Inducible protein-10 as a predictive marker of antiviral hepatitis C treatment: A systematic review

Table 1 Overview of the modified Delphi, 18-point quality assessment checklist for studies included in the review

Ref.	Yes response	No response	Partiel reported/ unclear	Assessment
Fattovich et al[21]	16	2	0	High-quality
Diago et al[7]	15	2	1	High-quality
Apolinario et al[9]	14	2	2	High-quality
Darling et al[31]	14	1	3	High-quality
Lagging et al[34]	14	3	1	High-quality
Al-Ashgar[19]	13	3	2	Low-quality
Derbala et al[32]	13	2	3	Low-quality
Kurelac et al[33]	12	3	3	Low-quality

Studies was ranked as high quality if the provided ≥ 14 “yes” answers, or low quality if they provided ≤ 13 “yes” answers.

Table 2 Baseline total patient number, number of male patients, mean age, body mass index and ethnicity for the 8 included studies

Ref.	Patients		Mean age	BMI	Ethnicity
	Males	Total (n)	(yr)	(kg/m2)	Caucasian	African American	Asian
Apolinario et al[9]	40	63	41 (± 9.3)5	Information not provided	Information not provided6
1Lagging et al[34]	169	2522			2529
IL28B rs12979860 CC	64	93	41.6 (± 10.1)5	25.1 (± 3.6)5
IL28B rs12979860 CT	77	123	41.9 (± 9.5)5	25.0 (± 3.5)5
IL28B rs12979860 TT	28	36	41.9 (± 11.4)5	25.0 (± 3.5)5
Diago et al[7]	77	137	42 (± 9.7)5	Information not provided	Information not provided
Fattovich et al[21]	133	2263	46 (± 11)5	24.7 (± 3.8)5	226
Kurelac et al[33]	17	46	41.5 (± 12.4)5	23.7 (21.9-25)4	46
Darling et al[31]	176	272	48.4 (± 7.4)5	Information not provided	138	134
Darbala et al[32]	144	159	46.47 (± 8.83)5	30.18 (± 5.05)5	Information not provided7
Al-Ashgar et al[19]	41	64	38.7 (± 11.5)5	Information not provided	Information not provided8

¹Study did not provide baseline characteristics for their entire population, but instead provided baseline demographics in accordance with IL-28 genotype (only baseline characteristics for rs12979860 are reported in the review, as these were representative for the study population);

²253 was reported to be enrolled, however when adding the males and female patients, it sums to 252;

³Only 226 out of 280 patients had serum available for iP-10 testing;

⁴Median (25-75 percentiles);

⁵Mean (SD);

⁶51 patients from clinical trials had Spanish nationality;

⁷Egyptian nationality;

⁸Saudi nationality;

⁹95% of the original DITTO patient population were Caucasian. BMI: Body mass index.

Table 3 Hepatitis C virus-RNA and patient liver enzyme status for the 8 included studies

Ref.	HCV-RNA					Liver enzyme level
	High viral load		Low viral load		All patients	AST	ALT
	n	Limit	n	Limit
Apolinario et al[9]	28	≥ 6.3 log IU/mL5	35	< 6.3 log IU/mL5			118 IU/L (± 64) $
1Lagging et al[34]
IL28B rs12979860 CC					6.3 log IU/mL (± 0.8)3	Information not provided
IL28B rs12979860 CT					6.1 log IU/mL (± 0.7)3
IL28B rs12979860 TT					5.9 log IU/mL (± 0.8)3
Diago et al[7]	85	≥ 5.7 log IU/mL5	52	< 5.7 log IU/mL5			117.2 IU/L (± 81.6)3
Fattovich et al[21]	147	≥ 5.6 log IU/mL5			5.74 log IU/mL (± 0.9)35		92 IU/L (± 78)3
Kurelac et al[33]					5.55 log IU/mL (5.52-6.1)25	Information not provided
Darling et al[31]					6.66 log IU/mL (± 6.76)35		90.9 IU/L (72.9)3
Darbala et al[32]					4.95 log IU/mL (3.6-5.63)45	38 IU/L (27-51)4	51 IU/L (34-87)4
Al-Ashgar et al[19]	45	≥ 5.78 log IU/mL	19	< 5.78 log IU/mL5		67.5 IU/L (43.5-106.8)2	56.0 IU/L (32.0-86.0)2

¹Lagging et al provided baseline demographics in accordance with IL-28 genotype (only baseline characteristics for rs12979860 are reported in the review, as these were representative for the study population);

²Median (25-75 percentiles);

³Mean (SD);

⁴Median (IQR);

⁵Recalculated into log IU/mL. HCV-RNA is shown as number of patients with high or low viral load or as the mean or median for the entire population. Depending of the presentation in the original article, levels of ALT, AST or both are shown. HCV: Hepatitis C virus; ALT: Alanine transaminase; AST: Aspartate transaminase.

