Gender differences in the relationships between meaning in life, mental health status and digital media use during Covid-19.

BACKGROUND: The COVID-19 pandemic has had a significant impact on individuals' social lives, mental health status, and meaning in life (MIL). Globally, the use of different types of digital media has become a proxy for pre-COVID social lives for many people. This study investigated gender differences in the relationship between use of digital media, mental health status and MIL, during COVID-19 in Hong Kong. METHODS: This cross-sectional study surveyed 1,488 young people recruited via city-wide random sampling in 2021. Respondents completed a phone survey on digital media use, Patient Health Questionnaire (PHQ-2), Generalized Anxiety Disorder (GAD-2), COVID-19 impact, meaning in life, and demographics. Gender differences in MIL were tested with an independent sample t-test. Gender-specific multiple linear regression models tested associations between MIL and explanatory variables of age, educational level, history of diagnosis, digital media use, and mental health status. RESULTS: There was a significant gender difference in MIL (males (M = 12.90, SD = 4.12); females (M = 13.45, SD = 3.96); t (1485) = -2.656, p = .008). For males, all variables significantly associated to MIL (F (9, 759) = 15.731, p < .000, R2 = .157). However, for females, while the overall model for MIL was significant (F (9, 709) = 12.105, p < .001, R2 = .133), the only significant associated variable was mental health status. CONCLUSION: Females had significantly better MIL under COVID-19 than males. Digital media use contributed to MIL in males but not females, and there were gender-specific associated factors of MIL.

A network approach to understand co-occurrence and relative importance of different reasons for suicide: a territory-wide study using 2002-2019 Hong Kong Coroner's Court reports.

Background: Suicide is a complex and multifaceted issue, and suicidal behaviors are often driven by multiple, interacting factors. It has been challenging to identify reasons for suicide using existing scientific methodologies. This study aims to identify critical reasons for suicide and suicidal behaviors through the application of novel network science methods. Methods: Based on cases investigated by the Hong Kong Coroner's Court from 2002 to 2019, we modelled identified reasons for 13,001 suicide cases as a co-occurrence network, and calculated each reason's eigencentrality to determine their respective relative importance. We then analyzed the temporal and demographic changes in the structure and eigencentrality of the network. We further conducted simulation studies based on the United Nations population projection to assess potential burden of different reasons for suicide on the population in the coming years. Findings: School-related issues had the highest eigencentrality (eigencentrality = 0.49) for individuals younger than 20 years of age. Financial issues were crucial for adults aged 20-59 years, but their importance differed between males (eigencentrality = 0.51) and females (eigencentrality = 0.14). Physical illness (eigencentrality = 0.80) was the core concern for adults over 60 years. Across the Hong Kong population, the reasons for suicide appear to have shifted from financial issues in the early 2000s (eigencentrality = 0.46) to issues related to physical illnesses since 2011 (eigencentrality = 0.58). Simulation findings indicate that, by 2050, most suicides in Hong Kong will be due to physical illness-related issues (eigencentrality = 0.69) due to the rapidly aging population. Interpretation: There have been important sex and age differences over time, in reasons for suicide. Given the projected increasing age of the Hong Kong population over the next decades, older adults with physical illnesses appear to be the highest contributors to suicide cases in the overall population. This novel network analysis approach provides important data-driven information upon which to base effective proactive public health suicide prevention strategies and interventions. Funding: Hong Kong Jockey Club Charities Trust, Collaborative Research Fund (C7151-20G), and General Research Fund (17606521).

Is internet gaming disorder associated with suicidal behaviors among the younger generation? Multiple logistic regressions on a large-scale purposive sampling survey.

