Ef Cacy of Pegylated Interferon
Ef Cacy of Pegylated Interferon
Ef Cacy of Pegylated Interferon
KEYWORDS
Introduction Three patients’ groups were defined in this study: the HBsAg
NOT clearance group (group A), which was defined as patients who
Interferons (IFNs) are immunomodulatory agents that can underwent treatment without HBsAg clearance; the HBsAg
induce the expression of hundreds of genes, including genes with clearance group (group B), which was defined as patients who
antiviral functions, thereby blocking viral replication at many levels achieved HBsAg clearance; and the treatment discontinued group
(1). There is increasing interest in functional cures for hepatitis B (group C), which was defined as patients whose treatment was
virus (HBV) infection; treatments explored for this goal include discontinued by the doctors. The patients’ clinical data were
IFNs, immune checkpoint inhibitors, therapeutic vaccines, and organized in the same way as the survival data for analysis.
gene-engineered T cells (2). Notably, IFNs combined with nucleos Ethical approval for this study protocol was obtained from the
(t)ide analogs (NUCs) or monotherapy have demonstrated promise Ethics Committee of the Chengdu Public Health Clinical Center,
in clinical practice, including a degree of efficacy in some adult and written informed consent was acquired from each patient
patients and children with favorable characteristics (3). before treatment. If the patients were over 8 years old, they
There are two types of pegylated interferons (peg-IFNs): a-2a needed to sign by themselves as well. The study complied with
and a-2b. These types substantially differ in terms of chemical and the ethical guidelines of the Declaration of Helsinki 2008.
structural characteristics, pharmacokinetic and pharmacodynamic
properties, and dosing and administration (4). To our knowledge,
there are limited available data regarding peg-IFN a-2b plus Follow-up
entecavir therapy for HBV infection in children. In this study, we
analyzed 76 patients aged <18 years with CHB who received IFN a- Baseline assessments included quantitative tests for HBsAg,
2b plus entecavir to understand its efficacy and the predictors for hepatitis B surface antibody (HBsAb), hepatitis B e antigen
treatment success. (HBeAg), hepatitis B e antibody (HBeAb), and hepatitis B core
antibody (HBcAb); blood routine, thyroid function, liver function,
and renal function tests; and the detection of hepatitis B virus DNA
(HBV-DNA). All patients underwent clinical follow-up and
Materials and methods laboratory tests approximately once per month during the
treatment process.
Patient enrollment
This study enrolled children with CHB who underwent Statistical analysis
treatment with IFN a-2b plus entecavir from 2021 to 2023. The
inclusion criteria for this study were diagnosis with HBV infection A competing risk model was used to understand the impact of
between 3 and 18 years of age, no obvious signs of liver cirrhosis, baseline status on HBsAg clearance. This type of model is useful in
and no other significant underlying diseases (e.g., psychiatric the context of censored data with competing risk. During treatment,
disorders, thyroid dysfunction, fundus abnormalities, or doctors decide to discontinue treatment based on a patient’s
autoimmune diseases). The exclusion criteria were significant response to IFN, typically when the patient shows a poor
underlying diseases or contraindications to the use of IFN treatment response. In such instances, patients who discontinue
or entecavir. treatment have a lower probability of achieving surface antigen
clearance compared with patients who continue treatment at the
same time point. Therefore, treatment discontinuation is
Study design considered a competing risk. The main endpoint in this study
was the serological clearance of HBsAg, which is considered a
The treatment comprised peg-IFN a-2b plus entecavir: 180 µg “failure event” in the model. As noted above, treatment
peg-IFN a-2b/1.73 m2 per week and 0.0015 mg entecavir/kg per discontinuation was considered a “competing risk” in the model.
day. The peg-IFN a-2b was manufactured by Techpool Bio-pharma The patients’ baseline features and early responses to treatment
Co., Ltd., and the entecavir was manufactured by Chia Tai Tianging were entered into competing risk models. Multiple regression
Pharmaceutical Group Co., Ltd. The study participants were models were constructed using various combinations of
evaluated approximately once per month to identify changes in independent variables. The best-fitting model was selected on the
medical indicators and the presence of any adverse reactions. After basis of statistical significance and professional expertise.
