Comparison of Interferon-α-based therapy and nucleos(t)ide analogs in preventing adverse outcomes in patients with chronic hepatitis B.

BACKGROUND: Whether interferon (IFN)-α therapy is better than nucleos(t)ide analogs (NAs) in the prevention of adverse outcomes, including hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is still uncertain or controversial. This study aimed to compare the cumulative incidence of adverse outcomes in patients with CHB on IFN-α- and NA-based therapies. METHODS: This was a retrospective study of patients with CHB on antivirals. Patients treated with IFN-α (IFN-α or peginterferon-α) with or without NAs were defined as the IFN-α group, and those only receiving NAs were defined as the NAs group. Propensity score matching (PSM) was used to minimize baseline bias. Cox regression models were performed to select possible factors related to adverse outcomes development. RESULTS: All 1247 patients were divided into the IFN-α (n = 877) and NAs (n = 370) groups. 26patients (20 and 6 in the NAs and IFN-α groups) developed adverse outcomes (decompensated cirrhosis, liver failure, HCC, liver transplantation and deaths) during a median follow-up of 5.2 years. The cumulative adverse outcomes occurrence at 10 years was significantly lower in the IFN-α group than in the NAs group in all (1.1% vs. 11.9%, P <0.001) and treatment-naïve (1.1% vs. 12.4%, P <0.001) patients. Similar trends were observed after PSM and differentiation of cirrhosis. Multivariate analysis before and after PSM showed that IFN-α-based treatment was independently associated with a lower adverse outcomes incidence (before/after PSM: P = 0.001/P = 0.002). HCC risk stratification analyses revealed that the superiority of IFN-α in preventing HCC was more significant in patients with high-risk HCC. CONCLUSIONS: IFN-α-based therapy was superior to NAs in preventing adverse outcomes in patients with CHB regardless of cirrhosis, and in reducing HCC in those with a high risk of HCC.

Predictive value of plasmacytoid dendritic cells and Toll-like receptor-9 regarding the treatment efficacy of interferon-α in HBeAg-positive chronic hepatitis B patients.

Hepatitis B virus (HBV) infection represents a public health threat and a challenge for the medical community. Untimely treatment may lead to liver cirrhosis and even liver cancer. At present, the major treatment for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients includes administration of interferon-α (IFN-α), which has anti-viral and immunomodulatory effects. Plasmacytoid dendritic cells (pDCs) and Toll-like receptor-9 (TLR-9) have important roles in anti-viral therapy. However, their predictive value regarding the efficacy of IFN-α treatment of HBeAg-positive chronic hepatitis B (CHB) patients has remained elusive. A total of 178 patients with CHB and HBeAg-positive status, who had not received any previous anti-HBV treatment, were enrolled in the present study. All patients were treated with IFN-α. HBV DNA load, hepatitis B surface antigen and serum alanine aminotransferase were measured prior to and following 48 weeks of treatment. According to HBV levels, the patients were divided into a response group and non-responders group. To determine the amount of pDCs, blood dendritic cell antigen 2 (BDCA-2)- and immunoglobulin-like transcript 7 (ILT7)-expressing cells in liver biopsies were detected using immunohistochemistry. TLR-9 expression in peripheral blood mononuclear cells was determined by reverse transcription-quantitative PCR. There was no significant difference in the proportion of pDCs (BDCA-2; ILT7) and TLR-9 mRNA expression between the response group and the non-responders group prior to IFN-α treatment. After IFN-α treatment, BDCA-2, ILT7 and TLR-9 mRNA expression was obviously increased in the response group compared with that in the non-responders group (P<0.05). Increased expression of BDCA-2, ILT7 and TLR-9 mRNA was negatively correlated with HBV DNA (P<0.05). Increased levels of pDCs and TLR-9 were negatively correlated with HBV DNA, and were thus capable of predicting the IFN-α treatment response in patients with CHB and HBeAg-positive status.

[Predictors and scoring system for sustained complete response to conventional interferon-alpha therapy on chronic hepatitis B].

