Copyright ©The Author(s) 2022.
World J Gastroenterol. Oct 28, 2022; 28(40): 5784-5800
Published online Oct 28, 2022. doi: 10.3748/wjg.v28.i40.5784
Table 1 Immune cells and their corresponding cytokines released
Immune cells
Released cytokines
NK cells IFN-γ, TNF-α, IL-10
NKT cells IFN-γ, IL-4, IL-13
MonocytesIFN-γ, TNF-α, IL-10
MacrophagesIFN-γ, IL-6, MCP-1, IL-1β, TNF-α, CXCL10
γδT cellsIL-17, TNF-α
HSCsIL-1β, IL-6, TGF-β
Kupffer cellsIL-10, TGF-β, IL-12, IL-6, TNF-α
CD8+ T cellsIFN-γ, TNF-α, IL-2, IL-10, IL-17, IL-21
CD4+ T cells IFN-γ, IL-21,IL-17
Regulatory T cellsIL-10, TGF-β, IL-35
Regulatory B cells IL-10
Table 2 Host genetic variants associated with hepatitis B virus infection[43-46]
Gene ontology
Genetic determinants (SNP/Hap/CNVs)
HLAHLA-A *33:03:01
HLA-B *13:01:01
HLA-B *07, *58
HLA-C Leu-15, rs2853953, rs3130542
HLA-DOA rs378352
HLA-DP rs9366816
HLA-DPA1 rs3077, rs2301220, rs2395309, rs9277341
HLA-DPB1 G-A-G-A-T-T1, G-G-G-G-T-C2, rs2281388, rs9277535, rs9277542, rs9277534, *0201, *0401, *0901, positions 84–87, *0402, *0501, *0201-*0401, *0201-*0402, *0201-*0501, *0401-*0402, *0401-*0501, *0402-*0402, *0402-*0501, *0501-*0501, *0501- *0901, *0501*others, rs9277378, rs10484569, rs3117222, rs9380343, rs3135021
HLA-DQ rs9275319, rs9275572, A1*0101-B1*0501, A1*0102-B1*0303, A1*0102-B1*0604, A1*0301-B1*0601, A1*0102-B1*0602, A1*0102-B1*0602, A1*0301-B1*0302, A1*0301-B1*0303, A1*0301-B1*0401, A1*0501-B1*0301
HLA-DPA1/ DPB1 A-A3, A-A4, T-A-T5,C-A-T6, A-A-C-T7, A-A-C-C//A-G-T-G-C-C8, A-A-C-T//A-G-T-G-C-C9, G-G-T-C//A-G-T-G-C-C10, A1*0103-B1*0401, A1*0103-B1*0402, A1*0202-B1*0301, A1*0202-B1*0501
HLA-DQA2 rs9276370
HLA-DQB1 *0201, *0301, *0303, *0502, *0604, rs2856718, *0401-*0501, *0402-*0402, *0402-*0501, *0501-*0501
HLA-DQB2 rs7453920, rs7756516
HLA-DRB1 *13
HLA-DP/DQ T-T-G-A-T11, T-T-G-G-T12, carrying 4–6 variant alleles, G-A13, A-G14, A-A15
Cytokines IL-10 −592
IL-10RB rs2834167
IL-12B rs3212227
IL-16 rs11556218
IL-21 rs2221903
IL-12B rs3212227
IL-18 −137
IFN-γ +874
IFN-α2 p.Ala120Thr
IFN-αR2 rs1051393, rs12233338
IFNLR1 rs4649203, rs7525481
IFN-γR1 rs3799488
IFN-γR2 rs1059293
TNF-α T-C-C-G-G-G16, C-A-C-G-G-G17 ,−238, −308, −857, −863
TGF-α +106151, +103461, A-T-G-T-T-T-T-C-T18
ChemokinesCCR5 Δ32
TLRs TLR-3 rs3775291, rs1879026
TLR-9 rs352140
MicroRNAsmiR-30a rs1358379
miR-101-2 T-C19, rs12375841
miR-106b-25 rs999885
miR-122 rs3783553, rs4309483
miR-196a-2 rs11614913
miR-let-7c rs6147150
miR-219-1 rs107822, rs213210, rs421446, C-A-C20, T-G-T21
miR-323b rs56103835
miR-423 rs6505162
miR-492 rs2289030
OthersC2 p.Glu318Asp, rs7746553, rs9267673, rs9267665, rs9267677, rs9279450, rs10947223
CD40 rs1883832
CFB rs12614
CTLA-4 C-A-C-C-G22, T/C-A-C-C-G23, T-A-C-C-A24, rs231775,rs3087243, rs5742909
EHMT2 rs7887, rs652888, rs35875104, rs41267090
ESR1 +29
IFN4/HLA-DQ rs12971396-rs9275319, rs12971396-rs12979860-rs9275319
INST10 rs7000921
MCP1 −2518, −2518/−2076(−/ht2), −2518/−2076(ht2/ht2)
MIF rs755622
MX1 rs467960
NF-κBrs2233406, rs3138053
NLRX1 p.Arg707Cys
NOTCH4 rs422951
NTCP rs2296651, rs943277, rs4646285
OCT4 rs13409, rs885952, rs879882, rs1265163, rs2394882, rs3094193, rs3130501, rs3130503, rs3130931, rs3132526, rs3757349, rs9263800, rs117265349