The ubiquity of Internet gaming as part of the younger generation's (11-35 year-olds) lifestyle to-day warrants a deeper understanding of its impact on their mental health. In particular, there has been scant research investigating the link between Internet Gaming Disorder (IGD) and suicidal behaviors in this demographic group, even though several mental health symptoms of the former are known risk factors for the latter. This paper aims to establish the presence or absence of association between IGD and each of suicidal ideation, self-harm, and suicide attempt among the younger generation. A large-scale online survey on Internet gamers in Hong Kong was conducted in February 2019. 3430 respondents were recruited through purposive sampling. Study samples were stratified into distinct age groups and multiple logistic regression was conducted for each measured suicidal behavior in each age group. After controlling for sociodemographics, Internet usage, self-reported bullying perpetration and bullying victimization, social withdrawal, and self-reported psychiatric diagnoses such as depression and psychosis, analyses revealed that adolescent (11-17 year-old) gamers with IGD were more likely than their peers who had no IGD to have had suicidal ideation, self-harm, and suicide attempt in their lifetime. These associations did not hold for 18-35 year-old gamers. Findings suggest that it may be prudent to recognize IGD as a growing public mental health priority for the young populace, particularly adolescents. Existing suicide prevention efforts can be complemented through screening adolescents for IGD, and could be expanded to online gaming platforms to reach more hidden at-risk individuals.

Uncovering sample heterogeneity in gaming and social withdrawal behaviors in adolescent and young adult gamers in Hong Kong.

OBJECTIVE: The current study aimed to examine the latent heterogeneity of gaming and social withdrawal behaviors in internet gamers and their associations with help-seeking behaviors. METHOD: The present study recruited 3430 young people (1874 adolescents and 1556 young adults) in Hong Kong in 2019. The participants completed the Internet Gaming Disorder (IGD) Scale, Hikikomori Questionnaire, and measures on gaming characteristics, depression, help-seeking, and suicidality. Factor mixture analysis was used to classify the participants into latent classes based on their latent factors of IGD and hikikomori in separate age groups. Latent class regressions examined the associations between help-seeking and suicidality. RESULTS: Both adolescents and young adults supported a 4-class, 2-factor model on gaming and social withdrawal behaviors. Over two-third of the sample were classified as healthy or low-risk gamers with low IGD factor means and low prevalence of hikikomori. Around one-fourth was moderate-risk gamers with elevated prevalence of hikikomori, higher IGD symptoms and psychological distress. A minority of the sample (3.8%-5.8%) belonged to high-risk gamers with the highest IGD symptoms and prevalence of hikikomori and heightened suicidal risks. Help-seeking in low-risk and moderate-risk gamers was positively associated with depressive symptoms and negatively associated with suicidal ideation. Perceived usefulness of help-seeking was significantly linked with lower likelihoods of suicidal ideation in the moderate-risk gamers and suicide attempt in the high-risk gamers. CONCLUSIONS: The present findings explicate the latent heterogeneity of gaming and social withdrawal behaviors and associated factors on help-seeking and suicidality among internet gamers in Hong Kong.

Shifts in patterns of help-seeking during the COVID-19 pandemic: The case of Hong Kong's younger generation.

RATIONALE: Help-seeking can convert an individual's bonding social capital into social support, which has been shown to buffer the impact of psychological distress. The younger generation (individuals aged 15-35 years) have been the least likely to actively seek help despite facing a rising burden of mental health problems. COVID-19 pandemic restrictions may have altered their help-seeking behaviors, but the extent of such shift remains little understood, particularly in Asian contexts. OBJECTIVE: To understand how the younger generation's patterns of help-seeking (activation of different combinations of support sources) have shifted in pandemic times, who have experienced the shift, and what explanatory factors are involved. METHODS: Data were obtained from two waves (2019, 2020) of online survey responses by 438 community-dwelling younger generation people in Hong Kong, recruited through the authors' affiliated institutions and territory-wide community outreach organizations. Latent class analysis was conducted on participants' self-reported help-seeking behaviors in each survey wave. Constituents' characteristics in each latent class were examined, and between-wave changes in individuals' class membership were identified. Logistic regressions identified explanatory factors that significantly explained the changes. RESULTS: Three consistent patterns of help-seeking were identified in both survey waves. A major shift was observed for individuals with poorer mental health histories who faced moderate distress. They relied on their family, friends, and partner pre-pandemic, but no longer activated these supports during the pandemic. Posting status updates on social media, along with various communication habits and sociodemographic factors that differed by age group, were associated with this shift. CONCLUSIONS: Shifts in the younger generation's patterns of help-seeking may be an early warning signal to invest additional resources in facilitating help-seeking among the younger generation. Findings also serve as a reminder that public health restrictions may have inadvertent mental health implications that should be considered in future scenarios.

