Intracellular interferon signalling pathways as potential regulators of covalently closed circular DNA in the treatment of chronic hepatitis B

Table 1 Treatment outcomes of nucleoside/nucleotide analogue and interferon therapy

Ref.	Treatment		% loss of HBV markers				% seroconvert		% normal ALT	% HBV reactivation
	n	Schedule	HBs	HBe	rcDNA	cccDNA	α-HBs	α-HBe
Reijnders et al[131]	132	NA: 16-43 mo	3	42	-	-	-	35	-	56
Song et al[132]	98	NA: 6-22 mo	-	35	-	-	-	35	-	49
Jeng et al[133]	691	NA: 1-8 yr	6	n.a.	n.a.	-	4	n.a.	-	79
Liem et al[134]	45	NA: ≥ 1 yr	2	n.a.	-	-	-	-	-	71
	22	NA: ≥ 2 yr	4	n.a.	-	-	-	-	-	18
Marcellin et al[135]	181	NA: 48 wk	0	n.a.	29	-	0	-	44	-
	177	PEG-IFN: 48 wk	4	n.a.	43	-	3	-	59	-
Lau et al[136]	272	NA: 48 wk	0	21	22	-	0	19	28	-
	271	PEG-IFN: 48 wk	3	34	32	-	3	32	41	-
van Zonneveld et al[137]	165	IFN: 16 wk	23	33	43	-	-	-	62	13
Niederau et al[138]	103	IFN: 4-6 mo	10	51	51	-	-	51	50	-
	53	Untreated	0	13	9	-	-	-	9	-
Liu et al[139]	38	IFN: 48 wk	-	-	-	47	-	-	Low	-
	38	PEG-IFN: 48 wk	-	-	-	63	-	-	High	-

HBV: Hepatitis B virus; rcDNA: Relaxed circular DNA; cccDNA: Covalently closed circular DNA; ALT: Alanine aminotransferase; NA: Nucleoside/nucleotide analogue; PEG: Pegylated form; IFN: Interferon; n.a.: Not applicable.

Table 2 Interferons with anti-hepatitis B virus properties

Types of Interferon		Effect on HBV				Remarks	Antiviral ISGs	Ref.
		cccDNA	rcDNA	HBs	HBe
I	IFN-α2a/PEG-IFN-α2a	↓	↓	↓	↓	Clinical anti-HBV agent	APOBEC3A1, APOBEC3F1, APOBEC3G1, STAT11, ISG201, TRIM38, MX1, etc.	[140-142]
	IFN-α2b/PEG-IFN-α2b	↓	↓	↓	↓	Clinical anti-HBV agent	IFITM1, IFITM3, TRIM14, RNASEL etc.	[143-145]
	IFN-α14	↓	-	↓	↓	Activates IFN-α and IFN-γ signalling	GBP4, GBP5	[146]
	IFN-β/PEG-IFN-β	↓	↓	↓	↓	-	MX1, CXCL10	[147]
	IFN-ω	-	↓	↓	↓	-	IRF1, IRF9, ISG15, OAS	[148-150]
II	IFN-γ	-	-	-	↓	-	APOBEC3G1, OAS, IDO	[151-153]
III	IFN-λ1a	-	↓	↓	↓	Increased HBe seroconversion	PKR, OAS	[154,155]
	IFN-λ2	↓	↓	-	↓	-	APOBEC3A1, APOBEC3B1, APOBEC3G1, MX1, OAS	[156]
	IFN-λ3	-	↓	↓	↓	Increased JAK/STAT signalling	APOBEC3G1, IRF91, IRF7, MX1, OAS, ISG15 etc.	[157-159]

↓: Reduced; -: Not determined.

¹Important for cccDNA elimination or silencing. HBV: Hepatitis B virus; rcDNA: Relaxed circular DNA; cccDNA: Covalently closed circular DNA; JAK: Activate janus kinase; STAT: Signal transducers and activators of transcription; ISGs: Interferon-stimulated genes; PEG: Pegylated form; IFN: Interferon.

Table 3 Updates on combination therapy

Ref.	Treatment		% loss of HBV markers				% seroconvert		% normal ALT	% HBV reactivation
	Type	Schedule	HBs	HBe	rcDNA	cccDNA	α-HBs	α-HBe
Hagiwara et al[160]	Sim	Combi: 48 wk	4	60	62	85	-	60	77	38
Zhang et al[63]	Sim	Combi: 48 wk	9	-	58	-	-	30	73	-
	Mono	IFN: 48 wk	6	-	31	-	-	25	56	-
	Add	IFN: 12 wk; +Combi: 36 wk; +NA: 12 wk	16	-	72	-	-	50	78	-
	Add	IFN: 24 wk; +Combi: 24 wk; +NA: 24 wk	9	-	69	-	-	31	78	-
Huang et al[48]	Swi	NA: ≥ 2 yr +IFN: 60 wk	33	91	n.a.	-	26	65	n.a.	-
	Mono	NA: ≥ 2 yr	0	38	n.a.	-	0	22	n.a.	-
Zhou et al[49]	Swi	NA: ≥ 4 yr +IFN: 48 wk	36	n.a.	n.a.	-	27	n.a.	-	25
	Mono	NA: ≥ 5 yr	4	n.a.	n.a.	-	0	n.a.	-	58

HBV: Hepatitis B virus; rcDNA: Relaxed circular DNA; cccDNA: Covalently closed circular DNA; ALT: Alanine aminotransferase; NA: Nucleoside/nucleotide analogue; IFN: Interferon; n.a.: Not applicable; Sim: Simultaneous therapy; Add: Add-on therapy; Mono: Monotherapy; Swi: Switch therapy.