treatment completion, follow-up visits were initiated; participants The Kaplan–Meier (KM) method and the log-rank test were
continue to attend these visits. IFN strategies to achieve functional used to compare the survival distributions of binary independent
cures of HBV infection were optimized by response-guided variables. Subdistribution hazard ratios (sHRs) of competing risk
treatment adjustment (RGT) rules (5, 6). These rules allowed models were reported with 95% confidence intervals; all tests were
doctors to decide whether to continue or discontinue treatment two-sided, and the significant threshold was regarded as P < 0.05.
based on the patient’s hepatitis B surface antigen (HBsAg) response All analyses were performed using Stata/MP 14.1 statistical software
to the IFN treatment. (StataCorp LLC, College Station, TX, USA).
Parameters All patients HBsAg NOT clearance HBsAg clearance Treatment discontinued P-
group(A) group(B) group(C) values
N=20 N=24 N=32
Age(Years) 82 (5-11)3 10.52 (5-12.5)3 5.52 (4.5-9)3 8.52 (6-11.5)3 0.0566
Sex
Male 454 (59%5) 114 (55%5) 124 (50%5) 224 (69%5) 0.3386
ALT(IU/mL) 352 (22.5- 54)3 302 (23-49)3 45.52 (26- 60)3 332 (26-42.5)3 0.2586
WBC count(109/L) 62 (4.83-6.69)3 5.372 (4.64-6.39)3 6.442 (5.12-7.495)3 5.745 (4.89-6.23)3 0.1236
PLT count(109/L) 268.52 (200.5-325)3 2722 (212-319.5)3 2772 (209.5-327)3 2452 (187.5-324.5)3 0.556
NEU count(109/L) 2.332 (2.045-3.2)3 2.2752 (2.01- 3.055)3 2.92 (2.13-3.485)3 2.3152 (2.065-3.125)3 0.3756
Immune-tolerant 674 (88%5) 174 (85%5) 214 (88%5) 294 (91%5) 0.9037
1
(HBsAg), hepatitis B surface antigen; (HBeAg), hepatitis B e antigen; (SD), standard deviation; (IQR), interquartile range; (ALT), alanine aminotransferase; (WBC), white blood cell; (PLT),
platelet. 2Median. 3IQR. 4Count data.5Rate. 6Kruskal–Wallis H test used. 7Fisher’s exact test used.
HBsAg clearance 8 8 5 2 1
Rate of HBsAg clearance in the period 10.5% 12.0% 12.0% 13.3% 33.3%
1
(W), weeks; (HBsAg), hepatitis B surface antigen.
95% CI
Variables sHR SE Z P-values
Baseline model
12-weeks HBsAg decrease >1 log10 3.479 1.357 3.200 0.001 1.620 7.471
FIGURE 3
FIGURE 2 Kaplan–Meier analysis of baseline HBsAg level1. 1(CI), Confidential
1 1
Kaplan–Meier analysis of age . (CI), Confidential interval. interval; (HBsAg), hepatitis B surface antigen.
FIGURE 4
Kaplan–Meier analysis of decrease in baseline HBsAg level1. 1 (CI), Confidential interval.
the immune-tolerant phase, a study using IFN a-2a plus entecavir European Society for Pediatric Gastroenterology Hepatology and
indicated a very low rate of surface antigen clearance and a high Nutrition only recommends performing a liver biopsy if the ALT
incidence of adverse reactions (12). However, another study level is persistently elevated; it recommends only providing treatment
(conducted in China) showed that combination therapy to children with at least moderate inflammation and fibrosis or
comprising lamivudine and IFN could achieve better results children with a positive family history of hepatocellular carcinoma
among children in the immune-tolerant phase, with a surface (19). Patients in the immune-tolerant phase of disease may exhibit
antigen clearance rate of 21.74% at the end of treatment (11). minimal fibrosis and inflammation, and they may display limited
Three studies utilizing peg-IFN (peg-IFN a-2b monotherapy in immune efficacy against HBV compared with other patients (20).
