Virological and immunological predictors of long term outcomes of peginterferon alfa-2a therapy for HBeAg-negative chronic hepatitis B.

BACKGROUND/PURPOSE: Predictors of long-term outcomes of peginterferon (PegIFN) therapy for patients with chronic hepatitis B (CHB) remain to be explored. This study aimed to evaluate the predictive value of virological and immunological biomarkers and outcomes of PegIFN for CHB. METHODS: 57 HBeAg-negative CHB patients receiving 48 weeks of PegIFN therapy were prospectively followed for a median period of 5.3 years after the end of treatment (EOT). Serum CXCL9 and IP-10 levels were measured. Flow cytometry analysis for T cell subsets was performed in 23 patients. Factors associated with long-term outcomes were analyzed. RESULTS: The cumulative incidences of virological relapse, clinical relapse and HBsAg loss at year 7 were 18.1%, 0%, 31.6%, respectively, in patients with sustained off-treatment virological response (SVR), and 100%, 67.4%, 6.7%, respectively, in patients without SVR. By multivariate analysis, baseline CXCL9 > 80 pg/mL (hazard ratio (HR) = 0.418, p = 0.018) and on-treatment HBsAg declines were associated with a lower risk of virological relapse. Non-SVR was the only predictor of clinical relapse. CXCL9 >200 pg/mL (HR = 8.154, p = 0.038) and HBsAg <750 IU/mL (HR = 10.507, p = 0.036) were baseline predictors of HBsAg loss, while HBsAg decline >1 log at EOT (HR = 23.296, p = 0.005) was the on-treatment predictor of HBsAg loss. In subgroup patients with available PBMC, populations of T cell subsets correlated with virological and clinical relapses in univariate analysis. CONCLUSION: Baseline serum CXCL9 and HBsAg levels could predict HBsAg loss after PegIFN therapy for HBeAg-negative CHB. Combining virological and immunological biomarkers could predict long-term outcomes of PegIFN therapy for HBeAg-negative CHB.

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.

Incidence and Predictors of HBsAg Loss After Peginterferon Therapy in HBeAg-Negative Chronic Hepatitis B: A Multicenter, Long-term Follow-up Study.

Background: The long-term incidence and factors associated with hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients receiving peginterferon is rarely reported. Methods: From 2004 to 2016, 233 HBeAg-negative CHB patients who completed 48 weeks of peginterferon treatment from 3 medical centers in Taiwan were retrospectively enrolled. Results: During a median follow-up of 7.4 years, 27 cases achieved HBsAg loss. The cumulative incidences of HBsAg loss and HBsAg seroconversion at 3, 5, 10 years after peginterferon treatment were 4.7%, 9.4%, 14.2%, and 3.5%, 6.4%, 12.5%, respectively, in overall patients, and 15.9%, 29.1%, 37.3%, and 13.1%, 19%, 30.6%, respectively, in patients achieving sustained off-treatment virological response (SVR). By multivariate analysis, age (<35 years; hazard ratio [HR] = 3.742, P = .007), baseline HBsAg levels (<1250 IU/mL; HR = 4.849, P = .002), HBsAg decline at week 24 (≥1 log; HR = 5.660, P = .002), and achieving SVR (HR = 8.546, P = .006) were predictors of HBsAg loss. After achieving SVR, HBsAg loss rates were higher than 30% in 5 years among patients with either younger age or lower HBsAg at baseline. Conclusions: HBsAg loss rate continues to increase after peginterferon treatment in HBeAg-negative CHB patients with SVR. Age, baseline HBsAg levels, on-treatment HBsAg decline, and achieving SVR are factors associated with long-term HBsAg loss.

Risk factors associated with hepatitis D virus infection and preventive strategies in Mongolia.

BACKGROUND: Hepatitis D virus (HDV) infection is highly prevalent in Mongolia. We aimed to identify the risk factors associated with HDV infection, propose preventive strategies, and evaluate the outcomes of a 3-year collaborative project between Taiwan and Mongolia. METHODS: In 2016 and 2018, we conducted onsite visits to Mongolia. Mongolian investigators collected questionnaires focusing on risk factors, demographic characteristics, and serum samples for acute HDV infections. Furthermore, 19 Mongolian seed teachers participated in a 1-week workshop on infection control in Taiwan. Subsequently, these seed teachers trained more than 400 medical personnel in Mongolia. To assess secular changes in acute HDV infection, we reviewed the registration data from the National Center for Communicable Disease (NCCD) in Mongolia between 2011 and 2021. RESULTS: Among the 194 Mongolian patients, 108 had dual infection with hepatitis B virus (HBV) and HDV, while 86 had acute hepatitis B (AHB). Patients with HBV/HDV dual infections were older (28.6 vs 25.5 years, p = 0.030) and had lower rates of positive hepatitis B e antigen in their sera, lower rates of serum HBV DNA exceeding 2000 IU/mL, and higher rates of having received dental treatment (59.4% vs 40.5%, p = 0.014) and injection therapy (64.2% vs 44.0%, p = 0.009) compared with those with AHB. Analysis of NCCD data revealed that new HDV infection cases were more prevalent between 2011 and 2015 (111.20 ± 29.79 cases/y) and decreased to 54.67 ± 27.34 cases/y between 2016 and 2021 ( p = 0.010). CONCLUSION: Dental treatment and injections were associated with a higher risk of acute HDV infections in Mongolia. Through collaborative efforts, the incidence rate of HDV infection has declined in recent years.

