In chronic hepatitis B (CHB), an indeterminate phase exists outside the typical predefined phases. Our study investigates this indeterminate phase's natural history and prognosis, focusing on antiviral treatment outcomes.

We conducted a retrospective cohort study to compare the risk of transitioning to immune active phase between inactive and indeterminate CHB and the incidence of hepatocellular carcinoma (HCC) and cirrhosis between untreated patients with indeterminate CHB (at baseline and throughout follow-up) and those who received treatment, following standard AASLD 2018 guidance.

The risk of transitioning to the immune active phase over 3, 5, and 10 years was 6.3%, 8.9%, and 14.2%, respectively, for inactive phase patients (n = 104). For HBeAg-negative indeterminate phase patients (n = 194), the risk was significantly higher at 23.0%, 31.9%, and 38.2%, and for HBeAg-positive indeterminate phase patients (n = 140), it was 40.4%, 52.0%, and 55.0% (p < 0.001). Inverse probability of treatment weighting (IPTW) was utilized to balance the groups of treated and untreated indeterminate patients. Following IPTW adjustment, the Kaplan-Meier curve analysis indicates that the risk of HCC and cirrhosis among untreated patients (n = 294) is higher than that among treated patients (n = 76), (p = 0.015 and 0.007, respectively). In the multivariable analysis, antiviral therapy remained an independent predictor of a reduced risk of HCC (aHR 0.128, 95% CI 0.031-0.522, p = 0.005) and cirrhosis (aHR 0.148, 95% CI 0.044-0.496, p = 0.002).

The indeterminate phase patients had a high-risk transition to active phase, and antiviral therapy can reduce the incidence of developing HCC and cirrhosis.

Non-hypervascular hypointense nodules (NHHNs) can transform into hypervascular hepatocellular carcinoma (HCC) during the long-term follow-up. However, the risk factors for NHHN hypervascular transformation in chronic hepatitis B virus (HBV)-infected populations are unknown. This study assessed the predictive value of gadoxetic acid-enhanced magnetic resonance imaging (MRI) for HCC development in patients with chronic HBV infection.

A total of 86 patients with HBV infection who underwent gadoxetic acid-enhanced MRI at the First Affiliated Hospital of Sun Yat-sen University between January 2011 and July 2019 and were followed up for 2 years were retrospectively reviewed. Imaging features, including cirrhosis, steatosis, and NHHNs, were collected. Radiomics features were extracted from the entire liver. The HCC development predictive models were built based on each patient's clinical data, MRI features, and radiomic features. We then collected the qualitative and quantitative features of each NHHN and investigated the risk factors of hypervascular transformation.

Thirteen patients developed HCC within two years. The risk factors for HCC development in patients with chronic HBV infection included older age, cirrhosis, and NHHNs. The MRI, radiomics, and integrated models developed all had an area under the curve (AUC) above 0.8. The potential risk factors for hypervascular transformation of NHHNs were the diameter of the NHHN (OR = 1.69, 95% CI:1.23, 2.32, P = 0.001) and the signal intensity (SI) ratio of the NHHN to the liver in the hepatobiliary phase (HBP SI ratio*10, OR = 0.36, 95% CI:0.11, 0.85, P = 0.044). The AUC of the hypervascular transformation model was 0.846 (95% CI:0.719, 0.972).

In chronic HBV infection population, patients with older age, cirrhosis and NHHNs are more likely to develop HCC within two years. Models based on these factors or radiomic features can effectively predict HCC development. The diameter of the NHHNs and the signal intensity ratio of NHHN to the liver in the hepatobiliary phase are potential risk factors for the hypervascular transformation of NHHNs.

We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation.

From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors.

We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy.

The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients.

HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy.

To evaluate the use of serum biomarkers to predict HBeAg loss.

HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated.

HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm.

Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon.

We set out to characterise chronic hepatitis B (CHB) in the primary care population in England and investigate risk factors for progression to hepatocellular carcinoma (HCC).

Retrospective cohort study.

