Prediction Model for the Clearance of Hepatitis B Surface Antigen in Patients with Chronic Hepatitis B before Interferon Therapy: A Prospective Case–Control Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Procedures
2.3. Host Genoty**
2.4. Statistical Analysis
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Schillie, S.; Vellozzi, C.; Reingold, A.; Harris, A.; Haber, P.; Ward, J.W.; Nelson, N.P. Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm. Rep. 2018, 67, 1–31. [Google Scholar] [CrossRef] [PubMed]
- Global Progress Report on HIV, Viral Hepatitis and Sexually Transmitted Infections, 2021. Accountability for the Global Health Sector Strategies 2016–2021: Actions for Impact [EB/OL]. Available online: https://apps.who.int/iris/bitstream/handle/10665/342808/9789240030985-eng.pdf (accessed on 5 February 2022).
- Trepo, C.; Chan, H.L.; Lok, A. Hepatitis B virus infection. Lancet 2014, 384, 2053–2063. [Google Scholar] [CrossRef] [PubMed]
- Terrault, N.A.; Bzowej, N.H.; Chang, K.M.; Hwang, J.P.; Jonas, M.M.; Murad, M.H.; American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016, 63, 261–283. [Google Scholar] [CrossRef] [PubMed]
- European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 2017, 67, 370–398. [Google Scholar] [CrossRef]
- Hou, J.; Wang, G.; Wang, F.; Cheng, J.; Ren, H.; Zhuang, H.; Sun, J.; Li, L.; Li, J.; Meng, Q.; et al. Guideline of Prevention and Treatment for Chronic Hepatitis B (2015 Update). J. Clin. Transl. Hepatol. 2017, 5, 297–318. [Google Scholar] [CrossRef] [PubMed]
- Brouwer, W.P.; Sonneveld, M.J.; Tabak, F.; Simon, K.; Cakaloglu, Y.; Akarca, U.S.; Zeuzem, S.; Ferenci, P.; Heathcote, J.E.; de Knegt, R.J.; et al. Polymorphisms of HLA-DP are associated with response to peginterferon in Caucasian patients with chronic hepatitis B. Aliment. Pharmacol. Ther. 2014, 40, 811–818. [Google Scholar] [CrossRef] [PubMed]
- Fan, R.; Sun, J.; Yuan, Q.; **e, Q.; Bai, X.; Ning, Q.; Cheng, J.; Yu, Y.; Niu, J.; Shi, G.; et al. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues. Gut 2016, 65, 313–320. [Google Scholar] [CrossRef] [PubMed]
- Zhu, H.; Wang, C.; Zhang, Y.; Wei, S.; Li, X.; Zhang, Z. Prediction model for sustained hepatitis B e antigen seroconversion to peginterferon alfa-2a in chronic hepatitis B. J. Gastroenterol. Hepatol. 2016, 31, 1963–1970. [Google Scholar] [CrossRef]
- Reijnders, J.G.; Perquin, M.J.; Zhang, N.; Hansen, B.E.; Janssen, H.L. Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 2010, 139, 491–498. [Google Scholar] [CrossRef]
- Zoulim, F.; Locarnini, S. Management of treatment failure in chronic hepatitis B. J. Hepatol. 2012, 56 (Suppl. 1), S112–S122. [Google Scholar] [CrossRef]
- Revill, P.A.; Chisari, F.V.; Block, J.M.; Dandri, M.; Gehring, A.J.; Guo, H.; Hu, J.; Kramvis, A.; Lampertico, P.; Janssen, H.L.A.; et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol. Hepatol. 2019, 4, 545–558. [Google Scholar] [CrossRef] [PubMed]
