Management of antiviral drug resistance in chronic hepatitis B

Table 1 Classifications and context cross-resistance profiles of antiviral drugs in chronic hepatitis B[8]

Classification	Amino acid substitution in the rt domain	LAM	LdT	ETV	ADV	TDF
	Wild-type	S	S	S	S	S
LAM + LdT resistance	M204I/V	R	R	I	S	S
ADV resistance	N236T	S	S	S	R	I
LAM + LdT + ADV (multi-drugs) resistance	A181T/V	R	R	S	R	I
ADV + TDF resistance	A181T/V + N236T	R	R	S	R	R
ETV resistance	L180M + M204I/V ± I169 ± T184 ± S202 ± M250	R	R	R	S	S
TDF resistance	A194T	R	S	S	NA	R

Adapted and modified from reference [8]. LAM: Lamivudine; LdT: Telbivudine; ETV: Entecavir; ADV: Adefovir; TDF: Tenofovir; S: Sensitive; I: Intermediate; R: Resistant; NA: Not available.

Table 2 Recommendations of guidelines for rescue therapy in chronic hepatitis B patients with antiviral drug resistance

Drugs to which antiviral resistance developed	AASLD (2009)[74]	EASL (2012)[6]	APASL (2008)[75]
LAM	Add ADV or TDF	Switch to TDF	Add-on ADV therapy
	Stop LAM, switch to Truvada®1	Add ADV, if TDF is not available	Switching to ETV therapy (1 mg/d) is an option
			Switching to interferon-based therapy is an option
LdT	Add ADV or TDF	Switch to TDF	Add-on ADV therapy
	Stop LdT, switch to Truvada®	Add ADV, if TDF is not available.	Switching to interferon-based therapy is an option
ADV	Add LAM2	If nucleoside-naive before ADV then switch to ETV or TDF	For LAM-naive patients who develop drug resistance while on ADV, add-on or switching to LAM, LdT, or ETV is indicated
	Stop ADV, switch to Truvada®	If the patient has high viremia then switch to ETV	Switching to interferon-based therapy is an option
	Switch to or add ETV2	If there is prior LAM resistance then switch to TDF or add a nucleoside analogue
ETV	Switch to TDF or Truvada®	Switch to or add TDF Add ADV, if TDF is not available

¹Truvada^® = combination pill with emtricitabine 200 mg and TDF 300 mg;

²Durability of viral suppression unknown, especially in patients with prior LAM resistance. AASLD: American Association for the Study of the Liver Diseases; EASL: European Association for the Study of the Liver Diseases; APASL: Asian-Pacific Assocation for the study of the Liver Diseases; LAM: Lamivudine; LdT: Telbivudine; ETV: Entecavir; ADV: Adefovir; TDF: Tenofovir.

Table 3 Antiviral drug efficacies in rescue settings

Virologic, serologic, and biochemical responses	ADV monotherapy[76]	ETV monotherapy[45,46]	ADV + LAM combination therapy[43]	ADV + LdT combination therapy[77]	ADV + ETV combination therapy[78,79]
Patients with undetectable HBV-DNA (%)
1 yr	22.8	54.5	61	70.3	88.8
2 yr	48.9	50.0	70		97.8
3 yr	56.8		79
4 yr	60.3		82
5 yr	60.3
Cumulative probability of genotypic resistance (%)
1 yr	4.4	6	0.7	0	0
2 yr	18.4	15	0.9		0
3 yr	34.3	36	1.3
4 yr	52.3	46
5 yr	65.6	51
Cumulative probability of HBeAg seroconversion (%)
1 yr	7.3	0		9.67	15.6
2 yr	12.7	0			26.7
3 yr	15.0		24
4 yr	17.0
5 yr	17.0
Cumulative probability of ALT normalization (%)
1 yr	80.3	77.3	84	64	100
2 yr	83.2	80	87		100
3 yr	86.7		89
4 yr	88.2
5 yr	88.2

ADV: Adefovir; ETV: Entecavir; LAM: Lamivudine; LdT: Telbivudine; TDF: Tenofovir; HBV-DNA: Hepatitis B virus deoxynucleic acid; HBeAg: Hepatitis B e antigen; ALT: Alanine aminotransferase.