Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant

Table 1 Characteristics of patients at baseline

Demography
Age, yr	57	41-70
Gender (male/female)	16/3
Body mass index (kg/m2)	26	21-33
Race, n/%	19	100
Caucasian, n/%	18	94.74
Hispanic, n/%	1	5.26
Immunosuppressive regimen
TAC/CSA	17/2
MMF (n)	8
Steroids (n)	0
Baseline clinical parameters
Duration of therapy	24	4-48
Ishak fibrosis score (grade)	2	0-4
Inflammation (grade)	1.5	0-2
Fibroscan baseline (kPa)	13.8	4.5-46.4
Time from LT to triple therapy (mo)	22	7-295
Baseline clinical chemistry
Bilirubin total (mg/dL)	0.8	0.3-3.2
GGT (U/L)	52	13-32
GPT (ALAT), U/L	41	21-159
GOT (ASAT), U/L	52	18-88
AP, U/L	101	53-404
Creatinine (mg/dL)	1.26	0.67-1.89
GFR (MDRD)	57.3	23-133
International normalized ratio	1	0.8-1.2
Hämoglobin (g/dL)	13.5	9-16.8
WBC (/μL)	3.73	1.6-8.3
Platelet count (/μL)	111	62-246
Basline viral characteristics
HCV GT
1a, n/%	7	36.8
1b, n/%	12	63.2
VL (log10 IU/mL)	1.95	0.13-14.9
Recipient IL-28b polymorphism, n/%
CC	5	26.3
CT	9	47.4
TT	5	26.3
History of any prior PEG-INF/RBV treatment, n/%	11	57.89
History of post-LT PEG-INF/RBV treatment, n/%	5	26.3
HCC prior to LT (n)	6
HBV coinfection (n)	0

TAC: Tacrolimus; HCV: Hepatitis C virus; LT: Liver transplantation; HBV: Hepatitis B virus; GFR: Glomerular filtration rate; WBC: White blood count; GT: Genotype; VL: Viral load; IL-28b: Interleukin-28b; PEG-INF: Pegylated-interferon; RBV: Ribavirine; GGT: Gamma-glutamyl transpeptidase; GPT: Glutamat pyruvat transaminase; ALAT: Alanin-aminotransferase; GOT: Glutamat oxalacetat transaminase; ASAT: Aspartate aminotransferase; CSA: Cyclosporine; MMF: Mycophenolate mofetil; AP: Alkaline phosphatase.

Table 2 Treatment response

	Sustained virological response												Treatment failure
	Pat. 1	Pat. 2	Pat. 3	Pat. 4	Pat. 5	Pat. 6	Pat. 7	Pat. 8	Pat. 9	Pat. 10	Pat. 11	Pat. 12	Pat. 13	Pat. 14	Pat. 15	Pat. 16	Pat. 17	Pat. 18	Pat. 19	Pat. 12
HCV GT	1b	1b	1a	1b	1b	1b	1b	1b	1b	1a	1b	1a	1a	1a	1b	1a	1b	1a	1b	1a
Basline	2763000	4860000	1183000	5758000	1713000	1950000	441000	14900000	1920000	456000	387700	10900000	11500000	1008000	2565000	1690000	1370000	135600	580400	10900000
TW 4 (RVR)	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	71	37	34	< Q	< Q	15	4668	< Q
TW 12 (EVR)	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	685	< Q	< Q	3322000	< Q	< Q	6848	< Q
TW 16	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	371	< Q	< Q	ND	6260	ND	ND	< Q
TW 24	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	164	466	55400	ND	ND	ND	ND	< Q
TW 48					< Q	< Q	< Q	< Q	< Q	< Q	< Q
12 wk pt	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	457200	9704	1657	1564794	ND	966400	27	660300	457200
24 wk pt	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	< Q	691400	4135000		3735000	ND	7420000	9824	3489000	691400

HCV: Hepatitis C virus; TW: Treatment weeks; GT: Genotype; RVR: Rapid virological response; EVR: Early viral response; pt: Post treatment; Pat: Patient; ND: Not determined.

Table 3 NS3 protease domain sequence information

HCV GT	Patient	TW	Outcome	Baseline	End of treatment
1b	Pat.1	24	SVR	Not detected	NA
1b	Pat.2	24	SVR	Not detected	NA
1a	Pat.3	24	SVR	Not detected	NA
1b	Pat.4	24	SVR	Not detected	NA
1b	Pat.5	48	SVR	Not detected	NA
1b	Pat.6	48	SVR	Not detected	NA
1b	Pat.7	48	SVR	Not detected	NA
1b	Pat.8	48	SVR	Not detected	NA
1b	Pat.9	48	SVR	Not detected	NA
1a	Pat.10	48	SVR	Not detected	NA
1b	Pat.11	48	SVR	Not detected	NA
1a	Pat.12	24	Relapse	Not detected	Not done
1a	Pat.13	24	Non response	Not detected	R155K
1a	Pat.14	24	VB	Not detected	V36M, R155K
1b	Pat.15	24	VB	Not detected	-
1a	Pat.16	24	Relapse	V36L	V36L, R155K
1b	Pat.17	16	VB	V36LV	V36L, T54ST
1a	Pat.18	4	Relapse	Not done	R155K
1b	Pat.19	8	VB	Not detected	A156F

