Management of chronic hepatitis B infection: Current treatment guidelines, challenges, and new developments

Table 1 Geographic distribution of hepatitis B virus genotypes

Genotypes	Geographic distribution	Tendency of chronicity	Clinical outcome
A	Europe, United States	Higher	Better
B	Eastern Asia	Lower	Better
C	Eastern Asia	Higher	Worse
D	Southern Europe, North Africa, Middle East, Indian Sub-Continent	Lower	Worse
E	Sub-Saharan Africa	-	-
F	South America	-	-
G	Europe, United States	-	-
H	Central America	-	-

Table 2 Comparison of antiviral agents for chronic hepatitis B

Antiviral agents	Immunomodulators			Nucleos(t)ide analogues
	IFN-α	PEG-IFN-α	Thymosin	Lamivudine	Adefovir	Entecavir	Telbivudine	Tenofovir
Route	SC	SC	Oral	Oral	Oral	Oral	Oral	Oral
Dose	5-10 MIU tiw	180 μg qw	1.6 mg biw	100 mg od	10 mg od	0.5-1 mg od	600 mg od	300 mg od
Year approved	1992	2005	Asia only	1998	2002	2005	2006	2008
Antiviral effects
HBV DNA	37	30	42	36-40	21	67	60	76
HBsAg clearance	++	++	N/A	-	-	+	-	-
HBeAg seroconversion	20-40	27	40	18-20	12	21	22	21
ALT normalization		39	42	62-77	48	68	77	68
Histological improvement		38	N/A	56-62	53	72	65	74
Side effects	Many	Many	Negligible	Negligible	Nephrotoxicity	Negligible	Negligible	Nephrotoxicity
Contraindications	Numerous	Numerous	Uncommon	Uncommon	Uncommon	Uncommon	Uncommon	Uncommon
Drug resistance (treatment-naïve patients)
1 yr	None, but non-response			24	None	0	4	0
2 yr				38	3	0.2	25	0
> 5 yr				80	29	1	N/A	0
Drug resistance (LAM resistant patients)
2 yr	None, but non-response			N/A	25	9	N/A	0
4 yr				N/A	N/A	39	N/A	0

PEG-IFN: Pegylated interferon; SC: Subcutaneous; tiw: Three times a week; qw: Once a week; biw: Twice a week; od: Once daily; ALT: Alanine transaminase; ETV: Entecavir; LAM: Lamivudine; ADV: Adefovir; TBV: Telbivudine; TDF: Tenofovir disoproxil fumarate; N/A: Not applicable.

Table 3 National Institute for Health and Care Excellence treatment guidelines

Guidelines	HBeAg positive	HBeAg negative	Decompensated
1st line	48-wk of PEG-IFN-α-2a	48-wk of PEG-IFN-α-2a	ETV or TDF (LAM resistance)
2nd line	TDF or ETV (TDF contraindication)	ETV or TDF
3rd line	LAM + TDFor ETV + TDF (LAM resistance)	ETV or TDF

In adults with compensated liver disease, current guidelines advise first-line treatment with 48 wk of PEG-IFN-α-2a. If PEG-IFN-α-2a is contraindicated, tenofovir or entecavir should be trialed. PEG-IFN: Pegylated interferon; HBeAg: Hepatitis B e antigen; ETV: Entecavir; LAM: Lamivudine; TDF: Tenofovir disoproxil fumarate.

Table 4 Recommendations for the use of pegylated interferon as initial antiviral therapy

HBV genotype	General recommendations for HBeAg positive patients
A	Either high ALT (≥ 2 × ULN) or low HBV DNA levels (< 9 log10 copies/mL)
B and C	Both high ALT (≥ 2 × ULN) and low HBV DNA levels (< 9 log10 copies/mL)
D	Not recommended

HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; ALT: Alanine transaminase; ULN: Upper limit of normal.

Table 5 Comparison of de novo combination therapy and monotherapy

Combination therapy	Monotherapy	HBeAg seroconversion	HBV DNA	HBsAg clearance	Histological improvement	Drug resistance
LAM + ADV	LAM	=	=	N/A	=	↓
LAM + ADV	ETV	N/A	=	N/A	N/A	N/A
ETV + TDF	ETV	=	=	N/A	=	=
LAM + PEG-IFN	LAM	↑	↓	↑	↑	↓
ADV + PEG-IFN	PEG-IFN	N/A	↓	↑	N/A	N/A
ETV + PEG-IFN	ETV	↑	↓	↑	N/A	N/A

In several randomized controlled trials, combination therapy with nucleos(t)ide analogues and PEG-IFN are superior to existing management options with regards to viral load, HBeAg seroconversion, and HBsAg clearance. HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; PEG-IFN: Pegylated interferon; ETV: Entecavir; LAM: Lamivudine; ADV: Adefovir; TBV: Telbivudine; TDF: Tenofovir disoproxil fumarate; N/A: Not applicable.

