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Copyright ©2014 Baishideng Publishing Group Inc.
World J Gastroenterol. May 28, 2014; 20(20): 6262-6278
Published online May 28, 2014. doi: 10.3748/wjg.v20.i20.6262
Table 1 Geographic distribution of hepatitis B virus genotypes
GenotypesGeographic distributionTendency of chronicityClinical outcome
AEurope, United StatesHigherBetter
BEastern AsiaLowerBetter
CEastern AsiaHigherWorse
DSouthern Europe, North Africa, Middle East, Indian Sub-ContinentLowerWorse
ESub-Saharan Africa--
FSouth America--
GEurope, United States--
HCentral America--
Table 2 Comparison of antiviral agents for chronic hepatitis B
Antiviral agentsImmunomodulators
Nucleos(t)ide analogues
Dose5-10 MIU tiw180 μg qw1.6 mg biw100 mg od10 mg od0.5-1 mg od600 mg od300 mg od
Year approved19922005Asia only19982002200520062008
Antiviral effects
HBV DNA37304236-4021676076
HBsAg clearance++++N/A--+--
HBeAg seroconversion20-40274018-2012212221
ALT normalization394262-7748687768
Histological improvement38N/A56-6253726574
Side effectsManyManyNegligibleNegligibleNephrotoxicityNegligibleNegligibleNephrotoxicity
Drug resistance (treatment-naïve patients)
1 yrNone, but non-response24None040
2 yr3830.2250
> 5 yr80291N/A0
Drug resistance (LAM resistant patients)
2 yrNone, but non-responseN/A259N/A0
4 yrN/AN/A39N/A0
Table 3 National Institute for Health and Care Excellence treatment guidelines
GuidelinesHBeAg positiveHBeAg negativeDecompensated
1st line48-wk of PEG-IFN-α-2a48-wk of PEG-IFN-α-2aETV or TDF (LAM resistance)
2nd lineTDF or ETV (TDF contraindication)ETV or TDF
3rd lineLAM + TDFor ETV + TDF (LAM resistance)ETV or TDF
Table 4 Recommendations for the use of pegylated interferon as initial antiviral therapy
HBV genotypeGeneral recommendations for HBeAg positive patients
AEither high ALT (≥ 2 × ULN) or low HBV DNA levels (< 9 log10 copies/mL)
B and CBoth high ALT (≥ 2 × ULN) and low HBV DNA levels (< 9 log10 copies/mL)
DNot recommended
Table 5 Comparison of de novo combination therapy and monotherapy
Combination therapyMonotherapyHBeAg seroconversionHBV DNAHBsAg clearanceHistological improvementDrug resistance
Table 6 Antiviral resistance patterns and rescue therapy
ResistanceMutation patternsTreatment adaptation
LAMM204V/I + L180M M204I M204V + L180M + V173L M204I + L180I Q215S + M204I/V + M204V I169T + V173L + L180M + M204V A181T T184S + M204I/V + L180M M204S + L180MSwitch to TDF or Switch to ETV + ADV combination therapy or Add ADV if TDF or ETV unavailable
ADVA181V/T N236T A181V/T + N236TSwitch to TDF and add ETV
ADV + LAMA181V/T + N236T L80V/ISwitch to TDF and add ETV
TBVM204I/V ± L180M L80I/V ± L180M A181T/VSwitch to or add TDF
ETVL180M + M204V/I ± I169T ± M250V L180M + M204V/I ± T184G ± S202I/GSwitch to or add TDF
TDFNo known mutationsN/A
Table 7 Treatment endpoints in clinical use
BiochemicalNormalization of serum ALT
HBeAg-positiveLoss of HBeAg, Anti-HBe antibodies, serum HBV-DNA < 2000 IU/mL
HBeAg-negativeSerum HBV-DNA < 2000 IU/mL
CompleteBiochemical and virological response with loss of serum HBsAg
HistologicalDecrease in necroinflammatory activity without worsening in fibrosis
Table 8 Emerging pipeline drugs for chronic hepatitis B virus infection
Drug nameMechanism of actionStatus
Nucleos(t)ide analogues
ClevudineInhibits DNA polymerasePartial approval
EmtricitabineInhibits DNA polymeraseFDA approved for HIV
Nucleos(t)ide analogue prodrugs
AmdoxovirInhibits DNA polymeraseII (for HIV)
LB80380Inhibits DNA polymeraseIIb
FamciclovirInhibits DNA polymeraseAbandoned
PradefovirInhibits DNA polymeraseAbandoned
Tenofovir alafenamide (GS 7340)Inhibits DNA polymeraseII/III
MIV-210Inhibits DNA polymeraseAbandoned
Non-nucleos(t)ide antivirals
NOV-205 (BAM 205)UnknownApproved in Russia
Myrcludex-BInhibits viral entryIb/IIa
Bay 41-4109Inhibits viral core formationI
GLS4Inhibits HBV viral core assemblyPre-clinical
Rep 9 ACBlocks HBsAg releaseII
NVR-1221Capsid inhibitorPre-clinical
Pegylated interferon lambdaCytokine modulating innate/adaptive immune responseI
GS-9620TLR-7 agonistPre-clinical
EHT899Immune enhancerII
Therapeutic vaccines
HBV core antigen vaccineEnhance T cell responseI
HI-8 HBVStimulates IFN-γ producing T cellsII
β-thujaplicinolBlocks viral ribonuclease H activityPre-clinical
ARC520RNA interferenceI
Herbal bushen formulaDown-regulate CD4+ and CD25+ T cellsTCM
Table 9 A partial list of ongoing clinical trials
PhaseTrial identifierDesignDrugsEnrollmentExpected end date
INCT01872065Double-blind, randomizedARC52044October 2013
NCT01590641Double-blind, randomizedGS-962048September 2013
IINCT00524173Open-label, randomizedTDF vs TDF + emtricitabine100January 2015
NCT01204762Double-blind, randomizedIFN-λ + ETV170July 2017
NCT01242787Open-label, randomizedLB80380115September 2012
IIINCT01595685Open-label, randomizedTBV vs ETV184December 2014
NCT01369199Open-label, randomized8 wk ETV followed by 40 wkPEG-IFN-α-2a + ETV250May 2016
IVNCT01804387Open-label, randomizedTBV + ADV vs LAM + ADV60May 2014
NCT01906580Open-label, randomizedPEG-IFN-α-2a vs ETV105July 2014