Occult hepatitis C virus infection in the Middle East and Eastern Mediterranean countries: A systematic review and meta-analysis

Table 1 Selected studies for systematic review and meta-analysis of occult hepatitis C virus infection prevalence in the Middle Eastern countries and Eastern Mediterranean Region

Ref.	Years of data collection	Country	Population	Serostatus	HCV RNA detection method	Sample size	OCI
							Number	Percent
Makvandi et al[21], 2014	2011-2012	Iran	Patients with unexplained abnormal ALT	Seronegative	Is-nested PCR	53	17	32.08
Zaghloul et al[22], 2010	2010	Egypt	(1) Patients with unexplained abnormal ALT and AST; (2) Patients with chronic hepatitis C who achieved SVR	Seronegative/seropositive	rRT-PCR	102	11	10.78
El Shazly et al[23], 2015	2014	Egypt	Healthy sexual partners of patients with HCV infection	Seronegative	rRT-PCR	50	2	4.00
Bozkurt et al[74], 2014	?	Turkey	Hemodialysis patients	Seronegative	rRT-PCR	84	3	3.57
Mohamed et al[25], 2017	2017	Egypt	Hemodialysis patients	Seronegative	RT-PCR	60	2	3.33
Donyavi et al[26], 2019	2015-2018	Iran	HIV positive injecting drug users	Seronegative/seropositive	RT-nested PCR	77	14	18.18
Ayadi et al[27], 2019	2017-2018	Iran	Hemodialysis patients	Seronegative	RT-nested PCR	515	95	18.45
El-Rehewy et al[29], 2015	2012-2014	Egypt	Hemodialysis patients	Seronegative	rRT-PCR	75	8	10.67
Sheikh et al[31], 2019	2017-2018	Iran	Injecting drug users(negative for HIV)	Seronegative/seropositive	RT-nested PCR	115	11	9.57
Jamshidi et al[33], 2020	2015-2019	Iran	HIV positive patients	Seronegative/seropositive	RT-nested PCR	143	14	9.79
Abd Alla et al[35], 2017	2015-2017	Egypt	(1) Patients with chronic hepatitis C; (2) Healthy individuals	Seronegative/seropositive	RT-nested PCR	174	41	23.56
Ramezani et al[16], 2014	2014	Iran	Hemodialysis patients	Seronegative/seropositive	RT-nested PCR	30	0	0.00
Muazzam et al[17], 2011	2007-2009	Pakistan	Patients with chronic hepatitis C who achieved SVR	Seronegative	rRT-PCR	104	0	0.00
Naghdi et al[36], 2017	2017	Iran	Hemodialysis patients	Seronegative	RT-nested PCR	198	6	3.03
Abdelrahim et al[38], 2016	2013-2014	Egypt	Hemodialysis patients	Seronegative	rRT-PCR	81	3	3.70
Ali et al[39], 2018	2014	Egypt	Hemodialysis patients	Seronegative	rRT-PCR	39	9	23.08
Keyvani et al[41], 2013	2007-2013	Iran	Patients with cryptogenic cirrhosis	Seronegative	RT-nested PCR	45	4	8.89
Serwah et al[42], 2014	2013-2014	Saudi Arabia	Hemodialysis patients	Seronegative	rRT-PCR	84	12	14.29
El-shishtawy et al[43], 2015	2015	Egypt	(1) Hemodialysis patients; (2) Healthy volunteers	Seronegative	Strand-specific RT-PCR	63	8	12.70
Nafari et al[44], 2020	2017-2018	Iran	Hemophilia patients	Seronegative	RT-nested PCR	450	46	10.22
Eslamifar et al[71], 2015	2013	Iran	Hemodialysis patients	Seronegative	RT-nested PCR	70	0	0.00
Bokharaei-Salim et al[46], 2011	2007-2010	Iran	Patients with cryptogenic liver disease	Seronegative	RT-nested PCR	69	7	10.14
Rezaee Zavareh et al[47], 2014	2012-2013	Iran	Patients with autoimmune hepatitis	Seronegative	RT-nested PCR	35	0	0.00
Ayadi et al[48], 2019	2017-2018	Iran	Thalassemia patients	Seronegative	RT-nested PCR	181	6	3.31
Mekky et al[50], 2019	2017	Egypt	Patients with chronic hepatitis C who achieved SVR	Seropositive	rRT-PCR	1280	50	3.91
El-Moselhy et al[51], 2015	2014-2015	Egypt	Hemodialysis patients	Unknown	RT-PCR/RT-nested PCR	66	18	27.27
Anber et al[76], 2016	2015	Egypt	Hemodialysis patients	Seronegative/seropositive	rRT-PCR	63	9	14.29
Abdelmoemen et al[53], 2018	2016	Egypt	Hemodialysis patients	Seronegative	rRT-PCR	62	3	4.84
Eldaly et al[54], 2016	?	Egypt	Blood donors	Seronegative	RT-nested PCR	138	8	5.80
Youssef et al[55], 2012	2010-2011	Egypt	(1) Patients with lymphoproliferative disorders; (2) Healthy volunteers	Seronegative	RT-PCR/RT-nested PCR	87	12	13.79
Bastani et al[57], 2016	2015	Iran	Thalassemia patients	Seronegative	RT-nested PCR	106	6	5.66
Farahani et al[58], 2013	2010-2011	Iran	Patients with lymphoproliferative disorders	Seronegative	RT-nested PCR	104	2	1.92
Yousif et al[59], 2018	2017	Egypt	Patients with chronic hepatitis C who achieved SVR	Seropositive	rRT-PCR	150	17	11.33
Bokharaei-Salim et al[60], 2016	2014-2015	Iran	HIV positive patients	Seronegative/seropositive	RT-nested PCR	82	10	12.20
Helaly et al[15], 2017	2014-2015	Egypt	(1) Patients with hematologic disorders; (2) Healthy subjects	Seronegative	RT-nested PCR	50	18	36.00
Alavian et al[69], 2013	?	Iran	Patients with chronic hepatitis C who achieved SVR	Seropositive	RT-PCR	70	9	12.86
Askar et al[49], 2010	?	Egypt	Patients with unexplained persistently abnormal liver function tests	Seronegative	RT-nested PCR	45	20	44.44

