Survival Outcomes and Safety of Programmed Cell Death/Programmed Cell Death Ligand 1 Inhibitors for Unresectable Hepatocellular Carcinoma: Result From Phase III Trials.

Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. The aim of this study was conducted a meta-analysis to assess the efficacy and safety of PD-1/PD-L1 inhibitors in patients with unresectable hepatocellular carcinoma (uHCC). A total of 1657 patients were included. The completed phase III trials with details data, such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects (AEs) were included. The pooled hazard ratio (HR) of OS and PFS were .75 (95% CI: .61-.92) and .74 (95% CI: .56-.97) with heterogeneity between PD-1/PD-L1 inhibitors groups and control groups. Sensitivity analysis revealed IMbrave-150 could be the most important factor of heterogeneity for OS, while CheckMate-459 was the main fact of heterogeneity for PFS. In addition, the relative risk (RR) of ORR and DCR were 2.43 (95% CI: 1.80-3.26) and 1.26 (95% CI: 1.11-1.43) with low heterogeneity in PD-1/PD-L1 inhibitors groups. The therapeutic effect of PD-1/PD-L1 inhibitors was better in females, Asia without Japan, BCLC status C and infected hepatitis groups. The RR of AEs from any cause and serious adverse events (SAEs) for patients receiving PD-1/PD-L1 inhibitors were 1.03 (95% CI: .93-1.13) and 1.13 (95% CI: .89-1.44), respectively. Pruritus was the most common AEs reported in 10% of patients or more (RR = 1.69, 95% CI: 1.33-2.15). In conclusion, PD-L1 inhibitor combined with anti-VEGF antibody could improve the prognosis of patients with uHCC. However, caution should be taken for AEs during patients receiving PD-1/PD-L1 inhibitors.

LAM add-on ADV combination therapy or ETV monotherapy for CHB patients with suboptimal response to ADV.

INTRODUCTION: Among the available nucleos(t)ide analogues adefovir dipivoxil (ADV) is relatively cheap and widely used in rural area in China. However, there are insufficient data on recommendation for patients with suboptimal response to ADV after 48 weeks of treatment in order to reduce the resistance rate in the long term. The aim of this study was to compare the efficacy and safety of LAM add-on combination therapy versus ETV monotherapy for patients with suboptimal response to ADV. MATERIAL AND METHODS: 136 patients with suboptimal response to ADV were randomly assigned to the add-on LAM with ADV combination therapy (68 patients) group and the ETV monotherapy (68 patients) group. Patients in the add-on group were prescribed 100 mg LAM and 10 mg ADV per day, while the monotherapy group received 0.5 mg ETV per day for 48 weeks. Tests for liver and kidney function, HBV serum markers, HBV DNA load, were performed every 3 months. RESULTS: The mean patient age in LAM add-on group and ETV monotherapy was 38.59 ± 7.65 and 37.56 ± 8.67 years respectively. The HBV DNA undetectable rate in the LAM add-on group and the ETV group were not significant difference at week 4, 12 and 24 (P > 0.05). However, the HBV undetectable rate in the ETV group was higher than that in the LAM add-on group at week 36 and 48 (P = 0.043 for week 36 and P = 0.038 for week 48). There was no significant difference both for HBeAg loss and HBeAg seroconversion between two groups (P > 0.05) at 48 weeks. Meanwhile, our study also demonstrated that the mean eGFR levels in LAM add-on group was decreased from 99.6 ± 8.71 at baseline to 86.4 ± 9.83 at the end of 48 weeks, which was significantly higher than that in the ETV monotherapy group (P < 0.05). 8.8% of patients in LAM add-on group experienced eGFR reduction by 20-30% from baseline at 48 weeks. No patients developed hyposphosphatemia in our study. CONCLUSION: Our study clearly showed that switch to ETV monotherapy was the more effective and more safe than that of LAM add-on combination therapy for patients with suboptimal response to ADV.

[Determination of five boswellic acids in Boswellia serrata].

OBJECTIVE: To develop an HPLC method for determinating the contents of five boswellic acids in Boswellia serrata. METHOD: Analysis was performed on a zorbax SB C18 column eluted with acetonitrile-0.1% phosphoric acid in water as mobile phases in gradient elution and the detection wavelengths were 210 nm and 250 nm. RESULT: The five ingredients were separated well. The content ranges of alpha-boswellic acid, beta-boswellic acid, 3-acetyl-beta-boswellic acid, 11-keto-beta-boswellic acid and 11-keto-beta-acetyl- boswellic acid were 8.68-16.1, 53.5-246.9, 38.4-192.9, 4.48-5.81, 32.7-44.2 mg x g(-1), respectively. CONCLUSION: The contents of five individual boswellic acids were different in 12 batches of B. serrata samples.

Infections Caused by Carbapenemase-Producing Klebsiella pneumoniae: Microbiological Characteristics and Risk Factors.