Resistance mutations before and after treatment in association with outcome and genotype. HCV: Hepatitis C virus; GT: Genotype; TW: Treatment week; VB: Viral breakthrough; SVR: Sustained viral response (undetectable HCV RNA 24 wk after end of antiviral therapy); NA: Not applied.

Table 4 Clinical baseline characteristics and their predictive value for sustained viral response

	SVR		Non SVR		P ≤
Patients, n/%	11	60%	8	42%
Age, yr	53	41-70	58	53-64	0.1151
Body mass index (kg/m2)	26	22-30	26	21-33.1	0.5051
Ischak fibrosis score (grade)
I-II	7	64%	6	75%
III-IV	4	36%	2	25%
Fibroscan baseline (kPa)	14.6	4.5-23.4	11.3	5.9-26	0.7731
Time from LT to triple therapy (mo)	22	7-156	23	8-295	0.8691
Bilirubin total (mg/dL)	0.6	0.3-1.1	1	0.4-3.2	0.0301
GPT (ALT) (U/L)	46	21-159	40	24-85	0.5631
GOT (AST) (U/L)	52	18-84	53.5	22-88	0.6201
Platelet count (/μL)	143	68-246	103.5	63-236	0.3021
Viral load (log10 IU/mL)	1.9	0.39-14.9	4.2	0.13-13.70	0.4091
HCV GT					0.0492
1a, n/%	2	18%	4	50%
1b, n/%	9	81%	4	50%
Recipient IL-28b polymorphism, n/%					0.5522
CC	4	36%	1	12.50%
CT	3	27%	6	75%
TT	4	36%	1	12.50%
History of any prior PEG-INF/RBV treatment, n/%	7	63%	4	50%	0.5522
History of post-LT PEG-INF/RBV treatment, n/%	2	18%	3	37.50%	0.3452

¹Pearson's χ² test;

²Mann-Whitney-U-test, P≤ 0.05 set as statistic significant. HCV: Hepatitis C virus; PEG-INF: Pegylated-interferon; RBV: Ribavirine; SVR: Sustained viral response; LT: Liver transplantation; GT: Genotype; GPT: Glutamat pyruvat transaminase; GOT: Glutamat oxalacetat transaminase; ALT: Alanine aminotransferases; AST: Aspartate aminotransferase.

Table 5 Appearance of adverse events in dependence on the course of therapy n (%)

	Moderate side effects		Severe side effects
	TW 1-12	TW 13-48	TW 1-12	TW 13-48
Hematological toxicity	0	0	0	0
Anemia	≤ 10 g/dL	≤ 10 g/dL	≤ 8 g/dL	≤ 8 g/dL
	9 (47.4)	11 (57.9)	8 (42.1)	2 (10.5)
Low WBC (< 1/μL)	< 3.4/μL	< 3.4/μL	< 1/μL	< 1/μL
	16 (84.2)	14 (73.7)	2 (10.5)	3 (15.8)
Low PT (< 50/μL )	< 50/μL	< 50/μL	< 20/μL	< 20/μL
	3 (15.7)	6 (31.6)	0	0
Renal failure	8 (42.1)	0	1 (5.2)	0
Dermatological toxicity	0	0	0	0
Rash std. I	7 (36.8)	0	0	0
Rash std. II	0	0	1 (5.2)	0
Rash std. III	0	0	0	0
Anorectal pain	9 (47.4)	0	10 (52.6)	0
Pruritus	4 (21.0)	0	4 (21.0)	0
Stomatitis	3 (15.7)	0	1 (5.2)	0
Loss of appetite	5 (26.3)	0	0	0
Loss off weight > 10%	6 (31.6)	0	1 (5.2)	0
Diarrhoe	5 (26.3)	0	1 (5.2)	0
Weakness	10 (52.6)	7 (36.8)	0	0
Hospitalisation	0	0	3 (10.5)	2 (15.8 )
Hepatic decompensation	0	0	1 (5.2)	0
Edema	0	0	3 (15.8)	0
Diabetes melitus	0	0	3 (15.8)	3 (15.8)
Psychiatric disorders	0	4 (21.0)	0	1 (5.2)
Medical induced fever	0	9 (47.4)	0	0
Infection	0	0	0	2 (10.5)

WBC: White blood count; TW: Treatment week; PT: Platelets.