Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients

Table 1 Patient characteristics at treatment initiation according to virological response

	Overall (n = 559)	SVR (n = 537)	Virological treatment failure (n = 22)	P value
Male sex	431 (77)	414 (77)	17 (77)	0.985
Age (yr)	52 (49-56)	52 (49-56)	53 (51-57)	0.586
CD4 (/mm3) (n = 557)	618 (426-850)	619 (429-861)	527 (346-704)	0.040
Undetectable HIV-RNA (n = 558)	486 (87)	469 (88)	17 (77)	0.186
ARV treatment	549 (98)	527 (98)	22 (100)	1.000
PI1	127 (23)	122 (23)	5 (23)
NNRTI2	98 (18)	95 (18)	3 (14)
II3	204 (37)	197 (37)	7 (32)
Others	120 (22)	113 (21)	7 (32)
Active tobacco consumption (n = 263)	153 (58)	148 (58)	5 (71)	0.703
Active alcohol consumption (n = 266)	135 (51)	132 (51)	3 (43)	0.719
Active drug consumption (n = 257)	7 (3)	7 (3)	0 (0)	1.000
HCV genotype (n = 558)				0.475
1 without precision	26 (5)	24 (5)	2 (9)
1a	232 (42)	221 (41)	11 (50)
1b	64 (12)	64 (12)	0 (0)
2	6 (1)	6 (1)	0 (0)
3	62 (11)	60 (11)	2 (9)
4	165 (30)	158 (30)	7 (32)
5	1 (0)	1 (0)	0 (0)
6	2 (0)	2 (0)	0 (0)
Cirrhosis (n = 555)	209 (38)	200 (38)	9 (41)	0.748
Child Pugh, if cirrhosis (n = 189)				0.537
A	172 (91)	165 (91)	7 (88)
B/C	17 (9)	16 (9)	1 (12)
FIB-4 (n = 405)	2.1 (1.4-3.7)	2.1 (1.4-3.7)	3.3 (1.9-7.3)	0.313
FIB-4 > 3.25 (n = 405)	120 (30)	113 (29)	7 (50)	0.132
Elastometry (kPa) (n = 115)	9 (6-14)	9 (6-14)	10 (6-17)	0.942
Elastometry ≥ 12.5 kPa (n = 115)	32 (28)	30 (27)	2 (50)	0.309
Elastometry ≥ 20 kPa (n = 115)	17 (15)	16 (14)	1 (25)	0.478
HCV treatment history				0.570
Naïve	210 (38)	203 (38)	7 (32)
Pretreated	349 (62)	334 (62)	15 (68)
HCV viral load (log10 IU/mL) (n = 558)	6.09 (5.59-6.51)	6.09 (5.59-6.51)	6.04 (5.72-6.49)	0.886
Prothrombin rate (n = 298)	99 (89-100)	99 (89-100)	92 (82-100)	0.116
Prothrombin rate < 85% (n = 298)	54 (18)	50 (17)	4 (40)	0.087
Platelets (Giga/L) (n = 408)	171 (131-219)	171 (133-219)	148 (97-184)	0.168
Platelets < 100 Giga/L (n = 408)	57 (14)	51 (13)	6 (43)	0.007
Albumin (g/L) (n = 301)	41 (38-44)	41 (38-44)	42 (37-45)	0.939
Albumin < 35 g/L (n = 301)	26 (9)	24 (8)	2 (25)	0.146
DAA-combination				NA5
SOF + DCV ± RBV4	240 (43)	231 (43)	9 (41)
SOF/LDV ± RBV	271 (49)	261 (49)	10 (46)
SOF + SMV ± RBV	26 (4)	23 (4)	3 (14)
Others4	22 (4)	22 (4)	0 (0)
Mean (SD) DAA treatment durationa	16 (6)	15 (5)	16 (6)

Results are presented as number (as percentages in brackets) or median (IQR in brackets) unless stated otherwise.

¹PI was boosted in 98 patients with SVR and in five patients with treatment failure;

²NNRTI molecule was rilpivirine in 60 patients with SVR and three with failure, and was efavirenz in 25 patients with SVR;

³II molecule was raltegravir in 153 patients with SVR and four patients with failure, and was dolutegravir in 38 patients with SVR and two with treatment failure;

⁴Initial doses of DCV were 30, 60, 90 mg/d in respectively 57, 159 and 21 patients. The dose was unknown for the five other patients;

⁵NA: not applicable, no formal statistical comparison was performed as the prescription of the DAA regimen was chosen by each patient’s physician. SVR: Sustained virological response; ARV: Antiretroviral; PI: Protease inhibitor; NNRTI: Non-nucleoside reverse-transcriptase inhibitor; II: Integrase inhibitor; DAA: All-oral direct-acting antiviral; SOF: Sofosbuvir; RBV: Ribavirin; DCV: Daclatasvir; LDV: Ledipasvir; SMV: Simeprevir.

