Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis

Table 1 Group of patients according to hepatitis C virus treatment history n (%)

	All patients	BOC	TVR	P value	Fibrosis	Non-F4	F4	P value
	(n = 1057) (100)	(n = 405) (38)	(n = 652) (62)		All patients	(n = 423) (44)	(n = 545) (56)
					(n = 958) (100)
TN	319 (30)	130 (32)	189 (29)	0.000	294 (30)	129 (31)	165 (30)	0.010
TE	738 (70)	275 (68)	463 (71)		664 (70)	294 (67)	380 (70)
R	298 (28)	77 (19)	221 (34)		270 (28)	138 (33)	132 (24)
PR	123 (12)	55 (14)	68 (10)		113 (12)	44 (10)	69 (13)
NR	260 (25)	119 (29)	141 (22)		238 (25)	86 (20)	152 (28)
Unknown responders	57 (5)	24 (6)	33 (5)		53 (6)	26 (6)	27 (5)

Bivariate analysis: χ² tests. TN: Treatment-naïve; TE: Treatment-experienced; R: Relapsers; PR: Partial responders; NR: Null responders; Unknown responders: Treatment-experienced with response unknown.

Table 2 Baseline characteristics of the study patients (unknown previous virologic response patients, n = 57)

	All patients (n = 1057)				TN (n = 319)			R (n = 298)			PR (n = 123)			NR (n = 260)
	All (n = 1057)	BOC (n = 405)	TVR (n = 652)	P value	BOC (n = 130)	TVR (n = 189)	P value	BOC (n = 77)	TVR (n = 221)	P value	BOC (n = 55)	TVR (n = 68)	P value	BOC (n = 119)	TVR (n = 141)	P value
Age (yr), mean ± SD	54 ± 8	54 ± 9	53 ± 8		52 ± 10	53 ± 9		54.6 ± 8	53 ± 8		54.6 ± 8	53 ± 8		54 ± 9	54 ± 7
Male sex	724 (69)	264 (65)	460 (71)	NS	85 (65)	124 (66)	NS	46 (60)	157 (71)	NS	35 (64)	55 (81)	0.03	85 (71)	101 (72)	NS
HCV genotype 1 subtype
1a	239 (26)	102 (28)	137 (24)	NS	32 (27)	47 (29)	NS	18 (25)	38 (20)	NS	15 (31)	13 (23)	NS	34 (32)	31 (24)	NS
1b	692 (74)	263 (72)	429 (76)		85 (73)	116 (71)		54 (75)	151 (80)		34 (69)	44 (77)		72 (68)	99 (76)
IL28b genotype
CC	157 (20)	55 (18)	102 (20)	NS	27 (26)	35 (23)	NS	8 (16)	46 (29)	NS	5 (13)	5 (9)	NS	9 (10)	9 (8)	NS
CT	510 (63)	191 (64)	319 (63)		57 (54)	94 (61)		36 (74)	97 (61)		24 (63)	38 (72)		61 (70)	77 (68)
TT	138 (17)	54 (18)	84 (17)		21 (20)	24 (16)		5 (10)	16 (10)		9 (24)	10 (19)		17 (20)	27 (24)
Stage of fibrosis
F0F1	81 (8)	46 (12)	35 (6)	0.002	19 (15)	4 (2)	0	11 (15)	27 (14)	NS	8 (16)	2 (3)	0.03	3 (3)	1 (1)	NS
F2	138 (14)	42 (11)	96 (16)		17 (14)	28 (16)		7 (10)	31 (16)		3 (6)	9 (14)		14 (12)	20 (16)
F3	204 (21)	76 (20)	128 (22)		27 (22)	34 (20)		21 (29)	41 (21)		7 (14)	15 (24)		16 (14)	32 (25)
F4	545 (56)	217 (57)	328 (56)		60 (49)	105 (62)		34 (46)	98 (49)		32 (64)	37 (59)		80 (71)	72 (58)
Hb (g/dL)	15 ± 1	15 ± 1.5	15.1 ± 1.5	NS	15 ± 1.6	14.8 ± 1.5	NS	15 ± 1.6	15.3 ± 1.3	NS	14.9 ± 1.5	15.2 ± 1.5	NS	15.2 ± 1.5	15.3 ± 1.6	NS
PMN (mL)	3228 ± 1305	3241.4 ± 1329.6	3220.4 ± 1290.3	NS	3317.8 ± 1250.4	3155.1 ± 1276.1	NS	3499 ± 1405	3366 ± 1392	NS	3002 ± 1364.5	3168 ± 1182.5	NS	3156 ± 1385.5	3176.0 ± 1208.1	NS
Platelets (%)	161358 ± 66199	162194.7 ± 65144.4	160841.2 ± 66889.7	NS	169727.3 ± 68082	159038.1 ± 72104.9	NS	172671 ± 69822	178393 ± 66412	NS	156907 ± 57085	147308 ± 61828	NS	154046 ± 62558	144128.6 ± 55066	NS
Prothrombin (%)	94 ± 14	94.7 ± 12.6	92.7 ± 14.8	NS	93.7 ± 11	95.6 ± 15.3	NS	94.2 ± 13.0	90 ± 15	NS	95.8 ± 16.0	93.4 ± 11.0	NS	95.6 ± 0.7	92.6 ± 15.5	NS
ALT (IU/mL)	89 ± 65	88.9 ± 70.1	89.8 ± 61.6	NS	80.6 ± 55	92.4 ± 62.0	NS	80 ± 64	76.0 ± 51.2	NS	90 ± 53	87 ± 46	NS	93.6 ± 48.8	106.3 ± 77.0	NS
GGT (IU/mL)	107 ± 103	115.3 ± 106.1	101.8 ± 101.3	0.050	90.6 ± 86.5	107.0 ± 133.8	NS	110 ± 144	81.2 ± 70.0	NS	116.8 ± 79.0	113.0 ± 87.5	NS	143.1 ± 107.0	117.7 ± 93.0	0.040
Alkaline phosphatase (mL)	95 ± 46	93.6 ± 40.8	95.2 ± 49.6	NS	88.4 ± 31	99 ± 57	NS	89.4 ± 30.0	89.3 ± 43.0	NS	99.6 ± 50.6	101.8 ± 48.1	NS	96.7 ± 46.6	95.1 ± 49.1	NS
Albumin (g/L)	4.0 ± 0.5	4.18 ± 0.428	4.25 ± 0.52	0.040	4.2 ± 0.5	4.2 ± 0.4	NS	4.2 ± 0.4	4.4 ± 0.4	0.030	4.1 ± 0.4	4.3 ± 0.5	0.020	4.2 ± 0.4	4.0 ± 0.6	NS
Creatinine (mg/dL)	0.8 ± 0.2	0.79 ± 0.16	0.81 ± 0.2	NS	0.8 ± 0.2	0.8 ± 0.1	NS	0.8 ± 0.2	0.8 ± 0.2	NS	0.8 ± 0.2	0.8 ± 0.2	NS	0.7 ± 0.2	0.8 ± 0.22	NS
HCV viral load (IU/mL)	3.3 × 106± 6 × 106	3.5 × 106± 5.9 × 106	3.2 × 106± 5.9 × 106	NS	3.5 × 106± 6.2 × 106	3.8 × 106± 8.9 × 106	NS	2.8 × 106± 3.8 × 106	3 × 106± 4.1 × 106	NS	4.1 × 106± 9.5 × 106	2.3 × 106± 2.6 × 106	NS	3.3 × 106± 4.7 × 106	3 × 106± 4 × 106	NS

