One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C.

BACKGROUND: Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM: To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS: In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS: Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION: Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Validation of prognostic scores to predict short-term mortality in patients with HBV-related acute-on-chronic liver failure: The CLIF-C OF is superior to MELD, CLIF SOFA, and CLIF-C ACLF.

Acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) patients has a high short-term mortality. Identification of effective models to predict the short-term mortality may enable early intervention and improve patients' prognosis. We aim to assess the performance of the CLIF Consortium Organ Failure score (CLIF-C OFs), CLIF sequential organ failure assessment score (CLIF-SOFAs), CLIF Consortium ACLF score (CLIF-C ACLFs), ACLF grade, and model for end-stage liver disease score (MELDs) in predicting the short-term mortality in CHB patients with ACLF.Among the 155 consecutive adult patients with liver failure as a discharge diagnosis were screened, and all the patients were treated at the Department of Infectious Diseases, Huashan Hospital, Fudan University (Shanghai, China) from January 2010 to February 2016. The diagnosis of ACLF was based on the criteria formalized by the ACLF consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Diagnostic accuracy for predicting short-term (28-day) mortality was calculated for CLIF-C OFs, CLIF-SOFAs, CLIF-C ACLFs, ACLF grade, and MELDs in all patients.One hundred fifty-five consecutive adult liver failure patients were screened and 85 patients including 73 males and 12 females were enrolled. Overall, the 28-day transplant-free mortality was 32% in all patients, and 100% in those with severe early course (ACLF-3). The area under the receiver operating characteristic curve (AUROC) of CLIF-C OFs (AUROC: 0.906, P = .0306, compared with MELDs) was higher than those of CLIF-SOFAs (AUROC: 0.876), CLIF-C ACLFs (AUROC: 0.858), ACLF grade (AUROC: 0.857), and MELDs (AUROC: 0.838) for predicting short-term mortality. The cut-point for baseline CLIF-C OFs in predicting death was 8.5, with 67% sensitivity, 90% specificity, and AUROC of 0.906 (95% CI: 0.8450-0.9679).The results indicate that short-term mortality is high in patients with ACLF and CLIF Consortium Organ Failure score is superior to MELD, CLIF SOFA, and CLIF-C ACLF in predicting its short-term mortality.

Fever of unknown origin: report of 107 cases in a university hospital.

Fever of unknown origin (FUO) is a challenging problem in clinical practice. Evaluation of patient's characteristics may illustrate the etiologies of FUO. In present study, 107 patients with FUO hospitalized in our inpatient department between 2010 and 2011 were investigated. The median age of the patients was 48 years (15-94). The median fever duration was 8.5 weeks (3-104). The median hospital stay was 8.5 days (1-51). Etiologies of FUO were identified as follows: infectious diseases 32 (29.9%), malignancies 19 (17.8%), inflammatory rheumatic diseases 18 (16.8%), and miscellaneous diseases 15 (14.0%). In 23 (21.5%) patients, the diagnosis remained unclear. Infection group had relative shorter average fever duration and hospital stay than other groups. Shortened mean fever duration was observed in geriatric age group. In conclusion, as the most common cause of FUO in the present study, infectious cases had relative shorter average fever duration and hospital stay, and geriatric patients had shortened average fever duration as well.

[Analysis of a randomized, double-blind, double-dummy, controlled, multicenter study confirmed the similar therapeutic efficacies of entecavir maleate and entecavir for treatment of HBeAg-positive chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of entecavir maleate (ETV) versus ETV in Chinese patients with hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB). METHODS: The patient population of this previously published randomized, double-blind, double-dummy, controlled, multicenter study was expanded by patients in the 0.5 mg/day ETV maleate group (total n = 110) and patients in the 0.5 mg/day ETV group (total n = 108). At treatment weeks 12, 24 and 48, hepatitis B virus (HBV) DNA levels were measured by the Roche Cobas Ampliprep/Cobas Taqman PCR assay. Adverse events (AE) were recorded. RESULTS: As in the original analysis, the two treatment groups showed similar characteristics at baseline. In addition, the results for the all therapeutic effects showed identical trends to the results obtained in the original analysis, including the statistically similar effects of ETV and ETV maleate treatment-induced decreases in mean HBV DNA level at weeks 12, 24, and 48 (ETV: by 4.28, 5.00, and 5.53 log10 IU/ml vs. ETV maleate: by 4.46, 4.99, and 5.51 log10 IU/ml, respectively; all vs. baseline P more than 0.05), achievement of undetectable levels of serum HBV DNA ( less than 20 IU/ml) at week 48 (ETV: 38.18% vs. ETV maleate: 35.19%; P more than 0.05), HBeAg loss rates at week 48 (ETV: 10.91% vs. ETV maleate: 12.96%; P more than 0.05), HBeAg seroconversion rates at week 48 (ETV: 7.77% vs. ETV maleate: 10.38%; P more than 0.05), normalization of alanine aminotransferase at week 48 (ETV: 75.47% vs. ETV maleate: 82.86%; P more than 0.05), and overall incidence of AE (ETV: 18.02% vs. ETV maleate: 17.43%; P more than 0.05). CONCLUSION: Performing analysis of the therapeutic efficacies of entecavir maleate versus entecavir with a larger study population confirmed our original findings of similar efficacy and safety profiles for these two drugs in patients with HBeAg-positive CHB.

