Non-invasive tests for predicting liver outcomes in chronic hepatitis C patients: A systematic review and meta-analysis

Table 1 Characteristics of the cohort studies included in the systematic review

Ref.	Country	n	NITs	Outcomes
Chun et al[49], 2020	South Korea	669	FIB-4	HCC
Chalouni et al[18], 2019	France	998	APRI, FIB-4, TE	LRE
Chen et al[45], 2019	China	691	FIB-4	OM
Hansen et al[20], 2019	Denmark	591	TE	OM, LRD, HD
Ioannou et al[13], 2019	United States	48135	FIB-4	HCC
Na et al[33], 2019	South Korea	295	APRI, FIB-4	HCC
Nakagomi et al[34], 2019	Japan	1146	TE	HCC
Ogasawara et al[38], 2019	Japan	398	FIB-4, TE	HCC, HD
Ogasawara et al[47], 2019	Japan	457	FIB-4	OM
Peleg et al[23], 2019	Israel	515	TE	HCC, OM, HD
Pons et al[14], 2019	Spain	572	TE	HCC
Rinaldi et al[15], 2019	Italy	258	TE	HCC
Shili-Masmoudi et al[28], 2019	France	1062	TE	OM, LRM
Sou et al[41], 2019	China	1884	APRI, FIB-4	HCC
Tamaki et al[30], 2019	Japan	346	FIB-4, MRE	HCC
Watanabe et al[44], 2019	Japan	1174	APRI, FIB-4	HCC
Bloom et al[17], 2018	Australia	780	TE	LRE
Hamada et al[29], 2018	Japan	196	FIB-4, SWE	HCC
Munteanu et al[22], 2018	France	3449	Fibrotest	OM, LRM
Cepeda et al[25], 2017	United States	964	TE	OM
Gomez-Moreno et al[19], 2017	Spain	343	TE	HCC, HD, LRM
Merchante et al[26], 2017	Spain	446	TE	HD
Thandassery et al[43], 2017	Qatar	1605	APRI, FIB-4	HCC, HD, LRE
Akuta et al[39], 2016	Japan	958	FIB-4	HCC
Lee et al[31], 2016	South Korea	598	APRI	HCC
Lee et al[46], 2016	South Korea	190	TE	LRE
Ng et al[36], 2016	China	105	APRI	HCC
Pérez-Latorre et al[24], 2016	Spain	957	TE	LRE, OM
Sato et al[40], 2016	Japan	355	APRI, FIB-4	HCC
Tada et al[48], 2016	Japan	1723	FIB-4	LRM, OM
Berenguer et al[12], 2015	Spain	903	FIB-4	LRE, OM
Macías et al[21], 2015	Spain	1046	TE	HD, OM
Narita et al[35], 2014	Japan	151	TE	HCC
Nojiri et al[37], 2014	Japan	142	APRI, FIB-4, Forns index	HCC
Tamaki et al[42], 2014	Japan	1046	FIB-4	HCC
Bambha et al[16], 2012	United States	450	APRI, FIB-4	OM
Nunes et al[27], 2010	United States	303	APRI, FIB-4	LRM
Masuzaki et al[32], 2009	Japan	984	TE	HCC
Yu et al[11], 2006	China	1338	APRI	HCC, OM

N/A: Not available; APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fibrosis-4 index; HCC: Hepatocellular carcinoma; HD: Hepatic decompensation; LSM: Liver stiffness measurement; LRM: Liver-related mortality; LRE: Liver-related event; NIT: Non-invasive test; OM: Overall mortality; TE: Transient elastography; MRE: Magnetic resonance elastography.

Table 2 Pooled unadjusted and adjusted hazard ratios of pre- and post-treatment fibrosis-4 index, aspartate aminotransferase to platelet ratio index, liver stiffness measurement for the prediction of hepatocellular carcinoma development

Analysis	HR				aHR
	Pooled HR (95%CI)	I2 (%)	Ref.	No. of cases	Pooled aHR (95%CI)	I2 (%)	Ref.	No. of cases
FIB-4	5.17 (4.03-6.63)	76	[13,29,30,38,40-42]	1831	2.48 (1.91-3.23)	96	[13,33,39-42,44,49]	1842
pre-Rx	4.91 (3.71-6.49)	81	[13,38,40-42]	1781	3.20 (1.77-5.80)	97	[13,33,39-40,42,44]	1699
post-Rx with SVR	5.44 (2.25-13.15)	69	[29,30,38,41]	173	3.01 (0.32-28.61)	89	[33,49]	21
APRI	5.27 (2.34-11.83)	91	[31,40,41]	150	4.24 (2.15-8.38)	20	[33,36,41]	149
pre-Rx	4.23 (1.42-12.62)	83	[31,40,41]	142	-	-	[33]	12
post-Rx with SVR	9.33 (5.85-14.88)	0	[31,41]	130	9.88 (2.21-44.16)	24	[33,41]	134
LSM	9.45 (4.49-19.92)	70	[14,15,29,30,34,38]	301	7.90 (3.98-15.68)	52	[15,29,30,32,34,35,38]	362
pre-Rx	4.68 (2.00-10.96)	40	[15,38]	54	3.76 (1.77-8.02)	7	[15,35,38]	63
post-Rx with SVR	8.90 (4.10-19.33)	36	[14,29,30,38]	76	6.33 (2.57-15.59)	17	[29,30,38]	51

aHR: Adjusted hazard ratio; APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fbrosis-4 index; HCC: Hepatocellular carcinoma; LSM: Liver stiffness measurement; pre-Rx: Pre-treatment; post-Rx with SVR: Post-treatment with sustained virologic response.