n (%) and χ² tests summarise the categorical variables; mean ± SD and Student’s t-test or Mann-Whitney U test summarise the continuous variables. NS: Not significant; BOC: Boceprevir; TVR: Telaprevir; TN: Treatment-naïve; R: Relapsers; PR: Partial responders; NR: Null responders.

Table 3 Analyses of factors related to sustained virologic response: Univariate and multivariate effectiveness analysis

	ITT						mITT
	Univariate			Multivariate			Univariate			Multivariate
	OR	95%CI	P value	OR	95%CI	P value	OR	95%CI	P value	OR	95%CI	P value
Previous response1
R	2.6	1.8-3.7	0.000	1.8	1.09-3.1	0.022	2.4	1.6-3.5	0.000	1.9	1.1-3.3	0.019
PR	0.9	0.6-1.3	NS	0.9	0.5-1.7	NS	0.9	0.6-1.3	NS	0.8	0.4-1.6	NS
NR	0.4	0.2-0.5	0.000	0.6	0.37-0.9	0.330	0.5	0.3-0.7	0.000	0.7	0.39-1.1	NS
IL28B2
CC	3.6	2.2-5.9	0.000	3.07	1.5-5.9	0.001	3.2	1.9-5.4	0.000	3.0	1.4-6.0	0.002
CT	1.8	1.2-2.6	0.003	1.6	1.001-2.6	0.049	1.8	1.2-2.8	0.004	1.6	0.9-2.7	NS
Fibrosis3
Non-F4	2.1	1.6-2.8	0.000	2.0	1.33-3.0	0.001	2.26	1.7-3.04	0.000	2.1	1.4-3.3	0.000
Treatment4
TVR	1.7	1.3-2.1	0.000	1.5	1.02-2.2	0.038	1.1	0.9-1.5	NS	1.1	0.7-1.7	NS
LogGGT	0.19	0.12-0.3	0.000	0.3	0.18-0.6	0	0.2	0.15-0.23	0.000	0.4	0.2-0.7	0.004
LogViral load	0.8	0.6-1.003	NS	0.7	0.5-0.99	0.048	0.8	0.6-1.003	NS	0.7	0.4-1.1	NS

¹TN;

²TT;

³F4;

⁴BOC. TN: Treatment-naïve patients; R: Relapsers; PR: Partial responders; NR: Null responders; BOC: Boceprevir; ITT: Intention-to-treatment; mITT: Modified intention-to-treatment.