The spread of carbapenemase-producing Klebsiella pneumoniae (CPKP) worldwide is a serious problem. This retrospective, matched case-control, parallel study in a tertiary teaching hospital analyzed the microbiological and clinical characteristics of CPKP infection, focusing on the risk factors for carbapenem resistance and patient mortality. The hospital department with the highest incidence of CPKP infections was the intensive care unit. All CPKP strains examined were positive for blakpc-2, and 84.8% of CPKP were ST11. Hypervirulent phenotype was identified in 22.7% of the patients with CPKP, with these strains displaying a high incidence of positivity for entB, ybtS, and iutA. Multivariate conditional logistic regression analysis demonstrated that Pitt bacteremia score >4, prior stomach tube, continuous renal replacement therapy (CRRT), and previous carbapenem exposure were associated with CPKP infection. Higher albumin concentration and use of cephalosporins after diagnosis were strong prognostic factors for crude 28-day mortality. Further, high APACHE II score, CRRT, use of carbapenems after diagnosis, and bacteremia were risk factors for crude in-hospital mortality. CPKP isolates showed clonal spread and were resistant to most antibiotics, resulting in higher financial burden. Critical illness was associated with increased mortality.

[The clinical efficacy of composite acoustic therapy in patients of sudden deafness with tinnitus].

OBJECTIVE: To determine whether the composite acoustic therapy is effective to treat tinnitus in patients with sudden deafness and to explore the mechanisms. METHOD: Ninety-six cases (96 ears) were divided into experimental group and control group, and all the patients underwent drug treatment. The patients in experimental group were given personalized composite acoustic therapy in the first 30 days, music therapy in next 31-90 days, however, the patients in control group were not given sound therapy. Additionally, pure tone audiogram, tinnitus pitch and loudness as well as questionnaires (including THI, VAS, and SAS) were conducted for each patient before treatment, at day 30 and day 90 posttreatment. RESULT: Eighty-nine patients (n = 47 for experimental group and n = 42 for control group) completed the trial. The results of day 30 posttreatment showed there were no significant differences in VAS and hearing recovery rate between these two groups, but THI and SAS showed significant differences. The results of day 90 posttreatment showed significant differences in VAS (P < 0.05), THI (P < 0.01) and SAS (P < 0.01), and no significant difference of hearing recovery rate was detected. The most significant changes of VAS appeared in the first 30 days of treatment. The hearing and tinnitus recovery in experimental group were better for the first 30 days of treatment than for the next 31-90 days, and similar results were obtaind in control group. (P < 0.01). CONCLUSION: Composite acoustic treatment combined with drug therapy can improve the tinnitus and anxiety symptoms of patients with sudden deafness, and the effect on hearing recovery still need to be confirmed in further studies.

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B.

AIM: To evaluate urine ß2-microglobulin (ß2-M), retinol-binding protein (RBP) excretion, and renal impairment with adefovir dipivoxil (ADV) for chronic hepatitis B. METHODS: We enrolled 165 patients with chronic hepatitis B infection who were treated with ADV monotherapy (n = 90) or ADV plus lamivudine combination therapy (n = 75). An additional 165 chronic hepatitis B patients treated with entecavir were recruited as controls. We detected serum creatinine, urine ß2-M, and RBP levels, and estimated the glomerular filtration rate (eGFR) at the initiation of antiviral therapy and every 6 mo for a period of five years. RESULTS: Urine ß2-M abnormalities were observed in patients during the first (n = 3), second (n = 7), third (n = 11), fourth (n = 16), and fifth (n = 21) year of ADV treatment. Urinary RBP abnormalities were observed in patients during the first (n = 2), second (n = 8), third (n = 12), fourth (n = 15), and fifth (n = 22) year of ADV treatment. eGFR decreased 20%-30% from baseline in 20 patients, 30%-50% in 12 patients, and > 50% in 3 patients during the five years of treatment. Further analysis indicated that decreases in eGFR of ≥ 30% relative to the baseline level correlated significantly with urine RBP and ß2-M abnormalities. In contrast, both serum creatinine and eGFR remained stable in patients treated with entecavir, and only one of these patients developed a urine ß2-M abnormality, and two developed urine RBP abnormalities during the five years of treatment. CONCLUSION: Urine RBP and ß2-M are biomarkers of renal injury during long-term ADV treatment for chronic hepatitis B, and indicate when treatment should be switched to entecavir.

HBsAg levels in HBeAg-positive chronic hepatitis B patients with different immune conditions.

