Long Term Efficacy of Antiviral Therapy: Mortality and Incidence of Hepatocellular Carcinoma

Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.ope

Comparison of clinical practice guidelines for the management of chronic hepatitis B: When to start, when to change, and when to stop

Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.ope

The diagnostic value of circulating tumor DNA in hepatitis B virus induced hepatocellular carcinoma: a systematic review and meta-analysis

Background/Aim New biomarkers are urgently needed to aid in the diagnosis of early stage hepatocellular carcinoma (HCC). We performed a meta-analysis on the diagnostic utility of circulating tumor DNA (ctDNA) levels in patients with hepatitis B virus-induced HCC. Methods We retrieved relevant articles from PubMed, Embase, and the Cochrane Library up to February 8, 2022. Two subgroups were defined; one subset of studies analyzed the ctDNA methylation status, and the other subset combined tumor markers and ctDNA assays. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) were analyzed. Results Nine articles including 2,161 participants were included. The overall SEN and SPE were 0.705 (95% confidence interval [CI], 0.629-0.771) and 0.833 (95% CI, 0.769-0.882), respectively. The DOR, PLR, and NLR were 11.759 (95% CI, 7.982-17.322), 4.285 (95% CI, 3.098-5.925), and 0.336 (0.301-0.366), respectively. The ctDNA assay subset exhibited an AUC of 0.835. The AUC of the combined tumor marker and ctDNA assay was 0.848, with an SEN of 0.761 (95% CI, 0.659-0.839) and an SPE of 0.828 (95% CI, 0.692-0.911). Conclusions Circulating tumor DNA has promising diagnostic potential for HCC. It can serve as an auxiliary tool for HCC screening and detection, especially when combined with tumor markers.ope

Ca2+/Calmodulin-Dependent Protein Kinase II Inhibits Hepatitis B Virus Replication from cccDNA via AMPK Activation and AKT/mTOR Suppression

Ca2+/calmodulin-dependent protein kinase II (CaMKII), which is involved in the calcium signaling pathway, is an important regulator of cancer cell proliferation, motility, growth, and metastasis. The effects of CaMKII on hepatitis B virus (HBV) replication have never been evaluated. Here, we found that phosphorylated, active CaMKII is reduced during HBV replication. Similar to other members of the AMPK/AKT/mTOR signaling pathway associated with HBV replication, CaMKII, which is associated with this pathway, was found to be a novel regulator of HBV replication. Overexpression of CaMKII reduced the expression of covalently closed circular DNA (cccDNA), HBV RNAs, and replicative intermediate (RI) DNAs while activating AMPK and inhibiting the AKT/mTOR signaling pathway. Findings in HBx-deficient mutant-transfected HepG2 cells showed that the CaMKII-mediated AMPK/AKT/mTOR signaling pathway was independent of HBx. Moreover, AMPK overexpression reduced HBV cccDNA, RNAs, and RI DNAs through CaMKII activation. Although AMPK acts downstream of CaMKII, AMPK overexpression altered CaMKII phosphorylation, suggesting that CaMKII and AMPK form a positive feedback loop. These results demonstrate that HBV replication suppresses CaMKII activity, and that CaMKII upregulation suppresses HBV replication from cccDNA via AMPK and the AKT/mTOR signaling pathway. Thus, activation or overexpression of CaMKII may be a new therapeutic target against HBV infection.ope

Efficacy and Safety of Tenofovir Disoproxil Orotate in Chronic Hepatitis B Patients Previously Treated with Tenofovir Disoproxil Fumarate: Multicenter, Open-Label, Prospective Study

