Ropeginterferon Alfa-2b administered every two weeks for patients with genotype 2 chronic hepatitis C.

BACKGROUND: Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to the 8 to 14 isomers of other on-market pegylated interferon products, allowing every-two-week injection with high tolerability. It received European Medicines Agency marketing authorization in 2019 and Taiwan Biologics License Applications Approval in 2020 for the treatment of polycythemia vera. This study aimed to evaluate the safety and efficacy of Ropeginterferon alfa-2b plus ribavirin in genotype 2 chronic hepatitis C (CHC) patients. METHODS: Eighty-six treatment naive patients with genotype 2 CHC were randomized to weekly peginterferon alfa-2a (Peg-IFN-α2a) at 180 µg (n = 22), or every-two-week Ropeginterferon alfa-2b at 270 µg (n = 23), 360 µg (n = 21), 450 µg (n = 20), plus daily oral ribavirin 1000 mg (≤75 kg) or 1200 mg (>75 kg). Patients with rapid virologic response received 16-week regimen while those without RVR received 24-week regimen. The primary endpoint was sustained virologic response at 24 weeks post-treatment (SVR24). RESULTS: SVR24 was achieved by 95.5%, 78.3%, 85.7%, and 60% of subjects in Peg-IFN-α2a 180 µg, Ropeginterferon alfa-2b 270 µg, 360 µg, and 450 µg groups, respectively. The safety profile was similar across 4 groups. The incidence rate of adverse event during the treatment period was 0.407, 0.252, 0.395, and 0.347 per patient-week, respectively. CONCLUSION: Ropeginterferon alfa-2b, although at only half the number of injections, is as safe and effective as Peg-IFN-α2a for genotype 2 CHC. A phase 3 study to confirm safety and efficacy of Ropeginterferon alfa-2b in genotype 2 CHC is ongoing.

Phase IV randomized clinical study: Peginterferon alfa-2a with adefovir or entecavir pre-therapy for HBeAg-positive chronic hepatitis B.

BACKGROUND: Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive. METHODS: This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment. RESULTS: No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (-0.56 IU/mL, -0.60 IU/mL, and -0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups. CONCLUSION: Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB. CLINICAL TRIAL ID: NCT: 00922207.

Peginterferon Is Superior to Nucleos(t)ide Analogues for Prevention of Hepatocellular Carcinoma in Chronic Hepatitis B.

BACKGROUND: Clinical factors associated with hepatocellular carcinoma (HCC) have been extensively studied in antiviral treatment-naive patients with chronic hepatitis B virus (HBV) infection but not in treatment-experienced patients. Owing to the wide availability of antiviral agents that effectively suppress HBV replication, we investigated HCC risk factors in treatment-experienced patients. METHODS: In a cohort of 330 patients who underwent pretherapeutic liver biopsy, we analyzed the HCC incidence in relationship to clinical parameters. Ultra-deep sequencing of the viral genome was performed on 11 entecavir-treated and pegylated interferon (peginterferon)-treated patients. RESULTS: Initial univariate/multivariate explorations indicated that cirrhosis and antiviral treatment were independently associated with HCC occurrence. The peginterferon-experienced patients had a lower HCC incidence than the nucleos(t)ide analogue-treated patients (P = .011). The peginterferon and entecavir monotherapy groups also differed in HCC incidence (P = .018). Results of analysis of baseline-matched subgroups concurred with cohort analysis (P = .009 for comparison of peginterferon-experienced vs nucleotide analogue-treated patients; P = .022 for comparison of peginterferon- vs entecavir-treated patients). Viral loads of entecavir-treated patients were constantly suppressed to levels lower than those of peginterferon-treated patients (P < .001). Oncogenic surface antigen truncation mutations were detected in entecavir-treated patients with HCC but not in peginterferon-treated patients (P = .015). CONCLUSIONS: Treatment by peginterferon was associated with a lower HCC incidence than nucleos(t)ide-analogue treatment in chronic HBV infection.

Emergence of hepatitis B virus S gene mutants in patients experiencing hepatitis B surface antigen seroconversion after peginterferon therapy.

UNLABELLED: With anti-hepatitis B virus (anti-HBV) therapy using peginterferon, the seroconversion of hepatitis B surface antigen (HBsAg), which is considered a cure of the disease, can be achieved in a small percentage of patients. Eight of 245 consecutive patients (3.27%) with chronic hepatitis B who received peginterferon therapy at our center achieved HBsAg seroclearance. Surprisingly, two of the eight patients remained viremic according to standard HBV DNA assays. The coding regions of the HBV pre-S/S gene, which were derived from serial serum samples, were analyzed. Site-directed mutagenesis experimentation was performed to verify the phenotypic alterations in Huh-7 cells. In patient 1, an sT125A mutant developed during the HBsAg-negative stage and constituted 11.2% of the viral population. The HBV DNA level was 2.73 × 10(4) IU/mL at the time of detection. This mutant was not detectable in the HBsAg-positive stages. A phenotypic study of Huh-7 cells showed a significant reduction of antigenicity. In patient 2, an sW74* truncation mutation was found during the HBsAg-negative stage and constituted 83.1% of the viral population. The HBV DNA level was 4.12 × 10(4) IU/mL at the time of detection. A phenotypic study of Huh-7 cells showed a complete loss of antigenicity. Patient 2 subsequently experienced an episode of hepatitis relapse 7 months after the end of treatment and was negative for HBsAg throughout the hepatitis flare. CONCLUSION: During antiviral therapy with peginterferon, the achievement of HBsAg seroconversion does not necessarily indicate viral eradication. The emergence of S gene mutants is another possibility, and a relapse with HBsAg-negative hepatitis can occur.

