Patients treated with ropeginterferon alfa-2b 450 μg achieved the earliest time to HBeAg seroconversion (starting from TW16), followed by those treated with ropeginterferon alfa-2b 350 μg (starting from TW24). Patients treated with PEG-IFN alfa-2a 180 μg had the latest time to HBeAg seroconversion (starting from TW48). This might be explained by the higher dose of interferon in the ropeginterferon alfa-2b groups, which is supported by the finding of Liaw et al, that the patients receiving PEG-IFN alfa-2a 180 μg achieved HBeAg seroconversion earlier than those receiving 90 μg .
The rates of HBeAg seroconversion at follow-up were 36.4% (4/11) in ropeginterferon alfa-2b 450 μg, followed by 27.3% (3/11) in ropeginterferon alfa-2b 350 μg, and 11.1% (1/9) in PEG-IFN alfa-2a 180 μg. The HBeAg seroconversion rate in patients treated with PEG-IFN alfa-2a 180 μg in this study was lower than rates reported in the previous studies (11.1% vs. 32–36.2%) [5, 16]. Compared to the registration trial of PEG-IFN alfa-2a, one possible reason is the mean age of patient in this study is approximately 11 years older than mean age of patients in the previous studies (mean aged 43–45 vs. 32–34 years). This implies that HBeAg seroconversion rate might be even higher in the ropeginterferon alfa-2b groups if the patient population is younger.
In the registration trial of PEG-IFN alfa-2a, around 15% of HBeAg positive patients in PEG-IFN alfa-2a plus placebo group have HBeAg seroconversion at treatment week 24 (TW24) and 27% at TW48 . In our study, in ropeginterferon alfa-2b groups (350 μg and 450 μg), 18.2% and 27.3%, respectively, had HBeAg seroconversion at TW24, 18.2% and 36.4%, respectively, at TW48. Thus, earlier HBeAg seroconversion was observed in ropeginterferon alfa-2b groups at most of the time-point when compared with PEG-IFN alfa-2a of the PEG-IFN alfa-2a registration trial. However, this possibly an earlier HBeAg seroconversion by ropeginterferon alfa-2b deserves further validation in the future trials. Nevertheless, HBeAg seroconversion among HBeAg-positive chronic HBV patients is an important treatment endpoint because it is associated with better long-term outcomes, including higher rate of HBsAg seroclearance, durable clinical remission, and slower rates of progression of liver diseases.
Our study showed that lower baseline HBV DNA level, lower baseline HBeAg level, higher baseline ALT, and lower HBsAg at TW12 were associated with HBeAg seroconversion in univariate analysis. However, these factors had no association with HBeAg seroconversion in multivariate analysis, which might be due to the small sample size of this study. Nevertheless, combination of immune-related parameters, e.g. toll-like receptors or anti-HBc antibody titer, might serve as better predictors for the response to PEG-IFN therapy [17,18,19]. Among the HBeAg-positive patients with HBeAg seroconversion, we observed relationships of mean increased ALT followed by decline of mean HBV DNA, indicating immunological responses to clear the virus.
The finding of the numerically lower incidence of rash in both the groups of ropeginterferon alfa-2b (9.5% and 4.5%, respectively) as compared to PEG-IFN alfa-2a (36.8%) might be explained by either the new formulation or by a more homogenous pegylated interferon isoforms. During the study period, only one serious adverse event (SAE) was observed in ropeginterferon alfa-2b 350 μg treatment group. The patient was hospitalized due to myocardial infarction and was treated by percutaneous intervention. He had the risk factors of smoking and hyperlipidemia. Overall, the majority of TEAEs reported in ropeginterferon alfa-2b groups were observed in PEG-IFN alfa-2a group. In addition, no new or unexpected TEAE was reported for ropeginterferon alfa-2b. One patient in Group 1 experienced acute flare [ALT 591 U/L and AST 252 U/L, with HBV DNA 421,000,000 IU/mL, and HBsAg 38,050.61 IU/mL] at FW12. The investigator decided to prescribe Telbivudine at his discretion, as the patient had discontinued the interferon therapy for 12 weeks.
IFN-α has immunomodulatory and has been used to treat chronic HBV since 1976 . Modification of IFN through the addition of polyethylene glycol molecule leads to improved pharmacokinetic and pharmacodynamic properties and has largely replaced conventional IFN. In 2003, Cooksley et al.  for the first time demonstrated PEG-IFN alfa-2a (40 kDa) had improved efficacy over conventional interferon in treating chronic HBV. Albinterferon alfa‐2b is an 85.7 kDa protein consisting of recombinant human IFN alfa‐2b genetically fused to recombinant human albumin and can be administrated every two to four weeks. Although studies had shown the non-inferiority of albinterferon alfa-2b for chronic hepatitis C as compared to PEG-IFN alfa, its use on-market was prohibited by lung toxicities, e.g. fibrosing alveolitis, hemoptysis, bronchospasm or interstitial lung disease [9, 10]. By contrast, ropeginterferon alfa-2b did not show the above adverse events of lung after being exposed to 102 healthy subjects, 214 patients with polycythemia vera (including 127 patients in a phase III study in which 95 of them continuously been treated for 36 months) , and 270 patients with chronic viral hepatitis (unpublished data). The safety profile is therefore validated. Furthermore, in the phase III study , the drug was well tolerated in an average of 48–67 years old PV patients. Similar benefits are expected in hepatitis B patients, a population growing older worldwide.
There are several limitations of this study. Firstly, the small sample size of this study on ropeginterferon alfa-2b in chronic HBV patients. Small sample size may reduce sensitivity of the analysis, e.g. the effect of ropeginterferon alfa-2b on HBsAg loss; and introduce some attrition bias. Secondly, HBV genotype was not tested in this study. Although HBV genotype had been reported to correlate with clinical outcomes and response to PEG-IFN therapy , it has not been widely used clinically. Furthermore, studies had confirmed chronic HBV patients in Taiwan were infected by genotype B and C .
The enthusiasm for interferon has recently been revived in many recent clinical trials by combining small molecules with interferon for hepatitis B or D to maximize treatment responses . Interferon would be the backbone of treatment in patients with chronic hepatitis D. Although most of patients with CHB are under NAs treatment, the unmet medical need is that the rate of HBsAg loss is low. Recent many new clinical trials for hepatitis B combine small molecules or other agents with interferon to maximize the therapeutic efficacy [26,27,28,29,30]. We anticipate a renewed interest in interferon as safe and reliable immunomodulator therapy in combination with emerging anti-HBV regimens.
Among the two dose levels of ropeginterferon alfa-2b, the 450 µg had higher cumulative HBeAg seroconversion rate of 36.4% at follow-up period (versus 27.3% in 350 µg), with the time to HBeAg seroconversion earlier at treatment week (TW) 16 in the 450 µg group (versus TW24 in the 350 µg group). In safety, the side effects among the two ropeginterferon alfa-2b groups were comparable, including the rash. However, the rate of ALT elevation was only higher in ropeginterferon alfa-2b 350 μg group (38.1%), while the rate of ALT elevation was similar in ropeginterferon alfa-2b 450 μg and PEG-IFN alfa-2a 180 μg (9.1% versus 10.5%). Due to small case number in this study, final dose selection will need further clinical trials to decide.
In conclusion, this preliminary study revealed that ropeginterferon alfa-2b, although in only half the number of injections, is tolerable with comparable safety and efficacy to PEG-IFN alfa-2a. The results show that patients’ time and visits can be saved, and lays the groundwork in developing this new regimen of interferon-based therapy for chronic hepatitis B or hepatitis D.