Background/aim: We aimed to demonstrate the efficacy and safety of tenofovir disoproxilorotate (TDO) compared with that of tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B. Methods: This multicenter, open-label, prospective clinical trial (KCT0004185) was conducted to evaluate the efficacy and safety of TDO on switching from TDF for 24 weeks in virologically suppressed chronic hepatitis B patients. The primary efficacy endpoint was the maintenance of virologic response. Safety was assessed by evaluating major adverse events, changes in renal function, and occurrence of hepatocellular carcinoma (HCC). Results: TDO treatment was not inferior in terms of virological response when compared with that on TDF treatment, with a noninferiority margin of -10% (risk difference, -3.17%; 95% confidence interval, -7.5%-1.15%). The biological response of TDO was also comparable to that of TDF, with no significant difference in the proportion of patients with normalized alanine transaminase levels. After 24 weeks of treatment, hepatitis B core-related antigen (HBcrAg) significantly decreased to a mean titer of 3.91 log U/mL from 4.15 log U/mL at baseline (p = 0.01). There were no cases of grade 3 or higher adverse events and HCC. The mean estimated glomerular filtration rate increased from 91.09 mL/min to 93.34 mL/min (p = 0.056), and the mean serum level of phosphorus increased from 3.33 mg/dL to 3.44 mg/dL (p = 0.045), suggesting improvement in renal function with TDO treatment. Conclusion: In patients with chronic hepatitis B, the efficacy of TDO was noninferior to that of TDF, with a significant decrease in the HBcrAg titer and improved renal function.ope

Natural antibody IgG levels are associated with HBeAg-positivity and seroconversion in chronic hepatitis B patients treated with entecavir

B1 cell-derived natural antibodies are non-specific polyreactive antibodies and can activate the complement pathway leading to lysis of enveloped virus particles before activation of the adaptive immune response. We investigated the relationship between natural antibody levels and treatment outcomes of 126 treatment-naïve chronic hepatitis B (CHB) patients, who underwent entecavir (ETV) treatment. Serum IgG1-3 and complement C3 levels were significantly higher in HBeAg-positive patients. In pre-treatment, IgG1 (odd ratios [OR] 2.3, p < 0.0001), IgG2 (OR 9.8, p < 0.0001), IgG3 (OR 7.4, p < 0.0001), and C3 (OR 7.2, p < 0.0001) were associated with HBeAg-positive patients. At baseline, IgG2 (OR 10.2, p = 0.025), IgG4, (OR 3.4, p = 0.026), and complement C1q (OR 5.0, p = 0.0068) were associated with seroconverters. Post-treatment levels of IgG1-4 and C3/C1q were also associated with HBeAg-positive patients and seroconverters. High levels of IgG2-4 and C1q were observed in seroconverters but not in virological responders. Thus, high pretreatment and post-treatment levels of natural antibody IgG1-4, complement C3, and/or C1q were significantly associated with HBeAg-positivity and HBeAg seroconverters in CHB patients with ETV treatment. These results suggest that the presence of preexisting host immunity against chronic hepatitis B is closely related to outcome of ETV treatment.ope

Should physicians go out of the way to differentiate between acute hepatitis B and acute exacerbation of chronic hepatitis B?

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Prognostic Factors of Radiofrequency Ablation plus Systemic Chemotherapy for Unresectable Colorectal Cancer with Liver Metastasis

Introduction: Survival outcomes in patients with unresectable colorectal cancer (CRC) liver metastasis treated by radiofrequency ablation (RFA) combined with systemic chemotherapy and correlation with potential prognostic factors were investigated. Material and Methods. A retrospective cohort study was conducted on 61 CRC patients with unresectable liver metastasis who underwent liver tumor-directed percutaneous RFA combined with conventional systemic chemotherapy between October 2013 and September 2018. Survival analyses were conducted using the Kaplan-Meier method, and the log-rank test was used to characterize differences in the median survival time and the 1-year, 3-year, and 5-year overall survival rates of subgroups to identify prognostic factors. Results: Median overall survival and progression-free survival of all patients were 32 and 14 months, respectively. The cumulative survival rates at 1-, 3-, and 5-years were 93.2%; 44.5%, and 38.2%, respectively. Univariate analysis revealed that pre-RFA serum CEA levels, Eastern Cooperative Oncology Group (ECOG) status, number of liver lesions, the size of the largest lesion, and the total lesion size were prognostic factors. However, multivariate analysis demonstrated that only the number of liver lesions and the size of the largest lesion were independent prognostic factors for survival. Conclusion: RFA plus systemic chemotherapy provides an encouraging survival outcome for patients with unresectable CRC liver metastasis. Multivariate analysis demonstrated that the number and size of liver metastatic lesions are independent prognostic factors for survival.ope

