Editor’s Note:
The annual highlight in the field of hepatology, the 2023 American Association for the Study of Liver Diseases (AASLD) Annual Meeting, is currently taking place in Boston, USA. Two research achievements related to the treatment and management of hepatitis B by Dr. Wenhong Zhang and Dr. Jiming Zhang ‘s team from Huashan Hospital, affiliated with Fudan University, have been included in the conference. One is a phase analysis of the Oasis Project, a study aimed at reducing the occurrence of liver cancer in Chinese hepatitis B patients, revealing the safety and benefits of interferon application in specific populations. The other explores the immune modulation effects of tenofovir alafenamide (TAF) treatment and predictive indicators of efficacy. “Hepatology Digest” hereby reports on these findings.
▲ AASLD2023 Poster Presentation
Research One: Safety and Effectiveness of IFN in Compensated Cirrhotic Patients
Research Method:
This study represents a phase subgroup data analysis of the Oasis Project, a multi-center, prospective real-world study in China that includes slow hepatitis B patients undergoing PEG IFNα-based or nucleoside analog (NA) treatment, with a 5-year follow-up. At 2.5 years into the Oasis Project, a subgroup analysis was conducted on compensated cirrhotic patients, focusing on virological and serological response analysis, cumulative incidence of liver cancer, and adverse event analysis.
Research Results:
A total of 1,944 compensated cirrhotic patients with complete baseline information were included, with 920 receiving PEG IFNα-based treatment and 1,024 receiving NA treatment. Additionally, 4,197 non-cirrhotic patients receiving PEG IFNα-based treatment were included as a supplemental control for safety assessment. At baseline, the majority of IFN group patients were Child-Pugh class A (897 cases, 97.5%), with the remaining being class B (23 cases, 2.5%).
In patients with normal or slightly elevated baseline ALT levels (IFN group 483 cases; NA group 687 cases), the IFN group had a significantly higher incidence of ALT elevation exceeding 3 × ULN (7.8%) compared to the NA group (1.5%, P<0.0001). The occurrence rates of ALT, bilirubin, or neutrophil abnormalities were similar between cirrhotic and non-cirrhotic patients receiving IFN treatment. However, cirrhotic patients had a significantly higher incidence of platelet reduction.
Up to the analysis cutoff, patients with abnormal indicators did not experience irreversible damage, liver function failure, or bleeding events. Eight patients developed liver cancer within 144 weeks. The cumulative incidence of liver cancer in the IFN group was lower than the NA group (0.14% vs. 1.05%), but after adjusting for covariates such as age, gender, and baseline HBsAg level, the difference did not reach statistical significance (P=0.0612). Compared to NA treatment, the HR for liver cancer occurrence in the IFN group was 0.264 (95% CI: 0.065–1.065).
By the analysis cutoff, 971 participants completed the 48-week follow-up, and 386 participants completed the 96-week follow-up. In cirrhotic patients with HBsAg <1500 IU/mL, IFN-based treatment showed significantly higher HBsAg clearance rates than the NA group at 48 weeks (11.2% vs. 2.9%, P=0.008) and 96 weeks (19.4% vs. 4.8%, P=0.047).
Research Conclusion:
In compensated cirrhotic patients with good liver function reserve, IFN has a significantly higher adverse reaction rate than NA, but except for the incidence of platelet reduction, the rates are comparable to those in non-cirrhotic individuals receiving IFN. IFN-based treatment is more effective in achieving clinical cure and reducing the risk of liver cancer in cirrhotic patients compared to NA.
Research Two: Dynamics of Cytokine Changes in TAF-Treated HBeAg-Positive Chronic Hepatitis B Patients
Research Method:
This prospective multicenter cohort study included HBeAg-positive chronic hepatitis B patients with HBV DNA >2×10^4 IU/mL and no prior antiviral treatment. Patients received TAF treatment for 48 weeks, and follow-ups with serum sample collection for the detection of IFN-λ3, IP-10, IL-12, IL-21, and IL-10 were conducted at baseline, 12 weeks, 24 weeks, and 48 weeks.