Table 6 Antiviral resistance patterns and rescue therapy

Resistance	Mutation patterns	Treatment adaptation
LAM	M204V/I + L180M M204I M204V + L180M + V173L M204I + L180I Q215S + M204I/V + M204V I169T + V173L + L180M + M204V A181T T184S + M204I/V + L180M M204S + L180M	Switch to TDF or Switch to ETV + ADV combination therapy or Add ADV if TDF or ETV unavailable
ADV	A181V/T N236T A181V/T + N236T	Switch to TDF and add ETV
ADV + LAM	A181V/T + N236T L80V/I	Switch to TDF and add ETV
TBV	M204I/V ± L180M L80I/V ± L180M A181T/V	Switch to or add TDF
ETV	L180M + M204V/I ± I169T ± M250V L180M + M204V/I ± T184G ± S202I/G	Switch to or add TDF
TDF	No known mutations	N/A

Common mutation patterns, and rescue therapies suggested by the American Association for the Society of Liver Disease, Asian Pacific Association for the Study of Liver; European Association for the Study of Liver and National Institute for Health and Care Excellence. LAM: Lamivudine; ETV: Entecavir; ADV: Adefovir; TBV: Telbivudine; TDF: Tenofovir disoproxil fumarate.

Table 7 Treatment endpoints in clinical use

Treatment	Description
Biochemical	Normalization of serum ALT
Virological
HBeAg-positive	Loss of HBeAg, Anti-HBe antibodies, serum HBV-DNA < 2000 IU/mL
HBeAg-negative	Serum HBV-DNA < 2000 IU/mL
Complete	Biochemical and virological response with loss of serum HBsAg
Histological	Decrease in necroinflammatory activity without worsening in fibrosis

ALT: Alanine transaminase; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen.

Table 8 Emerging pipeline drugs for chronic hepatitis B virus infection

Drug name	Mechanism of action	Status
Nucleos(t)ide analogues
Clevudine	Inhibits DNA polymerase	Partial approval
Emtricitabine	Inhibits DNA polymerase	FDA approved for HIV
Nucleos(t)ide analogue prodrugs
Amdoxovir	Inhibits DNA polymerase	II (for HIV)
LB80380	Inhibits DNA polymerase	IIb
Famciclovir	Inhibits DNA polymerase	Abandoned
Pradefovir	Inhibits DNA polymerase	Abandoned
Tenofovir alafenamide (GS 7340)	Inhibits DNA polymerase	II/III
MIV-210	Inhibits DNA polymerase	Abandoned
Non-nucleos(t)ide antivirals
NOV-205 (BAM 205)	Unknown	Approved in Russia
Myrcludex-B	Inhibits viral entry	Ib/IIa
Bay 41-4109	Inhibits viral core formation	I
GLS4	Inhibits HBV viral core assembly	Pre-clinical
Rep 9 AC	Blocks HBsAg release	II
NVR-1221	Capsid inhibitor	Pre-clinical
Immunomodulators
Pegylated interferon lambda	Cytokine modulating innate/adaptive immune response	I
GS-9620	TLR-7 agonist	Pre-clinical
Nitazoxanide	Unknown	II
EHT899	Immune enhancer	II
Therapeutic vaccines
HBV core antigen vaccine	Enhance T cell response	I
HBV-EPV	Immunogenic	Withdrawn
ePA-44	Immunogenic	II
HI-8 HBV	Stimulates IFN-γ producing T cells	II
Others
β-thujaplicinol	Blocks viral ribonuclease H activity	Pre-clinical
ARC520	RNA interference	I
Herbal bushen formula	Down-regulate CD4+ and CD25+ T cells	TCM

HBV: Hepatitis B virus; TCM: Traditional chinese medicine; HBsAg: Hepatitis B surface antigen; HIV: Human immunodeficiency virus; FDA: Food and Drug Administration; IFN: Interferon.

Table 9 A partial list of ongoing clinical trials

Phase	Trial identifier	Design	Drugs	Enrollment	Expected end date
I	NCT01872065	Double-blind, randomized	ARC520	44	October 2013
	NCT01590641	Double-blind, randomized	GS-9620	48	September 2013
II	NCT00524173	Open-label, randomized	TDF vs TDF + emtricitabine	100	January 2015
	NCT01204762	Double-blind, randomized	IFN-λ + ETV	170	July 2017
	NCT01242787	Open-label, randomized	LB80380	115	September 2012
III	NCT01595685	Open-label, randomized	TBV vs ETV	184	December 2014
	NCT01369199	Open-label, randomized	8 wk ETV followed by 40 wkPEG-IFN-α-2a + ETV	250	May 2016
IV	NCT01804387	Open-label, randomized	TBV + ADV vs LAM + ADV	60	May 2014
	NCT01906580	Open-label, randomized	PEG-IFN-α-2a vs ETV	105	July 2014

Full details of the clinical trials may be found on the United States National Institutes of Health. Available from: URL: http://www.clinicaltrials.gov. LAM: Lamivudine; ETV: Entecavir; ADV: Adefovir; TBV: Telbivudine; TDF: Tenofovir disoproxil fumarate; PEG-IFN: Pegylated interferon.