- Ying, S.Y.; Hu, Y.R.; Gao, G.S.; Lou, K.H.; Huang, Z. Interleukin-28B Polymorphisms Predict the Efficacy of Peginterferon Alpha in Patients with Chronic Hepatitis B: A Meta-Analysis. Front. Med. 2021, 8, 691365. [Google Scholar] [CrossRef]
- Stattermayer, A.F.; Scherzer, T.; Beinhardt, S.; Rutter, K.; Hofer, H.; Ferenci, P. Review article: Genetic factors that modify the outcome of viral hepatitis. Aliment. Pharmacol. Ther. 2014, 39, 1059–1070. [Google Scholar] [CrossRef] [PubMed]
- Chuaypen, N.; Tuyapala, N.; Pinjaroen, N.; Payungporn, S.; Tangkijvanich, P. Association of NTCP polymorphisms with clinical outcome of hepatitis B infection in Thai individuals. BMC Med. Genet. 2019, 20, 87. [Google Scholar] [CrossRef] [PubMed]
- Qi, X.; Li, F.; Zhang, Y.; Zhu, H.; Yang, F.; Li, X.; Jiang, X.; Chen, L.; Huang, Y.; Zhang, J. STAT4 genetic polymorphism significantly affected HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving Peginterferon-alpha therapy: A prospective cohort study in China. J. Med. Virol. 2022, 94, 4449–4458. [Google Scholar] [CrossRef] [PubMed]
- Wu, Y.; Zeng, Y.; Wu, W.; Lin, J.; Ou, Q. Polymorphisms of CYP27B1 are associated with IFN efficacy in HBeAg-positive patients. J. Clin. Lab. Anal. 2018, 32, e22367. [Google Scholar] [CrossRef] [PubMed]
- King, J.K.; Yeh, S.H.; Lin, M.W.; Liu, C.J.; Lai, M.Y.; Kao, J.H.; Chen, D.S.; Chen, P.J. Genetic polymorphisms in interferon pathway and response to interferon treatment in hepatitis B patients: A pilot study. Hepatology 2002, 36, 1416–1424. [Google Scholar] [CrossRef]
- Wu, X.; **n, Z.; Zhu, X.; Pan, L.; Li, Z.; Li, H.; Liu, Y. Evaluation of susceptibility locus for response to interferon-alpha based therapy in chronic hepatitis B patients in Chinese. Antiviral Res. 2012, 93, 297–300. [Google Scholar] [CrossRef]
- Tseng, T.C.; Yu, M.L.; Liu, C.J.; Lin, C.L.; Huang, Y.W.; Hsu, C.S.; Liu, C.H.; Kuo, S.F.; Pan, C.J.; Yang, S.S.; et al. Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-alpha-2a therapy. Antivir. Ther. 2011, 16, 629–637. [Google Scholar] [CrossRef]
- Kong, X.F.; Zhang, X.X.; Gong, Q.M.; Gao, J.; Zhang, S.Y.; Wang, L.; Xu, J.; Han, Y.; **, G.D.; Jiang, J.H.; et al. MxA induction may predict sustained virologic responses of chronic hepatitis B patients with IFN-alpha treatment. J. Interferon Cytokine Res. 2007, 27, 809–818. [Google Scholar] [CrossRef]
- Guo, P.F.; **, J.; Sun, X. Influence of IL10 gene polymorphisms on the severity of liver fibrosis and susceptibility to liver cirrhosis in HBV/HCV-infected patients. Infect. Genet. Evol. 2015, 30, 89–95. [Google Scholar] [CrossRef] [PubMed]
- Ganem, D.; Prince, A.M. Hepatitis B virus infection--natural history and clinical consequences. N. Engl. J. Med. 2004, 350, 1118–1129. [Google Scholar] [CrossRef] [PubMed]
- Rehermann, B.; Bertoletti, A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology 2015, 61, 712–721. [Google Scholar] [CrossRef] [PubMed]
- Laskus, T.; Radkowski, M.; Lupa, E.; Horban, A.; Cianciara, J.; Slusarczyk, J. Prevalence of markers of hepatitis viruses in out-patient alcoholics. J. Hepatol. 1992, 15, 174–178. [Google Scholar] [CrossRef] [PubMed]