Table 2 Adjusted logistic regression for factors associated with virological treatment failure

Covariables	Model 1		Model 2		Model 3		Model 4
	OR (95%CI)	P value	OR (95% CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
	n = 538		n = 538		n = 526		n = 395
Age at treatment initiation (per 10 yr)	1.2 (0.6-2.4)	0.58	1.3 (0.7-2.5)	0.48	1.2 (0.6-2.4)	0.53	1.6 (0.7-4.0)	0.29
Ribavirin vs no ribavirin	1.0 (0.3-3.0)	0.97	1.1 (0.3-3.2)	0.93	1.0 (0.3-3.0)	0.97	1.4 (0.4-5.5)	0.61
Male sex vs female	1.0 (0.4-2.8)	0.98	0.9 (0.3-2.7)	0.92	1.0 (0.3-2.8)	0.97	0.8 (0.2-2.7)	0.69
Treatment duration 24 wk vs 12 wk	0.4 (0.1-1.4)	0.15	0.5 (0.2-1.5)	0.21	0.4 (0.1-1.4)	0.16	0.2 (0.0-1.0)	0.05
Platelet count < 100 Giga/L vs ≥ 100							6.5 (1.8-22.6)	0.004
Cirrhosis vs no cirrhosis	1.4 (0.5-3.9)	0.51
HIV-RNA detectable vs undetectable			2.1 (0.7-5.9)	0.17
Severe cirrhosis vs no severe cirrhosis					2.1 (0.4-10.3)	0.35
HCV genotype 3 vs others							0.9 (0.1-7.5)	0.91

HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.

Table 3 Resistance-associated substitution results in 14 patients with virological treatment failure for whom sequencing was performed in routine care

Pat	HCV treatment history	Treatment received	HCV genotype		Cirrhosis	ARV treatment	RAS
			Before treatment	After treatment			NS3	NS5A	NS5B
A	Pretreated	SOF + SMV 12 wk	1a	1a	Yes	II	Q80K, I170T, S174N	Abs	Abs
B	Pretreated	SOF + SMV 12 wk	1a	1a	Yes	II	D168V	Abs	Abs
C	Pretreated	SOF/LDV 12 wk	4	4a	No	PI	Abs	Abs	Abs
G	Pretreated	SOF/LDV + RBV 12 wk	4	4d	No	Others	Abs	Abs	Abs
H	Pretreated	SOF + DCV 10 wk3	4	4	No	Others	Abs	ND	Abs
I	Naive	SOF/LDV 12 wk	1a	1a	No	PI	Abs	Abs	Abs
J	Pretreated	SOF/LDV 12 wk	1a	1a	No	Others	ND	Y93C	Abs
L	Naive	SOF + DCV 13 wk2	1a	1a	Yes	NNRTI	Q80K	Abs	Abs
M	Pretreated	SOF/LDV 12 wk	4	4a	No	PI	ND	Abs	A421V, M414L
N	Pretreated	SOF/LDV + RBV 12 wk	1a	1a	Yes	II	A168V	30E, 58D	Abs
P	Pretreated	SOF + DCV + RBV 12 wk1	1a	1a	No	PI	Abs	Y93N	Abs
Q	Pretreated	SOF + DCV + RBV 24 wk1	1a	1a	No	Others	T54S	Q30R	Abs
R	Pretreated	SOF + DCV 24 wk2	1a	1a	Yes	II	Q80K	Y93C	Y448H
W	Pretreated	SOF + DCV 24 wk1	1	1a	Yes	II	Abs	Q30H	Abs

¹Initial dose of DCV: 30 mg/d;

²Initial dose of DCV: 60 mg/d;

³Initial dose of DCV: 90 mg/d. Pat: Patient; ARV: Antiretroviral; RAS: Resistance-associated substitution; NS3: Non-structural-3; NS5A: Non-structural-5A; NS5B: Non-structural-5B; SOF: Sofosbuvir; RBV: Ribavirin; DCV: Daclatasvir; LDV: Ledipasvir; SMV: Simeprevir; ND: Not done; PI: Protease inhibitor; NNRTI: Non-nucleoside reverse-transcriptase inhibitor; II: Integrase inhibitor; Abs: No RAS found.