Daclatasvir plus asunaprevir in treatment-naïve patients with hepatitis C virus genotype 1b infection

doi:10.3748/wjg.v24.i12.1361

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Randomized Clinical Trial

World J Gastroenterol. Mar 28, 2018; 24(12): 1361-1372
Published online Mar 28, 2018. doi: 10.3748/wjg.v24.i12.1361

Table 1 Baseline demographics and disease characteristics n (%)¹

Characteristic	Immediate treatment, n = 155²	Placebo-deferred treatment, n = 52	Overall, n = 207²
Age, median (range) years	49 (18-73)	49 (23-69)	49 (18-73)
< 65 yr	142 (92)	45 (87)	187 (90)
≥ 65 yr	13 (8)	7 (14)	20 (10)
Male	61 (39)	23 (44)	84 (41)
Race
Asian	132 (85)	45 (87)	177 (86)
White	23 (15)	7 (14)	30 (15)
Country
Mainland China	119 (77)	42 (81)	161 (78)
Russia	23 (15)	7 (14)	30 (15)
South Korea	13 (8)	3 (6)	16 (8)
HCV RNA, median (range) log₁₀ IU/mL	6.78 (3.1-7.6)	6.86 (5.6-7.6)	6.79 (3.1-7.6)
≥ 6 million IU/mL	79 (51)	31 (60)	110 (53)
IL28B genotype
CC	107 (69)	34 (65)	141 (68)
CT	43 (28)	17 (33)	60 (29)
TT	5 (3)	1 (2)	6 (3)
Cirrhosis	19 (12)	7 (14)	26 (13)

¹Unless otherwise stated;

²Includes one patient from mainland China who was subsequently reclassified as having HCV genotype 1a infection by phylogenetic analysis of the HCV NS5A sequence. HCV: Hepatitis C virus.

Table 2 SVR12 in hepatitis C virus genotype 1b-infected patients with and without resistance-associated polymorphisms at baseline (immediate treatment arm) n (%)

	All patients - immediate treatment arm
	With RAPs at baseline				Without RAPs at baseline
	Mainland China	Russia	South Korea	Overall	Mainland China	Russia	South Korea	Overall
NS5A-L31M/V	1/1 (100)	1/1(100)	0	2/2 (100)	108/117 (92.3)	21/22 (95.5)	10/13 (76.9)	139/152 (91.4)
Y93H	7/13(53.8)	0	0/2 (0)	7/15 (46.7)	102/105 (97.1)	22/23 (95.7)	10/11(90.9)	134/139 (96.4)
L31M/V or Y93H	8/14 (57.1)	1/1 (100)	0/2 (0)	9/17 (52.9)	101/104 (97.1)	21/22 (95.5)	10/11(90.9)	132/137 (96.4)
NS3-D168E	0/1 (0)	0	0	0/1 (0)	109/117 (93.2)	22/23 (95.7)	10/13 (76.9)	141/153 (92.2)

RAP: Resistance-associated polymorphism; SVR12: Sustained virologic response at posttreatment week 12.

Table 3 SVR12 in cirrhotic and non-cirrhotic hepatitis C virus genotype 1b-infected patients with and without resistance-associated polymorphisms at baseline (immediate treatment arm) n (%)

	Patients with cirrhosis - immediate treatment arm
	With RAPs at baseline				Without RAPs at baseline
	Mainland China	Russia	South Korea	Overall	Mainland China	Russia	South Korea	Overall
Patients with cirrhosis
NS5A-L31M/V	0	0	0	0	15/16 (93.8)	0	2/3 (66.7)	17/19 (89.5)
Y93H	0	0	0	0	15/16 (93.8)	0	2/3 (66.7)	17/19 (89.5)
L31M/V or Y93H	0	0	0	0	15/16 (93.8)	0	2/3 (66.7)	17/19 (89.5)
NS3-D168E	0	0	0	0	15/16 (93.8)	0	2/3 (66.7)	17/19 (89.5)
Patients without cirrhosis
NS5A-L31M/V	1/1 (100)	1/1 (100)	0	2/2 (100)	93/101 (92.1)	21/22 (95.5)	8/10 (80.0)	122/133 (91.7)
Y93H	7/13 (53.8)	0	0/2 (0)	7/15 (46.7)	87/89 (97.8)	22/23 (95.7)	8/8 (100)	117/120 (97.5)
L31M/V or Y93H	8/14 (57.1)	1/1 (100)	0/2 (0)	9/17 (52.9)	86/88 (97.7)	21/22 (95.5)	8/8 (100)	115/118 (97.5)
NS3-D168E	0/1 (0)	0	0	0/1 (0)	94/101 (93.1)	22/23 (95.7)	8/10 (80.0)	124/134 (92.5)

