Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment

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
Monocytes	IFN-γ, TNF-α, IL-10
Macrophages	IFN-γ, IL-6, MCP-1, IL-1β, TNF-α, CXCL10
γδT cells	IL-17, TNF-α
HSCs	IL-1β, IL-6, TGF-β
Kupffer cells	IL-10, TGF-β, IL-12, IL-6, TNF-α
CD8+ T cells	IFN-γ, TNF-α, IL-2, IL-10, IL-17, IL-21
CD4+ T cells	IFN-γ, IL-21,IL-17
Regulatory T cells	IL-10, TGF-β, IL-35
Regulatory B cells	IL-10

HSCs: Hepatic stellate cells; IL: Interleukin; TGF-β: Transforming growth factor β; TNF-α: Tumor necrosis factor-α; IFN-γ: Interferon-γ; NK: Natural killer.

Table 2 Host genetic variants associated with hepatitis B virus infection[43-46]

Gene ontology	Gene	Genetic determinants (SNP/Hap/CNVs)
HLA	HLA-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
	HLA-J	rs400488
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
Chemokines	CCR5	Δ32
TLRs	TLR-3	rs3775291, rs1879026
	TLR-9	rs352140
MicroRNAs	miR-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
Others	C2	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
	KIF1B	A-T-A25
	MCP1	−2518, −2518/−2076(−/ht2), −2518/−2076(ht2/ht2)
	MIF	rs755622
	MxA	−123
	MX1	rs467960
	NF-κB	rs2233406, 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,
	VDR	FokI
	ZNRD1	G-G-A29, rs3757328

Haplotypes:

¹G-A-G-A-T-T, rs9277535-rs10484569-rs3128917-rs2281388-rs3117222-rs9380343.

²G-G-G-G-T-C, rs9277535-rs10484569-rs3128917-rs2281388-rs3117222-rs9380343.

³A-A, rs3077-rs9277535.

⁴A-A, rs2395309-rs9277535.

⁵T-A-T, rs3077-rs9277378-rs3128917.

⁶C-A-T, rs3077-rs9277378-rs3128917.

⁷A-A-C-T, rs2395309-rs3077- rs2301220-rs9277341.

⁸A-A-C-C//A-G-T-G-C-C, rs2395309-rs3077-rs2301220-rs9277341//rs9277535-rs10484569-rs3128917 -rs2281388-rs3117222-rs9380343.

⁹A-A-C-T//A-G-T-G-C-C, rs2395309-rs3077-rs2301220-rs9277341//rs9277535-rs10484569-rs3128917 -rs2281388-rs3117222-rs9380343.

¹⁰G-G-T-C//A-G-T-G-C-C, rs2395309-rs3077-rs2301220-rs9277341//rs9277535-rs10484569-rs3128917 -rs2281388-rs3117222-rs9380343;

¹¹T-T-G-A-T, rs9276370-rs7756516-rs7453920- rs9277535-rs9366816.

¹²T-T-G-G-T, rs9276370-rs7756516-rs7453920-rs9277535-rs9366816.

¹³G-A, rs2856718- rs9275572.

¹⁴A-G, rs2856718- rs9275572.

¹⁵A-A, rs2856718- rs9275572.

¹⁶T-C-C-G-G-G, -1031/-863/-857/-308/-238/-163.

¹⁷C-A-C-G-G-G, -1031/-863/-857/-308/-238/-163.

¹⁸A-T-G-T-T-T-T-C-T, +88344/+102906/+103432/+103437/+103461/+104261/+104802/+106151/+106318.

¹⁹T-C, rs12375841-rs17803780.

²⁰C-A-C, rs421446-rs107822-rs213210.

²¹T-G-T, rs421446-rs107822-rs213210.

²²C-A-C-C-G, -1722/-1661/-658/-319/+49.

²³T/C-A-C-C-G, -1722/-1661/-658/-319/+49.

²⁴T-A-C-C-A, -1722/-1661/-658/-319/+49.

²⁵A-T-A, rs17401966-rs12734551-rs3748578.

²⁶C-C, rs111033850-rs12953258.

²⁷T-T-C-T-A, -1800/-1627/+4645/+5806/+6139.

²⁸C-T-C-T-T, rs8179673-rs7574865-rs4274624-rs11889341-rs10168266.

²⁹G-G-A, rs3757328-rs6940552-rs9261204.

SNPs/Hap/CNVs: Single nucleotide polymorphisms/Haplotype/Copy number variations; HLA: Human leukocyte antigen; TLR: Toll-like receptors.

Table 3 Host genetic variants associated with interferon-α therapy[43,44,74-78,91]

Gene ontology	Gene	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

Haplotypes:

¹A-C, rs12980275-rs12979860.

²G-T-G-A, rs3177979-rs1293747-rs4767043-rs10849829.

³C-C-T-A, rs2285934-rs2072138-rs2072136-rs10849829.

⁴C-C-C-A, rs2285934- rs2072138-rs2072136-rs10849829.

⁵A-C-T-A, rs2285934-rs2072138-rs2072136-rs10849829.

SNPs/Hap/CNVs: Single nucleotide polymorphisms/Haplotype/Copy number variations; HLA: Human leukocyte antigen.

Table 4 Summary and timeline of interferon-α retreatment for chronic hepatitis B virus infection

Ref.	Year	The regimens of INF-α retreatment
van Zonneveld et al[10]	2004	One 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]	2001	Two 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]	1996	One 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]	1999	Fifty-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]	1998	After 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]	2016	Inappropriate 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]	2016	Asian-Pacific clinical practice guidelines 2015 recommended IFN-α retreatment to treat chronic HBV infection
Liaw et al[17]	2012	Asian-Pacific clinical practice guidelines 2012 recommended IFN-α retreatment to treat chronic HBV infection
Liaw et al[18]	2008	Asian-Pacific clinical practice guidelines 2008 recommended IFN-α retreatment to treat chronic HBV infection
Yin et al[64]	2021	IFN-α retreatment was recommended for patients on entecavir or tenofovir monotherapy with persistent low-level viremia

IFN-α: Interferon-α; HBV: Hepatitis B virus.