Table 4 Genotype and liver fibrosis stage for the 8 included studies

Ref.	Genotype (n)				Method	Liver fibrosis stage
	1	2	3	4		0	1	2	3	4	5	6
Apolinario et al[9]	43	20			Scheuer score	28		35
Lagging et al[34]4	1701	231	491	111	Ishak score	11	61	65	30	15	20	14
IL28B rs12979860 CC	44	13	33	3		3	18	27	11	5	12	5
IL28B rs12979860 CT	96	7	15	5		7	35	27	17	7	6	6
IL28B rs12979860 TT	30	3	1	3		1	8	11	2	3	2	3
Diago et al[7]	103	9	25		Ishak score	106				31
Fattovich et al[21]	92	87	47		Metavir2	121			21
Kurelac et al[33]	46				Ishak		34			12
Darling et al[31]	272				Ishak	220				52
Darbala et al[32]				159	Scheuer score		109		50
Ashgar et al[19]				64	Metavir	343			10 3

¹Baseline information for the sub analysis of IL28 12979860. Two hundred and fifty-two patients are reported to be enrolled, however adding the genotypes yields 253 patients. Likevise biopsies from 228 patients are described, however when adding the Ishak scores only yields 216 patients;

²Biopsies only available for 142 patients;

³Histology available for 44 patients;

⁴Lagging et al provided baseline demographics in accordance with IL-28 genotype (only baseline characteristics for rs12979860 are reported in the review, as these were representative for the study population). A box stretching over two - or more genotypes or fibrosis stage, indicates that the number refers to the combined group.

Table 5 Overview of the treatment regimens for pegylated interferon in combination with ribavirin, for the 8 studies included, in relation to dose and duration

Ref.	Genotype		Duration	Interferon treatment	Ribavirin treatment
Apolinario et al[9]	Multi-centerpatients	1	48 wk	180 μg peg-INF-α-2a once weekly	800 mg per day or 1000 mg < 75 kg, 1200 mg > 75 kg
		Non-1	24-48 wk
	Out patiens	1	48 wk	peg-INF-α2b 1.5 μg/kg per week	1000-1200 mg per day
		Non-1	24 wk
Lagging et al[34]	1		6 wk1	180 μg peg-INF-α-2a once weekly	1000 mg < 75 kg, 1200 mg > 75 kg per day
Diago et al[7]	1		48 wk	peg-INF-α-2b 1.5 μg/kg per week or 180 μg peg-INF-α-2a/week	1000 mg < 75 kg, 1200 mg > 75 kg per day
	Non-1		24 wk
Fattovich et al[21]	1 and 4		48 wk	peg-INF-α-2b 1.5 μg/kg per week or 180 μg peg-INF-α-2a/week	800-1200 mg per day
	2 and 3		24 wk
Kurelac et al[33]	1		48 wk	peg-INF-α-2b 1.5 μg/kg per week	Weight based ribavirin treatment2
Darling et al[31]	1		48 wk	180 μg peg-INF-α-2a once weekly	1000-1200 mg per day
Derbala et al[32]	4		48 wk	Peg-IFN once weekly3	1000 mg < 75 kg, 1200 mg > 75 kg per day
Al-Ashgar[19]	4		48 wk	180 μg peg-INF-α-2a once weekly	1000 mg < 75 kg, 1200 mg > 75 kg

¹After 6 wk, patients were randomized to differentiated treatment regimes;

²No further information on ribavirin treatment was provided;

³No further information on the subtype of peg-IFN was provided. Apolinario et al[9] feature patients from both an outpatient clinic as well as patients from two multicenter trials receiving different treatment regimens, illustrated by the segregation in the genotype column. peg-IFN: Pegylated interferon.

Table 6 Overview of the marker distribution, in the four studied that supplied information on interleukin 28B single nucleotide polymorphism

Ref.	Genotype (n)	rs12979860			rs12980275			rs8099917			rs11881222
		CC	CT	TT	AA	AG	GG	TT	TG	GG	AA	AG	GG
Lagging et al[30]	1 (253)	93	123	37	101	115	37	153	90	10
Fattovich et al[21]	1 (92)	33	44	15	33	45	14	49	38	5
	2 (87)	34	43	10	34	42	11	47	34	6
	3 (47)	25	21	1	25	20	2	34	13	0
Darling et al[31]	1 (201)	63	103	44
Derbala et al[32]	4 (159)	57	77	25				96	55	8	64	75	20

Genotype column indicates specific genotype, and total number of patients with the specific genotype. Each marker column is divided into allelic distribution for the IL28B SNP genotype. SNP: Single nucleotide polymorphism.

