Search

We report the case of a 76-year-old man who was diagnosed with advanced stage hepatocellular carcinoma and was treated with atezolizumab plus bevacizumab therapy. Two weeks after 1st dose, he presented with acute changes in consciousness followed by hypothermia. A cerebrospinal fluid test showed an elevated cell count, total protein, and albumin. Infectious, anatomical, endocrinal, and neoplastic etiologies were ruled out. Based on the findings, atezolizumab-induced encephalitis was suspected, and high dose steroid therapy was administered. The patient's conscious level and hypothermia recovered completely about 9 days after starting the steroids, and he recovered without any neurological sequelae. This case report reminds physicians that prompt administration of steroid treatment after early diagnosis of immune checkpoint inhibitor-related encephalitis is the key for patients to recover without apparent neurological sequelae. [ABSTRACT FROM AUTHOR]

Hepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear. Patients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups. From 2006 to 2021, 4084 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n = 887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n = 3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR], 1.43; 95% confidence interval [CI], 1.10–1.85; P =.007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR, 1.37; 95% CI, 1.00–1.86; P =.049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virologic profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR, 1.41; 95% CI, 1.09–1.84; P =.010). In untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB. [Display omitted] [ABSTRACT FROM AUTHOR]

Background& Aims: Pathologic data of non-alcoholic fatty liver disease (NAFLD) was limited and the association between NAFLD and chronic hepatitis B remained unclear in Taiwan. This study aimed to determine the pathological manifestations of NAFLD and the impact of concurrent hepatitis B virus (HBV) infection in a medical center.Methods: Retrospective review of 104 consecutive random liver biopsies with the histologic diagnosis of NAFLD or cryptogenic cirrhosis from 2009 to 2018 was conducted. Clinical, biochemical and histological data were compared among various stages of NAFLD and between those with or without concurrent HBV infection.Results: Advanced fibrosis was documented in 39.42% of Taiwanese patients with NAFLD according to METAVIR scoring system and was associated with aging (odds ratio, 1.06; 95% CI, 1.03-1.10), hypertension (odds ratio, 2.97; 95% CI, 1.31-6.74), diabetes mellitus (odds ratio, 4.36; 95% CI, 1.78-10.70) and concurrent HBV infection (odds ratio, 3.55; 95% CI, 1.46-8.58) by multivariate analyses. Concurrent HBV was found in 28.57% of the NAFLD patients. Patients with concurrent HBV had lower platelet counts, longer prothrombin time/INR and higher fibrosis stage than those without CHB.Conclusion: Advanced fibrosis in patients with NAFLD was common in the biopsy series, and was related to aging, hypertension, diabetes mellitus and concurrent HBV infection. [ABSTRACT FROM AUTHOR]

Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC). Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion. In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p <0.001). In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis. The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B. • Acute HEV superinfection was associated with a 1-year mortality rate of 2.4% in non-cirrhotic patients with chronic HBV infection. • The 1-year mortality rate increased to 35.7% in patients with compensated liver cirrhosis after HEV superinfection. • HEV superinfection increased the long-term risk of cirrhosis, HCC, and liver-related death in patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background: Mongolia has the highest prevalence of hepatitis C virus (HCV) infection worldwide. Ledipasvir/sofosbuvir (LDV/SOF) was introduced to Mongolia since 2016 for HCV eradication. It has been reported that HCV resistance-associated substitutions (RASs) would affect the effectiveness of LDV/SOF in western chronic hepatitis C (CHC) patients. We thus investigated the effectiveness of LDV/SOF and the impact of RAS on the treatment outcome in Mongolian CHC patients.Methods: Patients with genotype (GT) 1b HCV infection were prospectively enrolled in Mongolia and treated with LDV/SOF for 12 weeks. The proportion of pre-treatment NS5A Y93H RAS in viral quasispecies was measured with next-generation sequencing. The endpoint of LDV/SOF effectiveness was sustained virological response at post-treatment week 12 (SVR12).Results: A total of 94 CHC patients were evaluated. The baseline Y93H proportion was <1% in 74 patients, 1-15% in 7, 15-50% in 2, and ≥50% in 11. All patients completed 12-week LDV/SOF treatment and the SVR rate was 90.4%. The rate of failure to achieve SVR12 for patients with Y93H < 1%, 1-15%, and ≥15% were 0%, 14.3%, and 61.5%, respectively (p for trend = 0.001). In univariable analysis, older age, baseline alanine transaminase level <40 U/mL, and a higher proportion of Y93H were associated with treatment failure. In multivariable analysis, only a higher proportion of Y93H was associated with treatment failure (p = 0.022).Conclusion: LDV/SOF therapy achieves a high SVR rate in Mongolian CHC GT1b patients without baseline Y93H RAS. A higher proportion of Y93H may severely undermine the effectiveness of LDV/SOF. [ABSTRACT FROM AUTHOR]