AIM: To investigate hepatitis B surface antigen (HBsAg) levels in patients with HBeAg-positive chronic hepatitis B (CHB) and different immune conditions. METHODS: HBeAg-positive CHB patients with different immune conditions were enrolled in this cross-sectional study. These patients were grouped according to the following criteria: immune-tolerant patients, IT group; patients with a mild immune response in the immune clearance phase, IC-Mild group; and patients with a dramatic immune response in the immune clearance phase and exhibiting acute on chronic liver failure (ACLF), ACLF group. All these patients had not previously received antiviral therapy and were enrolled at a pre-settled ratio of 2:2:1. Serum HBsAg levels and the correlation between serum HBsAg level and serum hepatitis B virus (HBV) DNA level were evaluated in these groups. RESULTS: In total, 180 HBeAg-positive CHB patients [IT group (n = 72), IC-Mild group (n = 72), and ACLF group (n = 36)] were enrolled in this study. The median serum HBsAg levels varied among the groups (P < 0.001): IT, 4.86 log10 IU/mL; IC-Mild, 3.97 log10 IU/mL; and ACLF, 3.57 log10 IU/mL. Serum HBsAg level showed a moderate positive correlation with serum HBV-DNA level in the IC-Mild group (r = 0.60, P < 0.001), but exhibited a weaker correlation in the IT (r = 0.52, P < 0.001) and ACLF groups (r = 0.51, P = 0.001). The ratio of HBsAg/HBV DNA did not differ significantly among the IT, IC-Mild, and ACLF groups (medians: 0.56, 0.55, and 0.56, respectively; P = 0.179). CONCLUSION: Serum HBsAg levels varied significantly in HBeAg-positive patients with different immune conditions. These findings may have important implications for understanding the immune clearance of HBV in HBeAg-positive CHB patients.

Hepatitis B surface antigen levels during natural history of chronic hepatitis B: a Chinese perspective study.

AIM: To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China. METHODS: Six hundred and twenty-three hepatitis B virus or un-infected patients not receiving antiviral therapy were analyzed in a cross-sectional study. The CHB patients were classified into five phases: immune-tolerant (IT, n = 108), immune-clearance (IC, n = 161), hepatitis B e antigen negative hepatitis (ENH, n = 149), low-replicative (LR, n = 135), and liver cirrhosis (LC, n = 70). HBsAg was quantified (Abbott ARCHITECT assay) and correlated with hepatitis B virus (HBV) DNA, and serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) in each phase of CHB was also determined. RESULTS: Median HBsAg titers were different in each phase of CHB (P < 0.001): IT (4.85 log10 IU/mL), IC (4.36 log10 IU/mL), ENH (2.95 log10 IU/mL), LR (3.18 log10 IU/mL) and LC (2.69 log10 IU/mL). HBsAg titers were highest in the IT phase and lowest in the LC phase. Serum HBsAg titers showed a strong correlation with HBV viral load in the IC phase (r = 0.683, P < 0.001). No correlation between serum HBsAg level and ALT/AST was observed. CONCLUSION: The mean baseline HBsAg levels differ significantly during the five phases of CHB, providing evidence on the natural history of HBV infection. HBsAg quantification may predict the effects of immune-modulator or oral nucleos(t)ide analogue therapy.

De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis.

AIM: To compare efficacy of combined lamivudine (LAM) and adefovir dipivoxil (ADV) therapy with that of entecavir (ETV) monotherapy for hepatitis B virus (HBV)-related decompensated liver cirrhosis. METHODS: A total of 120 naïve patients with HBV-related decompensated cirrhosis participated in this study. Sixty patients were treated with combined LAM and ADV therapy (LAM + ADV group), while the other 60 were treated with ETV monotherapy (ETV group) for two years. Tests for liver and kidney function, alpha-fetoprotein, HBV serum markers, HBV DNA load, prothrombin time (PT), and ultrasonography or computed tomography scan of the liver were performed every 1 to 3 mo. Repeated measure ANOVA and the χ(2) test were performed to compare the efficacy, side effects, and the cumulative survival rates at 48 and 96 wk. RESULTS: Forty-five patients in each group were observed for 96 wk. No significant differences in HBV DNA negative rates and alanine aminotransferase (ALT) normalization rates at weeks 48 (χ(2) = 2.12 and 2.88) and 96 (χ(2) = 3.21 and 3.24) between the two groups were observed. Hepatitis B e antigen seroconversion rate in the LAM + ADV group at week 96 was significantly higher in the ETV group (43.5% vs 36.4%, χ(2) = 4.09, P < 0.05). Viral breakthrough occurred in 2 cases (4.4%) by week 48 and in 3 cases (6.7%) by week 96 in the LAM + ADV group, and no viral mutation was detected. In the ETV group, viral breakthrough occurred in 1 case (2.2%) at the end of week 96. An increase in albumin (F = 18.9 and 17.3), decrease in total bilirubin and in ALT (F = 16.5, 17.1 and 23.7, 24.8), reduced PT (F = 22.7 and 24.5), and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores (F = 18.5, 17.8, and 24.2, 23.8) were observed in both groups. The cumulative rates of mortality and liver transplantation were 16.7% (10/60) and 18.3% (11/60) in the LAM + ADV and ETV groups, respectively. CONCLUSION: Both LAM + ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication, improve liver function, and decrease mortality.