- He, Y.L.; Zhao, Y.R.; Zhang, S.L.; Lin, S.M. Host susceptibility to persistent hepatitis B virus infection. World J. Gastroenterol. 2006, 12, 4788–4793. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Z.; Wang, C.; Liu, Z.; Zou, G.; Li, J.; Lu, M. Host Genetic Determinants of Hepatitis B Virus Infection. Front. Genet. 2019, 10, 696. [Google Scholar] [CrossRef] [PubMed]
- Won, S.Y.; Park, J.J.; Shin, E.Y.; Kim, E.G. PAK4 signaling in health and disease: Defining the PAK4-CREB axis. Exp. Mol. Med. 2019, 51, 1–9. [Google Scholar] [CrossRef]
- Yu, F.X.; Zhang, X.L.; Wang, Y.P.; Ma, N.; Du, H.; Ma, J.M.; Liu, D.W. Gene polymorphisms of interleukin-28, p21-activated protein kinases 4, and response to interferon-alpha based therapy in Chinese patients with chronic hepatitis B. Chin. Med. J. 2013, 126, 1726–1731. [Google Scholar]
- Zanoni, I.; Granucci, F.; Broggi, A. Interferon (IFN)-lambda Takes the Helm: Immunomodulatory Roles of Type III IFNs. Front. Immunol. 2017, 8, 1661. [Google Scholar] [CrossRef]
- Lee, D.H.; Lee, J.H.; Kim, Y.J.; Park, N.H.; Cho, Y.; Lee, Y.B.; Yoo, J.J.; Lee, M.; Cho, Y.Y.; Choi, W.M.; et al. Relationship between polymorphisms near the IL28B gene and spontaneous HBsAg seroclearance: A systematic review and meta-analysis. J. Viral Hepat. 2014, 21, 163–170. [Google Scholar] [CrossRef]
- Sonneveld, M.J.; Wong, V.W.; Woltman, A.M.; Wong, G.L.; Cakaloglu, Y.; Zeuzem, S.; Buster, E.H.; Uitterlinden, A.G.; Hansen, B.E.; Chan, H.L.; et al. Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Gastroenterology 2012, 142, 513–520.e1. [Google Scholar] [CrossRef] [PubMed]
- Zanin, N.; Viaris de Lesegno, C.; Lamaze, C.; Blouin, C.M. Interferon Receptor Trafficking and Signaling: Journey to the Cross Roads. Front. Immunol. 2020, 11, 615603. [Google Scholar] [CrossRef] [PubMed]
- Zhou, J.; Smith, D.K.; Lu, L.; Poon, V.K.; Ng, F.; Chen, D.Q.; Huang, J.D.; Yuen, K.Y.; Cao, K.Y.; Zheng, B.J. A non-synonymous single nucleotide polymorphism in IFNAR1 affects susceptibility to chronic hepatitis B virus infection. J. Viral Hepat. 2009, 16, 45–52. [Google Scholar] [CrossRef] [PubMed]
- Tan, A.; Koh, S.; Bertoletti, A. Immune Response in Hepatitis B Virus Infection. Cold Spring Harb. Perspect. Med. 2015, 5, a021428. [Google Scholar] [CrossRef] [PubMed]
- Meng, Z.; Chen, Y.; Lu, M. Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection. Front. Immunol. 2019, 10, 3127. [Google Scholar] [CrossRef] [PubMed]
- Lange, C.M.; Gouttenoire, J.; Duong, F.H.; Morikawa, K.; Heim, M.H.; Moradpour, D. Vitamin D receptor and Jak-STAT signaling crosstalk results in calcitriol-mediated increase of hepatocellular response to IFN-alpha. J. Immunol. 2014, 192, 6037–6044. [Google Scholar] [CrossRef]
- Zhang, X.; Chen, C.; Wu, M.; Chen, L.; Zhang, J.; Zhang, X.; Zhang, Z.; Wu, J.; Wang, J.; Chen, X.; et al. Plasma microRNA profile as a predictor of early virological response to interferon treatment in chronic hepatitis B patients. Antivir. Ther. 2012, 17, 1243–1253. [Google Scholar] [CrossRef]