Background/purpose: The predictors of off-therapy response in patients treated with neucleos(t)ide analogue (NA) have not been elucidated. It remained unexplored whether serum level of hepatitis B core antibody (anti-HBc) at the end of NA therapy was associated with relapse risks.Methods: This prospective study monitored 82 chronic hepatitis B (CHB) patients after discontinuing entecavir. All patients had been treated for 3 years or longer and serologically negative for viral DNA and HBeAg at treatment cessation. Patients were monitored for virological relapse (viral DNA > 2000 IU/mL), and clinical relapse (serum alanine aminotransferase > 80 U/L plus virological relapse). The association between anti-HBc levels and the risk of relapse was assessed by the Cox analysis.Results: Clinical and virological relapses occurred in 29 and 60 participants, respectively, with the cumulative incidences of 23.7% (95% CI, 15.8-34.6%) and 62.0% (95% CI, 51.5-72.5%) at 1 year, and 36.2% (95% CI, 26.2-48.4%) and 78.8% (95% CI, 68.2-87.8%) at 2 years, respectively. There was a trend for an inverse association between anti-HBc and clinical relapse (crude hazard ratio [HR], 0.50; 95% CI, 0.24-1.05). All 3 patients with the level <100 IU/mL had a rapid clinical relapse (P = 0.002). This trend remained after adjustment for HBsAg and age (adjusted HR 0.50, 95% CI, 0.24-1.03). On the other hand, anti-HBc quantity was unrelated to virological relapse (crude HR, 0.97; 95% CI, 0.58-1.62; adjusted HR, 0.97; 95% CI, 0.58-1.60).Conclusion: This pilot study suggests a trend for an inverse association between anti-HBc levels and clinical relapse in CHB patients off entecavir. [ABSTRACT FROM AUTHOR]

Seroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core–related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg. We conducted a retrospective cohort study including 2614 treatment-naïve patients with chronic HBV infection who received long-term follow-up at the National Taiwan University Hospital. The primary end point was spontaneous HBsAg seroclearance. We aimed to explore whether HBcrAg levels could predict HBsAg seroclearance, especially for patients with HBsAg levels >1000 IU/mL. There were 465 patients who cleared HBsAg with 32,414.72 person-years of follow-up, with a mean clearance rate of 1.43% per year. We found that lower HBcrAg levels at baseline were associated with an increased likelihood of HBsAg seroclearance (log rank P <.001). When restricting the study population to 1539 patients with HBsAg levels >1000 IU/mL, only HBcrAg <10,000 U/mL (vs ≥100,000 U/mL) served as an independent viral predictor for HBsAg seroclearance, with adjusted hazard ratio of 1.95 (95% CI, 1.16–3.27). In contrast to the late decline of HBsAg levels (5–9 years before HBsAg seroclearance), HBcrAg levels became undetectable 10–14 years before HBsAg seroclearance. This finding was confirmed by the different annual HBsAg seroclearance rates in the first and second decades of follow-up (0.97% vs 3.75%; P <.001) in patients achieving undetectable HBcrAg levels. Lower serum HBcrAg levels were associated with increased probability of HBsAg seroclearance over time. In patients with HBsAg levels >1000 IU/mL, clearing HBcrAg may serve as an early biomarker for HBsAg seroclearance. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/purpose: Occult hepatitis B infection (OHB) is not rare in countries that are endemic for hepatitis B virus (HBV) and in patients with chronic hepatitis C virus (HCV) infection. Notably, OHB has been shown to play a role in the progression of liver diseases, including the development of hepatocellular carcinoma (HCC); however, the data is inconsistent. We aim to clarify the contribution of concurrent OHB to the progression of liver diseases in a long-term cohort of patients with HCV infection and to investigate the value of total anti-hepatitis B core (anti-HBc) antibody as a surrogate OHB biomarker.Methods: We included 250 chronic anti-HCV-positive patients who had resolved HBV infection (anti-HBc positive and hepatitis B surface antigen negative). OHB was then detected using a sensitive commercial assay for serum HBV DNA with a low limit of detection of 6 IU/mL. Clinical outcomes, including the development of liver cirrhosis, HCC, and all-cause deaths, were compared between OHB-positive and OHB-negative patients.Results: At baseline, only 183 (73.20%) patients had positive HCV ribonucleic acid, and 56 (30.60%) of these 183 patients with active HCV infection had OHB. The presence of OHB did not correlate with any adverse clinical outcome in multivariate analyses. In addition, chronic hepatitis C patients with OHB did not have a higher level of serum total anti-HBc.Conclusion: OHB infection may not contribute to the development of adverse liver outcomes in patients with chronic HCV. [ABSTRACT FROM AUTHOR]