Seroepidemiology of Hepatitis Viruses and Hepatitis B Genotypes of Female Marriage Immigrants in Korea.

PURPOSE: The Korean society has moved rapidly toward becoming a multicultural society. This study aimed to estimate the seroprevalence of hepatitis viruses and investigate hepatitis B virus (HBV) genotypic diversity in female marriage immigrants. MATERIALS AND METHODS: Screening program was conducted at support centers for multicultural families in 21 administrative districts in Korea between July 2011 and January 2017. A total of 963 female marriage immigrants were included in this study. Blood samples were tested for hepatitis viral markers and HBV genotype. RESULTS: Subjects' median age was 33 years (20-40 years), and they originated from nine countries including Vietnam (n=422, 43.8%), China (n=311, 32.3%), the Philippines (n=85, 8.8%), Cambodia (n=58, 6.0%), and Japan (n=39, 4.0%). About 30% (n=288) of subjects required hepatitis A vaccination. HBsAg positive rate was 5.4% (n=52). Positive HBsAg results were the highest in subjects from Southeast Asia (6.6%, n=38). Anti-HBs positive rate was 60.4% (n=582). About 34% (n=329) of subjects who were negative for anti-HBs and HBsAg required HBV vaccinations. Genotypes B and C were found in 54.6% (n=12) and 45.4% (n=10) of the 22 subjects with HBV, in whom genotypes were tested. Eight (0.8%) subjects were positive for anti-HCV. Positive anti-HCV results were the highest in subjects from Central Asia (7.9%, n=3). CONCLUSION: Testing for hepatitis viral marker (hepatitis A virus IgG and HBsAg/anti-HBs) is needed for female marriage immigrants. Especially, HBV genotype B is different from genotype C of Koreans. Therefore, interest and attention to vaccination programs for female marriage immigrants are necessary for both clinicians and public health institutes.ope

Efficacy and safety of selective internal radiation therapy with yttrium-90 for the treatment of unresectable hepatocellular carcinoma

Background: This retrospective analysis was undertaken to evaluate the efficiency of SIRT with Y-90 microspheres and determined prognostic factors affecting patients with unresectable HCC. Methods: A total of 97 patients diagnosed with unresectable HCC who underwent SIRT with Y-90 microspheres. Patient survival was assessed using the Kaplan-Meier method, and prognostic factors affecting survival were assessed using log-rank tests and Cox proportional hazards regression. Results: Among the 97 patients (90 males, mean age 60.4 ± 12.3 years) who underwent SIRT, the median clinical follow-up was 16.4 (1.8-62) months. The median overall survival (OS) was 23.9 ± 2.4 months. Tumor response according to the Modified RECIST in patients followed up beyond 6 months included a complete response (CR) to treatment in 12 patients (18.8%), partial response (PR) in 23 (35.8%), stable disease (SD) in 8 (12.5%), and progressive disease (PD) in 21 (32.8%). Factors associated with longer OS included age > 65 years, BCLC stage B, tumor size < 5 cm, tumor burden < 25%, and tumor response (CR/PR). In multivariate analysis, unilobar disease and objective tumor response (CR/PR) were predictors of longer OS. Conclusion: SIRT was an effective treatment for unresectable HCC. Unilobar disease before SIRT and tumor response (CR/PR) were positive prognostic factors.ope