Table 7 Overview of rapid virological response in the 3 studies providing information on baseline inducible protein-10’s, and hepatitis C virus RNA levels at week 4

Ref.	Patients (n)	IP-10 measurement method	Genotype (n)	Baseline IP-10 concentration, grouped by rapid virological response (pg/mL)			Overall RVR (n)
				RVR	Non-RVR	P-value	RVR	Non-RVR
Lagging et al[34]	170	ELISA (Quantikine, R and D systems, Minneapolis, MN, United States)	1 (170)	222	401	P < 0.01 (median)	33	137
1Fattovich et al[21]	226	ELISA (Quantikine, R and D systems, Minneapolis, MN, United States)	1 (92)	2.4 (± 0.28)	2.6 (± 0.25)	P < 0.01 (log mean ± SD)	172	108
			2 (87)	2.38 (± 0.31)	2.3 (± 0.30)	P > 0.05 (log mean ± SD)
			3 (47)	2.45 (± 0.23)	2.48 (± 0.39)	P > 0.05 (log mean ± SD)
Al-Ashgar et al[19]	64	ELISA (Quantikine, R and D systems, Minneapolis, MN, United States)	4 (64)	483.9 (± 261.6)	609.9 (±424.3)	P > 0.05 (mean ± SD)	12	52

¹Entire patient population was 280, genotype 4 infected were removed from the analyses, and IP-10 results was available for 226 patients. IP-10: Inducible protein-10; RVR: Rapid virological response.

Table 8 Overview of sustained viral response in the 8 studies providing information on baseline inducible protein-10’s, and hepatitis C virus-RNA levels 24 wk after end-of- treatment

Ref.	Patients (n)	IP-10 measurement method	Genotype (n)	Baseline IP-10 concentration, grouped by sustained virological response (pg/mL)			Overall SVR
				SVR	Non-SVR	P-value	SVR	Non-SVR
Apolinario et al[9]	63	ELISA (OptEIA, Pharmingen, San Diego, CA, United States)	1 (43)	245 (± 154)	381 (± 138)	P < 0.05 (mean ± SD)	36	27
Diago et al[7]	137	ELISA (Human immunoassay kit; BioSource Europe SA, Nivelles, Belgium	1 (103)	347 (± 197.4)	500.6 (± 311.2)	P < 0.01 (mean ± SD)	792	582
			1 (103)	332.4 (± 222.1)	476.8 (± 305.3)	P < 0.01 (mean ± SD)
			2 (9)
			3 (25)
1Fattovich et al[21]	226	ELISA (Quantikine, R and D systems, Minneapolis, MN, United States )	1 (92)	2.47 ± 0.23	2.65 ± 0.28	P < 0.001 (log mean ± SD)	2092	712
			2 (87)	2.37 ± 0.31	2.33 ± 0.35	P > 0.05 (log mean ± SD)
			3 (47)	2.42 ± 0.21	2.67 ± 0.46	P < 0.05a (log mean ± SD)
Kurelac et al[33]	46	ELISA (Quantikine, R and D systems, Minneapolis, MN, United States )	1 (46)	185 (63-518)	395.5 (111-926)	P < 0.0001 (median, range)	26	20
Darling et al[31]	272	ELISA (Quantikine, R and D systems, Minneapolis, MN, United States )	1 (272)	437 (± 31)	704 (± 44)	P < 0.001 (mean ± SD)	157	115
Derbala et al[32]	159	Luminex, Cytokine multiplex immunoassay kit (Merck Millipore, Billerica, MA, United States)	4 (159)	Exact data not provided, only graphic presentation		P < 0.001 (median, IQR)	98	61
Al-Ashgar et al[19]	64	ELISA (Quantikine, R andD systems, Minneapolis, MN, United States )	4 (64)	462 (± 282.6)	840.4 (± 490.6)	P < 0.01 (mean ± SD)	41	23

¹Entire patina population was 280, genotype 4 removed from the analyses, and IP-10 results was available for 226 patients Note that M. Derbala et al did not provide written specification on IP-10 levels for SVR compared to non-SVR, and only supplied a graphic depiction, which could not be interpreted to adequate results;

²SVR for the entire population.

^aP = 0.02. Only the results of statistical tests with a P value < 0.01 were considered of interest, because of the multiple comparisons between subjects with and without SVR. SVR: Sustained viral response; IP-10: Inducible protein-10.