one and peg-IFN a-2a in the others) yielded surface antigen However, a considerable proportion of patients in the immune-
clearance rates ranging from 5% to 52%. Notably, Fan et al. tolerant phase display progressive liver fibrosis and inflammation
reported an HBsAg clearance rate of 52%. In that study, the (21, 22); persistently high levels of HBV-DNA over many years likely
patients exhibited a high mean baseline ALT level (126 IU/mL) cause a gradual increase in the risk of hepatocellular carcinoma,
(12). These findings are consistent with our results, which indicated despite the absence of active liver inflammation and fibrosis (22).
that the probability of achieving HBsAg clearance increased with Guidelines from the EASL recommend treatment for patients with
increasing baseline ALT level. Notably, all previous studies used HBeAg-positive CHB, defined by persistently normal ALT and high
interventions that considerably differed from the pegylated IFN a- HBV-DNA levels, if those patients are aged ≥30 years; the histological
2b plus entecavir strategy used in the present study. severity of liver lesions does not change this recommendation. The
EASL guidelines also indicate that the course of disease is generally
mild, and most affected children do not meet the standard indications
Immunology status for treatment (18). The American Association for the Study of Liver
Diseases (AASLD) supports the avoidance of treatment for patients
There remains debate regarding whether antiviral therapy is (including children) in the immune-tolerant phase (23). Thus, there
necessary for children with CHB in the immune-tolerant phase. is some evidence that treatment for children in the immune-tolerant
The European Association for the Study of the Liver (EASL) did not phase is generally not supported; however, a treatment trial achieved
suggest antiviral treatment or liver biopsy for such children (18). The limited effects in these children (12). However, there is new evidence
TABLE 5 Literature reviews regarding the efficacy of IFN treatment for hepatitis B for children1.
Sokal (9) 1998 IFN a-2b 48W children 144 HBeAg clearance:26%
Hu (10) 2019 IFN a-2b vs peg-IFN a-2a 48W children 36 HBsAg clearance:
22.2% vs. 11.1%
Bortolottia (3) 2000 IFN a-2a 3-6 months children 107 HBsAg clearance:25% for responders (16 patients)
Fan (12) 2019 peg-IFN a-2a 48W children 41 HBeAg clearance: 66.7% HBsAg clearance: 52%
Rosenthal (13) 2019 peg-IFN a-2a +ETV 48W Immune 60 HBsAg clearance:3%
tolerant
Wang (14) 2021 IFN a 72W Immune 411 HBeAg clearance:39.87% HBsAg clearance:11.08%
active
of underlying active disease, based on pathological and virological fever, and fatigue; however, these adverse reactions gradually
analyses (21). A high frequency of HBV-DNA integration was improve or completely resolve after IFN discontinuation.
identified by inverse polymerase chain reaction. Random insertions Although most adverse reactions to IFN therapy are reversible,
of HBV-DNA result in genomic instability and have been associated the use of IFN strategies in children should be carefully considered
with hepatocarcinogenesis (24). before implementation (25, 26).
Concerning children in the immune-tolerant phase, there have
been some reports concerning the use of IFN therapy of children, but
response rates considerably vary. In 2006, one study showed that
Data availability statement
treating children in the immune-tolerant phase with IFN plus
The data supporting the findings of this study are available from
lamivudine resulted in an HBeAg seroconversion rate of 22% and
the corresponding author YZ on request.