Data regarding the long-term evolution of estimated glomerular filtration rate (eGFR) in patients receiving antiviral treatment for hepatitis C virus are limited. A total of 1987 patients with eGFR ≥15 mL/min/1.73m2 who received interferon or direct-acting antiviral treatment were prospectively enrolled in this cohort study. The eGFR was assessed biannually by the Chronic Kidney Disease Epidemiology Collaboration equation from the time point of sustained virologic response (SVR 12). Multivariate generalized estimated equation was used to assess the association between the factors of interest and evolution of eGFR following antiviral treatment. Multivariate Cox regression analysis was used to assess the relative risk of end-stage renal disease (ESRD), defined as an eGFR <15 mL/min/1.73m2. Patients who achieved SVR 12 (adjusted slope coefficient difference: 2.36 mL/min/1.73 m2/year; 95% confidence interval [CI], 1.50 to 3.32; P <.001) were associated with eGFR improvement, compared with those who did not achieve SVR 12. Among patients who achieved SVR 12 , the eGFR evolution was comparable (adjusted slope coefficient difference: 0.31 mL/min/1.73m2/year; 95% CI, −0.34 to 0.96; P =.35) in those treated with interferon or direct-acting antiviral. The incidence rates of ESRD in patients who achieved and did not achieve SVR 12 were 0.06 per 100 person-years and 0.37 per 100 person-years. Patients who achieved SVR 12 were associated with a lower risk of ESRD (adjusted hazard ratio, 0.24; 95% CI, 0.05–0.68; P =.021). The long-term eGFR evolution and risk of ESRD are significantly improved in patients who achieve SVR 12 with anti- hepatitis C virus treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/purpose: Clinical implications of IL28B gene in Taiwanese chronic hepatitis C (CHC) patients remain unknown. We thus investigated the prevalence and clinical implications of IL28B rs8099917 genotypes in CHC patients with different hepatitis C virus (HCV) genotypes and healthy controls.Methods: A total of 200 HCV genotype 1 patients and 200 HCV genotype 2 patients who received liver biopsy, as well as 197 healthy controls were enrolled to determine the frequencies of IL28B rs8099917 genotypes. In addition, the association of IL28B rs8099917 genotype with baseline data, including HCV RNA level, HCV genotype, histological activity grade, fibrosis stage, and body mass index, were evaluated and further stratified by covariant factors.Results: Compared with healthy controls, CHC patients had a lower prevalence rate of favorable IL28B rs8099917 TT genotype (81.0% vs. 89.3%, p = 0.025). In addition, the prevalence rates of favorable TT genotype in patients with HCV genotypes 1 and 2 were 76.0% and 86.0%, respectively (p = 0.007). Using ordered logistic regression analysis, higher fibrosis stages were found to be associated with a lower prevalence of TT genotype (p = 0.033), but not histological activity grades (p = 0.748). The association with fibrosis stages was more pronounced in female patients (p = 0.024).Conclusion: In Taiwan, CHC patients have a lower frequency of favorable IL28B TT genotype than healthy controls. Among patients with CHC, the frequency of TT genotype is higher in HCV genotype 2 patients than in HCV genotype 1 patients. In addition, CHC patients with TT genotype, particularly females, have a lower likelihood of advanced fibrosis. [ABSTRACT FROM AUTHOR]

Dual hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is not rare in HBV or HCV endemic areas, and can be found in populations at risk of parenteral viral transmission. Clinical observatory studies suggest a higher risk of liver disease progression in patients with dual HCV/HBV infection than in HBV or HCV monoinfected patients. Recent trials confirmed that combination therapy of peginterferon alfa-2a or alfa-2b and ribavirin was effective and safe in dually infected patients with positive HCV RNA. Moreover, about 30% of the dually infected patients cleared hepatitis B surface antigen within 5 years after the start of peginterferon-based therapy. The optimal treatment strategies for dually infected patients with active hepatitis B, with decompensated cirrhosis, or in other clinical situations should be explored in further studies. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may lead to the development of strategies for the treatment of dually infected patients with active hepatitis C, particularly for those not tolerating or not eligible for peginterferon-based therapy. Notably, direct-acting antivirals would not have any activity against HBV infection; simultaneous or on-demand nucleos(t)ide analogs would be needed if clinically indicated. [ABSTRACT FROM AUTHOR]

