Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos(t)ide analogues

Table 1 Primary antiviral drug resistance mutations in the polymerase gene[23]

	Domain A	Domain B	Domain C	Domain D	Domain E	Numbers of mutations
Lamivudine and Telbivudine		rtV173L
	--	rtL180M	rtM204V/I	--	--	1
		rtA181T/V
Adefovir	--	rtA181T/V		rtN236T	--	1
Tenofovir	--	rtA181T/V		rtN236T	--	?
Entecavir	--	rtL180M	rtM204I/V	--	rtM250I/V	3
		rtT184	rtS202

Table 2 Patterns and pathways of antiviral drug resistance in chronic hepatitis B in the context of cross-resistance[99]

Pathway	Amino acid substitution in the rt domain	LAM	LdT	ETV	ADV	TDF
	WT	S	S	S	S	S
L-nucleoside (LAM/LdT)	M204I/V	R	R	I	S	S
Acyclic phosphonate (ADV)	N236T	S	S	S	R	I
Shared (LAM, LdT, ADV)	A181T/V	R	R	S	R	I
Double(ADV, TDF)	A181T/V + N236T	R	R	S	R	R
D-Cyclopentane (ETV)	L180M + M204V/I ± I169 ± T184 ± S202 ± M250	R	R	R	S	S

I: Intermediate sensitivity; R: Resistant; S: Sensitive based on cell culture and clinical; LAM: Lamivudine; LdT: Telbivudine; ETV: Entecavir; TDF: Tenofovir; ADV: Adefovir.

Table 3 Management of antiviral-resistant hepatitis B virus in updated guidelines

	AASLD 2009[27]	EASL 2012[101]
LAM-resistance	Add ADV or TDF	Switch to TDF or add ADV
	In patients with no prior exposure to other NA: Add LAM or ETV	In patients with no prior exposure to other NA: Switch to ETV or TDF
ADV-resistance	In patients with prior LAM resistance: Switch to TDF plus LAM or ETV	In patients with prior LAM resistance: Switch to TDF and another NA
ETV-resistance	Switch to TDF	Switch to or add TDF
TDF-resistance	--	In patients with no prior exposure to LAM: Switch to ETV
		In patients with prior LAM resistance: Add ETV

LAM: Lamivudine; LdT: Telbivudine; ETV: Entecavir; TDF: Tenofovir; ADV: Adefovir; NA: Nucleos(t)ide analogues.