OBJECTIVE: To establish a predictive scoring system which may serve for the prediction of sustained response to conventional interferon-alpha (IFN-alpha) treatment on chronic hepatitis B. METHODS: A total of 474 IFN-alpha treated hepatitis B virus e antigen (HBeAg)-positive patients were enrolled in the present study. The patients' baseline characteristics, such as age, gender, aminotransferases, activity grading (G) of intrahepatic inflammation, score (S) of liver fibrosis, hepatitis B virus (HBV) DNA and genotype were evaluated; therapy duration and response of each patient at the 24th wk after cessation of IFN-alpha treatment were also recorded. A predictive scoring system for a sustained complete response (CR) to IFN-alpha therapy was established based on genetic algorithm. About 10% of the patients were randomly drawn out as the test set. Responses to IFN-alpha therapy were divided into CR, partial response (PR) and non-response (NR). The mixed set of PR and NR was recorded as PR + NR. RESULTS: For the scoring system, the sensitivity and specificity were 78.8% and 80.6%, respectively. CONCLUSION: This SCR scoring system has satisfying prediction efficiency and is easily employed in clinical practice. With this scoring system, practitioners can propose individualized decisions that have an integrated foundation on both evidence-based medicine and personal characteristics.

Precise prediction model and simplified scoring system for sustained combined response to interferon-alpha.

AIM: To establish a predictive algorithm which may serve for selecting optimal candidates for interferon-alpha (IFN-alpha) treatment. METHODS: A total of 474 IFN-alpha treated hepatitis B virus e antigen (HBeAg)-positive patients were enrolled in the present study. The patients' baseline characteristics, such as age, gender, blood tests, activity grading (G) of intrahepatic inflammation, score (S) of liver fibrosis, hepatitis B virus (HBV) DNA and genotype were evaluated; therapy duration and response of each patient at the 24th wk after cessation of IFN-alpha treatment were also recorded. A predictive algorithm and scoring system for a sustained combined response (CR) to IFN-alpha therapy were established. About 10% of the patients were randomly drawn as the test set. Responses to IFN-alpha therapy were divided into CR, partial response (PR) and non-response (NR). The mixed set of PR and NR was recorded as PR+NR. RESULTS: Stratified by therapy duration, the most significant baseline predictive factors were alanine aminotransferase (ALT), HBV DNA level, aspartate aminotransferase (AST), HBV genotype, S, G, age and gender. According to the established model, the accuracies for sustained CR and PR+NR, respectively, were 86.4% and 93.0% for the training set, 81.5% and 91.0% for the test set. For the scoring system, the sensitivity and specificity were 78.8% and 80.6%, respectively. There were positive correlations between ALT and AST, and G and S, respectively. CONCLUSION: With these models, practitioners may be able to propose individualized decisions that have an integrated foundation on both evidence-based medicine and personal characteristics.

[A study of the causes of poor antiviral responses in male chronic hepatitis B patients treated with recombinant interferon-alpha].

OBJECTIVE: To study the causes of poorer antiviral response to neutralizing anti-interferon-alpha antibodies (NA) in male chronic hepatitis B patients treated with recombinant interferon-alpha (rIFN-alpha). METHODS: Two hundred sixty-nine patients (198 males and 71 females) with histologically proven chronic hepatitis B were treated with 5 MU recombinant interferon-alpha 1b (rIFN-alpha 1b) subcutaneously thrice weekly for 6-37 (median 10.0) months. For each patient, serum HBV DNA levels were detected with fluorescent-quantitative PCR, HBeAg with enzymoimmunoassay, and NA with an antiviral neutralizing biological assay during therapy. RESULTS: NA was found in 70 (35.4%) of the 198 males and in 15 (21.1%) of the 71 females during treatment (x2 = 4.894, P = 0.027). At the end of treatment combined-response was achieved in 21 (24.7%) of the 85 NA-positive patients and in 100 (54.3%) of the 184 NA-negative cases (x2 = 20.642). Stratification analysis by NA showed that combined-response rate was significantly lower in males than in females (18.6%, 13/70 vs. 53.3%, 8/15, x2 = 8.024) among NA-positive patients while it was similar in males and in females (50.8%, 65/128, vs. 62.5%, 35/56, x2 = 2.156) among NA-negative patients. In stratification analysis by gender, it was significantly lower in NA-positive patients than in NA-negative ones (18.6%, 13/70 vs. 53.3%, 8/15, x2 = 8.024) among males but there was no significant difference between combined-response rates among females. CONCLUSION: The poorer antiviral response to recombinant interferon-alpha in male chronic hepatitis B patients than in female patients is related to the neutralizing anti-interferon antibodies.