Background/purpose: Liver biopsy is the gold standard to determine the severity of hepatic fibrosis despite its risk and invasiveness. The aspartate aminotransferase/platelet ratio index (APRI) could noninvasively predict the severity of hepatic fibrosis in chronic hepatitis C (CHC) patients. Whether fibrosis index based on four factors (FIB-4) could better predict the severity of hepatic fibrosis than APRI in CHC patients remains inconclusive.Methods: This retrospective study enrolled 1473 CHC patients (784 men and 689 women) with liver biopsy and clinical data including age, aspartate aminotransferase, alanine aminotransferase, and platelet count. FIB-4 and APRI were calculated with a formula using the four clinical parameters. Hepatic fibrosis was staged using the Metavir classification system.Results: The areas under the receiver operating characteristics of FIB-4 for the diagnosis of significant fibrosis (≥ F2), advanced fibrosis (≥ F3), and cirrhosis (F4) were 0.816 [95% confidence interval (CI), 0.795-0.836], 0.827 (95% CI, 0.806-0.849), and 0.849 (95% CI, 0.830-0.867), respectively, compared with those of APRI-0.799 (95% CI, 0.778-0.819), 0.791 (95% CI, 0.770-0.812), and 0.802 (95% CI, 0.781-0.922). In addition, the areas under the receiver operating characteristics of FIB-4 were significantly greater than those of APRI for patients with advanced fibrosis and cirrhosis, respectively (p < 0.0001).Conclusion: FIB-4 could predict hepatic fibrosis in CHC patients. By adding two parameters (age and alanine aminotransferase), FIB-4 better predicts advanced fibrosis and cirrhosis than APRI in CHC patients. [ABSTRACT FROM AUTHOR]

Background/Purpose To evaluate whether on-treatment HBV-DNA level could predict the treatment response to entecavir in hepatitis B e antigen (HBe)-positive chronic hepatitis B (CHB) patients. Methods A total of 68 treatment-naïve HBeAg-positive patients (75% male, mean age at 46.6 ± 11.9 years) receiving at least 2 years of entecavir therapy were enrolled. The primary therapeutic endpoint was HBeAg loss. On-treatment complete virological response was defined as serum HBV-DNA < 63 IU/mL. Results The median baseline alanine aminotransferase (ALT) and HBV-DNA levels were 199.5 (27–1622) U/L and 7.7 (3.8–13.2) log 10 IU/mL, respectively. The median treatment duration was 31.7 (24.3–69.6) months. The rate of HBeAg loss at 2 years was 30.9%. By univariate analysis, on-treatment complete virological response at Month 6 was associated with HBeAg loss at 2 years ( p = 0.019). After adjustment for age, sex, cirrhosis, baseline ALT, and HBV-DNA levels, this factor remained significant in multivariate analysis (odds ratio: 4.35; 95% confidence interval: 1.24–15.24, p = 0.021). Conclusion On-treatment complete virological response at Month 6 is a favorable factor predictive of HBeAg loss at 2 years of entecavir therapy. Therefore, measurement of serum HBV-DNA level at 6 months of entecavir therapy is optimal to predict HBeAg loss at 2 years of therapy in HBeAg-positive CHB patients. [ABSTRACT FROM AUTHOR]

Background/Purpose Several anti-viral drugs are approved for the treatment of hepatitis B virus (HBV) infection. However, whether quantitative hepatitis B surface antigen (qHBsAg) can predict the therapeutic response during long-term entecavir treatment remains unclear. Methods Fifty-five chronic hepatitis B (CHB) patients who received entecavir for more than 2 years were enrolled. The serum qHBsAg level was measured by HBsAg II quant immunoassay. A significant decline in the qHBsAg level was defined as > 1 log reduction from baseline to 6 months of entecavir treatment. Results Of the 55 patients (41 males and 14 females with a mean age of 48.3 ± 11.4 years), 23 patients were positive for hepatitis B e antigen (HBeAg). The median treatment period was 34 months, and ranged from 26 months to 43 months. A total of 288 serum samples were used to determine the qHBsAg levels. At year 3 of entecavir therapy, one (1.8%) patient had HBsAg seroclearance. A high qHBsAg level was defined as greater than 10,000 IU/mL. Patients with a high baseline qHBsAg level had a lower rate of virologic response at year 1 (37.5% vs. 89.7%, p < 0.001) and year 2 (56.2% vs. 94.9%, p = 0.001). In this study population, 14.5% had a significant decline of the qHBsAg level. A significant decline could not predict HBeAg loss in HBeAg-positive or virologic response in all patients. Conclusion The baseline serum qHBsAg level can predict virologic response in entecavir-treated CHB patients. However, a significant decline in the qHBsAg level cannot predict serologic or virologic response of entecavir treatment. [ABSTRACT FROM AUTHOR]