[Study on type I interferon and phospho-IRF3 in murine liver dendritic cells after intervened by HBV].

OBJECTIVE: To detect the secretions of type I interferon and the expressions of phospho-IRF3 in murine liver dendritic cells intervened by HBV. METHODS: The murine liver dendritic cells were isolated via anti-CD11c microbeads and were incubated in the presence of GM-CSF and IL-4 to induce the DC generation and proliferation in 24-well cell culture plates. HBV virions were isolated via ultracentrifugation and were detected by quantitative Realtime-PCR. The DCs were divided into two groups: one group was cultured with HBV virions for 24 hours, the other group was cultured without HBV as control group. The cells were harvested at Oh, 1h, 2h, 6h and 24h after being stimulated with poly I:C and the expressions of p-IRF3 and the concentration of IFN beta in supernatants were detected with western blot and ELISA respectively. RESULTS: The IFN beta concentrations at 0 h, 6 h and 24 h in the supernatants of the HBV group and the control group were (12.38 +/- 3.71) pg/ml, (88.67 +/- 9.01) pg/ml and (69.89 +/- 5.80) pg/ml vs (10.83 +/- 4.11) pg/ml, (137.68 +/- 12.28) pg/ml and (72.25 +/- 8.61) pg/ml, respectively. No statistical differences found at 0 h (t = 0.8398, P > 0.05) and 24 h (t = 0.6820, P > 0.05) between the two groups except that at 6 h (t = 9.653, P < 0.01). The expressions of phospho-IRF3 in HBV group were lower than that in control group. CONCLUSIONS: The type I interferon secretion and the phospho-IRF3 expression were decreased in murine liver dendritic cells when intervened by HBV.

Correlation of the expression of toll-like receptors in monocyte-derived dendritic cells with prognosis of chronic severe hepatitis B.

OBJECTIVE: This study aims to measure the expression of toll-like receptors (TLR) in monocyte-derived dendritic cells (MoDC) from chronic severe hepatitis B (CSHB), to assess the contribution of TLRs in CSHB. METHODS: Peripheral blood was collected from 40 CSHB patients, 30 chronic hepatitis B (CHB) patients, and 30 healthy individuals who served as healthy controls (HCs). Purified monocytes were isolated by a combination of Histopaque-1.077 and CD14 Microbeads. MoDCs were induced with granulocyte macrophage colony-stimulating factor and interleukin-4 for 6 days from CD14(+) monocytes. The expression of TLRs in MoDC was measured using real-time PCR and flow cytometry. RESULTS: The expressions of TLR-1, -2, -7 were significantly higher in MoDC of CSHB than that of HCs, of which the level of TLR-3 was decreased. Particularly in CSHB patients, the TLR-3 expression was further decreased compared to CHB patients. In non-survival CSHB patients, TLR-3 level was significantly decreased, while TLR-2 expression was dramatically increased. Linear correlation analysis demonstrated significant correlations between TLR-3 level and disease severity markers (total bilirubin, prothrombin activity, creatinine, white blood cell count, and maximum volume of ascitic fluid) in individual CSHB patients. CONCLUSIONS: TLR-2 and TLR-3 may be involved in the pathogenesis of CSHB, and TLR-3 may influence the prognosis of CSHB.

[Expression of nuclear factor-κB and its regulated cytokines in dendritic cells in patients with chronic severe hepatitis B and its clinical significance].

