Risk factors for hepatocellular carcinoma associated with hepatitis C genotype 3 infection: A systematic review

Table 1 Study level characteristics, risk estimates of hepatocellular carcinoma and adjusted covariates of included studies

Ref.	Country	Journal	SJR ranking quartile	Study design	Enrolment period	Study setting	Average follow-up (months)	HCV diagnosis	HCC diagnosis	Risk estimates of HCC	Covariates adjusted for
Aziz et al[27], 2019	Pakistan	Pak J Med Sc	Q3	Cross-sectional	June 2016 to January 2018	Hospital	6.0	HCV Ab, HCV RNA, and genotyping	USS abdomen, serum AFP, CT abdomen	Crude numbers	Exclusions: HBV, HIV, age < 18 yr or > 70 yr, pregnancy, previous liver lesion, “extremely fragile”, low bodyweight (not defined), known mental health issues, patients who were taking phenytoin, rifampicin, carbamazepine, patients with pancytopenia
Cha et al[29], 2016	Korea	Medicine	Q3	Retrospective case-control	January 2005 to December 2014	Hospital	59.6	HCV Ab, HCV RNA, and genotyping	USS abdomen, serum AFP, CT abdomen, histological examination	HR with 95% confidence interval	Patients with < 6 months of follow-up or patients with HCC diagnosed within 6 months of enrolment in the study
Khan et al[30], 2009	Pakistan	Journal of Medical Virology	Q1	Retrospective case-control	January 2006 to September 2007	Hospital	6.0	HCV Ab, HCV RNA, and genotyping	2 of 3 criteria: Serum AFP > 400 IU/mL, CT/MRI or liver biopsy	Crude numbers	Co-infection with HBV or HDV
Kanwal et al[19], 2014	United States	Journal of Hepatology	Q1	Retrospective cohort study	October 1999 to September 2009	Hospital	12.0	HCV Ab, HCV RNA, and genotyping	HCC (ICD-9 code 155.1)	HR with 95% confidence interval	< 1 yr of follow-up
Maryam et al[32], 2018	Pakistan	Journal of Medical Virology	Q1	Retrospective case-control	ND	Hospital	ND	HCV RNA and genotyping	Liver biopsy	Crude numbers	Nil
Park et al[35], 2019	Korea	BMC Cancer	Q1, Q2	Retrospective cohort study	January 2005 to December 2016	Hospital	24.0	HCV Ab, HCV RNA, and genotyping	USS abdomen, serum AFP, CT Abdomen, histological examination	Crude numbers	People with HIV and/or HBV, < 6 months of follow-up
Tayyab et al[34], 2020	Pakistan	BMC Gastroenterology	Q2	Prospective cohort	October 2014 to March 2017	Hospital	12.0	HCV Ab, HCV RNA, and genotyping	USS abdomen, serum AFP, CT abdomen	HR with 95% confidence interval	HBV co-infection

HCV: Hepatitis C virus; Ab: Antibody; MRI: Magnetic resonance imaging; CT: Computed tomography; USS: Ultrasound sonography; AFP: Alpha fetoprotein; HBV: Hepatitis B virus; HIV: Human immunodeficiency virus; SJR: Scimago Journal & Country Rank; Q: Quartile; HR: Hazard ratio; HCC: Hepatocellular carcinoma.