We identified 8039 individuals with CHB in individuals aged ≥18 years between 1999 and 2019 in the English primary care database QResearch. HCC risk factors were investigated using Cox proportional hazards modelling.

Most of those with a record of CHB were males (60%) of non-White ethnicity (>70%), and a high proportion were in the most deprived Townsend deprivation quintile (44%). Among 7029 individuals with longitudinal data, 161 HCC cases occurred. Increased HCC hazards were significantly associated with male sex (adjusted hazards ratio [aHR] 3.17, 95% confidence interval [95% CI] 1.92-5.23), in the fifth deprivation quintile as compared to the third quintile (aHR 1.69, 95% CI 1.01-2.84), with older age (for age groups 56-65 and ≥66 years, compared to 26-35 years, aHRs 2.82 [95% CI 1.45-5.46] and 3.76 [95% CI 1.79-7.9], respectively), Caribbean ethnicity (aHR 3.32, 95% CI 1.43-7.71, compared to White ethnicity), ascites (aHR 3.15, 95% CI 1.30-7.67), cirrhosis (aHR 6.55, 95% CI 4.57-9.38) and peptic ulcer disease (aHR 2.26, 95% CI 1.45-3.51).

Targeting interventions and HCC surveillance at vulnerable groups is essential to improve CHB outcomes and to support progress towards international goals for the elimination of hepatitis infection as a public health threat.

Patients with chronic hepatitis B (CHB) are regularly monitored for HBV DNA and liver enzymes in order to assess disease progression and the need for antiviral therapy. Identifying patients with a stable course of disease can potentially prolong the intervals between visits, withhold unnecessary tests and save money. Accordingly, we aimed to find predictors for a stable disease course in patients with CHB. 579 patients with CHB, who were followed in a tertiary referral center between January 2004-December 2018, were retrospectively analyzed. Patients with low and steady viral load titer (< 2000 IU/ml) and normal ALT levels (< 40 IU/ml) in 6 consecutive clinic encounters were considered to have a stable course of CHB. A stepwise multivariate logistic regression analysis and a decision tree model were used to identify predictors of a stable disease course. Following exclusion of ineligible patients, a total of 220 patients were included in the final analysis. 64/220 patients had a stable disease course. Patients with a stable disease were older (62.99 ± 12.36 Vs. 54.07 ± 13.64, p < 0.001) with a higher percentage of women (53% vs. 38%) and had lower baseline levels of AST, ALT and viral load (VL). In a multivariate analysis, age (OR 0.94, 95% CI 0.91-0.98), baseline ALT (OR 1.06, 95% CI 1.01-1.1) and VL (OR 1.05 95% CI 1.02-1.08), were significantly associated with a stable disease. In a decision tree model, patients 46-67 years old, with baseline VL < 149 IU/mL and ALT < 40 IU/mL had the best probability (91%) for a stable disease course over 4.4 ± 2.2 years. We conclude that integrating patients' age with baseline VL and ALT can predict a stable disease course in patients with CHB off treatment.

HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase.

We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log 10 IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively ( p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase

CONCLUSIONS

Antiviral therapy reduces HCC risk by 70% among patients with indeterminate-phase CHB. These data have important implications for the potential expansion of CHB treatment criteria.

Collapse

The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019.

We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology.

In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8).

The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males.

The number of patients with fatty liver has been increasing worldwide; however, the significance of fatty liver in patients with chronic hepatitis B who are receiving nucleic acid analog (NA) therapy remains unclear. Thus, we aimed to determine whether fatty liver affects the development of hepatocellular carcinoma (HCC) in patients receiving NA therapy. This study included 445 patients who received NA therapy, and the development of HCC was investigated. The primary outcome was the association between fatty liver and HCC development. During a mean follow-up period of 7.4 years, 46 patients (10.3%) developed HCC. No significant difference in the cumulative incidence of HCC was observed between patients with fatty liver and those without (p = 0.17). Multivariable analysis for age, gender, platelet count, alanine aminotransferase level at 1 year following NA therapy, and fatty liver revealed that the presence of fatty liver was not a significant factor for HCC development (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.5-1.9). In another multivariable analysis for advanced fibrosis, gender, and fatty liver, advanced fibrosis was found to be a significant factor for HCC development (HR: 9.50, 95% CI: 5.1-18) but not fatty liver (HR: 0.90, 95% CI: 0.5-1.7). In conclusion, in patients with chronic hepatitis B who received NA therapy, advanced fibrosis was found to be an important risk factor for HCC development but not fatty liver, suggesting the importance of providing treatment before the progression of liver fibrosis regardless of the presence of fatty liver.