OBJECTIVE: To investigate the correlation of nuclear factor-κB (NF-κB) level and its regulated cytokines in monocyte-derived dendritic cells (MoDC) with illness severity and prognosis in patients with chronic severe hepatitis B (CSHB). METHODS: Peripheral blood mononuclear cells (PBMC) were isolated by Ficoll density gradient separation from 37 patients with CSHB, 20 chronically HBV-infected patients, and 20 normal controls. Monocytes were acquired using immunomagnetic anti-CD14-beads. Next, monocytes were induced into immature DC (iDC) in vitro. On day six, polyI:C was added to induce DC maturation. Then mature DCs (mDCs) were collected at 48 h after polyI:C treatment to test the expression of NF-κB p50 by real time PCR. The supernatants were also collected respectively. The expression of TNFα and IL-6 in the supernatants were measured by ELISA. RESULTS: The expression of NF-κB p50 in mDCs of patients with CSHB was the highest in three groups (F=19.01, P<0.01). The secretion of TNFα and IL-6 in mDCs from group CSHB was extremely high when compared with the other two groups, the secretions of TNFα in groups CSHB, CHB and NC were(15317.69+/-4124.90) pg/ml, (9670.29+/-3654.68) pg/ml and (6547.43+/-1027.20) pg/ml (F=45.77, P<0.01) respectively, and the productions of IL-6 in groups CSHB, CHB and NC were (1423.78+/-375.14) pg/ml, (862.68+/-93.68) pg/ml and (567.26+/-167.04) pg/ml (F = 67.60, P is less than 0.01), respectively. NF-κB p50 showed significant correlations with TNFα(r=0.52, P<0.01) and IL-6 (r=0.65, P<0.01) in mDCs. Furthermore, the secretions of TNFα and IL-6 in mDCs from group CSHB were negatively associated with PTA (r=-0.41, P=0.01; r=-0.40, P=0.01), but not with ALT, TBil and virus loads (r=-0.03, P=0.85, r=0.01, P=0.93, r=0.01, P=0.95; r=-0.09, P=0.58, r=0.16, P=0.34, r=0.09, P=0.59). No significant difference found in the expression of TNFα and IL-6 between the survival subgroup and the death subgroup in group CSHB (t=0.42, P=0.67; t=0.76, P=0.45). CONCLUSIONS: The expression levels of NF-κB and its regulated cytokines in monocyte-derived DCs in patients with chronic severe hepatitis B were up-regulated and perhaps associated positively with the illness severity.

[Clinical analysis of 6 cases with cerebral sparganosis mansoni].

A retrospective study was carried out to analyze 6 cases of cerebral sparganosis mansoni in Huashan Hospital from August 2005 to August 2009. The epidemiological features, clinical characteristics, therapeutic approaches and outcome of this disease were investigated. Among the patients, 4 cases had a history of eating raw frogs or snakes. 5 showed eosinophilia in peripheral blood, all with positive anti-Sparganum mansoni antibody in serum and cerebrospinal fluid. Cerebral MRI showed placeholder in all patients. Diagnosis was confirmed by pathological examination of operation and species identification. All patients were cured by operation removal and praziquantel treatment.

[A multicenter clinical study of nafate for treatment of hepatic fibrosis in patients with chronic liver diseases].

OBJECTIVES: To investigate the effect of nafate (compound fetal cow liver extract tablets) in hepatic fibrosis patients with chronic liver diseases. METHODS: One hundred fifteen hepatic fibrosis patients with chronic liver diseases from 3 medical centers were included in this study. All patients were given nafate orally for twenty-four weeks. Before treatment and 12, 24 and 36 weeks after the treatment, serum levels of hyaluronic acid (HA), laminin (LN) and type IV collagen (IV-C) of the patients were measured by radioimmunoassay and their liver biopsy specimens were also assessed. RESULTS: Before treatment and 24 and 36 weeks after the nafate treatment, serum levels of HA were (279.2+/-81.4) ng/ml, (136.8+/-56.7) ng/ml and (86.9+/-40.7) ng/ml respectively, serum levels of LN were (170.8+/-73.0) ng/ml, (112.5+/-39.5) ng/ml, and (60.8+/-31.8) ng/ml respectively, and IV-C levels were (153.7+/-60.1) ng/ml, (112.4+/-43.1) ng/ml, and (96.3+/-44.1) ng/ml respectively. There was a significant reduction in these serum values after the treatments. Histopathological examinations of the liver biopsies showed that the degree of hepatic fibrosis obviously declined by one or two degrees after the treatments. CONCLUSIONS: nafate has positive effects in treating hepatic fibrosis.

[Phenotypes and functions of dendritic cells derived from peripheral blood monocytes of chronic hepatitis B patients with different HBV DNA loads].