PAPL rs423058
SOCS3 C-C26, T-T-C-T-A27, rs111033850, rs12953258,
SPP1 −1800
STAT4 C-T-C-T-T28, rs7574865,rs8179673, rs10168266, rs11889341,
TCF19 rs1419881
TMEM2 p.Ser1254Asn
TMEM2/IFNA2/ NLRX1/C2 p.Ser1254-Asn/p.Ala120Thr/p.Arg707Cys/p.Glu318Asp
UBE2L3 rs2266959, rs4821116
VARS2 rs1043483, rs1264295, rs2249464, rs2517459, rs2532932, rs9394021,
ZNRD1 G-G-A29, rs3757328
Table 3 Host genetic variants associated with interferon-α therapy[43,44,74-78,91]
Gene ontology
Genetic determinants (SNP/Hap/CNVs)
HLA HLA-DP rs3077, rs9277535
HLA-DQA1-DQB1-DRB1 *0302-*0303-*09
HLA-DQB1 *0303
HLA-DRB1 *08
HLA-A, B, C *1101-*4601-*0102
Cytokines IL-28B A-C1,rs8099917, rs12979860, rs12980275
Others CYP24A1 rs2248359
CYP27B1 rs10877012, rs4646536
G3BP2 rs3821977
OAS G-T-G-A2, C-C-T-A3, C-C-C-A4, A-C-T-A5
OAS3 rs2072136
PRELID2 rs371991
STAT4 rs7574865
TRAPPC9 rs78900671
VDBP rs7041
VDR rs1544410, rs731236, rs11568820, rs10735810
Table 4 Summary and timeline of interferon-α retreatment for chronic hepatitis B virus infection
The regimens of INF-α retreatment
van Zonneveld et al[10]2004One hundred and sixty-five patients received their first IFN-α treatment. Of them, 48 non-responders received 2-3 courses of IFN-α
Manesis and Hadziyannis[11]2001Two hundred and sixteen patients received IFN-α therapy, of whom 51 received a second IFN-α treatment and 9 were treated with three courses of IFN-α
Niederau et al[12]1996One hundred and three cases were treated IFN-α. Of them, 29 received a second course of therapy, and 17 received a third course of IFN-α
Carreño et al[13]1999Fifty-seven patients underwent a course of IFN-α therapy. Of them, 27 received a second course of IFN-α; and 30 others who did not receive IFN-α retreatment served as controls. IFN-α retreatment was found to enhance the antiviral effects against HBV
Ballauff et al[14]1998After all the children received the first course of IFN-α treatment, 15 were given the second course of IFN-α (study group), while the other 19 did not receive the second course of IFN-α, serving as the control group. HBV DNA clearance and anti-HBe seroconversion occurred in 5 of 15 children (33%) in the study group and 5 of 19 children (26%) in the control group
Yin and Zhong[15]2016Inappropriate therapies induced HBV resistance, multi-drug resistance and failure of combination therapy with nucleoside plus nucleotide in China. An IFN-α regimen, i.e. (1) Switch from nucleoside plus nucleotide to IFN-α therapy; and (2) subsequent IFN-α retreatment, was used to treat these patients. IFN-α switching therapy leaded to safe cessation of nucleoside plus nucleotide combination therapy, and IFN-α retreatment induced sustained response of IFN-α
Sarin et al[16]2016Asian-Pacific clinical practice guidelines 2015 recommended IFN-α retreatment to treat chronic HBV infection
Liaw et al[17]2012Asian-Pacific clinical practice guidelines 2012 recommended IFN-α retreatment to treat chronic HBV infection
Liaw et al[18]2008Asian-Pacific clinical practice guidelines 2008 recommended IFN-α retreatment to treat chronic HBV infection
Yin et al[64]2021IFN-α retreatment was recommended for patients on entecavir or tenofovir monotherapy with persistent low-level viremia