The safety and probable therapeutic effect of routine use of antibiotics and simultaneously treating bleeding gastric varices by using endoscopic cyanoacrylate injection and concomitant esophageal varices with banding ligation: a pilot study.

BACKGROUND: Gastroesophageal varices are the most common type of gastric varices. Although endoscopic injection of N-butyl-2-cyanoacrylate is the current treatment of choice for acute gastric variceal bleeding, whether the concomitant esophageal varices should be ligated simultaneously with the first treatment session is currently not known. OBJECTIVE: The aim of this study was to evaluate the safety and probable therapeutic effect of simultaneous cyanoacrylate injection for bleeding gastric varices obliteration (GVO) and endoscopic band ligation (EBL) for concomitant esophageal varices in combination with routine antibiotics (simultaneous group), and to compare our results with historical results in which the patients underwent GVO first and then EBL for concomitant esophageal varices (separate group). DESIGN: A single-center pilot study. SETTING: A tertiary referral center. PATIENTS: Patients with liver cirrhosis and gastroesophageal varices, who presented with acute gastric varices bleeding. INTERVENTIONS: Simultaneous treatment in the form of GVO and EBL for concomitant esophageal varices in combination with routine antibiotics. MAIN OUTCOME MEASUREMENT: Rebleeding and mortality within the first year of index bleeding. RESULTS: Twenty patients in the simultaneous group and 67 patients in the separate group were included in the study. The 2 groups had similar baseline characteristics. The hemostasis of active bleeding was 100% in both groups (7/7 vs 20/20). The 1-year rebleeding rate was 10% (2/20) in the simultaneous group and 37.31% (25/67) in the separate group (P = .041). Kaplan-Meier analysis showed higher probability of remaining free of rebleeding in the simultaneous group (88.5% vs 61.1%; P = .044). Multivariate analysis indicated that treatment method (separate group) and high model for end-stage liver disease score (> or = 13) were independent risk factors of rebleeding in 1 year. The treatment failure, complications, 1-year mortality, and survival were similar in both groups. CONCLUSION: Simultaneous endoscopic treatment for gastric varices bleeding and concomitant esophageal varices is a safe and effective procedure in combination with antibiotic prophylaxis for patients with cirrhosis. The 1-year mortality rate was similar between the 2 groups. The results need further validation.

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.

A 12-week rescue therapy by PrOD-based regimen for advanced fibrotic genotype-1 CHC patients who failed to pegylated interferon plus ribavirin.

BACKGROUND: Treatment of chronic hepatitis C (CHC) evolved rapidly due to the invention of interferon-free direct antiviral agents. Previous clinical trials showed combination therapy with paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin (RBV) can cure over 95% of genotype 1 CHC patients, regardless with cirrhosis or not. However, real-world data regarding the efficacy and safety of PrOD-based therapy in Asian HCV genotype 1 CHC patients are limited, especially for advanced-fibrotic patients who failed previous therapy with pegylated interferon (PEG-IFN) plus RBV. METHODS: Between January and October 2017, 60 advanced fibrotic (≥F3) genotype 1 CHC patients who failed previous therapy with PEG-IFN and received PrOD-based therapy for 12 weeks were retrospectively enrolled. Weight-based RBV 800 to 1200 mg/d was added for genotype 1b patients with cirrhosis and all genotype 1a patients. Sustained virological response (SVR) was defined by undetectable HCV RNA at the end and 12 weeks after the completion of therapy. RESULTS: The mean age was 63.2 ± 9.3 years, 26 (43.3%) of them were males and 20 (33.3%) were diagnosed to have liver cirrhosis. The mean baseline HCV RNA level was 6.19 ± 0.88 log10 IU/mL and 86.7% (52/60) of patients were infected by HCV genotype 1b. After PrOD-based therapy, the rates undetectable HCV RNA (<15 IU/mL) at week 2, 4, and 12 were 61.7%, 90.0%, and 100%, respectively; 69.6% (16/23) of patients with detectable HCV RNA at week 2 were < 100 IU/mL. Pruritus, fatigue, headache, insomnia, and dizziness were the most common patient-reported adverse events. Grade 2 hyperbilirubinemia were found in 21.6% (13/60) of patients during study period and all belonged to unconjugated hyperbilirubinemia. After posttherapy follow up, all 60 patients (100%) achieved SVR. CONCLUSION: Our real-world data in Taiwan revealed that PrOD-based rescue therapy is well-tolerated and highly effective for genotype 1 CHC patients with advanced fibrosis failing previous therapy with PEG-IFN plus RBV.