Background/Purpose Insulin resistance (IR) affects sustained virological response (SVR) to peginterferon alfa plus ribavirin (PR) in patients with chronic hepatitis C (CHC). Whether add-on oral hypoglycemic agents (OHAs) to PR improve SVR remains unclear; therefore, we conducted a prospective, randomized pilot trial on 23 consecutive patients with genotype 1 CHC and IR in Taiwan. Methods Patients were randomized to receive acarbose (Arm A; n = 7) or metformin (Arm B; n = 6) or pioglitazone (Arm C; n = 5) in addition to peginterferon alfa-2b (1.5 μg/kg/week) plus ribavirin (1000–1200 mg/day) or just PR (Arm D; n = 5). The primary end point was SVR, and secondary end points were viral clearance at Weeks 17, 29, and 53. There were no differences among all arms at baseline. Results Using intent-to-treat analysis, SVR was observed in 66.7% (4/6), 83.3% (5/6), 66.7% (4/6), and 60% (3/5) in Arms A, B, C, and D, respectively. SVR was higher in female patients receiving OHA [90% (9/10)] than in male patients [50% (4/8)]. Results of per protocol analysis showed that SVR was 80.0% (4/5) in Arm A, 100% (5/5) in Arm B, 66.7% (4/6) in Arm C, and 60% (3/5) in Arm D. Patients receiving OHA had a higher rapid virologic response: 11/18 (61%) versus 2/5 (40%). Complete early virologic response was comparable between patients receiving OHA and PR [15/18 (83%) vs. 4/5 (80%)]. Conclusion Our preliminary data show add-on OHAs to PR might achieve better early viral kinetics and SVR. However, further larger studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Background/Purpose: Ultrasonography has long been recognized as a useful tool for detecting hepatic steatosis in clinical practice. However, whether it can assess the severity of hepatic steatosis and which factors affect its diagnostic accuracy remain unclear. Methods: A total of 171 patients with various causes of hepatitis undergoing liver biopsies were retrospectively reviewed. The clinical, serologic data and ultrasonographical findings were recorded. Hepatic steatosis was graded as negative, mild, moderate, or severe by ultrasonography and histology. Histology was used as gold standard and the agreement rates were calculated. Results: Our data showed that the agreement rate of ultrasonography was 61.4% in assessing the severity of hepatic steatosis and 74.3% in diagnosing hepatic steatosis compared with histology (crude kappa=0.46 vs. 0.46). Using univariate analyses, body mass index and histology activity index score were associated with the agreement in assessing the severity of hepatic steatosis (p =0.008 and 0.035), whereas Ishak fibrosis score had a trend association (p =0.066). Multivariate analyses indicated that age, body mass index, and Ishak fibrosis score could affect the agreement (odds ratio=0.72, 0.89, and 1.41; 95% confidence interval=0.54–0.97, 0.83–0.97, and 1.1–1.8). Conclusion: Ultrasonography could assess the severity of hepatic steatosis with moderate accuracy. Obese patients are difficult ultrasonographically. In addition, age and hepatic fibrosis could affect the performance of ultrasonography in assessing the severity of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC). Serum levels of HB core–related antigen (HBcrAg) have been associated with active replication of HBV. We investigated whether HBcrAg levels are associated with development of HCC, especially in patients who do not require antiviral treatment. We collected data from 2666 adults positive for hepatitis B surface antigen (HBsAg), infected with HBV genotypes B or C, and without liver cirrhosis, who had long-term follow-up at the National Taiwan University Hospital from 1985 through 2000. None of the patients received antiviral treatment during the follow-up. Baseline levels of HBV DNA, HBsAg, and HBcrAg were determined retrospectively and participants were followed for a mean of 15.95 years. The primary end point was an association between serum level of HBcrAg and HCC development. HCC developed in 209 patients in the cohort (incidence rate, 4.91 cases/1000 person-years). We found a positive association between baseline level of HBcrAg and HCC development; HBcrAg level was an independent risk factor in multivariable analysis. In the subgroup of hepatitis B e antigen–negative patients with HBV DNA levels from 2000 to 19,999 IU/mL (intermediate viral load [IVL]) and normal levels of alanine aminotransferase, HBcrAg levels of 10 KU/mL or more identified patients at increased risk of HCC (hazard ratio, 6.29; confidence interval, 2.27–17.48). Patients with an IVL and a high level of HBcrAg had a risk for HCC that did not differ significantly from that of patients with a high viral load (≥20,000 IU/mL). Patients with an IVL but a low level of HBcrAg had a low risk of HCC, with an annual incidence rate of 0.10% (95% confidence interval, 0.04%–0.24%). In a long-term follow-up study of 2666 patients with chronic HBV infection (genotypes B or C), level of HBcrAg is an independent risk factor of HCC. Moreover, HBcrAg level of 10 KU/mL identifies patients with an IVL who are at high risk for HCC. [ABSTRACT FROM AUTHOR]