- Tan, B.; Liu, M.; Wang, L.; Wang, J.; **ong, F.; Bao, X.; Gao, Y.; Yu, L.; Lu, J. Serum microRNAs predict response of patients with chronic hepatitis B to antiviral therapy. Int. J. Infect. Dis. 2021, 108, 37–44. [Google Scholar] [CrossRef]
- Wang, J.; Du, L.; Tang, H. Suppression of Interferon-alpha Treatment Response by Host Negative Factors in Hepatitis B Virus Infection. Front. Med. 2021, 8, 784172. [Google Scholar] [CrossRef]
Characteristics | Non-Clearance, n = 56 | HBsAg Clearance, n = 75 | p | |
---|---|---|---|---|
Age, mean ± SD | 41.5 ± 10.8 | 40.5 ± 11.1 | 0.590 | |
Sex, n (%) | Male | 28 (50) | 45 (60) | 0.250 |
Female | 28 (50) | 30 (40) | ||
ALT (U/L), mean ± SD | 77.5 (105) | 64.8 (71.7) | 0.410 | |
ALT elevation, n (%) | Yes | 37 (67.3) | 56 (74.7) | 0.36 |
No | 18 (32.7) | 19 (25.3) | ||
HBV DNA Log (IU/mL), n (%) | n ˃ median | 29 (51.8) | 21 (28.0) | 0.006 |
n ≤ median | 27 (48.2) | 54 (72.0) | ||
Baseline HBsAg (IU/mL), n (%) | ≤99 | 4 (7.1) | 21 (28.0) | 0.003 |
100–1000 | 20 (35.7) | 29 (38.7) | ||
1001–2000 | 9 (16.1) | 12 (16.0) | ||
˃2000 | 23 (41.1) | 13 (17.3) | ||
HBeAg status, n (%) | Baseline negative | 36 (64.3) | 45 (60.0) | <0.001 |
Seroconversion | 11 (19.6) | 30 (40.0) | ||
No seroconversion | 9 (16.1) | 0 (0.0) |
Polymorphism | Polymorphism Distribution | Odd Ratio, 95% CI | p | |||
---|---|---|---|---|---|---|
Non-Clearance, n = 56 | HBsAg Clearance, n = 75 | |||||
PAK4, rs9676717, n (%) | TT | 29 (51.8) | 19 (25.3) | CC vs. TT | 16.026, 3.36–76.38 | <0.001 |
CC | 2 (3.6) | 21 (28.0) | ||||
CT | 25 (44.6) | 35 (46.7) | ||||
IL28B, rs12979860, n (%) | TT | 1 (1.9) | 17 (22.7) | TT vs. CT | 15.534, 1.998–120.777 | <0.001 |
CT | 53 (98.1) | 58 (77.3) | ||||
IFNAR1, rs2850015, n (%) | TT | 7 (12.5) | 3 (4.0) | CT vs. TT | 4.940, 1.136–21.5 | 0.024 |
CC | 32 (57.1) | 36 (48.0) | ||||
CT | 17 (30.4) | 36 (48.0) | ||||
HLA-DPB1, rs9277535, n (%) | AA | 8 (14.3) | 20 (26.7) | AA vs. AG | 2.812, 1.048–7.548 | 0.037 |
GG | 21 (37.5) | 31 (41.3) | ||||
AG | 27 (48.2) | 24 (32.0) | ||||
CYP27B1, rs4646536, n (%) | GG | 24 (43.6) | 26 (34.7) | AG vs. AA | 2.455, 0.805–7.480 | 0.108 |
AA | 9 (16.4) | 7 (9.3) | ||||
AG | 22 (40.0) | 42 (56.0) | ||||
HLA-DPA1, rs3077, n (%) | GG | 25 (44.6) | 35 (46.7) | AA vs. AG | 2.286, 0.797–6.552 | 0.120 |
AA | 7 (12.5) | 16 (21.3) | ||||
AG | 24 (42.9) | 24 (32.0) | ||||
IL28B, rs12980275, n (%) | AA | 50 (89.3) | 59 (78.7) | AG vs. AA | 2.119, 0.765–5.869 | 0.143 |
GG | 0 | 1 (1.3) | ||||
AG | 6 (10.7) | 15 (20.0) | ||||
IL28B, rs8099917, n (%) | GG | 0 | 1 (1.3) | GT vs. TT | 2.119, 0.765–5.869 | 0.143 |
TT | 50 (89.3) | 59 (78.7) | ||||
GT | 6 (10.7) | 15 (20.0) | ||||
IL10-592, rs1800872, n (%) | TT | 18 (32.7) | 31 (41.3) | TT vs. GT | 1.670, 0.783–3.562 | 0.183 |
GG | 5 (9.1) | 11 (14.7) | ||||
GT | 32 (58.2) | 33 (44.0) | ||||
MxA, rs469083, n (%) | TT | 6 (10.7) | 5 (6.7) | CT vs. TT | 1.548, 0.745–3.219 | 0.241 |
CC | 29 (51.8) | 33 (44.0) | ||||