an HBsAg seroconversion rate of 17% (16). In 2012, a study showed
that treatment with lamivudine plus IFN resulted in an HBsAg
clearance rate of 21.4% (17). However, a 2019 study showed that
Ethics statement
an HBsAg clearance rate of only 3% was achieved with entecavir plus
IFN (12). In the present study, most patients (88%) were in the
The studies involving humans were approved by the Ethics
immune-tolerant phase. Our results showed no significant differences
Committee of the Chengdu Public Health Clinical Center (reference
in HBsAg clearance between patients in the immune-tolerant phase
number: [2018Y]001), and complied with the ethical guidelines of
and those who were not (31% vs 33%, P=1.00 according to Fisher’s
the Declaration of Helsinki 2008. The studies were conducted in
exact test). Furthermore, competing risk model analysis showed that
accordance with the local legislation and institutional requirements.
the phase of disease (immune-tolerant or not) was not statistically
Written informed consent for participation in this study was
significant. The results suggest the need for a rethink of the immune-
provided by the patients’ parents and by the patients who were
tolerant phase in children.
over 8 years old.
References
1. Katze MG, He Y, Gale M. Viruses and interferon: a fight for supremacy. Nat Rev 14. Wang L, Zhao J, Liu J, Zhen C, Zhang M, Dong Y, et al. Long-term benefits of
Immunol (2002) 2:675–87. doi: 10.1038/nri888 interferon-a therapy in children with HBeAg-positive immune-active chronic hepatitis
2. Wong GLH, Gane E, Lok ASF. How to achieve functional cure of HBV: Stopping B. J Viral Hepat. (2021) 28:1554–62. doi: 10.1111/jvh.13598
NUCs, adding interferon or new drug development? J Hepatol (2022) 76:1249–62. doi: 15. Choe B-H, Lee JH, Jang YC, Jang CH, Oh KW, Kwon S, et al. Long-term
10.1016/j.jhep.2021.11.024 therapeutic efficacy of lamivudine compared with interferon-alpha in children with
3. Bortolotti F. Long term effect of alpha interferon in children with chronic hepatitis chronic hepatitis B: the younger the better. J Pediatr Gastroenterol Nutr (2007) 44:92–8.
B. Gut (2000) 46:715–8. doi: 10.1136/gut.46.5.715 doi: 10.1097/01.mpg.0000243439.47334.4e
4. Foster GR. Pegylated interferons: chemical and clinical differences: REVIEW: 16. D’Antiga L, Aw M, Atkins M, Moorat A, Vergani D, Mieli-Vergani G. Combined
PEGYLATED INTERFERONS. Aliment Pharmacol Ther (2004) 20:825–30. doi: lamivudine/interferon-a treatment in ‘immunotolerant’ children perinatally infected with
10.1111/j.1365-2036.2004.02170.x hepatitis B: A pilot study. J Pediatr (2006) 148:228–233.e1. doi: 10.1016/j.jpeds.2005.09.020
5. Zhang W, Zhang D, Dou X, Xie Q, Jiang J, Chen X, et al. Consensus on pegylated 17. Poddar U, Yachha SK, Agarwal J, Krishnani N. Cure for immune-tolerant
interferon alpha in treatment of chronic hepatitis B. J Clin Transl Hepatol (2018) 6:1– hepatitis B in children: is it an achievable target with sequential combo therapy with
10. doi: 10.14218/JCTH.2018.00022 lamivudine and interferon? J Viral Hepat (2013) 20:311–6. doi: 10.1111/jvh.12007
6. Peng H, Wei F, Liu J-Y, Hu H-D, Ren H, Hu P. Response-guided therapy of 18. Lampertico P, Agarwal K, Berg T, Buti M, Janssen HLA, Papatheodoridis G, et al.
regimens based on PEG-interferon for chronic hepatitis B using on-treatment hepatitis EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus
B surface antigen quantification: a meta-analysis. Hepatol Int (2015) 9:543–57. doi: infection. J Hepatol (2017) 67:370–98. doi: 10.1016/j.jhep.2017.03.021
10.1007/s12072-015-9644-y 19. Sokal EM, Paganelli M, Wirth S, Socha P, Vajro P, Lacaille F, et al. Management
7. Jonas MM, Chang M, Sokal E, Schwarz KB, Kelly D, Kim KM, et al. Randomized, of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus
controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen– of an expert panel on behalf of the European Society of Pediatric Gastroenterology,
positive chronic hepatitis B. Hepatology (2016) 63:377–87. doi: 10.1002/hep.28015 Hepatology and Nutrition. J Hepatol (2013) 59:814–29. doi: 10.1016/j.jhep.2013.05.016
8. Damdinsuren B, Nagano H, Wada H, Kondo M, Ota H, Nakamura M, et al. 20. McMahon BJ. The natural history of chronic hepatitis B virus infection.