ALT: Alanine transaminase; AST: Aspartate aminotransferase; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; Is-PCR: In situ-PCR; PCR: Polymerase chain reaction; RT-PCR: Reverse transcription PCR; rRT-PCR: Real time RT-PCR; SVR: Sustained virologic response.

Table 2 Subgroup-specific pooled estimates of occult hepatitis C virus infection prevalence across the Middle Eastern and Eastern Mediterranean countries

Prevalence by	Number of studies	Sample sizes	OCI prevalence across studies		Pooled OCI prevalence		Heterogeneity
			Range (%)	Median	Mean (%)	95%CI	Cochran’s Q	I-squared (%)
Studied population
Blood donors	1	138	-	-	5.80	2.93-11.16	-	-
Hemodialysis patients	13	1427	0-27.27	4.84	9.06	5.83-13.80	64.0a	81.2
Healthy sexual partners of patients with chronic hepatitis C	1	50	-	-	4.00	1.00-14.63	-	-
Patients with chronic hepatitis C who achieved SVR	4	1604	0-12.86	7.62	6.70	3.08-13.99	25.4a	88.2
Patients with cryptogenic liver disease	4	212	8.89-44.44	21.11	21.70	11.26-37.72	22.6a	86.7
Patients with autoimmune hepatitis	1	35	-	-	1.39	0.09-18.67	-	-
Patients with lymphoproliferative disorders	1	104	-	-	1.92	0.48-7.36	-	-
Hemophilia patients	1	450	-	-	10.22	7.74-13.38	-	-
Thalassemia patients	2	287	3.31-5.66	4.49	4.32	2.47-7.46	0.9	0.00
HIV positive individuals	2	225	9.79-12.20	10.99	10.72	7.29-15.50	0.3	0.00
HIV positive injecting drug users	1	77	-	-	18.18	11.07-28.39	-	-
Injecting drug users	1	115	-	-	9.57	5.38-16.45	-	-
Mixed population1	5	476	10.78-36	13.79	18.15	10.20-30.20	18.2b	78.1
Countries
Egypt	17	2585	3.33-44.44	11.33	12.34	8.32-17.92	186.2a	91.4
Iran	17	2343	0-32.08	9.57	8.48	5.51-12.84	86.5a	81.5
Pakistan	1	104	-	-	0.48	0.03-7.15	-	-
Saudi Arabia	1	84	-	-	14.29	8.30-23.49	-	-
Turkey	1	84	-	-	3.57	1.16-10.49	-	-
Temporal duration2
Before 2015	18	1227	0-44.44	9.52	9.58	6.26-14.40	88.5a	80.8
2015 and thereafter	19	3973	3.03-36	10.22	10.33	7.21-14.61	192.07a	90.6
Method of HCV RNA detection
RT-nested PCR	22	2833	0-44.44	9.97	11.75	8.52-15.99	159.3a	86.8
Real time RT-PCR	12	2174	0-23.08	7.75	7.88	4.96-12.30	58.4a	81.2
RT-PCR	2	130	145.71-173.33	159.52	7.75	2.34-22.75	3.3	69.5
Strand-specific PCR	1	63	-	-	12.70	6.48-23.39	-	-
Patients’ HCV serostatus
Seronegative	25	2774	0-44.44	5.80	9.32	6.76-12.73	164.0a	85.4
Seropositive	4	1604	6.20-66.50	37.62	6.64	2.94-14.30	25.4a	88.2
Seronegative/ Seropositive	7	756	27.27-109.09	73.53	13.58	8.01-22.11	17.8b	66.3
Undetermined	1	66	-	-	27.27	17.91-39.19	-	-
Sample size
