抗HCV新型直接抗病毒药物相关耐药位点研究进展

doi:10.3877/cma.j.issn.1674-1358.2016.05.005

近年来，新型直接抗病毒药物（DAAs）药物研发取得了突破性进展，使其在抗HCV过程中具备高SVR率、广泛基因型谱、治疗周期短以及耐药率低等优点。但随着新型抗病毒药物在临床中的广泛应用，已发现多个相关耐药位点直接影响抗HCV的疗效，本文针对新型DAAs药物（包括NS3/4A蛋白酶抑制剂、NS5A蛋白抑制剂及NS5B聚合酶抑制）及其相关耐药位点进行总结。

关键词: 肝炎病毒, 丙型, 基因型, DAAs抑制剂, 耐药位点

In recent years, the development of direct-acting antiviral agents (DAAs) has made a breakthrough and had a variety of advantages of a high SVR rate, a wide genotype spectrum, a short treatment cycle and a low resistance rate in the treatment for HCV infection process. With the development of new antiviral drugs in clinical application, it has been found that the efficacy of treatment for HCV infection was directly affected by some related resistance loci. In this paper, the new DAAs drugs (including NS3/4A protease inhibitors, NS5A inhibitors and NS5B polymerase inhibition) and the related drug resistance loci were summarized.

Key words: Hepatitis C virus, Genotype, Direct-acting antiviral agents inhibitor, Resistance mutations

表1 HCV NS3/4A蛋白酶相关耐药位点

耐药位点	HCV NS3/4A蛋白酶抑制剂
耐药位点	Boceprevir	Telaprevir	Simprevir	Faldaprevir	ABT-450	Danoprevir
36	V36A/M	V36A/M/G/L	V36M		V36M/A/G	V36M/A/G
43			F43S
54	T54A/S/G/C	T54A/S	T54S
55	V55A/I				V55I	V55I
80			Q80K/R/L
122			S122A/R
132		I132V**
138			S138T
155	R155K/T	R155K/T/G/M	R155K	R155K	R155K	R155K
156	A156S/T/V	A156S/T/V	A156T/V	A156T/V	A156T/V
158	V158I
168		D168N^**	D168A/V/E/H/T	D168A/V/E/H/Y/N/P/I	D168A/V/Y/E/K	D168E/T
170	I^V170F^A/T^*T
175	M175L

表1 HCV NS3/4A蛋白酶相关耐药位点

耐药位点	HCV NS3/4A蛋白酶抑制剂
耐药位点	Boceprevir	Telaprevir	Simprevir	Faldaprevir	ABT-450	Danoprevir
36	V36A/M	V36A/M/G/L	V36M		V36M/A/G	V36M/A/G
43			F43S
54	T54A/S/G/C	T54A/S	T54S
55	V55A/I				V55I	V55I
80			Q80K/R/L
122			S122A/R
132		I132V**
138			S138T
155	R155K/T	R155K/T/G/M	R155K	R155K	R155K	R155K
156	A156S/T/V	A156S/T/V	A156T/V	A156T/V	A156T/V
158	V158I
168		D168N^**	D168A/V/E/H/T	D168A/V/E/H/Y/N/P/I	D168A/V/Y/E/K	D168E/T
170	I^V170F^A/T^*T
175	M175L

表2 NS5A蛋白抑制剂变异位点及EC₅₀增加倍数

DAAS	GT1a	EC₅₀增加倍数	GT1b	EC₅₀增加倍数
Daclatasvir	M28V（3.1%）	1.3	L28M/V	2.0
	Q30E/H/R/K		R30H
	L31M（3.1%）	341	L31M（6.6%）	3
Ledipasvir	L31M（3.1%）	140	L31M
GSK805	L31M（3.1%）	> 150	L31M
	I280V		I280V（6.6%）
	V298A		V298A
	V362A		V362A
	S364P		S364P
	S368P		S368P
Samatasvir	L31M		L31M（6.6%）
	p32L		P32L
	Y93C/H/N		Y93H（10%）	3.6
	V153M		V153M
	R157W		R157W
	V198V		V198A	93
	M202L		M202L
	P223S		P223S
	M265V		M265V

Daclatasvir	Q54H/L/N		Q54H（26.6%）	1.0
Daclatasvir	H58P（6.2%）	1.2			P58S/T/L
	N69T	N69T
	A92V	A92V
Daclatasvir	Y93C/H/N		Y93H（10%）	24
Ledipasvir	Y 93C/H/N		Y93H（10%）	1 319