[Expressions of vascular endothelial growth factor and nm23-H1 gene and their relation to the prognosis of breast cancer in young women].

OBJECTIVE: To investigate the expressions of vascular endothelial growth factor (VEGF) and nm23-H1 gene in breast cancer tissues and their relation to the prognosis in young women. METHODS: The expressions of VEGF and nm23-H1 gene were detected using immunohistochemical method (SP) in the breast cancer tissues of 48 young and 30 postmenopausal women with breast cancer and in breast fibroadenoma tissues of 10 patients for analysis of the association of the expressions with the patients' clinical and pathological characteristics, with also observation of the 5-year survival rate in each patient group. RESULTS: The rates of axillary lymph node metastasis was higher in the young women than in the postmenopausal women, who also had significantly different rates of VEGF and nm23-H1 expressions in the breast cancer tissues (P<0.01, P<0.01 and P<0.05, respectively); between the two breast cancer groups and breast fibroadenoma group, the expressions were also different (P<0.01). In both young and postmenopausal women with breast cancer, patients with axillary lymph node metastasis had significantly higher positivity rate of VEGF expression than those without (P<0.01 and P<0.01), but the reverse was found true in the expression of nm23-H1 gene. VEGF expression was inversely correlated with nm23-H1 expression in young patients (P<0.01), and the 5-year survival rate of patients with nm23-H1 gene expression was higher than that of p53-positive patients (P<0.05). No significant correlation of VEGF and nm23-H1 expressions with the differentiation of the tumor was found (P>0.05). CONCLUSION: The expressions of VEGF and nm23-H1 indicate the angiogenetic activity and invasion of breast cancer, and have a close relation to the prognosis in young women.

[Efficacy of interferon-alpha therapy for HBeAg-negative chronic hepatitis B and its influencing factors].

OBJECTIVE: To investigate the efficacy of interferon-alpha (IFN-alpha) therapy for HBeAg-negative chronic hepatitis B. METHODS: Sixty-five Chinese HBeAg-negative chronic hepatitis B patients were treated with 5 MU recombinant rIFN-alpha 1b subcutaneously thrice weekly for 5 to 24 months, followed by 12 months of treatment-free follow-up; one hundred and eighty-eight Chinese HBeAg-positive patients served as controls. For each patient, serum alanine transaminase (ALT) was measured biochemically and serum HBV DNA level was detected with fluorescent-quantitative PCR, HBeAg with enzymoimmunoassay every 1 to 3 months during therapy and during the follow-up period. HBeAg loss (only for HBeAg-positive cases), HBV DNA undetectable, and ALT normalization: the three together were considered a combined response. RESULTS: Rates of combined response were similar in HBeAg-negative patients (58.5%, 38/65) or HBeAg-positive ones at the end of treatment (weighted chi square test, chi2 = 1.878, P<0.05), but were higher at the end of the follow-up period in the HBeAg-negative cases (75.4%, 49/65) (weighted chi square test, chi2 = 4.796, P<0.05). Furthermore, relapse rates at the end of the follow-up period, were also similar in HBeAg-negative patients (15.8%, 6/38) or HBeAg positive (chi2 = 0.205, P>0.05). Combined response was achieved at a median of 6.0 months (2-16 months) of treatment course in HBeAg-negative patients while at a median of 6.0 months (1-22 months) in HBeAg-positive cases (Z = -0.186, P>0.05, by the Wilcoxon rank sum test). The only factor predictive of combined response, by binary logistic regression analysis, was inflammatory activity in the liver biopsy. Gender, age, baseline ALT level, baseline HBV DNA level, and anti-HBe were not predictive factors. CONCLUSION: Interferon-alpha therapy induces a similar primary and sustained response in HBeAg-negative and in HBeAg-positive chronic hepatitis B patients.