Liver Complications in Untreated Treatment-Ineligible versus Treated Treatment-Eligible Patients with Hepatitis B.

BACKGROUND: A substantial number of patients who do not meet treatment criteria for chronic hepatitis B (CHB) later develop adverse outcomes such as cirrhosis and hepatocellular carcinoma (HCC). Our aim was to determine whether current practice guidelines adequately identify CHB patients who will benefit from antiviral therapy. METHODS: We performed a retrospective cohort study comparing the incidence of adverse liver outcomes (cirrhosis and/or HCC) in untreated treatment-ineligible (at baseline and throughout follow-up) versus treated treatment-eligible patients according to standard American Association for the Study of Liver Diseases (AASLD) 2018 guidance (alanine aminotransferase [ALT] >70/50 U/L for men/women plus hepatitis B virus [HBV] DNA >20,000/2,000 IU/mL for HBeAg+/-) and with a sensitivity analyses using a lower threshold (ALT >40 U/L and HBV DNA >2,000 IU/mL). RESULTS: We reviewed records of 5,840 patients from 5 clinics in California and identified 2,987 treatment-naive non-HCC CHB patients. Of those, 271 patients remained untreated treatment-ineligible, 514 patients were treatment-eligible and initiated treatment, with 5-year cumulative adverse liver incidences of 12.5% versus 7.2%, p = 0.074. On multivariable analysis adjusting for age, sex, diabetes, albumin, platelet count, and HBV DNA, compared to treated treatment-eligible patients, untreated treatment-ineligible patients had a significantly higher risk of adverse liver outcomes (adjusted hazard ratio: 2.38, 95% confidence interval 1.03-5.48, p = 0.04) in main analysis by AASLD 2018 criteria but not in sensitivity analysis using the lower treatment threshold (p = 0.09). CONCLUSION: Patients never meeting standard AASLD 2018 criteria for antiviral therapy and never treated had twice the risk of developing cirrhosis and/or HCC when compared to eligible and treated patients.

Youth Bullying and Suicide: Risk and Protective Factor Profiles for Bullies, Victims, Bully-Victims and the Uninvolved.

Bullying is closely associated with suicide. This study validates mixed evidence on whether young bullies, victims, bully-victims, and those uninvolved in bullying differ in suicidality, risk, protective factor profiles, and predictors of suicide. A total of 2004 Hong Kong adolescents and young adults completed the Hong Kong Online Survey on Youth Mental Health and Internet Usage in 2018. Bullies, victims, and bully victims, as opposed to the uninvolved, were found to possess higher tendencies of suicidal thoughts and behaviors. They had more distinct rather than overlapping risk and protective factor profiles yet shared psychological distress and diagnosis of a psychiatric disorder as common predictors of suicide. The results indicate that suicide screening assessments and training to detect common suicide predictors can benefit youngsters regardless of their bullying involvement. From the discussion, group-specific interventions include restorative justice approaches to promote reintegration and help-seeking among bullies, peer, and professional support programs geared towards lowering victim isolation and equipping gatekeepers such as teachers with skills to connect with both bullies and victims.

An evaluation of the long-term sustainability of suicide prevention programs in an offshore Island.

INTRODUCTION: In 2002, a suicide prevention program for visitors was implemented in Cheung Chau, an offshore island with 21,000 residents and many visitors. This research revisited the intervention and evaluated its long-term effectiveness. Insights are provided into implementing a sustainable intervention. METHODS: Suicide death records (2007-2017) of Cheung Chau residents and visitors were retrieved. Information related to suicide method and sociodemographic characteristics of people who died by suicide were explored. Bivariate analyses were conducted to examine differences between visitors and residents; visitors and residents who died in Cheung Chau; and residents who died in or outside Cheung Chau. RESULTS: After post-implementation period, suicide rate for visitors and residents increased. Visitors were generally younger than the residents with a different distribution of type of housing. Most of the visitors killed themselves by charcoal burning, and nearly half of the residents used hanging. CONCLUSION: Long-term evaluation and monitoring of suicide prevention programs and sustained efforts are crucial to ensure program success. The prevention program in Cheung Chau was initially effective, but its long-term effects wore off. Both the mental health needs of visitors and residents should be addressed. Refinement of the current program and sustainable efforts are required for ensuring long-term success.