Table 2 Patients level characteristics for studies included in the meta-analysis

Ref.	Total number of participants	Percentage genotype 3, n (%)	Number of HCV GT3 participants	Age, yr, median or mean	Sex (M/F)	Number of HCC, n (%)	Patients without HCC, n (%)	Risk factor	Number with risk factor who developed HCC, n (%)	Cirrhosis (%)	Active HCV (%)	Cleared HCV, n (%)	HIV, n (%)	HBV, n (%)	Hazards ratio of risk factor	OR/HR/RR calculation (in study or calculated independently)
Aziz et al[27], 2019	300	300 (100.00)	300	55.08 +/-5.62	179/121	10 (3.33)	290 (96.67)	DAA treatment (SOF + DAC +/-RBV)	10 (3.33)	100	100	276 (92.00)	0 (0)	0 (0)		Independent calculation
								Child Pugh A (compensated cirrhosis) and SVR not achieved	2 (0.67)	100	100	276 (92.00)	0 (0)	0 (0)		Independent calculation
								Child Pugh B (compensated cirrhosis) and SVR achieved	5 (1.67)	100	100	276 (92.00)	0 (0)	0 (0)		Independent calculation
								Child Pugh B (Decompensated cirrhosis) and SVR not achieved	3 (1.00)	100	100	276 (92.00)	0 (0)	0 (0)		Independent calculation
								Male	7 (2.33)	100	100	276 (92.00)	0 (0)	0 (0)		Independent calculation
								Female	3 (1.00)	100	100	276 (92.00)	0 (0)	0 (0)		Independent calculation
Cha et al[29], 2016	1335	98 (7.30)	98	41.8 +/-10.5	79/19	4 (4.10)	94 (95.92)	Age > 40 yr	ND	25.50	100	34 (34.70)	0 (0)	4 (4.1)	2.697 (0.436-16.683), P = 0.286	Calculated in study
								Cirrhosis at enrolment	25 (25.50)	25.50	100	34 (34.70)	0 (0)	4 (4.1)	33.834 (2.088-548.269), P = 0.013	Calculated in study
								Alcohol intake > 40 g/d	53 (54.60)	25.50	100	34 (34.70)	0 (0)	4 (4.1)	8.556 (0.693-105.623), P = 0.094	Calculated in study
								SVR	34 (34.70)	25.50	100	34 (34.70)	0 (0)	4 (4.1)	0.848 (0.063-11.445), P = 0.901	Calculated in study
								Decompensated cirrhosis and achieved SVR*	1	25.50	100	34 (34.70)	0 (0)	4 (4.1)		Independent calculation
								Did not achieve SVR*	1	25.50	100	34 (34.70)	0 (0)	4 (4.1)		Independent calculation
								Low platelet count	ND	25.50	100	34 (34.70)	0 (0)	4 (4.1)	1.00 (1.00- 1.00), P = 0.872	Calculated in study
Khan et al[30], 2009	158	147 (93.00)	147	47.3 +/-12.5	102/56	65 (44.20)	82 (55.78)	Male	51	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								Female	14	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								Age > 46.9 yr	65	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								High AFP	65	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								High HCV VL	65	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								ALP > 68	65	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								Anti-HBc*	46	17.69	87.10	30 (18.99)	0 (0)	5		Independent calculation
								HCV viraemia*	58	17.6	87.10	30 (18.99)	0 (0)	5		Independent calculation
Kanwal et al[19], 2014	110484	8337 (7.54)	8337	50.2 +/-6.4	8095/242	ND	ND	Cirrhosis	ND	12	86	1167 (14.00)	242 (2.9)	0 (0)	1.44 (1.23-1.68)	Calculated in study
								Diabetes	ND	12	86	1167 (14.00)	242 (2.9)	0 (0)	1.30 (1.88-1.90)	Calculated in study
								Age > 50 yr	ND	12	86	1167 (14.00)	242 (2.9)	0 (0)	1.79 (1.53-2.11)	Calculated in study
								Age < 50 yr	ND	12	86	1167 (14.00)	242 (2.9)	0 (0)	1.86 (1.56-2.22)	Calculated in study
Maryam et al[32], 2018	50	50 (100.00)	50	58 (47-73)	37/23	27 (54.00)	23 (46.00)	NRAS oncogene	27 (54.00)	ND	100	0	ND	ND		Independent calculation
								Male*	22	ND	100	0	ND	ND		Independent calculation
								Female*	5	ND	100	0	ND	ND		Independent calculation
Park et al[35], 2019	180	16 (8.88)	16	46 (40-53)	45306	16 (100.00)	0 (0)	Male	15 (93.80)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								Diabetes	6 (40.00)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								Cirrhosis	16 (100.00)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								Alcohol intake > 60 g/d	3 (18.80)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								High HCV VL	6 (37.70)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								MELD-score > 9.5	16 (100.00)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								Female	1 (6.25)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								High AFP	16 (100.00)	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
								Not achieved SVR*	2	100	100	2 (12.50)	0 (0)	0 (0)		Independent calculation
Tayyab et al[34], 2020	653	593 (90.81)	593	50 (41-56)	319/334	40 (6.13)	613 (93.87)	Age, per 10-yr increase	ND	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	1.71 (1.25-2.33), P = 0.001	Calculated in study
								Use of SOF/DCV/RBV	9 (22.50)	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	17.05 (2.09-139.47), P = 0.01	Calculated in study
								Cirrhosis	40 (6.13)	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								Male*	18	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								Female*	22	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								High BMI*	5	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								Hypertension*	3	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								Diabetes*	19	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								HBV Co-infection*	12	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								Achieved SVR*	35	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								Not achieved SVR*	5	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								SOF/RBV use*	29	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								SOF/RBV/PEG-IFN use*	1	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation
								SOF/DCV use*	1	49.31	54 (8.27)	599 (91.78)	ND	0 (0)	ND	Independent calculation

