Second-generation direct-acting-antiviral hepatitis C virus treatment: Efficacy, safety, and predictors of SVR12

Table 1 Characteristics of study cohort patients

Demographics
n		260
Age	(yr)1	53 (44-60)
Sex	Male/Female n (%)	157 (60)/103 (40)
Baseline viral characteristics
Genotype 1a/1b/1x	n (%)/n (%)/n (%)	76 (29)/115 (44)/3(1)
Genotype 2/3	n (%)/n (%)	8 (3)/44 (17)
Genotype 4/5/6	n (%)/n (%)	11 (4)/1 (0.4)/2 (0.8)
Baseline viral load	(IU/mL)1	1.33 Mio. (414.750-3.4 Mio.)
Baseline viral load ≥ 800.000 IU/mL	n (%)	169 (65)
Baseline viral load ≥ 6 Mio IU/mL	n (%)	28 (11)
Special populations
LCi2	n (%)	89 (34)
Low platelets ( ≤ 100/nL)	n (%)	56 (22)
Post Liver Transplantation	n (%)	17 (7)
Patients ≥ 60 yr	n (%)	72 (28)
Patients with MELD score ≥ 10	n (%)	25 (10)
Treatment history
Treatment experienced	n (%)	144 (55)
Treatment regimens [thereof liver cirrhosis n (%)]
SOF PR	n (%)/LCi n (%)	51 (20)/6 (12)
SOF R	n (%)/LCi n (%)	10 (4)/4 (40)
SOF SMV	n (%)/LCi n (%)/R n (%)	30 (12)/16 (53)/15 (19)
SOF DCV	n (%)/LCi n (%)/R n (%)	81 (31)/42 (52)/12 (40)
SOF LDV	n (%)/LCi n (%)/R n (%)	73 (28)/17 (23)/16 (22)
3D	n (%)/LCi n (%)/R n (%)	15 (6)/4 (27)/6 (40)
Baseline clinical chemistry
WBC	(/μL)1	5935 (4683-7670)
Hemoglobin	(g/dL)1	14.5 (13.1-15.6)
Platelets	(thousand/μL)1	174 (113-228)
Creatinine	(mg/dL)1	0.7 (0.6-0.8)
Total Bilirubin	(mg/dL)1	0.7 (0.5-1.0)
INR	INR1	1 (1-1)
ALT	IU/l1	67 (44-105)

¹Data are presented as medians (interquartile ranges in parentheses);

²By liver histology, Fibroscan (> 12.5 kPa), or by clinical diagnosis (e.g., esophageal varices, ascites, distinct ultrasound signs of portal hypertension or liver cirrhosis). 1x: Genotype 1, no subtype differentiable; LCi: Liver cirrhosis; MELD: Model of end stage liver disease; P: Pegylated Interferon; R: Ribavirin; SOF: Sofosbuvir; SMV: Simeprevir; LDV: Ledipasvir; DCV: Daclatasvir; 3D: Dasabuvir, Ombitasvir, and Paritaprevir/r; WBC: White blood cell count; INR: International normalized ratio; ALT: Alanine-aminotransferase.

Table 2 Predictive model of sustained virological response analyzed for all patients treated with second generation direct acting antiviracombination therapy (n = 256)