Background & Aims Seroclearance of hepatitis B surface antigen (HBsAg) is a marker for clearance of chronic hepatitis B virus (HBV) infection, but reported annual incidence rates of HBsAg seroclearance vary. We performed a systematic review and meta-analysis to provide more precise estimates of HBsAg seroclearance rates among subgroups and populations. Methods We searched PubMed, Embase, and the Cochrane library for cohort studies that reported HBsAg seroclearance in adults with chronic HBV infection with more than 1 year of follow-up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, and 15-year cumulative incidence rates were pooled using a random effects model. Results We analyzed 34 published studies (with 42,588 patients, 303,754 person-years of follow-up, and 3194 HBsAg seroclearance events), including additional and updated aggregated data from 19 studies. The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79–1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49–5.93), 8.16% at 10 years (95% CI, 5.24–11.72), and 17.99% at 15 years (95% CI, 6.18–23.24). There were no significant differences between the sexes. A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76–2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25–0.59) (P <.01). Having HBsAg seroclearance was also associated with a lower baseline HBV DNA level (6.61 log 10 IU/mL; 95% CI, 5.94–7.27) vs not having HBsAg seroclearance (7.71 log 10 IU/mL; 95% CI, 7.41–8.02) (P <.01) and with a lower level of HBsAg at baseline (2.74 log 10 IU/mL; 95% CI, 1.88–3.60) vs not having HBsAg seroclearance (3.90 log 10 IU/mL, 95% CI, 3.73–4.06) (P <.01). HBsAg seroclearance was not associated with HBV genotype or treatment history. Heterogeneity was substantial across the studies (I 2 = 97.49%). Conclusion In a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate, approximately 1%). Seroclearance occurred mainly in patients with less active disease. Patients with chronic HBV infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed. Graphical abstract [ABSTRACT FROM AUTHOR]

