A randomized, open-label clinical study of combined pegylated interferon Alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B.

BACKGROUND: Treatment with pegylated interferon (peg-IFN) alfa-2a (40KD) results in hepatitis B "e" antigen (HBeAg) seroconversion 6 months after treatment in up to 36% of HBeAg-positive chronic hepatitis B patients. This study explored the efficacy of a novel combination of peg-IFN alfa-2a and entecavir (ETV), a potent nucleoside analogue. METHODS: In total, 218 treatment-naive Chinese HBeAg-positive patients were randomized to peg-IFN alfa-2a (180 µg/week) for 48 weeks, either as monotherapy (n = 72), or with 24 weeks of ETV (0.5 mg/daily) added at week 13 (ETV add-on, n = 73), or pretreatment with a 24-week course of ETV, starting peg-IFN alfa-2a at week 21 (ETV pretreatment, n = 73). The primary endpoint was reduction in quantitative HBeAg from baseline to 24 weeks posttreatment. RESULTS: Significant reductions in HBeAg from baseline were achieved in all treatment groups 24 weeks posttreatment; reductions were comparable across treatment arms (shown as log10 Paul Ehrlich international units [PEIU]/mL): monotherapy: -1.4 (SD, 1.8); ETV add-on: -1.6 (SD, 1.8); ETV pretreatment: -1.3 (SD, 1.7). Rates of HBeAg seroconversion were similar across treatment groups posttreatment (monotherapy: 22 [31%]; ETV add-on: 18 [25%]; ETV pretreatment: 19 [26%]). Significantly greater reductions of hepatitis B virus DNA were achieved with ETV add-on while on treatment, but were not sustained posttreatment. Safety profiles were comparable between treatment groups; adverse events were experienced by 62 (86%) monotherapy, 65 (89%) ETV add-on, and 58 (81%) ETV pretreatment patients. CONCLUSIONS: Neither ETV add-on nor ETV pretreatment demonstrated superiority compared with 48 weeks of peg-IFN alfa-2a monotherapy. The optimal treatment strategy using nucleos(t)ide analogues and peg-IFN alfa-2a remains to be determined. Clinical Trials Registration. NCT00614471.

Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial).

BACKGROUND & AIMS: Durable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a. METHODS: Hepatitis B e antigen (HBeAg)-positive CHB patients who had received ETV for 9-36 months, with HBeAg <100 PEIU/ml and HBV DNA ⩽1000 copies/ml, were randomised 1:1 to receive peginterferon alfa-2a 180 µg/week or ETV 0.5mg/day for 48 weeks. The primary endpoint was HBeAg seroconversion at week 48 (ClinicalTrials.gov: NCT00940485). RESULTS: 200 patients were randomised; 197 received ⩾1 study drug dose. Five patients who were anti-HBe-positive at baseline were excluded from the modified intention-to-treat population (peginterferon alfa-2a, n = 94; ETV, n = 98). Patients who switched to peginterferon alfa-2a achieved higher week 48 HBeAg seroconversion rates vs. those who continued ETV (14.9% vs. 6.1%; p = 0.0467). Only patients receiving peginterferon alfa-2a achieved HBsAg loss (8.5%). Among peginterferon alfa-2a-treated patients with HBeAg loss and HBsAg <1500 IU/ml at randomisation, 33.3% and 22.2% achieved HBeAg seroconversion and HBsAg loss, respectively. Early on-treatment HBsAg decline predicted response at week 48; highest rates were observed in patients with week 12 HBsAg <200 IU/ml (HBeAg seroconversion, 66.7%; HBsAg loss, 77.8%). Alanine aminotransferase elevations were not associated with viral rebound (n = 38). Peginterferon alfa-2a was well-tolerated. CONCLUSIONS: For patients who achieve virological suppression with ETV, switching to a finite course of peginterferon alfa-2a significantly increases rates of HBeAg seroconversion and HBsAg loss. A response-guided approach may identify patients with the greatest chance of success.

Sustained immune control in HBeAg-positive patients who switched from entecavir therapy to pegylated interferon-α2a: 1 year follow-up of the OSST study.

BACKGROUND: In the OSST study, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who switched from long-term entecavir (ETV) therapy to pegylated interferon-α2a (PEG-IFN-α2a; 40 kDa) achieved higher rates of HBeAg seroconversion and hepatitis B surface antigen (HBsAg) loss than those who continued ETV. Herein we report the sustainability of serological responses during 1 year of untreated follow-up in patients who switched from ETV to PEG-IFN-α2a therapy. METHODS: A total of 62 patients who completed 48 weeks of PEG-IFN-α2a therapy were followed-up for 48 weeks off treatment. Primary end points were HBeAg seroconversion and maintenance of HBeAg seroconversion at 48 weeks post-treatment. Secondary end points included HBsAg loss, HBV DNA <1,000 copies/ml and alanine aminotransferase normalization (<1× upper limit of normal). RESULTS: The HBeAg seroconversion rate increased from 17.7% (11/62) at the end of treatment to 38.7% (24/62) 1 year post-treatment. Sustained HBeAg seroconversion was achieved by 63.6% (7/11) patients with end-of-treatment responses, while late HBeAg seroconversion was achieved by 33.3% (17/51) of patients who did not have end-of-treatment responses. Sustained HBsAg loss was documented in 6 of 7 patients, and sustained HBV DNA suppression was achieved in 60% (27/45) of patients with an end-of-treatment response. CONCLUSIONS: In patients who do not achieve HBeAg seroconversion during long-term ETV therapy, switching to finite treatment with PEG-IFN-α2a produces HBeAg seroconversion in a substantial proportion of patients at end of treatment and during 1 year of follow-up. Moreover, HBeAg seroconversion and HBsAg loss are sustained in most patients during 1 year of untreated follow-up.

[Study on the mechanism of DDP-resistance mediated by phosphate JNK in gastric cancer].

OBJECTIVE: To investigate the mechanism of DDP-resistance in gastric cancer cell line SGC7901/DDP mediated by phosphate(p)-JNK. METHODS: The p-JNK expression was blocked by the JNK inhibitor SP600125. The drug sensitivity was detected by MTT. Cell apoptosis rate was measured by flow cytometry. The expression of p-JNK and P-glycoprotein (P-gp) was examined by Western blot. The expression of both proteins were detected in a tissue microarray containing 168 spots of cancer tissue and 27 spots of normal gastric tissue by SP immunohistochemistry. Pearson method was used to analyze the correlation between p-JNK and P-gp. RESULTS: The drug sensitivity and cell apoptosis rate significantly increased (P<0.01), and the protein expression levels of p-JNK and P-glycoprotein were down-regulated after the inhibition of p-JNK by SP600125 in both SGC7901(p-JNK: 1.17+/-0.03 vs 0.38+/-0.071, P-gp: 0.21+/-0.01 vs 0.06+/-0.01) and SGC7901/DDP (p-JNK: 2.56+/-0.14 vs 1.02+/-0.12, P-gp: 0.77+/-0.05 vs 0.52+/-0.06 )cells(all P<0.01). The protein expression rates of p-JNK and P-glycoprotein were 45.8% and 51.8% respectively in gastric cancer tissue, which were significantly higher than those in normal gastric tissue 7.4% and 18.5% (P<0.01). The correlation of protein expression of p-JNK and P-gp was positive (P<0.01). CONCLUSION: JNK anti-apoptosis pathway with the regulation of P-gp expression plays an important role in the DDP-resistance of gastric cancer, which may be a novel target for reversing multidrug resistance.