	SVR 12 (n/N; %)2	Univariate analysis		Multivariate analysis
		Odds ratio (95%CI)	Wald P value	Odds ratio (95%CI)	Wald P value
Viral kinetics
RVR	143/152; 94%
vs Non-RVR	83/89; 93%	1.149 (0.395, 3.341)	0.799		0.728
Baseline demographic parameters
Fibrosis
Liver Cirrhosis	76/87; 87%
vs no Liver Cirrhosis	164/169; 97%	0.211 (0.071, 0.627)	0.005		0.290
Transplant Status
LTx	15/17; 88%
vs no LTx	225/239; 94%	0.467 (0.097, 2.246)	0.467		0.972
Sex
Male	140/153; 92%
vs female	100/103; 97%	0.329 (0.091, 1.184)	0.089		0.282
Age
Patients ≥ 60 yr	68/71; 96%
vs < 60 yr	172/185; 93%	0.999 (0.959, 1.04)	0.948		0.078
Baseline viral load
High viral load (> 6 Mio IU/mL)	28/28; 100%
vs low viral load ( ≤ 6 Mio IU/mL)	212/228; 93%	NA	0.998		0.251
Genotype
1	180/192; 93%
vs 3	38/42; 90%	1.606 (0.510, 5.060)	0.418		0.424
Genotype1
1 IFN-free, per protocol	160/164/; 98%
vs 3 IFN-free, per protocol	16/20/; 80%	5.000 (1.355, 18.45)	0.016		NA
Baseline platelet count
Platelets ≤ 100/nL	45/55; 82%
vs > 100/nL	195/201; 97%	0.138 (0.048, 0.401)	< 0.0001	0.24 (0.072, 0.88)	0.031
Baseline MELD ≥ 10
MELD ≥ 10	18/25; 72%
vs MELD < 10	222/231; 96%	0.104 (0.035, 0.313)	< 0.0001	0.117 (0.037, 0.373)	< 0.0001
Previous treatment response
Pre-treated	133/142; 94%
vs treatment-naive	107/114; 94%	0.967 (0.349, 2.681)	0.948		0.457

¹This analysis excluded patients co-treated with IFN, and patients with premature discontinuation (“per protocol analysis”);

²Number of patients who achieved SVR12 in category/total number in category. Univariate and multivariate models for prediction of SVR [n = 256, modified intention-to-treat (mITT) analysis] were used. This mITT analysis excluded patients, who were lost to follow-up (n = 4). Significant calculations (P < 0.05). RVR: Rapid viral response (hepatitis C virus RNA negative at treatment week 4); LTx: Liver transplantation; SVR: Sustained virological response; NA: Not available.

Table 3 Characteristics of patients, who died during treatment, discontinued treatment prematurely, or suffered from virological relapse after end of treatment

	Age (yr)	Sex	BL viral load, IU/mL	GT	LCi	BL MELD	Previous treatment	Current treatment	Treatment duration	Cause for premature discontinuation	Outcome	RAV NS3 protease	RAV NS5A	RAV NS5B polymerase
Patients, who died during treatment, or discontinued treatment prematurely
No. 1	63	male	1.41 Mio	1b	Yes	12	PR	SOF/SMV	12	Sepsis	death
No. 2	66	male	1.69 Mio	1b	Yes, HTx	14	-	SOF/LDV	5	Intracranial bleeding	death
No. 3	55	male	56200	1b	Yes, LTx	24	TVR/PR	SOF/SMV/R	14	Re-LTx, sepsis	death
No. 4	49	male	157000	1a	Yes,	14	PR	SOF/LDV/R	8	Right-heart failure	death
No. 5	79	female	5.85 Mio	1b	Yes	6	TVR/PR	SOF/SMV	10	Back-pain	SVR 24
No. 6	55	male	396000	1a	Yes, TIPSS	10	PR	SOF/DCV	16	Hepatic encephalopathy	SVR 24
Patients with relapse after end of treatment
No. 7	54	male	10300	1a	Yes	8	PR	SOF/PR	12			NA	NA	NA
No. 8	63	male	321000	1b	-	6	-	SOF/PR	12			NA	NA	NA
No. 9	43	female	408000	1a	Yes	8	-	SOF/PR	12			NA	NA	NA
No. 10	40	male	2.74 Mio	1b	-	6	PR	SOF/PR	12			NA	NA	NA
No. 11	48	male	4.89 Mio	3a	No, LTx	11	PR	SOF/DCV/R	24			F43F/L	A30K	-
No. 12	56	female	1.38 Mio	3a	Yes	7	PR	SOF/DCV	24			-	Y93H	S282S/T
No. 13	38	male	3.39 Mio	1b	-	6	-	SOF/DCV	12			Q80K	L31M, Y93H	-
No. 14	52	male	2.47 Mio	3a	Yes	10	-	SOF/DCV/R	24			-	Y93H	-
No. 15	55	female	3.03 Mio	1a	-	6	TVR/PR	SOF/DCV	12			T54S, R155K	L31M/L	-
No. 16	49	male	8340	3	Yes	6	-	SOF/LDV/R	24			-	A30S	-
No. 17	52	male	239000	1b	Yes	6	-	SOF/LDV/R	12			T54S, V55I, Q80K	Q30E	-
No. 18	57	male	137 (on SOF/R)	1a	Yes, HCC	11	SOF/R	SOF/DCV	12			-	L31M, P58S, Y93C	-