Ropeginterferon alfa-2b every 2 weeks as a novel pegylated interferon for patients with chronic hepatitis B.

BACKGROUND: Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to 8-14 isomers of other on-market pegylated interferon, allowing injection every two or more weeks with higher tolerability. It received European Medicines Agency and Taiwan marketing authorization in 2019 and 2020, for treatment of polycythemia vera. This phase I/II study aimed to have preliminary evaluation of safety and efficacy in chronic hepatitis B. METHODS: Thirty-one HBeAg-positive and 31 HBeAg-negative were stratified by HBeAg status and randomized at 1:1:1 ratio to q2w ropeginterferon alfa-2b 350 µg (group 1), q2w 450 µg (group 2) or q1w PEG-IFN alfa-2a 180 µg (group 3). Each patient received 48-week treatment (TW48) and 24-week post-treatment follow-up (FW24). RESULTS: The baseline demographics were comparable among the three groups, except for mean HBeAg in HBeAg-positive patients (2.90, 2.23, 2.99 log10 S/CO, respectively). Cumulative HBeAg seroconversion rate at follow-up period was 27.3% (3/11), 36.4% (4/11), and 11.1% (1/9) with time to HBeAg seroconversion starting from TW24, TW16, and TW48 in group 1, 2, and 3, respectively. The rate of HBV DNA < 2000 IU/mL and HBsAg levels < 1500 IU/mL at FW24 were comparable in all groups. Ropeginterferon alfa-2b (group 1 & 2) had numerically lower incidence of rash (9.5% and 4.5%) as compared to PEG-IFN alfa-2a (36.8%). Ropeginterferon alfa-2b 350 µg (group 1) had more ALT elevation (38.1%), however the rate was comparable in group 2 (9.1%) and group 3 (10.5%). CONCLUSION: In this preliminary study, ropeginterferon alfa-2b, although in only half the number of injections, is as safe and effective as pegylated interferon alfa-2a for chronic hepatitis B.

Clinical Predictors for Neutrophil-to-Lymphocyte Ratio Changes in Patients with Chronic Hepatitis B Receiving Peginterferon Treatment.

BACKGROUND: A lower neutrophil-to-lymphocyte ratio (NLR) was found to be associated with better clinical outcomes in hepatitis B-related liver cirrhosis and hepatocellular carcinoma. We aimed to identify pre-therapeutic variables capable of predicting NLR changes in patients with hepatitis B receiving peginterferon therapy. PATIENTS AND METHODS: The baseline clinicopathological data were analyzed to correlate with NLR changes before and 1 year after peginterferon treatment in 71 patients with hepatitis B. RESULTS: Univariate analysis revealed that pre-treatment NLR itself negatively predicted NLR changes following peginterferon treatment (odds ratio(OR)=0.320, p=0.013). Further analysis identified pre-treatment NLR, hemoglobin and hepatitis B surface antigen level as independent predictors for NLR changes (adjusted p=0.028, 0.005, and 0.028, respectively). A predictive score composed of these three factors had an area under the curve of 76.5% (p<0.001). CONCLUSION: Pretreatment NLR, hemoglobin and hepatitis B surface antigen level in combination, effectively predicted NLR changes following peginterferon treatment.

A double-blind randomized controlled study to evaluate the efficacy of low-dose oral interferon-alpha in preventing hepatitis C relapse.

Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500 IU/day (n=59), 1,500 IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4-1.7, relapse occurred in 1/12 (8.3%) 500 IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500 IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500 IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500 IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy.

Impact of the novel hepatotropic viruslike agent NV-F during chronic hepatitis C virus infection.

NV-F is a novel hepatotropic viruslike agent. To investigate the impact of the NV-F agent during chronic hepatitis C virus (HCV) infection, 101 consecutive patients with chronic HCV infection were evaluated. NV-F DNA in serum samples and NV-F antigen expression in liver tissues were assessed. All patients subsequently received a 6-month course of interferon-based antiviral therapy. Of the 101 patients, 30 (29.7%) were positive for serum NV-F DNA. Immunohistochemical analysis revealed positive NV-F antigen expression in the liver in 14 of these 30 patients. Patients positive for serum NV-F DNA had significantly higher serum aminotransferase levels (P < .001) and higher Knodell histology activity index values (P < .001). The sustained virological response rate for HCV clearance was not significantly different between patients with and those without detectable serum NV-F DNA. In conclusion, coinfection of the NV-F agent in chronic HCV infection is associated with more severe hepatitis activity.