RAP: Resistance-associated polymorphism; SVR12: Sustained virologic response at posttreatment week 12.

Table 4 SVR12 in hepatitis C virus genotype 1b-infected patients with and without resistance-associated polymorphisms at baseline (placebo-deferred treatment arm) n (%)

	All patients - placebo-deferred treatment arm
	With RAPs at baseline					Without RAPs at baseline
	Mainland China		Russia	South Korea	Overall	Mainland China	Russia	South Korea	Overall
NS5A-L31M/V		0	0	0	0	33/41 (80.5)	6/6 (100)	3/3 (100)	42/50 (84.0)
Y93H		2/8 (25.0)	0	0	2/8 (25.0)	31/33 (93.9)	6/6 (100)	3/3 (100)	40/42 (95.2)
L31M/V or Y93H		2/8 (25.0)	0	0	2/8 (25.0)	31/33 (93.9)	6/6 (100)	3/3 (100)	40/42 (95.2)
NS3-D168E		0	0	0	0	33/41 (80.5)	6/6 (100)	3/3 (100)	42/50 (84.0)

RAP: Resistance-associated polymorphism; SVR12: Sustained virologic response at posttreatment week 12.

Table 5 SVR12 in cirrhotic and noncirrhotic hepatitis C virus genotype-1b-infected patients with and without resistance-associated polymorphisms at baseline (placebo-deferred treatment arm) n (%)

	Patients with cirrhosis - placebo-deferred treatment arm
	With RAPs at baseline				Without RAPs at baseline
	Mainland China	Russia	South Korea	Overall	Mainland China	Russia	South Korea	Overall
Patients with cirrhosis
NS5A-L31M/V	0	0	0	0	3/5 (60.0)	1/1 (100)	1/1 (100)	5/7 (71.4)
Y93H	1/3 (33.3)	0	0	1/3 (33.3)	2/2 (100)	1/1 (100)	1/1 (100)	4/4 (100)
L31M/V or Y93H	1/3 (33.3)	0	0	1/3 (33.3)	2/2 (100)	1/1 (100)	1/1 (100)	4/4 (100)
NS3-D168E	0	0	0	0	3/5 (60.0)	1/1 (100)	1/1 (100)	5/7 (71.4)
Patients without cirrhosis
NS5A-L31M/V	0	0	0	0	30/36 (83.3)	5/5 (100)	2/2 (100)	37/43 (86.0)
Y93H	1/5 (20.0)	0	0	1/5 (20.0)	29/31 (93.5)	5/5 (100)	2/2 (100)	36/38 (94.7)
L31M/V or Y93H	1/5 (20.0)	0	0	1/5 (20.0)	29/31 (93.5)	5/5 (100)	2/2 (100)	36/38 (94.7)
NS3-D168E	0	0	0	0	30/36 (83.3)	5/5 (100)	2/2 (100)	37/43 (86.0)

RAP: Resistance-associated polymorphism; SVR12: Sustained virologic response at posttreatment week 12.