Less than 100	23	1440	0-44.44	12.20	12.43	8.87-17.15	102.4a	78.5
100 and above	14	3760	0-23.56	7.69	7.43	4.86-11.19	153.0a	91.5
Patients’ sex
Female	11	602	0-35.29	8.62	9.92	5.39-17.55	32.4a	69.2
Male	11	1785	0-30.56	9.09	10.17	5.85-17.10	70.8a	85.9
All studies	37	5200	0-44.44	10.14	10.04	7.66-13.05	284.1a	87.3

^aP < 0.001.

^bP < 0.01.

¹Four studies investigated occult hepatitis C virus infection among healthy volunteers along with hemodialysis patients, patients with chronic hepatitis C, or patients with hematologic and lymphoproliferative disorders. Also one study investigated both the patients with chronic hepatitis C and patients with cryptogenic liver disease.

²Based on the last year reported for the data collection. If the collection date was not clear, publication year was considered instead. CI: Confidence interval; Min: Minimum; Max: Maximum; PCR: Polymerase chain reaction; RT-PCR: Reverse transcription polymerase chain reaction; OCI: Occult hepatitis C virus infection.

Table 3 Subgroup-specific pooled estimates of occult hepatitis C virus infection prevalence among multi-transfused patients across the Middle Eastern and Eastern Mediterranean countries

Prevalence by	Number of studies	Sample sizes	OCI prevalenceacross studies		Pooled OCI prevalence (%)		Heterogeneity
			Range (%)	Median	Mean (%)	95%CI	Cochran’s Q	I-squared (%)
Studied population
Hemodialysis patients	14	1480	0-27.27	7.75	9.52	6.30-14.12	64.0a	79.7
Thalassemia patients	2	287	3.31-5.66	4.49	4.32	2.47-7.46	0.9	0.0
Hemophilia patients	1	450	-	-	10.22	7.74-13.38	-	-
Countries
Egypt	8	499	3.33-27.27	12.48	11.43	6.55-19.17	26.8a	73.8
Iran	7	1550	0-18.45	3.31	5.93	3.09-11.09	54.8a	89.0
Saudi Arabia	1	84	-	-	14.29	8.30-23.49	-	-
Turkey	1	84	-	-	3.57	1.16-10.49	-	-
Temporal duration1
Before 2015	7	463	0-23.08	3.70	7.89	4.10-14.65	20.6b	70.8
2015 and thereafter	10	1754	3.03-27.27	7.94	9.04	5.69-14.09	66.5a	86.5
Method of HCV RNA detection
RT-nested PCR	8	1616	0-27.27	4.49	7.79	4.38-13.47	65.6a	89.3
Real time RT-PCR	7	488	3.57-23.08	10.67	9.52	5.26-16.61	17.4b	65.4
RT-PCR	1	60	-	-	3.33	0.84-12.37	-	-
Strand-specific PCR	1	53	-	-	15.09	7.73-27.38	-	-
Sample size
Less than 100	12	767	0-27.27	7.75	9.49	5.85-15.04	40.6a	72.9
100 and above	5	1450	3.03-18.45	5.66	7.05	3.61-13.33	47.9a	91.6
Participants’ sex
Female	6	322	3.7-33.33	8.86	11.56	6.47-19.81	12.7c	60.8
Male	6	506	0-16	6.45	10.74	5.91-18.75	13.5c	63.1
All studies	17	2217	0-27.27	5.66	8.71	6.05-12.39	88.56a	81.93