表2 NS5A蛋白抑制剂变异位点及EC₅₀增加倍数

DAAS	GT1a	EC₅₀增加倍数	GT1b	EC₅₀增加倍数
Daclatasvir	M28V（3.1%）	1.3	L28M/V	2.0
	Q30E/H/R/K		R30H
	L31M（3.1%）	341	L31M（6.6%）	3
Ledipasvir	L31M（3.1%）	140	L31M
GSK805	L31M（3.1%）	> 150	L31M
	I280V		I280V（6.6%）
	V298A		V298A
	V362A		V362A
	S364P		S364P
	S368P		S368P
Samatasvir	L31M		L31M（6.6%）
	p32L		P32L
	Y93C/H/N		Y93H（10%）	3.6
	V153M		V153M
	R157W		R157W
	V198V		V198A	93
	M202L		M202L
	P223S		P223S
	M265V		M265V

Daclatasvir	Q54H/L/N		Q54H（26.6%）	1.0
Daclatasvir	H58P（6.2%）	1.2			P58S/T/L
	N69T	N69T
	A92V	A92V
Daclatasvir	Y93C/H/N		Y93H（10%）	24
Ledipasvir	Y 93C/H/N		Y93H（10%）	1 319

图1 NS5A区常见耐药位点核苷序列与氨基酸对照图

表3 NS5B聚合酶抑制剂变异位点及EC₅₀增加倍数

DAAS	GT1a	EC₅₀增加倍数	GT1b	EC₅₀增加倍数
Sofosbuvir + Mericitabine	S96T		S96T
	N142T		N142T
	L159F		L159F（23.3%）
	C223H/Y		C223H/Y
	S282T		S282T
	L320F		L320F
PSI-352938	V321I（3.1%）	2.0	V321I（3.3%）
Tegobuvir + HCV796	C316Y/N/F/S		C316N（36.6%）
	V362A		V362A
	S365A/T		S365A/T
	M414T		M414T
	L419M/S		L419M/S
	A421V		A421V
	R422K		R422K
	M423I/V/T		M423I/V/T
Filibuvir	M426L（3.1%）	0.8	M426L（6.6%）	0.8
Filibuvir	C445F		C445F
Tegobuvir	Y448H（3.1%）		Y448H
	Y452H（3.1%）		Y452H（3.3%）
	R465G		R465G（3.3%）
	I482L/T	36.0	I482L/T	6.9
	A486V	6.9	A486V	1.1
	V494A		V494A
	P495A/L/S/T		P495A/L/S/T
	P496A/S		P496A/S
JIK109 + Deleobuvir	A499T		V499A（13.3%）	3.0
	G554D		G554D
	S556G/D/N		S556G/D/N
	D559G/N		D559G/N

表3 NS5B聚合酶抑制剂变异位点及EC₅₀增加倍数

DAAS	GT1a	EC₅₀增加倍数	GT1b	EC₅₀增加倍数
Sofosbuvir + Mericitabine	S96T		S96T
	N142T		N142T
	L159F		L159F（23.3%）
	C223H/Y		C223H/Y
	S282T		S282T
	L320F		L320F
PSI-352938	V321I（3.1%）	2.0	V321I（3.3%）
Tegobuvir + HCV796	C316Y/N/F/S		C316N（36.6%）
	V362A		V362A
	S365A/T		S365A/T
	M414T		M414T
	L419M/S		L419M/S
	A421V		A421V
	R422K		R422K
	M423I/V/T		M423I/V/T
Filibuvir	M426L（3.1%）	0.8	M426L（6.6%）	0.8
Filibuvir	C445F		C445F
Tegobuvir	Y448H（3.1%）		Y448H
	Y452H（3.1%）		Y452H（3.3%）
	R465G		R465G（3.3%）
	I482L/T	36.0	I482L/T	6.9
	A486V	6.9	A486V	1.1
	V494A		V494A
	P495A/L/S/T		P495A/L/S/T
	P496A/S		P496A/S
JIK109 + Deleobuvir	A499T		V499A（13.3%）	3.0
	G554D		G554D
	S556G/D/N		S556G/D/N
	D559G/N		D559G/N

图2 上市Sofosbuvir的结构图

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