Demographic and epidemiological decomposition analysis of global changes in suicide rates and numbers over the period 1990-2019.

BACKGROUND: Suicide presents an ongoing public health challenge internationally. Nearly 800 000 people around the world lose their life to suicide every year, and many more attempt suicide. METHODS: A decomposition analysis was performed using global suicide mortality and population data from the Global Burden of Disease Study 2019. RESULTS: Despite a significant decrease in age-specific suicide rate between 1990 and 2019 (-4.01; from 13.8% to 9.8% per 100 000), the overall numbers of suicide deaths increased by 19 897 (from 738 799 to 758 696) in the same time period. The reductions in age-specific suicide rates (-6.09; 152%) contributed to the overall reductions in suicide rates; however, this was offset by overtime changes in population age structure (2.08; -52%). The increase in suicide numbers was partly attributable to population growth (300 942; 1512.5%) and population age structure (189 512; 952.4%), which was attenuated by the significant reduction in overall suicide rates (-470 556; 2364.9%). The combined effect of these factors varied across the World Bank income level regions. For example, in the upper-middle-income level region, the effect of the reduction in age-specific suicide rates (-289 731; -1456.1%) exceeded the effect of population age structure (124 577; 626.1%) and population growth (83 855; 421.4%), resulting in its substantial decline in total suicide deaths (-81 298; -408.6%). However, in lower-middle income region, there was a notable increase in suicide death (72 550; 364.6%), which was related to the net gain of the reduction in age-specific suicide rates (-115 577; -580.9%) and negated by the increase in the number of suicide deaths due to population growth (152 093; 764.4%) and population age structure (36 034; 181.1%). CONCLUSION: More support and resources should be deployed for suicide prevention to the low-income and middle-income regions in order to achieve the reduction goal. Moreover, suicide prevention among older adults is increasingly critical given the world's rapidly ageing populations in all income level regions.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase.

BACKGROUND & AIMS: Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk. METHODS: This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance. RESULTS: At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P < .0001) and adjusted hazard ratio for HCC of 14.1 (P = .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P = .005) was associated independently with HCC development. CONCLUSIONS: Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.

Who seeks help online? Comparing online and offline help-seeking preferences amongst youths with suicidal ideation.

BACKGROUND: Research consistently report an inverse relationship between suicide risk and help-seeking. The increasingly available internet-based support potentially offers an attractive alternative to traditional forms of assistance. The study compared the characteristics of suicidal youths in Hong Kong and their online and offline help-seeking behaviours. METHODS: Participants (N = 1214, age-range = 15-24 years) responded to the anonymous 2018 Hong Kong Online Survey on Youth Mental Health and Internet Usage. Respondents with suicidal thoughts were classified into those who sought help online and offline, or online only ("online-help"); those who sought help offline only ("offline-help"); and those who never sought help ("no-help"). They responded to questions concerning mental health, perception towards online support, internet use, help sources, and demographic information. RESULTS: The online-help group differed significantly from other groups, with greater suicidal ideation, distress, risk behaviours, and spent more time online for non-work-related purposes. Their perceived benefits of online support include anonymity, avoiding embarrassment, and social support. They are more likely to seek help from a combination of informal and formal sources. LIMITATIONS: No data on whether participants sought help online or offline first, and their current treatment status is available. Our study adopted conveniences sampling, and few respondents have sought help online exclusively. CONCLUSION: Online support offers an alternate way of engaging at-risk youths. Future clinical practice should consider online platforms as a complement, rather than a replacement, of offline platforms.

One-year Fibrosis-4 index helps identify minimal HCC risk in non-cirrhotic chronic hepatitis B patients with antiviral treatment.