Background & Aims Tests for hepatitis B virus (HBV) DNA are expensive, and levels of hepatitis B surface antigen (HBsAg) can help determine the risk for hepatocellular carcinoma (HCC) in patients with chronic HBV infection. We investigated how adding data to knowing the level of HBsAg or excluding measurement of HBV DNA affected the accuracy of the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) scoring system in determining the risk for HCC. Methods We collected data from 3584 patients with chronic HBV infection who were positive for HBsAg, free of cirrhosis, and participated in the community-based Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-HBV cohort (208 cases of HCC) from 1991 through 1992; they were followed up until December 31, 2008. Data from this cohort were used to derive our scoring system. We validated our system using data from 2688 HBsAg-seropositive patients (191 cases of HCC) who participated in the hospital-based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers (ERADICATE-B) study at the National Taiwan University Hospital from 1985 through 2000; they were followed up until December 31, 2010. We also validated the system using data from 426 patients with chronic HBV infection who participated in the Chinese University of Hong Kong (CUHK) study (46 cases of HCC) from 1997 through 2000; patients were followed up for a median of 225 weeks. Discrimination and calibration were evaluated using area under the receiver operating characteristic (AUROC) curves and calibration charts. Results When data on HBsAg were added to the REACH-B scoring system, it identified patients in the ERADICATE-B study who developed HCC within 3, 5, and 10 years, with AUROC curve values of 0.92 (95% confidence interval [CI], 0.82–1.02), 0.78 (95% CI, 0.70–0.86), and 0.80 (95% CI, 0.76–0.84), respectively. It identified patients in the CUHK study who developed HCC in 3, 5, and 10 years, with AUROC curve values of 0.85 (95% CI, 0.75–0.95), 0.82 (95% CI, 0.70–0.93), and 0.78 (95% CI, 0.70–0.870), respectively. When data on HBV DNA were removed from the REACH-B scoring system, it identified patients in the ERADICATE-B cohort who developed HCC in 3, 5, and 10 years, with AUROC curve values of 0.90 (95% CI, 0.81–1.0), 0.76 (95% CI, 0.68–0.85), and 0.78 (95% CI, 0.73–0.82), respectively. It identified patents in the CUHK cohort who developed HCC in 3, 5, and 10 years, with AUROC curve values of 0.84 (95% CI, 0.79–0.92), 0.81 (95% CI, 0.71–0.91), and 0.79 (95% CI, 0.72–0.87). These modified systems identified patients who developed HCC with similar levels of accuracy as the original REACH-B score ( P > .05 in tests of noninferiority). Conclusions Including data on serum level of HBsAg or removing data on level of HBV DNA do not alter the accuracy of the REACH-B scoring system in determining HCC risk in patients with chronic HBV infection without cirrhosis. It might be cost effective to replace the test for HBV DNA with assays to measure HBsAg in determining HCC risk. These modified scoring systems might replace the REACH-B system in specific situations. [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with lower levels of hepatitis B surface antigen (HBsAg) have higher chances of losing HBsAg than those with high levels. However, little is known about whether higher levels of HBsAg increase risk for HCC. Methods: We followed 2688 Taiwanese HBsAg-positive patients without evidence of cirrhosis for a mean time period of 14.7 years. In addition to the known risk factors of HCC, we investigated the association between levels of HBsAg and development of HCC. Results: Of the patients followed, 191 developed HCC, with an average annual incidence rate of 0.5%. Baseline levels of HBsAg and HBV were associated with development of HCC, and risk increased with level. Compared to HBsAg level, by receiver operating characteristic curve analysis, HBV DNA level better predicted the development of HCC during 10-year and 15-year periods (both, P < .001). However, when we evaluated hepatitis B e antigen−negative patients with levels of HBV DNA <2000 IU/mL, factors that determined HCC risk included sex, age, and levels of alanine aminotransferase and HBsAg (≥1000 IU/mL), but not level of HBV DNA. Multivariate analysis showed that the adjusted hazard ratio for HCC in patients with levels of HBsAg ≥1000 IU/mL versus <1000 IU/mL was 13.7 (95% confidence interval: 4.8−39.3). Conclusions: Among patients infected with HBV genotype B or C, determinants of HCC risk include their sex, age, hepatitis B e antigen status, HBV genotype, and levels of alanine aminotransferase and HBV DNA, but not level of HBsAg. Among hepatitis B e antigen−negative patients with low viral loads, HCC risk is determined by levels of HBsAg and alanine aminotransferase and age, but not HBV DNA. [Copyright &y& Elsevier]

Background & Aims: Loss of hepatitis B surface antigen (HBsAg) usually indicates that hepatitis B virus (HBV) infection has been cured. However, little is known about factors predicting HBsAg loss in patients who spontaneously clear hepatitis B e antigen (HBeAg). Methods: We studied 390 Taiwanese HBeAg-positive patients with chronic hepatitis who had spontaneously cleared HBeAg (seroconversion) during follow-up. Serum levels of HBV DNA and HBsAg were determined 1 year after HBeAg seroconversion, and their relationships with subsequent HBsAg loss were investigated. Results: In a mean follow-up of 7.4 years, the average annual rate of HBsAg loss was 0.62%. Serum levels of HBsAg and HBV DNA were inversely associated with HBsAg loss in a dose-response manner. Compared with patients with HBsAg levels ≥1000 IU/mL, the HBsAg loss rate was higher for those with HBsAg levels of 100 to 999 and <100 IU/mL, with hazard ratios of 4.4 (95% confidence interval, 1.1–17.0) and 24.3 (8.7–67.5), respectively. Among those who underwent HBsAg loss within 6 years of follow-up, serum HBsAg levels were a better predictor than HBV DNA levels by receiver operating characteristic curve analysis (area under the receiver operating characteristic curve, 0.90 vs 0.69; P = .012); an HBsAg level <100 IU/mL predicted HBsAg loss within 6 years with a diagnostic accuracy of 91.5%, sensitivity of 83.3%, specificity of 92.1%, positive predictive value of 45.5%, and negative predictive value of 98.6% in patients with an HBV DNA level <200 IU/mL. Conclusions: Low serum levels of HBsAg, alone or in combination with HBV DNA levels, 1 year after HBeAg seroconversion can predict HBsAg loss in patients with HBV genotype B or C infection. [ABSTRACT FROM AUTHOR]