[Clinical significance of neutralizing anti-interferon antibodies in chronic hepatitis B patients treated with recombinant interferon-alpha].

OBJECTIVE: To investigate the clinical significance of neutralizing anti-interferon-alpha antibodies (NA) in chronic hepatitis B patients treated with recombinant interferon-alpha(rIFN-alpha). METHODS: One hundred and eighty-one patients (128 male and 53 female) with histological proven chronic hepatitis B were treated with 5 MU recombinant interferon-alpha 1b (rIFN-alpha 1b) subcutaneously thrice weekly for 6 to 37 (median 10) months. For each patient, Specific detection of serum HBV DNA level with fluorescent-quantitative PCR, HBeAg with enzymoimmunoassay and NA with an antiviral neutralizing biological assay were performed during therapy. RESULTS: NA was found in 61 (33.7%) of 181 patients. At the end of treatment, complete-response was achieved in 17 (27.9%) of 61 patients with NA and in 54 (45.0%) of 120 patients without NA, respectively (chi2=4.979). For NA positive patients, the complete-response rate was significantly lower in those who had not achieved partial-response prior to or at the same time as NA occurred than in those who did (3.8%, 1/26, vs. 45.7%, 16/35, chi2 = 7.457). Moreover, it was lower in patients who either had 20pg/ml of serum HBV DNA or above or HBV DNA had being reduced by less than 60% recent 3 months, but higher in those who had less than 20pg/ml of HBV DNA and HBV DNA had being reduced by 60% or above (20.0%, 9/45, vs. 56.3%, 9/16, chi2 = 11.009). CONCLUSION: NA may negate the antiviral effects of rIFN-alpha in chronic hepatitis B patients treated with rIFN-alpha, especially if they appear before partial-response or at the occasion at which serum HBV DNA level was not below 20pg/ml or HBV DNA had being reduced by less than 60% recent 3 months.

[Generation of neutralizing anti-interferon antibodies and factors influencing their production in chronic hepatitis B patients receiving recombinant interferon-alpha treatment].

OBJECTIVE: To investigate the generation of neutralizing anti-interferon-alpha antibodies (NA) in patients with chronic hepatitis B in the course of interferon-alpha treatment, and analyze the factors influencing the production of the antibodies. METHODS: A total of 181 patients with histologically confirmed chronic hepatitis B were enrolled in this study. Recombinant interferon-alpha 1b (rIFN-alpha 1b) was given subcutaneously 3 times a week (5 MU once) in a treatment course lasting for 6 to 37 months (median 10.0 months). In each case, serum NA was detected with antiviral neutralization bioassay, HBeAg with enzyme-linked immunoassay (EIA) and hepatitis B virus DNA with fluorescent quantitative PCR every 1 to 3 months starting from 3 months after the initiation of the treatment. RESULTS: Of the 181 patients, 61 were positive for NA during the treatment course, resulting in an overall NA occurrence rate of 33.7%. The overall incidence rate, as well as the overall prevalence rate, was significantly higher in male than in female patients (39.1% vs 20.8%, (2)=5.622, P=0.018), and no correlations of NA generation was observed with age, pretreatment serum ALT level, serum HBeAg, serum HBV DNA level, liver histological findings or treatment course. Binary logistic regression analysis showed that the only factor in relation with NA production was gender. The prevalence rates of NA varied significantly with the treatment courses ( (2)=98.051, P=0.000). Bivariate correlation analysis showed that the prevalence rate of NA, but not the incidence of NA, was strongly related with the treatment course (r=0.855, P<0.001). CONCLUSIONS: In chronic hepatitis B patients treated with rIFN-alpha 1b, the prevalence rate of NA, instead of the incidence of NA, is significantly related to the treatment course. NA was more likely to develop in male patients to contribute to their poorer antiviral response in comparison with the female patients.