The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection

Table 1 Antiviral activities of second and third-generation nucleosides and nucleotides in the woodchuck model of chronic HBV infection

Antiviraldrug	Oral dose(mg/kgper day)	Treatmentduration(wk)	Follow upduration(wk)	Serum WHVDNA reduction(log)	Time to viralrecrudescence(wk)	Drug-associatedtoxicity	Other viral markers	Ref.
Lamivudine	1	24	24	1.5	within 1-2	none	WHV RI red. (3-fold)	[141]
							no WHV RNA red.
							no serum WHsAg red.
	5	4	12	3.4	within 1	none	WHV RI red. (4-fold)	[21]
							no WHV RNA red.
							no serum WHsAg red.
	5	12	12	1.9	within 1-2	none	WHV RI red. (3-fold)	[157]
							no WHV RNA red.
							no serum WHsAg red.
	15	4	12	5.4	within 1	none	WHV RI red. (12-fold)	[21]
							no WHV RNA red.
							no serum WHsAg red.
Adefovir	5	12	6	1.7	within 6	none		[144]
	15	12	6	2.5	within 6	none		[144]
Entecavir	0.02	12	12	7-81	within 2-10	none	WHV RI red. in individual animals to undetectable levels	[139]
	0.1	12	12	7-8	within 6-10	none	WHV RI red. in most animals to undetectable levels	[139]
Tenofovir	5	4	12	1.5	within 1-4	none	no WHV RI red.	[147]
							no WHV RNA red.
							no serum WHsAg red.
	15	4	12	1.2	within 1-4	none	no WHV RI red.	[147]
							no WHV RNA red.
							no serum WHsAg red.
Emtricitabine	3	4	12	1.4	within 1-2	none	WHV RI red. (3-fold)	[149]
							no WHV RNA red.
							no serum WHsAg red.
	10	4	12	3.2	within 1-2	none	WHV RI red. (13-fold)	[149]
							no WHV RNA red.
							no serum WHsAg red.
	30	4	12	4.9	within 1-2		WHV RI red. (80-fold)	[149]
							no WHV RNA red.
							no serum WHsAg red.
	202	4	4	1.4	within 1-2	none		[148]
	302	4	4	1.8	within 1-2	none	WHV RI red. (2-fold)	[148]
Telbivudine	10	4	8	8	within 4-8	none	serum WHsAg red.	[151-153]
Valtorcitabine	10	4	8	4-6	within 1-8	none		[151-153]
Clevudine	3	4	12	9.2	within 2-10	none	WHV RI red. (28-fold)	[154]
							no WHV RNA red.
							serum WHsAg red. (2-fold)
	10	4	12	8.2	within 8-123	none	WHV RI red. (68-fold)	[154]
							WHV RNA red. (2.7-fold)
							serum WHsAg red. (4-fold)
							WHV cccDNA red. (2-6-fold or to undetectable levels)

¹Two of 6 woodchucks with modest reduction in serum WHV DNA of approximately 2.0 logs were not included.

²Dosage was given twice daily by intraperitoneal administration.

³One woodchuck had suppressed serum WHV DNA at the end of the study. WHV RI, hepatic WHV DNA replicative intermediates; WHV RNA, intrahepatic WHV RNA; red., reduction.

Table 2 Immunotherapeutic approaches in the woodchuck model of chronic HBV infection

Treatment	Outcome	Additional results	Ref.
Vaccination
WHsAg vaccine/adjuvant	Anti-WHs response	CMI to WHsAg	[55,56,155]
WHsAg vaccine/adjuvant	Anti-WHs response (antibodies mainly directed against preS region)		[173]
WHsAg vaccine/Th peptide epitope	Anti-WHs response	Two woodchucks died	[174]
	Transient serum WHV DNA red. in a few animals (1 log)
Cytokines
IFN-α (adenoviral vector)	Transient serum WHV DNA red. (1 log)	Transient WHV RI red. (1 log)	[181]
IFN-α (adeno-associated viral vector)	Transient serum WHV DNA red. (2 logs)		[182]
	Sustained serum WHV DNA red. in 2 animals
IFN-γ (adenoviral vector)	No antiviral effect		[181]
Adoptive immunotransfer
Liver transplantation	Serum WHV DNA red.	WHV RI red., WHV RNA red.	[188]
Combination treatment
Lamivudine + WHsAg vaccine/ Th peptide epitope	No additional benefit beyond lamivudine-induced antiviral effect	CMI to WHsAg/WHcAg
Lamivudine + β-galactosidase (adenoviral vector)	Transient but sustained serum WHV DNA red. (> 1 log) in addition to lamivudine-induced antiviral effect	WHV RI red., WHV cccDNA red., WHV RNA red.	[191]
Clevudine + β-galactosidase/+ IFN-γ/+ IFN-α (adenoviral vector)	Transient but sustained serum WHV DNA red. in addition to clevudine-induced antiviral effect	WHV RI red.	[156]
Clevudine + emtricitabine + IFN-γ (adenoviral vector)	No additional benefit beyond clevudine + emtricitabine-induced antiviral effect	Increased liver inflammation with IFN-γ	[150]
Clevudine + WHsAg vaccine	Anti-WHs response	WHV cccDNA red.,	[55,56,155]
	Sustained serum WHV DNA red. (> 6 to 8 log)	CMI to WHsAg/WHcAg
		Delay in onset of disease progression

WHV RI, hepatic WHV DNA replicative intermediates; WHV cccDNA, covalently closed circular WHV DNA, WHV RNA, intrahepatic WHV RNA; red., reduction.