Data regarding the nephrotoxicity of sofosbuvir (SOF) remain controversial. We compared the evolution of estimated glomerular filtration rate (eGFR) in patients with chronic HCV infection receiving SOF-based or SOF-free direct-acting antivirals (DAAs). A total of 481 patients with compensated liver diseases and eGFR ≥30 ml/min/1.73m2, receiving SOF-based (n = 308) or SOF-free (n = 173) DAAs for 12 weeks, were prospectively enrolled. The eGFR was assessed from baseline to off-treatment week 24 using the chronic kidney disease (CKD)-epidemiology collaboration equation. Differences in the evolution of eGFR between regimens were compared by a generalized linear mixed-effects model. Multivariate analysis was performed for factors affecting eGFR evolution. Patients receiving SOF-based DAAs experienced a significant on-treatment decline in eGFR (adjusted slope coefficient difference: −1.24 ml/min/1.73m2/month; 95% CI −1.35 to −1.13; p <0.001) and a significant off-treatment improvement (adjusted slope coefficient difference: 0.14 ml/min/1.73m2/month; 95% CI 0.08 to 0.21; p = 0.004) compared to patients receiving SOF-free DAAs. Multivariate analysis showed age per 1-year increase (adjusted slope coefficient difference: −0.05 ml/min/1.73m2/month; 95% CI −0.05 to −0.04; p <0.001), SOF-based DAAs (adjusted slope coefficient difference: −0.33 ml/min/1.73m2/month; 95% CI −0.49 to −0.17; p <0.001), and CKD stage (adjusted slope coefficient difference: −1.44 ml/min/1.73m2/month; 95% CI −1.58 to −1.30; p <0.001 for stage 3 vs. 1, and −3.59 ml/min/1.73m2/month; 95% CI −3.88 to −3.30; p <0.001 for stage 2 vs. 1) were independent factors affecting eGFR evolution from baseline to off-treatment week 24. Patients receiving SOF-based DAAs exhibited a quadratic trend, with eGFR worsening on treatment and improving off treatment. Increasing age, SOF-based DAAs, and more advanced baseline CKD stage are independently associated with a decline in eGFR in patients with HCV receiving DAAs. While the efficacy of sofosbuvir for the treatment of hepatitis C virus is clear, data regarding its possible nephrotoxicity are controversial. Herein, we showed that sofosbuvir worsened on-treatment kidney function but led to an off-treatment improvement. Our findings suggest that treating physicians should be alert to risk factors for kidney dysfunction before initiating direct-acting antiviral treatment for patients with hepatitis C virus infection. NCT04047680 • Patients receiving SOF-based DAAs exhibit a quadratic trend, with eGFR worsening on treatment and improving off treatment. • Patients receiving SOF-free DAAs have a linear trend with eGFR improving on and off treatment. • Increasing age, use of SOF-based DAAs, and more advanced baseline CKD stage are independent risk factors of eGFR decline. [ABSTRACT FROM AUTHOR]

Abstract: Background: Viral kinetics and host interleukin 28B (IL-28B) genotype determine treatment outcome in hepatitis C virus genotype 1 (HCV-1) infection. Objectives: We aimed to explore the interplay between interferon responsiveness at treatment week 4 and IL28B genotype in the achievement of a sustained virological response (SVR; undetectable HCV RNA 24-weeks after end-of-treatment). Study designs: Rs8099917 genotypes were determined in 528 HCV-1 patients with peginterferon/ribavirin. Interferon responsiveness were evaluated by the degree of week 4 viral reduction: <1 log10 IU/mL, 1–2 logs10 IU/mL, 2–3 logs10 IU/mL, 3–4 logs10 IU/mL and ≥4 logs10 IU/mL reduction and/or undetectable HCV RNA, respectively. Results: The SVR rate was significantly higher in patients with great interferon responsiveness at week 4. A great interferon responsiveness was associated with younger age (P <0.0001), lower body mass index (P =0.0056), lower aspartate aminotransferase levels (P =0.0009), higher hemogloblin concentration (P =0.0033), higher platelet counts (P <0.0001), male gender (P <0.0001) and rs809997 TT-genotype (P <0.0001). Comparing to non-TT genotype patients, TT genotype patients had a significantly higher SVR rate with moderate viral reduction (1–3 logs10 IU/mL) at week 4 (58.9% vs. 18.2%, P <0.001), and the SVR rate did not differ between TT/non-TT patients on the extreme ends (<1 or >3 log10 IU/mL reduction) of week 4 interferon responsiveness. For non-TT genotype carriers who were with <3 logs10 reduction, none (0/15) could have a complete early virological response and only 10.9% (7/64) of the patients had an SVR. Conclusions: More profound interferon responsiveness is mandatory for HCV-1 patients with unfavorable IL-28B genotype. [Copyright &y& Elsevier]