Effect of spleen operation on antiviral treatment in hepatitis C virus-related cirrhotic patients

Table 1 Characteristics of included studies and schedules of antiviral treatment

Ref.	Number of patients, n (total/SO + IFN1)	Country	Study design	Spleen operation	Antiviral agents	Doses of IFN and RBV	Therapy duration
Aizawa et al[17], 2013	90/30	Japan	Retrospective, controlled	Splenectomy (2 PSE)	PegIFN-α-2a or PegIFN-α-2b + RBV	PegIFN-α-2a: 180 ug/wk; PegIFN-α-2b: 1.0-1.5 μg/kg per week; RBV: 600-1000 mg/d	GT 1: at least 48 wk;
							GT 2/3: at least 24 wk
Akahoshi et al[18], 2012	100/97	Japan	Retrospective, cohort	Splenectomy	PegIFN-α-2b + RBV	PegIFN-α-2b: 1.5 μg/kg per week; RBV: 600-1000 mg/d	GT 1: 48 wk;
							GT 2/3: 24 wk
Hayashi et al[11], 2006	6/6	United States	Retrospective, cohort	Splenectomy	PegIFN-α-2b + RBV	PegIFN-α-2b: 1.5 μg/kg per week; RBV: 600-1000 mg/d	GT 1: 48 wk;
							GT 2/3: 24 wk
Ikezawa et al[19], 2010	10/10	Japan	Retrospective, cohort	Splenectomy	PegIFN-α-2a or PegIFN-α-2b + RBV	PegIFN-α-2a: 180 ug/wk; PegIFN-α-2b: 1.5 μg/kg per week; RBV: 600-1000 mg/d	GT 1: 48 wk;
							GT 2/3: 24 wk
Ji et al[20], 2013	13/13	China	Prospective, cohort	Splenectomy	PegIFN-α-2a (2) or PegIFN-α-2b (3) or IFN-α-2b (8) + RBV	PegIFN-α-2a: 180 ug/wk; PegIFN-α-2b: 1.5 μg/kg per week; IFN-α-2b: 2.1-3.0 MU, tiw; RBV: 800-1000 mg/d	GT 1: 48 wk;
							GT 2/3: 24 wk
Kedia et al[21], 2012	6/6	Japan	Retrospective, cohort	Splenectomy	PegIFN (2) or IFN (4) + RBV	NA	NA
Kercher et al[22], 2004	11/11	United States	Prospective, cohort	Splenectomy	PegIFN + RBV	NA	NA
Liang et al[23], 2008	9/9	China	Retrospective, cohort	Splenectomy	PegIFN-α-2a (6) or IFN-α-2b (3) + RBV	PegIFN-α-2a: 180 ug/wk; IFN-α-2b: 5MU tiw; RBV: 900-1200 mg/d	GT 1: 48 wk;
							GT 2/3: 24 wk
Morihara et al[24], 2009	48/16	Japan	Retrospective, controlled	Splenectomy	PegIFN-α-2b (2) or IFN-α (14) + RBV	PegIFN-α-2b: 50 μg/wk; IFN-α: 3.0-6.0 MU, tiw; RBV: 400 mg/d	1.4 yr (range: 0.2-12.4 yr)
Motomura et al[25], 2012	127/37	Japan	Retrospective, controlled	Splenectomy	PegIFN + RBV	NA	NA
Shigekawa et al[26], 2011	29/292	Japan	Retrospective, cohort	Splenectomy	PegIFN-α-2a or PegIFN-α-2b + RBV	PegIFN-α-2a: 90 μg/wk; or PegIFN-α-2b: 0.75 μg/kg per week; RBV: 800 mg/d	GT 1: 48 wk;
							GT 2/3: 24 wk
Xie et al[27], 2012	49/49	China	Retrospective, controlled	Splenectomy PSE	PegIFN-α-2a + RBV	PegIFN-α-2a: 135 or 180 μg/wk; RBV: 800-1200 mg/d	NA
Foruny et al[28], 2005	8/8	Spain	Retrospective, cohort	PSE	PegIFN-α-2a (2) or PegIFN-α-2b (6) + RBV	PegIFN-α-2a: 180 ug/wk; PegIFN-α-2b: NA; RBV: 8.8-18.18 mg/kg per day	24-48 wk
Miyake et al[29], 2008	20/10	Japan	Case controlled	PSE	PegIFN-α-2b (5) or IFN-α-2b (5) + RBV	PegIFN-α-2b: 1.2 μg/kg per week; IFN-α-2b: 6MU tiw; RBV: 400 - 800 mg/d	24-48 wk
Tahara et al[30], 2011	53/30	Japan	Case controlled	PSE	PegIFN-α-2a (2) or PegIFN-α-2b (2) + RBV	NA	24-48 wk
Takahara et al[31], 2011	24/11	Japan	Case controlled	PSE	PegIFN-α-2b + RBV	PegIFN-α-2b: 1.2 μg/kg per week;	GT 1: 48 wk;
						RBV: 400-800 mg/d	GT 2/3: 24 wk
Summary	603/372

¹Total: All patients received IFN and RBV treatment; SO + IFN: Patients treated with spleen operation before IFN and RBV treatment;

²Among 35 patients enrolled in this study, six did not receive antiviral therapy because of HCC (2), cerebral infarction (2), colonic perforation (1) or other cancer (1). SO: Spleen operation; IFN: Interferon; RBV: Ribavirin; GT: Genotype; PSE: Partial splenic embolization; NA: Not available.