Table 4 Stop treatment modified-intention-to-treatment group n (%)

	All patients (n = 952)							TN (n = 298)			TE (n = 654)
	All patients (n = 952)	TN (n = 298)	TE (n = 654)	P value	BOC (n = 321)	TVR (n = 631)	P value	BOC (n = 112)	TVR (n = 186)	P value	BOC (n = 209)	TVR (n = 445)	P value
Stop treatment	263/952 (28)	97/298 (33)	166/654 (25)	0.022	88/321 (27)	175/631 (28)	NS	33/112 (30)	64/186 (34)	NS	55/209 (26)	111/445 (25)	NS
Non-VR	133/263 (51)	39/97 (40)	94/166 (57)	0.010	48/88 (54)	85/175 (49)	NS	11/33 (33)	28/64 (44)	NS	37/55 (67)	54/111 (51)	NS
Severe AE	83/263 (31)	31/97 (32)	52/166 (31)	NS	22/88 (25)	61/175 (35)	NS	10/33 (30)	21/64 (33)	NS	12/55 (22)	40/111 (36)	NS
Abandonment	6/263 (2)	2/97 (2)	4/166 (2)	NS	4/88 (4)	2/175 (1)	NS	2/33 (6)	0/64 (0)	NS	2/55 (4)	2/111 (2)	NS
Infection	6/263 (2)	2/97 (2)	4/166 (2)	NS	4/88 (4)	2/175 (1)	NS	2/33 (6)	0/64 (0)	NS	2/55 (4)	2/111 (2)	NS
Exitus	11/263 (4)	8/97 (8)	3/166 (2)	0.020	3/88 (3)	8/175 (5)	NS	2/33 (6)	6/64 (9)	NS	1/55 (2)	2/111 (2)	NS
Other	14/263 (5)	5/97 (5)	9/166 (5)	NS	3/88 (3)	11/175 (6)	NS	2/33 (6)	3/64 (5)	NS	1/55 (2)	8/111 (7)	NS

Bivariate analysis: χ² tests. NS: Not significant; BOC: Boceprevir; TVR: Telaprevir; Non-VR: Non-virologic response; AE: Adverse effect; TN: Treatment-naïve patients; TE: Treatment-experienced patients.

Table 5 Haematological adverse events n (%)

	All patients	Boceprevir	Telaprevir	P value	Non-F4	F4	P value
Neutropaenia	n = 943	n = 360	n = 583		n = 369	n = 505
Grade 0-1-2:	707 (75)	241 (67)	466 (80)	0	289 (78)	370 (73)	NS
> 750 μL
Grade 3-4:	236 (25)	119 (33)	117 (20)		80 (22)	135 (27)
≤ 750 μL
Thrombocytopaenia	n = 935	n = 359	n = 576		n = 365	n = 501
Grade 0-1-2:							0.000
> 50.000 μL	753 (81)	293 (82)	460 (80)	NS	337 (92)	371 (74)
Grade 3-4:
≤ 50.000 μL	182 (20)	66 (18)	116 (20)		28 (8)	130 (26)
Anaemia	n = 1036	n = 397	n = 639		n = 411	n = 539
Grade 0-1-2:	943 (91)	367 (92)	576 (90)	NS	384 (93)	481 (89)	0.025
> 8 g/dL
Grade 3-4:	93 (9)	30 (8)	63 (10)		27 (7)	58 (11)
< 8 g/dL
Transfusion	n = 1036	n = 397	n = 639	0.001	n = 411	n = 539	NS
	150 (15)	39 (10)	111 (17)		49 (12)	85 (16)
EPO	n = 1033	n = 396	n = 637	0	n = 410	n = 539	NS
	218 (21)	60 (15)	158 (25)		75 (18)	117 (22)
Onset of anaemia ( ≤ 9.5 g/dL)	12 ± 8	15 ± 11	9.5 ± 6.1	0	11.3 ± 7.2	11.5 ± 9	NS

n (%) and χ² tests summarise the categorical variables; mean ± SD and Student’s t-test. NS: Not significant.