The etiology of liver diseases has changed in recent years, but its impact on the comparative burden of liver cancer between males and females is unclear. We estimated sex differences in the burden of liver cancer across 204 countries and territories from 2010 to 2019.

We analyzed temporal trends in the burden of liver cancer using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of liver cancer incidence, death, and disability-adjusted life-years (DALYs) by sex, country, region, and etiology of liver disease. Globally in 2019, the frequency of incident cases, deaths, and DALYs due to liver cancer were 376,483, 333,672, and 9,048,723 in males, versus 157,881, 150,904, and 3,479,699 in females. From 2010 to 2019, the incidence ASRs in males increased while death and DALY ASRs remained stable; incidence, death, and DALY ASRs in females decreased. Death ASRs for both sexes increased only in the Americas and remained stable or declined in remaining regions. In 2019, hepatitis B was the leading cause of liver cancer death in males, and hepatitis C in females. From 2010 to 2019, NASH had the fastest growing death ASRs in males and females. The ratio of female-to-male death ASRs in 2019 was lowest in hepatitis B (0.2) and highest in NASH (0.9).

The overall burden of liver cancer is higher in males, although incidence and death ASRs from NASH-associated liver cancer in females approach that of males.

With the improved efficacy and accessibility of antiviral agents as well as the concerns about disease progression, there is a hot discussion on whether HBeAg-negative chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and positive HBV DNA should be treated. According to the international guidelines on the stages of the natural history of HBV infection, HBeAg-negative CHB patients with normal ALT and positive HBV DNA can be divided into two groups: one is the well-known "inactive carrier phase", which is defined as serum HBV DNA < 2000 IU/ml and no significant liver inflammation; and the other is the "indeterminate phase", which is defined as serum HBV DNA ≥ 2000 IU/mL regardless of the pathological changes in liver tissue, or HBV DNA < 2000 IU/mL but accompanied by significant pathological changes in the liver. In this minireview, we will expound the disease characteristics, disease progression, and clinical management status of these two groups. Based on the analysis, we propose that HBeAg-negative patients with normal ALT but detectable serum HBV DNA should be treated, regardless of their age, family history of hepatocellular carcinoma (HCC) or the severity of liver necroinflammation. Expanding the indications of antiviral therapy will help improve the survival and quality of life of patients by preventing disease progression, and consequently reduce the risk of HCC development.

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.

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.

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.

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.

Liver cancer epidemiology is changing due to increasing alcohol consumption, rising prevalence of obesity, and advances in hepatitis B virus (HBV) and hepatitis C virus (HCV) treatment. However, the impact of these changes on global liver cancer burden remains unclear. We estimated global and regional temporal trends in the burden of liver cancer and the contributions of various liver disease etiologies using the methodology framework of the Global Burden of Disease study. Between 2010 and 2019, there was a 25% increase in liver cancer deaths. Age-standardized death rates (ASDRs) increased only in the Americas and remained stable or fell in all other regions. Between 2010 and 2019, non-alcoholic steatohepatitis (NASH) and alcohol had the fastest growing ASDRs, while HCV and HBV declined. Urgent measures are required at a global level to tackle underlying metabolic risk factors and slow the growing burden of NASH-associated liver cancer, especially in the Americas.