Table 2 Baseline characteristics of spleen operation plus interferon-treated subjects and hematologic parameters pre-/post-spleen operation

Ref.	Age	Male/female	HCV genotype, n (1/2 and 3)	HCV RNA(low/high)	Child-Pugh, n (A/B/C)	Pre-spleen operation			Post-spleen operation
						Leukocyte(×109/L)	Hemoglobin(g/L)	Platelet count(×109/L)	Leukocyte(×109/L)	Hemoglobin(g/L)	Platelet count (×109/L)
Aizawa et al[17], 2013	61.0 ± 7.1	16/14	25/5	0/30	NA	3.41 ± 1.27	125 ± 22	60 ± 14	5.13 ± 1.34	122 ± 19	167 ± 51
Akahoshi et al[18], 2012	58.1 ± 7.0	54/46	80/20	12/88	61/39/0	3.19 ± 1.14	128 ± 15	56 ± 21	5.17 ± 1.34	125 ± 14	222 ± 98
Hayashi et al[11], 2006	45.4 ± 11.1	4/3	4/21	NA	5/2/0	2.20 ± 1.70	NA	32.4 ± 12.3	NA	NA	224.4 ± 74.9
Ikezawa et al[19], 2010	62.5 (51-69)	4/6	9/1	8/2	9/1/0	3.84 ± 0.36	NA	64.2 ± 6.9	5.53 ± 0.64	NA	209 ± 40.6
Ji et al[20], 2013	51.8 ± 8.0	4/9	9/4	11/2	9/4/0	2.10 ± 0.49	NA	48.2 ± 15.9	5.70 ± 1.42	NA	186.0 ± 70.6
Kedia et al[21], 2012	NA	NA	1/5	NA	NA	NA	NA	NA	NA	NA	NA
Kercher et al[22], 2004	45.4 (27-55)	7/4	NA	NA	11/0/0	NA	NA	55.4 ± 20.8	NA	NA	441.1 ± 164.8
Liang et al[23], 2008	47.6 ± 13.9	6/3	4/5	NA	6/3/0	2.10 ± 0.70	121 ± 16	36 ± 12	5.10 ± 1.20	131 ± 14	190 ± 65
Morihara et al[24], 2009	52 (36-60)	13/3	11/5	NA	7/1/2008	3.20 (1.80-5.60)	NA	44 (27-78)	5.20 (3.70-9.00)	NA	110 (79-275)
Motomura et al[25], 2012	58 ± 1	19/18	32/5	NA	NA	NA	125 ± 3	59 ± 2	NA	NA	168.7 ± NA
Shigekawa et al[26], 2011	63.3 ± 6.6	12/23	26/9	NA	10/1/2024	3.05 ± 1.05	NA	48 ± 15	4.52 ± 0.98	NA	155 ± 55
Xie et al[27], 2012	45.6 (32-65)	22/27	NA	NA	NA	NA	NA	NA	NA	NA	NA
Foruny et al[28], 2005	NA	5/3	7/1	NA	2/6/0	2.11 (1.30-0.59)	129 (101-149)	46.2 (21-70.3)	5.57 (3.51-7.05)	141 (124-152)	180.5 (113-214)
Miyake et al[29], 2008	61 (42-70)	2/8	6/4	0/10	NA	3.59 (2.62-6.33)	130 (112-151)	75 (44-115)	5.70 (2.48-8.34)	122 (111-138)	161 (113-293)
Tahara et al[30], 20112	57.5 (36-71)	12/13	13/12	0/30	25/0/0	3.55 (1.50-7.20)	134 (99-160)	70 (32-101)	5.40 (2.60-8.10)	126 (101-160)	174 (90-338)
Takahara et al[31], 2011	62 (44-72)	5/6	10/1	NA	NA	4.71 (2.95-6.33)	127 (112-151)	93 (61-117)	7.20 (2.84-11.8)	122 (111-138)	191 (113-302)
Summary		185/186	237/79	31/162	160/72/2

¹Genotype was unavailable in one patient;

²Authors compared PSE-treated patients (25) with PSE-untreated patients (23) with thrombocytopenia receiving PEG-IFN-α-2b plus RBV over the same period. Another five patients were treated with IFN-α-2b (3) or PEG-IFNα-2a (2) plus RBV. SO: Spleen operation; IFN: Interferon; NA: Not available; PSE: Partial splenic embolization.

