated. Clinical and histological characteristics were compared between patients on and off-NA therapy. Results: 50 patients were included in our analysis, of which 26 (52%) were on NA therapy at the time of the biopsy. Overall, 8% stained for HBV core antigen and 86% stained for HBV surface antigen. On and off-NA groups had similar degrees of fibrosis and inflammation, however NA patients had an odds ratio of 7.15 for membranous staining and 0.13 for scattered granular staining (p = 0.001). No association was found with markers of disease severity or viral activity, with nonetheless a lower score of total inflammation noted in biopsies with a positive membranous stain (8.5 vs. 10.3 p = 0.04). Conclusion: In chronic HDV infection, patients treated with nucleos(t)ide analogs demonstrate a unique membranous staining pattern for hepatitis B surface antigen, which is not associated with HBV or HDV replicative activity. These findings may help improve the understanding of the role of HBV directed therapy in HDV pathophysiology. Highlights: Histological staining is associated with viral activity in chronic HBV, however this has been infrequently explored in HDV. In HDV, staining patterns differ based on HBV treatment status and do not appear to be associated with markers of viral activity.

Population Segmentation for COVID-19 Vaccine Outreach: A Clustering Analysis and Implementation in Missouri.

OBJECTIVES: The purpose of this work was to segment the Missouri population into unique groups related to COVID-19 vaccine acceptance using data science and behavioral science methods to develop tailored vaccine outreach strategies. METHODS: Cluster analysis techniques were applied to a large data set that aggregated vaccination data with behavioral and demographic data from the American Community Survey and Deloitte's HealthPrism™ data set. Outreach recommendations were developed for each cluster, specific to each group's practical and motivational barriers to vaccination. RESULTS: Following selection procedures, 10 clusters-or segments-of census tracts across Missouri were identified on the basis of k -means clustering analysis of 18 different variables. Each cluster exhibited unique geographic, demographic, socioeconomic, and behavioral patterns, and outreach strategies were developed on the basis of each cluster's practical and motivational barriers. DISCUSSION: The segmentation analysis served as the foundation for "working groups" comprising the 115 local public health agencies (LPHAs) across the state. LPHAs with similar community segments in their service area were grouped together to discuss their communities' specific challenges, share lessons learned, and brainstorm new approaches. The working groups provided a novel way for public health to organize and collaborate across the state. Widening the aperture beyond Missouri, population segmentation via cluster analysis is a promising approach for public health practitioners interested in developing a richer understanding of the types of populations they serve. By pairing segmentation with behavioral science, practitioners can develop outreach programs and communications campaigns that are personalized to the specific behavioral barriers and needs of the population in focus. While our work focused on COVID-19, this approach has broad applicability to enhance the way public health practitioners understand the populations they serve to deliver more tailored services.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

COVID-19 and Psychosocial Well-Being: Did COVID-19 Worsen U.S. Frontline Healthcare Workers' Burnout, Anxiety, and Depression?

Healthcare workers are highly regarded for their compassion, dedication, and composure. However, COVID-19 created unprecedented demands that rendered healthcare workers vulnerable to increased burnout, anxiety, and depression. This cross-sectional study assessed the psychosocial impact of COVID-19 on U.S. healthcare frontliners using a 38-item online survey administered by Reaction Data between September and December 2020. The survey included five validated scales to assess self-reported burnout (Maslach Summative Burnout Scale), anxiety (GAD-7), depression (PHQ-2), resilience (Brief Resilience Coping Scale), and self-efficacy (New Self-Efficacy Scale-8). We used regression to assess the relationships between demographic variables and the psychosocial scales index scores and found that COVID-19 amplified preexisting burnout (54.8%), anxiety (138.5%), and depression (166.7%), and reduced resilience (5.70%) and self-efficacy (6.5%) among 557 respondents (52.6% male, 47.5% female). High patient volume, extended work hours, staff shortages, and lack of personal protective equipment (PPE) and resources fueled burnout, anxiety, and depression. Respondents were anxious about the indefinite duration of the pandemic/uncertain return to normal (54.8%), were anxious of infecting family (48.3%), and felt conflicted about protecting themselves versus fulfilling their duty to patients (44.3%). Respondents derived strength from their capacity to perform well in tough times (74.15%), emotional support from family/friends (67.2%), and time off work (62.8%). Strategies to promote emotional well-being and job satisfaction can focus on multilevel resilience, safety, and social connectedness.

Hepatitis B virus and hepatitis D virus infection in women with or at risk for HIV infection in the United States.

Hepatitis D virus (HDV) requires co-infection with hepatitis B virus (HBV). Human immunodeficiency virus (HIV) shares transmission routes with these viruses. Among 4,932 US women infected with or at-risk for HIV during 1994-2015, HBV surface antigen (HBsAg) positivity was more common in women with HIV (2.8% vs. 1.2%; p = 0.001); HDV was more common among participants enrolled during 2013-2015 (p = 0.0004) and those with resolved rather than active hepatitis C (1.9% vs. 0.5%; p = 0.02). Among HBsAg-positive women (n = 117), HDV antibody prevalence was 22% and did not vary by HIV status; HDV infection was associated with the presence of advanced fibrosis/cirrhosis at enrollment (adjusted odds ratio, 5.70; 95% confidence interval, 1.46-22.29). Our results demonstrate the importance of HDV testing in HBV-infected US women.

Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial.

BACKGROUND AND AIMS: HDV infection leads to the most aggressive form of human viral hepatitis for which there is no FDA-approved therapy. PEG IFN-lambda-1a (Lambda) has previously demonstrated a good tolerability profile in HBV and HCV patients compared to PEG IFN-alfa. The goal of Phase 2 LIMT-1 trial was to evaluate the safety and efficacy of Lambda monotherapy in patients with HDV. APPROACH AND RESULTS: An open-label study of Lambda 120 or 180 mcg, administered once weekly by subcutaneous injections for 48 weeks, followed by 24 weeks of posttreatment follow-up. Thirty-three patients were allocated to Lambda 180 mcg (n=14) or 120 mcg (n=19). Baseline mean values: HDV RNA 4.1 log10 IU/mL (SD±1.4); ALT 106 IU/L (35-364); and bilirubin 0.5 mg/dL (0.2-1.2). Intention-to-treat rates of virologic response to Lambda 180 mcg and 120 mcg, 24 weeks following treatment cessation were 5 of 14(36%) and 3 of 19 (16%), respectively. The posttreatment response rate of 50% was seen in low BL viral load (≤4 log10) on 180 mcg. Common on-treatment adverse events included flu-like symptoms and elevated transaminase levels. Eight (24%) cases of hyperbilirubinemia with or without liver enzyme elevation, leading to drug discontinuation, were mainly observed in the Pakistani cohort. The clinical course was uneventful, and all responded favorably to dose reduction or discontinuation. CONCLUSIONS: Treatment with Lambda in patients with chronic HDV may result in virologic response during and following treatment cessation. Clinical phase 3 development of Lambda for this rare and serious disease is ongoing.

Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

The Impact of Community Health Information Exchange Usage on Time to Reutilization of Hospital Services.

PURPOSE: Few studies have determined whether clinician usage of a community health information exchange (HIE) directly improves patient care transitions. We hypothesized that lookup in the HIE by primary care physicians of patients recently released from the hospital would increase the time until hospital reuse. METHODS: We identified a retrospective cohort of 8,216 hospital inpatients aged over 18 years that were discharged from January 1, 2021 through November 30, 2021 using the Paso del Norte Health Information Exchange, in El Paso County, Texas. All patients had a primary care physician visit within 30 days after hospital discharge, and we identified patients that were looked up in the HIE close to that visit. Of the cohort, 2,627 were rehospitalized and 3,809 visited an emergency department (ED) during the follow-up window. The remaining 1,780 patients were controls. We conducted survival analysis, censoring at the second ED or inpatient visit or end of the study window (January 31, 2022). The model was adjusted by ethnicity, gender, insurance, and age. RESULTS: Lookup in the HIE was significantly associated with reducing the likelihood of visiting the ED by 53% and being rehospitalized by 61%. Lookup in the HIE was associated with an increased median time to use of the ED after inpatient discharge from 99 to 238 patient days. Ethnicity, insurance, gender, and age were also significant predictors of hospital reuse. CONCLUSIONS: Increased utilization of community HIEs by primary care physicians on behalf of their recently discharged patients may dramatically increase the time until inpatient or ED reuse.

Inferring sleep disturbance from text messages of suicide attempt survivors: A pilot study.

OBJECTIVE: Identifying digital markers of sleep disturbance-a known suicide risk factor-may aid in the detection of imminent suicide risk. This study examined sleep-related communication and texting patterns in personal text messages (N = 86,705) of suicide attempt survivors. METHOD: Twenty-six participants provided dates of past suicide attempts and 2-week periods of positive mood, depressed mood, or suicidal ideation. Linguistic Inquiry Word Count was used to identify sleep-related texts via a custom dictionary. Mixed effect models were fitted to test the association between suicide/mood episode type (e.g., attempt versus ideation) and three outcomes: likelihood of a text including sleep-related content, nightly count of texts sent from midnight to 5:00 AM, and sum of unique hour bins from midnight to 5:00 AM with outgoing texts. RESULTS: Analyses with a sleep dictionary that was manually revised to be more accurate (but not the original unedited dictionary) showed sleep-related communication was more likely during depressed mood episodes than positive mood episodes. Otherwise, there were no significant differences in sleep-related communication or objective texting patterns across episode type. CONCLUSIONS: Although we did not detect differences in sleep-related communication tied to suicidal thoughts or behaviors, sleep-related communication may differ as a function of within-person mood level.

Modeling the Interplay between HDV and HBV in Chronic HDV/HBV Patients.

Hepatitis D virus is an infectious subviral agent that can only propagate in people infected with hepatitis B virus. In this study, we modified and further developed a recent model for early hepatitis D virus and hepatitis B virus kinetics to better reproduce hepatitis D virus and hepatitis B virus kinetics measured in infected patients during anti-hepatitis D virus treatment. The analytical solutions were provided to highlight the new features of the modified model. The improved model offered significantly better prospects for modeling hepatitis D virus and hepatitis B virus interactions.