Predictors of response to pegylated interferon in chronic hepatitis B: a real-world hospital-based analysis.

Information on the efficacy of pegylated interferon (PEG-IFN) treatment of chronic hepatitis B (CHB) patients and predictors of the response based on real-world data is limited. Consecutive 201 patients who underwent PEG-IFN treatment for CHB were reviewed. A virological response (VR) was defined as a serum HBV DNA of <2000 IU/mL, and a combined response (CR) was defined a VR accompanied by serological response for hepatitis B e antigen (HBeAg)-positive CHB. For HBeAg-positive CHB patients, the HBeAg seroconversion rate and CR rate were 30.5% and 21.2% at 48 weeks after end of treatment (EOT), respectively. Baseline alanine aminotransferase (ALT) level was associated with HBeAg seroconversion, while baseline hepatitis B s antigen (HBsAg) levels of <250 IU/mL and HBV DNA <2.5 × 10(7) IU/mL were strongly associated with sustained off-treatment CR. For HBeAg-negative CHB, the VR rates were 85.5%, and 27.7% at EOT, and 48 weeks after EOT, respectively; a baseline HBsAg <1,250 IU/mL was associated with sustained off-treatment VR. PEG-IFN treatment has durable HBeAg seroconversion in HBeAg-positive CHB, but results in a high risk of relapse among HBeAg-negative CHB patients. Pre-treatment HBsAg level is an important predictor of VR in CHB patients undergoing PEG-IFN treatment.

Rapid Prediction of Treatment Futility of Boceprevir with Peginterferon-Ribavirin for Taiwanese Treatment Experienced Hepatitis C Virus Genotype 1-Infected Patients.

The efficacy and safety of the boceprevir (BOC)-containing triple therapy in Taiwanese treatment-experienced patients remains elusive. After 4 weeks of peginterferon/ribavirin lead-in therapy, patients with cirrhosis or previous null-response received triple therapy for 44 weeks; whereas others received 32 weeks of triple therapy followed by 12 weeks of peginterferon/ribavirin therapy. Patients with HCV RNA > 100 IU/mL at week 12 or with detectable HCV RNA at week 24 of treatment were viewed as futile. A total of 123 patients received treatment. The rates of sustained virological response (SVR) and relapse were 66.7% and 8.9%, respectively by using intention-to-treat analysis. Multivariate analysis revealed that factors associated with SVR included HCV-1b (odds ratio [OR]/ 95% confidence intervals [CI]: 19.23/1.76-525.15, P = 0.01), BOC adherence (7.69/1.55-48.78, P = 0.01), serum albumin (OR/CI:6.25/1.14-40.07, P = 0.03) levels and HCV RNA levels (OR/CI:0.34/0.12-0.79, P = 0.01). Twenty-six (21.1%) patients experienced severe adverse events (SAEs). Multivariate analysis revealed that APRI > 1.5 was the single factor associated with occurring SAEs (OR/CI: 3.77/ 0.97-14.98, P = 0.05). Merging the cut-off values of HCV RNA > 7 log IU/mL at baseline and HCV RNA > 6 log IU/mL at week 4 provided the earliest and best combing viral kinetics in predicting week 12/24 futility with the PPV of 100% and accuracy of 93.5%. HCV-1 treatment experienced Taiwanese patients treated with boceprevir-containing triple therapy in real world had comparable efficacy and safety profiles with those reported in clinical trials. Early viral kinetics before week 4 of treatment highly predicted futility at week 12 or 24 of treatment.

CXCL9 associated with sustained virological response in chronic hepatitis B patients receiving peginterferon alfa-2a therapy: a pilot study.