Table 3 Outcomes of antiviral therapy in cirrhotic patients with spleen operation plus interferon treatment

Ref.	SVR rate	SVR rate (GT)	IFN dosage reduction	Discontinuation of therapy	Reasons of discontinuation therapy	HCC
Aizawa et al[17], 2013	6/30	GT 1: 3/25	12/30	41/1202	HCC occurrence 10; No VR 10; Fatigue 5; Thrombocytopenia 3; Fundal hemorrhage 2; Interstitial pneumonia 2; Anemia, auditory disturbance, pruritus, depression, presyncope, liver function flare, infection and death of accident 1,respectively	112
		GT 2/3: 3/5
Akahoshi et al[18], 2012	36/971	GT 1: 19/80	NA	8/97	Depression 3; Neutropenia 2; Appearance of HCC 2; Pneumococcal meningitis 1	2
		GT 2/3: 17/20
Hayashi et al[11], 2006	2/6	GT 1: 1/3	0/6	0/6	NO	NA
		GT 2/3: 1/2
Ikezawa et al[19], 2010	5/10	GT 1: 4/9	2/10	1/10	Angina 1	NA
		GT 2/3: 1/1
Ji et al[20], 2013	8/13	GT 1: 4/9	1/13	0/13	NO	NA
		GT 2/3: 4/4
Kedia et al[21], 2012	4/6	GT 1: 1/1	0/6	0/6	NO	NA
		GT 2/3: 3/4
Kercher et al[22], 2004	3/11	NA	8/11	0/11	NO	NA
Liang et al[23], 2008	3/9	GT 1: 1/4	0/9	2/9	Neutropenia 1; Anemia 1	NA
		GT 2/3: 2/5
Morihara et al[24], 2009	4/16	GT 1: 0/7	0/16	3/16	Severe thrombocytopenia 1; NSAID-induced liver injury 1; peripheral neuropathy 1	4
		GT 2/3: 4/4
Motomura et al[25], 2012	16/37	NA	NA	NA	NA	NA
Shigekawa et al[26], 2011	9/29	GT 1: 3/21	NA	11/29	HCC 9; Neutropenia 1; Peritonitis 1	9
		GT 2/3: 6/8
Xie et al[27], 2012	30/49	GT 1: 30/49	NA	1/49	Hypothyroidism 1	NA
Foruny et al[28], 2005	3/8	GT 1: 2/7	0/8	2/8	Intolerance (with no evidence of hematological toxicity) 1; Neutropenia 1	NA
		GT 2/3: 1/1
Miyake et al[29], 2008	6/10	GT 1: 2/6	3/10	2/10	Hepatic coma 1; Plural effusion 1	NA
		GT 2/3: 4/4
Tahara et al[30], 2011	9/30	GT 1: 1/15	16/30	4/30	Neutropenia2; Severe fatigue 2	4
		GT 2/3: 8/15
Takahara et al[31], 2011	3/11	GT 1: 2/10	5/11	1/11	Hepatic coma 1	NA
		GT 2/3: 1/1
Summary	147/3723	GT 1: 73/246	47/160	35/3054		19/1604
		GT 2/3: 55/74

¹Among a total of 100 patients, three did not start IFN therapy because of no recovery of platelet counts (2) and the appearance of HCC before IFN therapy (1);

²Not classified on the basis of spleen operation or no spleen operation;

³Among the 372 subjects who underwent spleen operation followed by anti-HCV therapy, 11 were still receiving treatment when the paper was drafted;

⁴Excluding Aizawa et al (2013) because no classification on the basis of spleen operation or no spleen operation. SVR: Sustained virological response; GT: Genotype; IFN: Interferon; HCC: Hepatocellular carcinoma; NA: Not available.

Table 4 Comparison of antiviral therapy between patients with and without spleen operation based on controlled studies

Ref.	SVR		SVR for GT-1		SVR for GT-2/3		IFN dosage reduction		Discontinuation		HCC
	SO	Non-SO	SO	Non-SO	SO	Non-SO	SO	Non-SO	SO	Non-SO	SO	Non-SO
Aizawa et al[17], 2013	6/30	12/60	3/25	8/50	3/5	4/10	NA	NA	NA	NA	NA	NA
Morihara et al[24], 2009	4/111	7/32	0/7	1/18	4/4	6/14	0/16	8/32	3/16	8/32	4/16	16/32
Motomura et al[25], 2012	16/37	38/90	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Miyake et al[29], 2008	6/10	3/10	2/6	0/6	4/4	3/4	3/10	5/10	2/10	1/10	NA	NA
Tahara et al[30], 2011	9/30	5/23	1/15	1/14	8/15	4/9	16/30	10/23	4/30	2/23	4/30	NA
Takahara et al[31], 2011	3/11	6/13	2/10	4/8	1/1	2/5	5/11	11/13	1/11	1/13	NA	NA
Summary	44/129	71/228	8/63	14/96	20/29	19/42	24/67	34/78	10/67	12/78	8/46	16/32

¹Five patients were receiving treatment. SO: Spleen operation; Non-SO: No spleen operation; SVR: Sustained virological response; GT: Genotype; IFN: Interferon; HCC: Hepatocellular carcinoma; NA: Not available.