BACKGROUND AND AIMS: Fibrosis-4 (FIB-4) index is a HCC predictor in chronic hepatitis B (CHB) patients. However, little is known about whether FIB-4 helps identify non-cirrhotic CHB patients with minimal HCC risk after prolonged nucleos(t)ide analogue (NA) therapy. METHODS: A total of 1936 ethnically diverse, non-cirrhotic CHB patients were enrolled in this retrospective multi-national study. All patients received prolonged NA treatment, including entecavir and tenofovir disoproxil fumarate. We explored whether FIB-4 cutoff of 1.30, a marker indicative of mild fibrosis severity, could stratify HCC risks in these patients. RESULTS: A total of 48 patients developed HCC after a mean follow-up of 6.98 years. FIB-4 level at 1 year after treatment (1-year FIB-4) was shown to be associated with HCC development and was superior to pre-treatment FIB-4 value. When patients were stratified by 1-year FIB-4 of 1.30, the high FIB-4 group was at an increased HCC risk compared to the low FIB-4 group, with a hazard ratio of 4.87 (95% confidence interval: 2.48-9.55). Multivariable analysis showed that sex and 1-year FIB-4 were independent predictors, with none of the 314 female patients with low 1-year FIB-4 developing HCC. Finally, 1-year FIB-4 of 1.30 consistently stratified HCC risks in patients with low PAGE-B score, a score composed of baseline age, sex and platelet count, and the annual incidence rate of HCC was 0.11% in those with PAGE-B < 10 + 1-year FIB-4 < 1.30. CONCLUSIONS: In non-cirrhotic CHB patients receiving prolonged NA therapy, 1-year FIB-4 < 1.30 is useful for identifying those with minimal HCC risk by combining with female sex or low PAGE-B score.

Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.

BACKGROUND: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. METHODS: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. RESULTS: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. CONCLUSION: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Development and Validation of a Risk Score for Liver Cirrhosis Prediction in Untreated and Treated Chronic Hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) can progress to cirrhosis, but there are limited noninvasive tools available to estimate cirrhosis risk, including in patients receiving antiviral therapy. This study developed and validated a simple model to assess risk in CHB patients. METHODS: The derivation cohort included 3000 CHB patients from 6 centers in the United States, with 52.60% receiving antiviral therapy. External validation was performed for 4552 CHB individuals from similar cohorts in Taiwan, with 21.27% receiving therapy. Cox proportional hazards regression analyses were used to screen predictors and develop the risk score for cirrhosis. Areas under receiver operating characteristic curves (AUROCs) were calculated for predictive value. RESULTS: Sex, age, diabetes, antiviral treatment status/duration, hepatitis B e-antigen, and baseline alanine aminotransferase/aspartate aminotransferase levels were significantly associated with increased cirrhosis risk. A 13-point risk score was developed based on these predictors. The AUROCs for predicting cirrhosis risk were 0.82 at 3 years, 0.85 at 5 years, and 0.89 at 10 years in the derivation cohort, and 0.82, 0.79, and 0.77 in the validation cohort, respectively. CONCLUSIONS: We developed and validated a simple cirrhosis prediction model with an independent external cohort that can be applied to both treatment-naive and treatment-experienced CHB patients in diverse settings and locations.

Association Between Fatty Liver and Cirrhosis, Hepatocellular Carcinoma, and Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) and fatty liver (FL) are common, natural history data on concurrent FL and CHB (FL-CHB) are limited. This study aimed to evaluate the effect of FL on cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance incidence in CHB patients. METHODS: In a retrospective cohort study of 6786 adult CHB patients, we used propensity score matching (PSM) to balance the FL-CHB and non-FL CHB groups. Kaplan-Meier methods were used to compare cumulative cirrhosis, HCC, and HBsAg seroclearance rates between subgroups. RESULTS: Before PSM, compared to non-FL CHB, FL-CHB patients had lower 10-year cumulative rates of cirrhosis, HCC, and a higher HBsAg seroclearance rate. Similar results were found in the matched FL-CHB and non-FL CHB patients, as well as in the antiviral-treated PSM cohort. Cox proportional hazards model indicated FL to remain significantly and strongly associated with lower risk of cirrhosis and HCC (hazard ratio [HR], 0.19 [95% confidence interval {CI}, .12-.33], P < .001 and HR, 0.21 [95% CI, .09-.51], P = .001, respectively) in antiviral-treated patients but not in untreated patients. CONCLUSIONS: FL was significantly associated with lower cirrhosis and HCC risk and higher HBsAg seroclearance. Further studies are needed to confirm our funding and investigate the mechanisms underlying the impact of FL on CHB.

Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism.

The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known as CD39, is highly expressed in the TME, both on infiltrating immune cells and tumor cells across a broad set of cancer indications. CD39 processes pro-inflammatory extracellular ATP to ADP and AMP, which is then processed by Ecto-5'-nucleotidase/CD73 to immunosuppressive adenosine. Directly inhibiting the enzymatic function of CD39 via an antibody has the potential to unleash an immune-mediated anti-tumor response via two mechanisms: 1) increasing the availability of immunostimulatory extracellular ATP released by damaged and/or dying cells, and 2) reducing the generation and accumulation of suppressive adenosine within the TME. Tizona Therapeutics has engineered a novel first-in-class fully human anti-CD39 antibody, TTX-030, that directly inhibits CD39 ATPase enzymatic function with sub-nanomolar potency. Further characterization of the mechanism of inhibition by TTX-030 using CD39+ human melanoma cell line SK-MEL-28 revealed an uncompetitive allosteric mechanism (α < 1). The uncompetitive mechanism of action enables TTX-030 to inhibit CD39 at the elevated ATP concentrations reported in the TME. Maximal inhibition of cellular CD39 ATPase velocity was 85%, which compares favorably to results reported for antibody inhibitors to other enzyme targets. The allosteric mechanism of TTX-030 was confirmed via mapping the epitope to a region of CD39 distant from its active site, which suggests possible models for how potent inhibition is achieved. In summary, TTX-030 is a potent allosteric inhibitor of CD39 ATPase activity that is currently being evaluated in clinical trials for cancer therapy.

Real-World Effectiveness From the Asia Pacific Rim Liver Consortium for HBV Risk Score for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Treated With Oral Antiviral Therapy.

BACKGROUND: Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS: Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score. RESULTS: A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001). CONCLUSIONS: The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.

Tenofovir Versus Entecavir for Hepatocellular Carcinoma Prevention in an International Consortium of Chronic Hepatitis B.

INTRODUCTION: It is unclear whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differ in their effectiveness for preventing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: This retrospective cohort study analyzed an international consortium that encompassed 19 centers from 6 countries or regions composed of previously untreated CHB patients then treated with either ETV or TDF monotherapy. Those who developed HCC before antiviral treatment or within 1 year of therapy were excluded. The association between antiviral regimen and HCC risk was evaluated using competing-risk survival regression. We also applied propensity score matching (PSM) to 1:1 balance the 2 treatment cohorts. A total of 5,537 patients were eligible (n = 4,837 received ETV and n = 700 received TDF) and observed for HCC occurrence until December 23, 2018. Before PSM, the TDF cohort was significantly younger and had generally less advanced diseases. RESULTS: In the unadjusted analysis, TDF was associated with a lower risk of HCC (subdistribution hazard ratio [SHR], 0.45; 95% confidence interval [CI], 0.26-0.79; P = 0.005). The multivariable analysis, however, found that the association between TDF and HCC no longer existed (SHR, 0.81; 95% CI, 0.42-1.56; P = 0.52) after adjustment for age, sex, country, albumin, platelet, α-fetoprotein, cirrhosis, and diabetes mellitus. Furthermore, the PSM analysis (n = 1,040) found no between-cohort differences in HCC incidences (P = 0.51) and no association between regimens (TDF or ETV) and HCC risk in the multivariable-adjusted analysis (adjusted SHR, 0.89; 95% CI, 0.41-1.92; P = 0.77). DISCUSSION: TDF and ETV did not significantly differ in the prevention of HCC in patients with CHB.

Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity.

We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specific T-cell transfer. SIGNIFICANCE: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-inflammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer.This article is highlighted in the In This Issue feature, p. 1631.