Table 6 Safety during the 12-wk double-blind period n (%)

Parameter	Immediate treatment, n = 155	Placebo-deferred treatment, n = 52
AEs leading to discontinuation	0 (0)	1 (2)¹
Serious AEs	5 (3)²	3 (6)¹³
AEs (any grade), ≥ 5%
ALT elevation	5 (3)	12 (23)
AST elevation	2 (1)	8 (15)
Hypertension	11 (7)	4 (8)
Upper respiratory tract infection	10 (6)	3 (6)
Platelet count decrease	3 (2)	4 (8)
Pyrexia	1 (1)	3 (6)
On-treatment grade 3-4 laboratory abnormalities
ALT	1 (1)	5 (10)
AST	1 (1)	3 (6)
Total bilirubin	1 (1)	0 (0)
Hemoglobin	3 (2)	0 (0)

¹Hepatitis E virus infection and liver injury (n = 1);

²Treatment related: Study drug overdose (n = 2); Unrelated to treatment: Ventricular extrasystoles (n = 1), acute cholecystitis (n = 1) and intervertebral disc protrusion (n = 1);

³ALT elevation (n = 1) and coronary artery disease (n = 1). AE: Adverse event; ALT: Alanine transaminase; AST: Aspartate transaminase.

Table 7 Safety during 24 wk of daclatasvir plus asunaprevir treatment in either arm n (%)

Parameter	Immediate treatment, n = 155	Placebo-deferred treatment, n = 51¹	Overall, n = 206
AEs leading to discontinuation	1 (1)²	1 (2)³	2 (1)
Serious AEs	7 (5)⁴⁵	1 (2)³	8 (4)
Deaths	0 (0)	1 (2)³	1 (< 1)
AEs (any grade), ≥ 5%
ALT elevation	17 (11)	5 (10)	22 (11)
Upper respiratory tract infection	13(8)	8(16)	21(10)
Hypertension	11 (7)	6 (12)	17 (8)
AST elevation	13 (8)	3 (6)	16 (8)
INR elevation6	11 (7)	2 (4)	13 (6)
Blood bilirubin elevation	12 (8)	0 (0)	12 (6)
Fatigue	5 (3)	6 (12)	11 (5)
On-treatment grade 3-4 laboratory abnormalities
ALT	7 (5)²	2 (4)⁷	9 (4)
AST	5 (3)²	1 (2)⁷	6 (3)
Total bilirubin	1 (1)	0 (0)	1 (< 1)
Hemoglobin	3 (2)	0 (0)	3 (1)
Platelets	1 (1)	0 (0)	1 (< 1)
Absolute lymphocyte count	0 (0)	1 (2)	1 (< 1)
Absolute neutrophil count	1 (1)	0 (0)	1 (< 1)
Lipase	3 (2)	0 (0)	3 (1)

¹Excludes the patient who discontinued during the double-blind phase;

²Jaundice and nausea, which followed concomitant but reversible treatment-related ALT, AST and total bilirubin elevations (patient met the biochemical criteria for Hy’s law; aminotransferases, jaundice and nausea resolved off-treatment and patient achieved SVR12);

³Fatality (stab wound) unrelated to treatment;

⁴Treatment related: Study drug overdose (n = 2);

⁵Unrelated to treatment: Ventricular extrasystoles (n = 1), acute cholecystitis (n = 1), intervertebral disc protrusion (n = 1), retinal detachment (n = 1) and appendicitis (n = 1); ⁶No grade 3-4 INR laboratory abnormalities were observed;

⁷One patient experienced vomiting, decreased appetite and myalgia (all resolved), plus grade 3 ALT and AST abnormalities (both reversible), and interrupted DUAL treatment for 2 d (patient achieved SVR12). AE: Adverse event; ALT: Alanine transaminase; AST: Aspartate transaminase; INR: International normalized ratio.

Citation: Wei L, Wang FS, Zhang MX, Jia JD, Yakovlev AA, Xie W, Burnevich E, Niu JQ, Jung YJ, Jiang XJ, Xu M, Chen XY, Xie Q, Li J, Hou JL, Tang H, Dou XG, Gandhi Y, Hu WH, McPhee F, Noviello S, Treitel M, Mo L, Deng J. Daclatasvir plus asunaprevir in treatment-naïve patients with hepatitis C virus genotype 1b infection. World J Gastroenterol 2018; 24(12): 1361-1372
URL: https://www.wjgnet.com/1007-9327/full/v24/i12/1361.htm
DOI: https://dx.doi.org/10.3748/wjg.v24.i12.1361