BL: Baseline; GT: Genotype; HCC: Hepatocellular carcinoma; LCi: Liver cirrhosis; MELD: Model of end stage liver disease; P: Pegylated Interferon; R: Ribavirin; SOF: Sofosbuvir; SMV: Simeprevir; LDV: Ledipasvir; DCV: Daclatasvir; TVR: Telaprevir; RAV: Resistance associated variant; HTx: Heart transplantation; LTx: Liver transplantation; TIPSS: Transjugular portosystemic stent shunt; NA: Not available.

Table 4 Patient self-reported side effects during treatment, and for comparison of self-reported side effects of PEG-interferon containing regimen and interferon-free treatment Fisher’s exact test was used

Side effects	Overall1		PEG-IFN co-treatment2		IFN-free treatment3		P value
Fatigue	93	39.2%	26	54.2%	67	35.4%	0.020
Cephalgia	52	21.9%	9	18.8%	43	22.8%	0.697
Bone/joint pain/myalgia	38	16.0%	12	25.0%	26	13.8%	0.077
Nausea/vomiting	38	16.0%	14	29.2%	24	12.7%	0.008
							0.163
Insomnia	28	11.8%	16	33.3%	12	6.3%	< 0.0001
Vertigo	16	6.8%	6	12.5%	10	5.3%	0.102
Flu-like symptoms	14	5.9%	12	25.0%	2	1.1%	< 0.0001
Abdominal discomfort/pain	17	7.2%	3	6.3%	15	7.9%	1.000
Pruritus	18	7.6%	4	8.3%	13	6.9%	0.755
Diarrhea	13	5.5%	7	14.6%	6	3.2%	0.006
Any rash	14	5.9%	7	14.6%	7	3.7%	0.010
Anorexia	9	3.8%	4	8.3%	5	2.6%	0.085
Nervousness	7	3.0%	4	8.3%	3	1.6%	0.033
Depression/fear	5	2.1%	2	4.2%	3	1.6%	0.267
Dyspnoea	7	3.0%	4	8.3%	3	1.6%	0.030
Concentration weakness	4	1.7%	2	4.2%	2	1.1%	0.183
Visual changes	4	1.7%	1	2.1%	3	1.6%	1.000
Loss of hair	4	1.7%	1	2.1%	3	1.6%	1.000
Tachycardia/palpitations	2	0.8%	2	4.3%	0	0.0%	0.040
Meteorism	3	1.3%	0	0.0%	3	1.6%	1.000
Aggression	2	0.8%	2	4.2%	0	0.0%	0.040
Fever/chills	1	0.4%	1	2.1%	0	0.0%	0.200
Attacks of sweating	1	0.4%	1	2.1%	0	0.0%	0.200
Gingivitis	1	0.4%	0	0.0%	1	0.5%	1.000
Cough	1	0.4%	1	2.1%	0	0.0%	0.200
Neurological symptoms	1	0.4%	0	0.0%	1	0.7%	1.000

¹Side effect reports were available in 237 of 260 patients;

²In PEG-IFN co-treated patients (n = 51), side effect reports were available in 48 patients;

³In IFN-free treated patients (n = 209), side effects reports were available in 189 patients. Significant calculations (P < 0.05) are printed in bold. IFN: Interferon.