NB: *Risk factor not deemed statistically significant in the study’s own analysis. Crude numbers were extracted to pool and calculate hazard ratios. HR: Hazard ratio; OR: Odds ratio; RR: Relative risks; ND: Not determined; SOF: Sofosbuvir; RBV: Ribavirin; PEG-IFN: Pegylated interferon; DCV: Daclatasvir; SVR: Sustained virologic response; HBV: Hepatitis B virus; HCV: Hepatitis C virus; Anti-HBc: Total antibody to hepatitis B core antigen; AFP: Alpha feto protein; MELD: Model for end-stage liver disease; VL: Viral load; HCC: Hepatocellular carcinoma.

Table 3 The Newcastle-Ottawa Scale assessment for included studies

Ref.	Type of Study	Selection								Comparability	Exposure						Total score
		Adequate case definition1	Representativeness of cases1	Selection of controls1	Definition of controls1	Representative of exposed cohort2	Selection of non-exposed cohort2	Ascertainment of exposure2	Demonstration that outcome of interest was not present at start of study2	Comparability based on the design or analysis	Ascertainment of exposure1	Same method of ascertainment for participants1	Nonresponse rate1	Assessment of outcome2	Was follow-up long enough for outcomes to occur2	Adequacy of follow up of cohorts2
Aziz et al[27], 2019	Cross-Sectional	NA	NA	NA	NA	*	*	*	*	*	NA	NA	NA	*		*	7
Cha et al[29], 2016	Cohort	NA	NA	NA	NA	*	*	*	*	*	NA	NA	NA	*	*	*	8
Khan et al[30], 2009	Case-control	*			*	NA	NA	NA	NA	*	*	*	*	NA	NA	NA	6
Kanwal et al[19], 2014	Cohort	NA	NA	NA	NA	*	*	*	*	*	NA	NA	NA	*	*	*	8
Maryam et al[32], 2018	Case-control				*	NA	NA	NA	NA			*	*	NA	NA	NA	3
Park et al[35], 2019	Cohort	NA	NA	NA	NA	*	*	*	*	*	NA	NA	NA	*	*	*	8
Tayyab et al[34], 2020	Cohort	NA	NA	NA	NA	*	*	*	*	*	NA	NA	NA	*	*	*	8

¹For case-control studies.

²For cohort or cross-sectional studies.

NA: Not applicable.

Table 4 Pooled individual participant data for all participants with hepatitis C genotype 3 who developed hepatocellular carcinoma

Risk factor	Number of participants
Patient-dependent factors
Cirrhosis	66
Male	118
Female	62
Age > 40 yr	65
Alcohol intake > 40 g/d	56
Anti-HBc	46
Diabetes	25
Age < 50 yr	0
NRAS oncogene	27
Age, per 10-yr increase	0
High BMI	5
Hypertension	3
HBV co-infection	12
Treatment dependent factors
DAA treatment	66
SVR achieved	74
SVR not achieved	13
Decompensated cirrhosis and achieved SVR	1
Use of SOF/DCV/RBV	9
Biochemical factors
Low platelet count	16
High AFP	65
High HCV VL	71
ALP > 68	65
HCV viraemia	58
MELD-score > 9.5	16

HBc: Hepatitis B virus core protein; BMI: Body mass index; DAA: Direct-acting antiviral; SVR: Sustained virologic response; SOF: Sofosbuvir; DCV: Daclatasvir; RBV: Ribavirin; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AFP: Alpha feto protein; MELD: Model for end-stage liver disease; VL: Viral load.