Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients.

BACKGROUND: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.

Rapid Decline Rather Than Absolute Level of HBsAg Predicts Its Seroclearance in Untreated Chronic Hepatitis B Patients From Taiwanese Communities.

INTRODUCTION: Hepatitis B surface antigen (HBsAg) clearance leads to favorable outcomes in patients with chronic hepatitis B. HBsAg levels <200 IU/mL with HBsAg decline >0.5 log 10 IU/mL in 1 year have been reportedly predictive of HBsAg loss. This study aimed to use the REVEAL-hepatitis B virus cohort to validate and simplify this prediction rule and verify whether the simplified algorithm can be used among various clinical subgroups. METHOD: We analyzed 707 patients with untreated chronic hepatitis B who had 3 or more HBsAg measurements within 5 years before HBsAg seroclearance or last visit, greater than 1 year apart from one another. Rapid HBsAg decline was defined as HBsAg decline >0.5 log 10 IU/mL in 1 year or >1 log 10 IU/mL in 2 years. Sensitivity, specificity, positive predictive values, and negative predictive values were compared to assess the predictability of HBsAg seroclearance. RESULTS: During a median follow-up of 10.7 years, 41 of the 707 patients cleared serum HBsAg. HBsAg levels at all measurements were lower ( P < 0.0001) and HBsAg decline was greater ( P < 0.0001) in patients with seroclearance compared with non-seroclearance patients. The predictive accuracy of predicting 1-year HBsAg loss using only the rapid decline algorithm (sensitivity = 0.4412, specificity = 0.9792, positive predictive value = 0.5172, negative predictive value = 0.972) was the same as the model combining rapid HBsAg decline and HBsAg levels <200 IU/mL. The simplified algorithm including only the rapid decline performed similarly among various levels of HBsAg, hepatitis B virus DNA, and alanine aminotransferase and was independent of inactive carrier state. DISCUSSION: HBsAg decline >0.5 log 10 IU/mL/yr was a practical predictor of HBsAg seroclearance within 1 year in our community-based untreated cohort.

High Potency of SN-38-Loaded Bovine Serum Albumin Nanoparticles Against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a worse prognosis than other types. There are currently no specific approved treatments for TNBC. Albumin is a promising biomimetic material that may be fabricated into nanoparticles to possibly exert passive effects on targeted tumors. Irinotecan has been extensively used in clinical settings, although a high dosage is required due to its low efficiency of conversion into the active metabolite SN-38, also known as 7-ethyl-10-hydroxy-camptothecin. The aim of this work was to optimize SN-38-loaded bovine serum albumin nanoparticles (sBSANPs) and evaluate their potency against TNBC. The sBSANPs were characterized by a small size of about 134-264 nm, a negative charge of -37 to -40 mV, an entrapment efficiency of 59-71%, and a particle yield of 65-86%. The cytotoxicity assays using sBSANPs showed a higher potency specifically against both MDA-MB-468 and MDA-MB-231 cells (ER-, PR-, HER2-) compared to MCF-7 (ER+, PR+, HER2-), and exhibited an extremely low IC50 at the nanomolar levels (2.01-6.82 nM). The release profiles indicated that SN-38 presented an initial burst release within 12 h, and sBSANPs had a slow release pattern. Flow cytometry results showed that the fluorescence intensity of sBSANPs was significantly higher than that of the control group. The confocal images also confirmed that sBSANPs were taken up by MDA-MB-468 cells. Moreover, we found that a larger BSANP size resulted in an increased hemolytic effect. In vivo animal studies demonstrated that loading of SN-38 into bovine serum albumin nanoparticles could minimize the initial concentration without extending the elimination half-life, but significantly minimized the Cmax (p < 0.001) as compared with irinotecan treatment.

SN38-loaded <100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study.

BACKGROUND: SN38 (7-ethyl-10-hydroxycamptothecin) is a camptothecin derivative acts against various tumors. However, SN38 is hydrolyzed in the physiological environment (pH 7.4), and this instability interferes with its potential therapeutic effect. Our objective was to investigate SN38-loaded liposomes to overcome the poor solubility of SN38 and its biodistribution, which further diminish its toxicity. MATERIALS AND METHODS: The sub-100 nm targeted liposomes was employed to deliver SN-38 and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay. RESULTS: The SN38-loaded targeted liposomes consisted of small (100.49 nm) spherical nanoparticles with negative charge (-37.93 mV) and high entrapment efficiency (92.47%). The release behavior of the SN38-loaded targeted liposomes was fitted with Higuchi kinetics (R2=0.9860). Free SN38 presented initial burst release. The IC50 for the SN38-loaded targeted liposomes (0.11 µM) was significantly lower than for the SN38 solution (0.37 µM) in the MCF7 cell line (P<0.01). Confocal laser scanning microscopy also confirmed highly efficient accumulation in the MCF7 cells. Pharmacokinetics demonstrated that the SN38-loaded targeted liposomes had a slightly increased half-life and mean residence time and decreased area under the concentration-time curve and maximum concentration. The results suggested that retention was achieved while the exposure of SN38 was significantly decreased. A noninvasive in vivo imaging system also showed that the targeted liposomes selectively targeted MCF7 tumors. In vivo toxicity data demonstrated that the decrease in platelets was significantly improved by SN38-loaded targeted liposomes, and diarrhea was not observed in BALB/c mice. CONCLUSION: In summary, SN38-loaded targeted liposomes could be a good candidate for application in human breast cancer.