OBJECTIVE: To investigate the phenotypes and functions of peripheral blood monocyte derived dendritic cells (DC) of chronic hepatitis B (CHB) patients with different HBV DNA loads. METHODS: Twenty-eight CHB patients were included in this study. All patients were treated with nucleoside analogues (lamivudine or LdT or adefovir) for 24 weeks. Peripheral blood HBV DNA loads and liver biopsies were assessed before and after the treatment. The patients were divided into two groups according to their peripheral blood HBV DNA loads: a high-load group with HBV DNA loads higher than 10(5) copies/ml, and a low-load group with HBV DNA loads lower than 10(3) copies/ml. Ten healthy people were included as controls. Peripheral blood DC of each subject was enriched. The phenotypes of DC were subjected to flow cytometric analysis. The lymphocyte allo-stimulatory capacity of DC was evaluated through MTT assay. IL-10 and IL-12 production were quantified by ELISA. RESULTS: DC proliferated successfully when stimulated by cytokines in vitro; however, DC of the CHB patients proliferated much slower than those of the healthy controls. The expression of DC surface molecules such as HLA-DR, CD86, CD80 and CD83 had a positive rate of over 80% in the normal population. However in our CHB patients they showed lower than normal expressions, especially the HLA-DR, CD86, CD80 and CD83, but the differences were not significant between the two groups with different virus loads. The stimulatory capacity of the DC in mixed lymphocyte reaction showed no difference between the two groups of patients, but both were lower than that of the healthy controls. The production of IL-12 and IL-10 also decreased significantly in the patients. CONCLUSIONS: Peripheral DC of CHB patients have some defects in their phenotypes and their stimulatory capacity. The changes in phenotypes and down-regulation of the functions are not relevant to peripheral HBV DNA loads of the patients.

[Hepatic safety of itraconazole intravenous solution in treatment of invasive fungal infection].

OBJECTIVE: To investigate the hepatic safety of itraconazole intravenous solution in the treatment of invasive fungal infection. METHODS: Forty-nine patients with invasive fungal infection, such as pneumonia, meningitis, endocarditis, and blood stream infection, caused by Aspergillus spp. Cryptococcus neoformans, Candida spp. Penicillium marneffei, and Prototheca wickerhamii, 50 of which had underlying diseases, including hepatic diseases, such as hepatitis, cirrhosis, fatty liver etc. were treated with intravenous itraconazole for 12.6 days (2 - 42 days). Liver function test was conducted before and after the treatment. The relationship between liver adverse reaction and itraconazole treatment was evaluated. RESULTS: Liver function test was abnormal in 20 patients. The patients with liver enzyme abnormalities before itraconazole treatment were easier to suffer from hepatic damage during itraconazole treatment (chi(2) = 11.54, P = 0.001). However, only in 2 patients with mild liver function test abnormality the liver adverse reaction could be associated with itraconazole treatment. CONCLUSION: Itraconazole treatment for invasive fungal infection is rather safe, even in the patients with underlying hepatic diseases. Liver function test is recommended for all patients suggestive of liver dysfunction and protective therapy for liver is needed.

Effects of oxymatrine on experimental hepatic fibrosis and its mechanism in vivo.

AIM: Hepatic fibrogenesis has close relation with hepatic stellate cells (HSC) and tissue inhibitors of metalloproteinase (TIMP). Oxymatrine (OM) is a kind of Chinese herb that is found to have some effects on liver fibrosis. We aimed to determine the effects of OM on hepatic fibrosis and explore the possible mechanism. METHODS: Thirty-two rats were randomly divided into four groups; 16 were used to develop hepatic fibrosis by carbon tetrachloride (CCl4) and treated with or without OM, and 16 were used as controls. The expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and alpha-smooth muscle actin (alpha-SMA) in the livers of rats was detected by immunohistochemical assay. Liver pathology was determined by H and E staining and reticulum staining. RESULTS: In CCl4-injured rats, the normal structure of lobules was destroyed, and pseudolobules were formed. Hyperplasia of fibers was observed surrounding the lobules. While the degree of fibrogenesis in liver tissues was significantly decreased in those rats with OM-treatment compared with those without OM treatment. The pseudolobules were surrounded by strong, multi-layer reticular fibers, which netted into pseudolobules in CCl4-injured rats, however, there was a significant decrease in reticular fibers in OM-treated rats. The expression of TIMP-1 in hepatic cells was weak in control groups, but strong in CCl4-injured groups, however, the expression of TIMP-1 was significantly inhibited by OM (F = 52.93, P<0.05). There was no significant change in the expression of alpha-SMA between CCl4-injured rats with or without OM treatment (F = 8.99, P>0.05). CONCLUSION: OM effectively inhibits CCl4-induced fibrogenesis in rat liver tissues, probably by reducing the expression level of TIMP-1.