Stronger growth-inhibitory effect of interferon (IFN)-beta compared to IFN-alpha is Hepatology (2009) 49:S45–55. doi: 10.1002/hep.22898
mediated by IFN signaling pathway in hepatocellular carcinoma cells. Int J Oncol 21. Seto W-K, Yuen M-F. “Immune tolerance” in HBV infection: danger lurks. Nat
(2007) 30:201–8. doi: 10.3892/ijo.30.1.201 Rev Gastroenterol Hepatol (2016) 13:627–8. doi: 10.1038/nrgastro.2016.145
9. Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM, Goyens P, et al.
22. Kennedy P, Litwin S, Dolman G, Bertoletti A, Mason W. Immune tolerant
Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized
chronic hepatitis B: the unrecognized risks. Viruses (2017) 9:96. doi: 10.3390/v9050096
controlled trial. Gastroenterology (1998) 114:988–95. doi: 10.1016/S0016-5085(98)70318-X
10. Hu Y, Ye Y-Z, Ye L-J, Wang X-H, Yu H. Efficacy and safety of interferon alpha- 23. Terrault NA, Lok ASF, McMahon BJ, Chang K, Hwang JP, Jonas MM, et al.
2b versus pegylated interferon alpha-2a monotherapy in children with chronic hepatitis Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018
B: a real-life cohort study from Shanghai, China. World J Pediatr (2019) 15:595–600. hepatitis B guidance. Hepatology (2018) 67:1560–99. doi: 10.1002/hep.29800
doi: 10.1007/s12519-019-00303-w 24. Mason WS, Gill US, Litwin S, Zhou Y, Peri S, Pop O, et al. HBV DNA integration
11. Zhu S, Zhang H, Dong Y, Wang L, Xu Z, Liu W, et al. Antiviral therapy in and clonal hepatocyte expansion in chronic hepatitis B patients considered immune
hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open- tolerant. Gastroenterology (2016) 151:986–998.e4. doi: 10.1053/j.gastro.2016.07.012
label randomized study. J Hepatol (2018) 68:1123–8. doi: 10.1016/j.jhep.2018.01.037 25. Jonas MM, Balistreri W, Gonzalez-Peralta RP, Haber B, Lobritto S, Mohan P,
12. Fan H, Lin L, Jia S, Xie M, Luo C, Tan X, Ying R, Guan Y, Li F. Interferon alpha et al. Pegylated interferon for chronic hepatitis C in children affects growth and body
treatment leads to a high rate of hepatitis B surface antigen seroconversion in Chinese composition: Results from the pediatric study of hepatitis C (PEDS-C) trial. Hepatology
children with chronic hepatitis B. J Viral Hepat (2019) 26:77–84. doi: 10.1111/jvh.13165 (2012) 56:523–31. doi: 10.1002/hep.25690
13. Rosenthal P, Ling SC, Belle SH, Murray KF, Rodriguez-Baez N, Schwarzenberg 26. Druyts E, Thorlund K, Wu P, Kanters S, Yaya S, Cooper CL, et al. Efficacy and
SJ, et al. Combination of entecavir/peginterferon alfa-2a in children with hepatitis B e safety of pegylated interferon Alfa-2a or Alfa-2b plus ribavirin for the treatment of
antigen–positive immune tolerant chronic hepatitis B virus infection. Hepatology chronic hepatitis C in children and adolescents: A systematic review and meta-analysis.
(2019) 69:2326–37. doi: 10.1002/hep.30312 Clin Infect Dis (2013) 56:961–7. doi: 10.1093/cid/cis1031