Research Results:
A total of 108 patients were included, with 98 completing the follow-up. The analysis focused on the 98 patients who completed the follow-up. Baseline HBV DNA and HBsAg levels were 7.7 log10 IU/mL and 4.3 log10 IU/mL, respectively.
During the 48-week treatment, plasma IP-10 levels gradually decreased (median at 0W, 12W, 24W, and 48W: 671.3 vs. 431.3 vs. 287.3 vs. 269.5 pg/mL, P<0.001). Plasma IFN-λ3 levels also gradually decreased. Plasma IL-12, IL-21, and IL-10 remained at low and stable levels throughout the treatment.
By multifactorial analysis, it was found that baseline IP-10 >1000 pg/mL was an independent predictor for achieving complete viral response (HBV DNA ≤20 IU/mL) at 48 weeks (OR=5.26, 95% CI: 1.27–21.71, P=0.022). Additionally, baseline HBsAg >4.6 log10 IU/mL, ALT >299 U/L, and IP-10 >680 pg/mL were independently correlated with a >1 log10 IU/mL decline in HBsAg at 48 weeks.
Research Conclusion:
We described the spectrum of cytokine changes in HBeAg-positive chronic hepatitis B patients undergoing TAF treatment. Higher baseline plasma IP-10 levels were associated with a good antiviral response.
Dr. Wenhong Zhang ‘s Comments:
Compensated cirrhotic patients are one of the populations with the highest risk of primary hepatocellular carcinoma (HCC) occurrence among slow hepatitis B patients. However, the safety of interferon application in this population is a major concern for clinicians. Whether interferon in compensated cirrhotic patients carries the risk of inducing acute decompensation, causing more liver damage and bone marrow suppression than in non-cirrhotic individuals is still under debate.
Our first study, based on a phase subgroup analysis of the Oasis Project, provides preliminary evidence for these questions. In terms of safety, we compared the differences between IFN and NA treatment in cirrhotic patients and also compared the differences in IFN application between cirrhotic and non-cirrhotic populations. Up to the analysis cutoff, this study has not observed severe events such as acute liver failure, and
most adverse reaction rates are similar to those in the non-cirrhotic population, suggesting specific monitoring considerations (such as platelet reduction). Although due to the small number of total HCC cases, the statistical difference disappeared after adjusting factors (P=0.06), a trend of IFN being more effective in reducing HCC (HR=0.264) and significant advantages in clinical cure were still observed. These results suggest that the application of interferon may be relatively safe and beneficial in compensated cirrhotic patients with good liver function reserve.
The second study primarily explores the changes in the cytokine spectrum during TAF treatment. Some studies suggest that, compared to ETV, TAF may have immune modulation effects, but there is currently no prospective study exploring or verifying this. Dr. Jiming Zhang ‘s team’s study provides a preliminary demonstration of changes in the cytokine spectrum during the treatment process, and the application value of IP-10 as a predictive indicator of efficacy is also observed.
Both of the above studies are still ongoing, and we hope that with the extension of follow-up time and an increase in the number of enrolled patients, more solid data accumulation can provide more information for the individualized treatment and optimization of treatment regimens for hepatitis B patients, ultimately improving the long-term prognosis of hepatitis B patients.
Reference:
[1] Zhang Q, Sun F, Yu Y, et al. Interferon-Based Therapies Are Beneficial in Cirrhotic Hepatitis B Patients with Good Liver Function Reserve: Real-World Evidence from Oasis Project 2.5-Year Data. AASLD2023. Poster 1425-C.
[2] Han J, Zhang Y, Guo Y, et al. Efficacy and Safety of Tenofovir Alafenamide For 48 Weeks in HBeAg-Positive CHB Patients: A Real-World, Multicenter Cohort Study. AASLD2023. Poster 1415-C.