BACKGROUND AND AIMS: There is lack of a practical biomarker to predict sustained virological response (SVR) in chronic hepatitis B (CHB) patients undergoing peginterferon alfa-2a (PEG-IFN). The aim of this pilot study was to identify immunological features associated with SVR. METHODS: Consecutive 74 CHB patients receiving 24 weeks (for hepatitis B e antigen (HBeAg)-positive) or 48 weeks (for HBeAg-negative) PEG-IFN, were prospectively enrolled. Serum HBV viral loads, hepatitis B surface antigen (HBsAg), CXCL9, IFN-γ-inducible protein 10 (IP-10), interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-ß) were measured at baseline and week 12. SVR was defined as HBeAg seroconversion combined with viral load <2000 IU/mL in HBeAg-positive (n=36), and viral load <2000 IU/mL in HBeAg-negative patients (n=38) at 48 weeks after the end of treatment. RESULTS: Nineteen patients (25.7%), 7 in HBeAg-positive and 12 in HBeAg-negative, achieved SVR. There were significant declines of HBV DNA, HBsAg, IP-10 and IFN-γ levels at week 12. In multivariate analysis, pre-treatment CXCL9 >80 pg/mL, HBV DNA <2.5 x 10(7) IU/mL and on-treatment HBV viral load, HBsAg decline >10% at week 12 were predictors of SVR. The performance of CXCL9 in predicting SVR was good in patients with HBV DNA <2.5 x 10(7) IU/mL, particularly in HBeAg-negative CHB cases (positive predictive value, PPV= 64.3%). CONCLUSIONS: Pre-treatment CXCL9 level has the potential to select CHB patients who can respond to PEG-IFN, especially in HBeAg-negative patients with low viral loads.

Citrus reticulata peel improves patient tolerance of low-volume polyethylene glycol for colonoscopy preparation.

BACKGROUND: Adequate adjuncts help to reduce the volume of polyethylene glycol-electrolyte lavage solution (PEG-ELS) needed, to ameliorate patient discomfort, and to improve colonic visibility during colonoscopy. This study aimed to assess the effect of Citrus reticulata peel (CRP) as an adjunct to low-volume PEG for colonic preparation. METHODS: A total of 1092 health examination examinees received colonoscopy during the study period. After excluding those who refused to participate and those who did not meet our criteria, 212 examinees were enrolled into this study. They were divided into the PEG group and the PEG + CRP group according to their date of examination. All examinees received 2 L of PEG-ELS one day before colonoscopy. The PEG + CRP group also received additional CRP in the form of a "buccal tablet" between drinks. Tolerance and adverse events were assessed by questionnaire, while the quality of bowel preparation for colonoscopy was scored by an endoscopist. RESULTS: There were 107 examinees in the PEG group and 105 examinees in the PEG + CRP group. The demographic characteristics of the examinees were comparable between these two groups. Examinees in the PEG + CRP group had a trend of better colonic visibility than those in the PEG group (p = 0.056). Moreover, examinees in the PEG + CRP group had higher rate of acceptable taste (p = 0.015) and lower rate of difficulty swallowing (p = 0.001). The incidences of adverse events including vomiting (p = 0.045), bloating (p = 0.035), and difficulty sleeping (p < 0.001) were also significantly lower in the PEG + CRP group. CONCLUSION: Compared with conventional colonic preparation, the application of CRP as an adjunct could improve examinees' tolerance, decrease the incidence of adverse events, and maintain the quality of colonic cleansing.

Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-α-2a therapy.

BACKGROUND: Pegylated interferon (PEG-IFN)-α-2a improves the hepatitis B e antigen (HBeAg) seroconversion rate in HBeAg-positive chronic hepatitis B patients. However, baseline factors predicting favourable responses to PEG-IFN-α-2a remain largely unknown. METHODS: A total of 115 HBeAg-positive chronic hepatitis B patients who had a pre-therapy serum alanine aminotransferase (ALT) level over two times the upper limit of normal and received PEG-IFN-α-2a for 6-12 months were consecutively enrolled according to the local reimbursed guidelines. HBeAg seroconversion and combined response defined as HBeAg seroconversion, HBV-DNA level <20,000 IU/ml as well as ALT normalization at 6 months off therapy were primary and secondary therapeutic end points, respectively. Baseline viral factors, including viral load, genotype and major sequences of precore stop codon/basal core promoter (BCP), and host factors, including three single nucleotide polymorphisms among the HLA-DPA1, HLA-DPB1 and IL28B regions, were determined to correlate with therapeutic end points. RESULTS: HBeAg seroconversion and combined response rates were 26.1% and 18.3%, respectively. By multivariate analysis, BCP mutation (OR 8.04, 95% CI 2.00-32.28) and rs3077 G/G genotype (OR 3.49, 95% CI 1.12-10.84) were associated with a higher HBeAg seroconversion rate; BCP mutation (OR 9.28, 95% CI 1.92-44.99) and baseline viral load <2 × 10(6) IU/ml (OR 4.78, 95% CI 1.37-16.69) were associated with a higher combined response rate. CONCLUSIONS: BCP mutation is associated with higher HBeAg seroconversion and combined response rates at 6 months off therapy in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN-α-2a. Genetic variants in the HLA-DPA1 region may also affect treatment-induced HBeAg seroconversion.