^aP < 0.001.

^bP < 0.01.

^cP < 0.05.

¹Based on the last year reported for the data collection. If the collection date was not clear, publication year was considered instead. CI: Confidence interval; Min: Minimum; Max: Maximum; PCR: Polymerase chain reaction; RT-PCR: Reverse transcription polymerase chain reaction; OCI: Occult hepatitis C virus infection.

Table 4 Subgroup-specific pooled estimates of occult hepatitis C virus infection prevalence among patients with chronic liver diseases across the Middle Eastern and Eastern Mediterranean countries

Variables	Number of studies	Sample sizes	OCI prevalence across studies		Pooled OCI prevalence (%)		Heterogeneity
			Range (%)	Median	Mean (%)	95%CI	Cochran’s Q	I-squared (%)
Countries
Egypt	5	1689	3.91-44.44	11.33	16.08	5.81-37.35	152.4a	97.4
Iran	5	272	0-32.08	10.14	11.46	3.64-30.73	16.6b	76.0
Pakistan	1	104	-	-	0.48	00.03-7.15	-	-
Temporal duration1
Before 2015	8	523	0-44.44	10.46	11.83	4.84-26.14	46.0a	84.8
2015 and thereafter	3	1542	3.91-34.82	11.33	12.28	3.23-36.99	111.1a	98.2
Method of HCV RNA detection
RT-nested PCR	6	359	0-44.44	21.11	21.38	11.73-35.75	30.5a	83.6
Real time RT-PCR	4	1636	0-11.33	7.35	6.29	2.73-13.84	23.9a	87.4
RT-PCR	1	70	-	-	12.86	6.83-22.90	-	-
Patients’ subpopulation
Post-HCV non-viremic cases2	5	1716	0-34.82	11.33	9.14	3.02-24.53	116.8a	96.6
Cryptogenic liver diseases3	4	212	8.89-44.44	21.11	20.81	6.87-48.35	22.6a	86.7
Chronic HCV infection and Cryptogenic liver diseases2,3	1	102	-	-	10.78	6.07-18.43	-	-
Autoimmune hepatitis	1	35	-	-	1.39	0.09-18.67	-	-
Patients’ HCV serostatus
Seronegative	5	247	0-44.44	10.14	16.13	5.41-39.28	27.7a	85.6
Seropositive	5	1716	0-34.82	11.33	9.11	2.97-24.69	116.8a	96.6
Seronegative/seropositive	1	102	-	-	10.78	6.07-18.43	-	-
Sample size
Less than 100	6	317	0-44.44	11.50	15.63	6.08-34.67	32.2a	84.5
100 and above	5	1748	0-34.82	10.78	8.88	3.04-23.26	116.0a	96.5
All studies	11	2065	0-44.44	10.78	12.04	5.87-23.10	179.3a	94.4

^aP < 0.001.

^bP < 0.01.

¹Based on the last year reported for the data collection. If the collection date was not clear, publication year was considered instead.

²Including those patients who achieved sustained virologic response after treatment with anti-virals.

³Including unexplained persistently abnormal liver enzymes and cryptogenic cirrhosis. CI: Confidence interval; Min: Minimum, Max: Maximum; PCR: Polymerase chain reaction; RT-PCR: Reverse transcription polymerase chain reaction; OCI: Occult hepatitis C virus infection.