Conventional meta-analyses with aggregated study-level data have yielded conflicting results for the comparative effectiveness of tenofovir disoproxil fumarate vs entecavir in reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis B virus. Within-study heterogeneity, between-study heterogeneity, and the inability of conventional meta-analyses to capture time-to-event data were associated with these results.

To perform a reconstructed individual patient data meta-analysis of high-quality propensity score-matched studies to provide robust estimates for comparative HCC risk between groups receiving tenofovir or entecavir.

Medline and Embase databases were searched from inception to October 6, 2021.

The initial search yielded 3435 articles. Fourteen studies that used propensity score matching to balance baseline characteristics were included in the final analysis.

The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Individual patient data were reconstructed from Kaplan-Meier curves. Risk of HCC was evaluated using random-effects hazard ratios (HRs) via a shared-frailty model and a Cox proportional hazards model stratified by study group. Restricted mean survival time (RMST) analysis was conducted to account for varying estimated treatment effect across time.

The comparative risk of HCC with tenofovir vs entecavir treatment.

From analysis of 14 studes with 24 269 patients (10 534 receiving tenofovir and 13 735 receiving entecavir; mean age, 49.86 [95% CI, 48.35-51.36] years; 65.05% [95% CI, 58.60%-71.00%] men), tenofovir was associated with decreased HCC incidence compared with entecavir (stratified Cox HR, 0.85 [95% CI, 0.76-0.94] at 5 years; P = .002). However, there was no significant difference in subanalysis of clinical cohort studies (stratified Cox HR, 0.92 [95% CI, 0.80-1.06] at 5 years; P = .24). Among administrative database studies, proportionality was violated, and HRs could not be obtained via Cox proporational hazards-based models. The mean time to HCC development in RMST analysis was 2.8 (95% CI, 1.8-3.7) weeks longer (P < .001) for tenofovir vs entecavir at 5 years. The RMST analyses for other subgroups revealed either insignificant or minimal differences (<3 weeks) in the mean time to HCC at 5 years.

In this meta-analysis, there was no clinically meaningful difference in the risk of HCC between patients who received entecavir and patients who received tenofovir. There was no difference between tenofovir and entecavir among clinical cohort studies, whereas the mean time to HCC development was less than 3 weeks longer for patients who received tenofovir vs those who received entecavir at year 5 among administrative database studies. The choice between tenofovir or entecavir should be decided based on patient convenience and tolerability.

Outcomes after liver resection (LR) and liver transplantation (LT) for hepatocellular carcinoma (HCC) are heterogenous and may vary by region, over time periods and disease burden. We aimed to compare overall survival (OS) and disease-free survival (DFS) between LT versus LR for HCC within the Milan criteria.

Two authors independently searched Medline and Embase databases for studies comparing survival after LT and LR for patients with HCC meeting the Milan criteria. Meta-analyses and metaregression were conducted using random-effects models.

We screened 2,278 studies and included 35 studies with 18,421 patients. LR was associated with poorer OS [hazard ratio (HR) =1.44; 95% confidence interval (CI): 1.14-1.81; P<0.01] and DFS (HR =2.71; 95% CI: 2.23-3.28; P<0.01) compared to LT, with similar findings among intention-to-treat (ITT) studies. In uninodular disease, OS in LR was comparable to LT (P=0.13) but DFS remained poorer (HR =2.95; 95% CI: 2.30-3.79; P<0.01). By region, LR had poorer OS versus LT in North America and Europe (P≤0.01), but not Asia (P=0.25). LR had inferior survival versus LT in studies completed before 2010 (P=0.01), but not after 2010 (P=0.12). Cohorts that underwent enhanced surveillance had comparable OS after LT and LR (P=0.33), but cohorts undergoing usual surveillance had worse OS after LR (HR =1.95; 95% CI: 1.24-3.07; P<0.01).

Mortality after LR for HCC is nearly 50% higher compared to LT. Survival between LR and LT were similar in uninodular disease. The risk of recurrence after LR is threefold that of LT.

Sarcopenia and frailty influence clinical patients' outcomes. Low alanine aminotransferase (ALT) serum activity is a surrogate marker for sarcopenia and frailty. In-hospital hypoglycemia is associated, also with worse clinical outcomes.