CT | 21 (37.5) | 37 (49.3) | ||||
STAT4, rs7574865, n (%) | GG | 31 (55.4) | 36 (48.0) | GT vs. GG | 1.312, 0.632–2.724 | 0.466 |
TT | 4 (7.1) | 7 (9.3) | ||||
GT | 21 (37.5) | 32 (42.7) | ||||
MxA-123, rs17000900, n (%) | AA | 1 (1.8) | 3 (4.1) | AA vs. CC | 2.423, 0.243–24.154 | 0.437 |
CC | 42 (75.0) | 52 (70.3) | ||||
AC | 13 (23.2) | 19 (25.7) | ||||
IPS1, rs2464, n (%) | CC | 31 (56.4) | 42 (56.0) | TT vs. CC | 1.107, 0.288–4.260 | 0.882 |
TT | 4 (7.3) | 6 (8.0) | ||||
CT | 20 (36.4) | 27 (36.0) |
Characteristics | OR (95% CI) | p |
---|---|---|
HLA-DPA1, rs3077 | 1.308 (0.264–6.492) | 0.743 |
CYP27B1, rs4646536 | 0.155 (0.030–0.807) | 0.027 |
PAK4, rs9676717 | 11.237 (1.768–71.409) | 0.010 |
IFNAR1, rs2850015 | 2.353 (0.297–18.641) | 0.418 |
IL28B, rs12979860 | 0.059 (0.006–0.604) | 0.017 |
HLA-DPB1, rs9277535 | 0.696 (0.140–3.469) | 0.659 |
HBsAg, (IU/mL), | 0.170 (0.040–0.716) | 0.016 |
HBeAg status | 3.971 (1.138–13.859) | 0.031 |
HBV DNA, Log (IU/mL) | 0.843 (0.648–1.096) | 0.202 |
Factors | AUC | Sensitivity | Specificity | TP (a) | FP (b) | FN (c) | TN (d) |
---|---|---|---|---|---|---|---|
rs3077, rs4646536, rs9676717, rs2850015, rs12979860, baseline HBsAg, HBeAg status, baseline HBV DNA | 0.877 | 0.795 | 0.811 | 58 | 10 | 15 | 43 |
rs9277535, rs3077, rs4646536, rs9676717, rs2850015, rs12979860, | 0.877 | 0.753 | 0.849 | 55 | 8 | 18 | 45 |
baseline HBsAg, HBeAg status, baseline HBV DNA | |||||||
rs4646536, rs9676717, rs2850015, rs12979860, baseline HBsAg, HBeAg status, baseline HBV DNA | 0.876 | 0.781 | 0.830 | 57 | 9 | 16 | 44 |
rs4646536, rs9676717, rs12979860, baseline HBsAg, HBeAg status | 0.863 | 0.740 | 0.849 | 54 | 8 | 19 | 45 |
Baseline HBsAg, HBeAg status, baseline HBV DNA | 0.793 | 0.671 | 0.804 | 49 | 11 | 24 | 45 |
rs3077, rs4646536, rs9676717, rs2850015, rs12979860 | 0.788 | 0.720 | 0.736 | 54 | 14 | 21 | 39 |
Baseline HBsAg, HBeAg status | 0.772 | 0.562 | 0.857 | 41 | 8 | 32 | 48 |
rs4646536, rs9676717, rs12979860 | 0.754 | 0.427 | 0.943 | 32 | 3 | 43 | 50 |
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Geng, N.; Ma, L.; **, Y.; Lu, J.; Zheng, Y.; Wang, J.; Wang, X.; Chen, X. Prediction Model for the Clearance of Hepatitis B Surface Antigen in Patients with Chronic Hepatitis B before Interferon Therapy: A Prospective Case–Control Study. Diagnostics 2024, 14, 118. https://doi.org/10.3390/diagnostics14010118
Geng N, Ma L, ** Y, Lu J, Zheng Y, Wang J, Wang X, Chen X. Prediction Model for the Clearance of Hepatitis B Surface Antigen in Patients with Chronic Hepatitis B before Interferon Therapy: A Prospective Case–Control Study. Diagnostics. 2024; 14(1):118. https://doi.org/10.3390/diagnostics14010118
Chicago/Turabian StyleGeng, Nan, Lina Ma, Yi **, Junfeng Lu, Yanhong Zheng, Junli Wang, **aoxiao Wang, and **nyue Chen. 2024. "Prediction Model for the Clearance of Hepatitis B Surface Antigen in Patients with Chronic Hepatitis B before Interferon Therapy: A Prospective Case–Control Study" Diagnostics 14, no. 1: 118. https://doi.org/10.3390/diagnostics14010118