We evaluated the association between low ALT, risk of in-hospital hypoglycemia and subsequent mortality.

This was a retrospective cohort analysis.

We included patients hospitalized in a tertiary hospital between 2007 and 2019. Patients' data were retrieved from their electronic medical records.

The cohort included 51 831 patients (average age 70.88). The rate of hypoglycemia was 10.8% (amongst diabetics 19.4% whereas in non-diabetics 8.3%). The rate of hypoglycemia was higher amongst patients with ALT < 10 IU/l in the whole cohort (14.3% vs. 10.4%, P < 0.001) as well as amongst diabetics (24.6% vs. 18.8%, P < 0.001). Both the overall and in-hospital mortality were higher in the low ALT group (57.7% vs. 39.1% P < 0.001 and 4.3% vs. 3.2%, P < 0.001). A propensity score matching, after which a regression model was performed, showed that patients with ALT levels < 10 IU/l had higher risk of overall mortality (HR = 1.21, CI 1.13-1.29, P < 0.001).

Low ALT values amongst hospitalized patients are associated with increased risk of in-hospital hypoglycemia and overall mortality.

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Chronic hepatitis B virus (HBV) infection is a global healthcare burden in the form of chronic liver disease, cirrhosis, liver failure and liver cancer. There is no definite cure for the virus and even though extensive vaccination programs have reduced the burden of liver disease in the future population, treatment options to eradicate the virus from the host are still lacking. In this review, we discuss in detail current updates on the structure and applied biology of the virus in the host, examine updates to current treatment and explore novel and state-of-the-art therapeutics in the pipeline for management of chronic HBV. Furthermore, we also specifically review clinical updates on HBV-related acute on chronic liver failure (ACLF). Current treatments for chronic HBV infection have seen important updates in the form of considerations for treating patients in the immune tolerant phase and some clarity on end points for treatment and decisions on finite therapy with nucleos(t)ide inhibitors. Ongoing cutting-edge research on HBV biology has helped us identify novel target areas in the life cycle of the virus for application of new therapeutics. Due to improvements in the area of genomics, the hope for therapeutic vaccines, vector-based treatments and focused management aimed at targeting host integration of the virus and thereby a total cure could become a reality in the near future. Newer clinical prognostic tools have improved our understanding of timing of specific treatment options for the catastrophic syndrome of ACLF secondary to reactivation of HBV. In this review, we discuss in detail pertinent updates regarding virus biology and novel therapeutic targets with special focus on the appraisal of prognostic scores and treatment options in HBV-related ACLF.

Hepatitis B virus (HBV) infects the liver, causing cirrhosis and cancer. In developed countries, five international guidelines have been used to make a decision for the management of patients with chronic HBV infection. In this review, since the guidelines were established by clinical and epidemiological data of developed countries, we aimed to evaluate whether (1) HBV patient profiles of developing countries are similar to developed countries, and (2) which guideline can be applicable to resource-limited developing countries. First, as an example of the most recent data of HBV infections among developing countries, we evaluated the national HBV viral load study in Nepal, which were compared with the data from other developing countries. In Nepal, the highest number of patients had viral loads of 20-2000 IU/mL (36.7%) and belonged to the age group of 21-30 years; HBV epidemiology in Nepal, based on the viral loads, gender, and age groups was similar to those of not only other developing countries but also developed countries. Next, we reviewed five international HBV treatment guidelines of the World Health Organization (WHO), American Association for the Study of Liver Diseases (AASLD), National Institute for Health and Care Excellence (NICE), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). All guidelines require the viral load and alanine aminotransferase (ALT) levels for decision making. Although four guidelines recommend elastography to assess liver cirrhosis, the WHO guideline alternatively recommends using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), which is inexpensive and conducted routinely in most hospitals. Therefore, in resource-limited developing countries like Nepal, we recommend the WHO guideline for HBV treatment based on the viral load, ALT, and APRI information.