Table 3 Area under the receiver operating characteristic curves of non-invasive tests for overall mortality, liver-related mortality, and composite outcomes

Ref.	NIT1	Outcome	AUROC (95%CI)
Chalouni et al[18], 2019	APRI	OM	0.58 (N/A)
		LRM	0.80 (N/A)
		LRE	0.75 (N/A)
	FIB-4	OM	0.66 (N/A)
		LRM	0.88 (N/A)
		LRE	0.78 (N/A)
	TE	OM	0.69 (N/A)
		LRM	0.88 (N/A)
		LRE	0.88 (N/A)
Hansen et al[20], 2019	TE	OM	0.70 (0.62–0.78)
		LRM	0.93 (0.89–0.98)
		HD (HCC included)	0.89 (0.82–0.97)
Munteanu et al[22], 2018	Fibrotest	OM	0.74 (0.71-0.77)
		LRM	0.88 (0.85-0.90)
Thandassery et al[43], 2017	APRI (Pre-Rx)	HD	0.54 (0.06–0.78)
	FIB-4 (Pre-Rx)	HD	0.85 (0.74–0.96)
Pérez-Latorre et al[24], 2016	TE	OM	Estimation cohort 0.87 (0.84-0.90)
			Validation cohort 0.88 (0.84-0.91)
Lee et al[46], 2016	TE (Post-Rx)	A composite outcome of HD, HCC, and/or LRM	0.92 (0.84-1.00)
Berenguer et al[12], 2015	FIB-4 (Pre-Rx)	LRE (HD or HCC)	0.75 (0.72-0.78)
Yu et al[11], 2006	APRI (Pre-Rx)	OM	0.53 (0.35-0.72)
	APRI (Post-Rx)	OM	0.87 (0.81-0.93)

¹NITs are not classified as either pre-treatment or post-treatment once the study did not specify when the NIT measurement regarding the initiation of hepatitis C virus therapy was done. N/A: Not available; APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fibrosis-4 index; HCC: Hepatocellular carcinoma; HD: Hepatic decompensation; LSM: Liver stiffness measurement; LRM: Liver-related mortality; LRE: Liver-related event; NIT: Non-invasive test; OM: Overall mortality; pre-Rx: Pre-treatment; post-Rx: Post-treatment; AUROC: Area under the receiver operating characteristic curves; TE: Transient elastography.

Table 4 Unadjusted and adjusted hazard ratios of non-invasive test for the prediction of liver-related mortality

Unadjusted hazard ratio (HR)
Ref.	NIT1	HR (95%CI)	P value
Hansen et al[20], 2019	TE	97.00 (13.20–713.00)	< 0.005
Shili-Masmoudi et al[28], 2019	TE	29.65 (8.88–99.01)	< 0.001
Nunes et al[27], 2010	APRI	10.18 (4.86–21.32)	N/A
	FIB-4	9.45 (4.51–19.79)	N/A
Adjusted hazard ratio (aHR)
Ref.	NIT1	aHR (95%CI)	P value	Adjustment variables
Hansen et al[20], 2019	TE	11.00 (1.22–98.60)	0.018	SVR
Shili-Masmoudi et al[28], 2019	TE	20.60 (5.99–70.78)	< 0.001	Gender, alcohol consumption, drug consumption, CD4 count, HCV genotype, metabolic disorders, previous HCV treatment
Macías et al[21], 2015	TE	29.90 (4.30–217.00)	0.001	Age, gender, platelet counts, AIDS at baseline, alcohol use, treatment against HCV, time-varying CD4 cell counts, undetectable HIV RNA
Tada et al[48], 2016	FIB-4 (Pre-Rx)	13.02 (4.16–40.77)	< 0.001	Age, gender, AST concentration, ALT concentration, albumin, total bilirubin concentration, prothrombin time, platelet count, AFP concentration, FIB-4 index
Nunes et al[27], 2010	FIB-4	1.19 (1.12–1.27)	< 0.001	Gender, MELD
	FIB-4	1.13 (1.05–1.21)	0.001	Gender, CPT
	APRI	1.11 (1.01–1.22)	0.035	Gender, CPT
	APRI	1.25 (1.15–1.35)	< 0.001	Gender, MELD

¹Non-invasive tests are not classified as either pre-treatment or post-treatment if the study did not specify when the non-invasive test measurement was done with regards to the initiation of hepatitis C virus therapy. NIT: Non-invasive test; HR: Hazard ratio; AFP: alpha-fetoprotein; APRI: Aspartate aminotransferase to platelet ratio index; CTP: Child-Turcotte-Pugh score; FIB-4: Fibrosis-4 index; N/A: Not available; LSM: Liver stiffness measurement; MELD: Model for end-stage liver disease score; pre-Rx: Pre-treatment; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; SVR: Sustained virologic response; TE: Transient elastography.

Table 5 Unadjusted and adjusted hazard ratios of non-invasive tests for the prediction of hepatic decompensation and other composite outcomes

Unadjusted hazard ratio (HR)
Ref.	Outcomes	NIT1	HR (95%CI)	P value
Hansen et al[20], 2019	HD (HCC included)	TE	59.00 (17.40–200.00)	< 0.005
Ogasawara et al[38], 2019	HD	TE (Pre-Rx)	7.77 (1.29–46.20)	0.025
		TE (Post-Rx)	17.80 (1.85–171.30)	0.013
Bloom et al[17], 2018	LRE (HD, HCC and OM)	TE	56.00 (7.00–415.00)	< 0.001
Gomez-Moreno et al[19], 2017	LRE (HD, HCC or LRM)	TE	33.27 (7.25–152.63)	< 0.001
Pérez-Latorre et al[24], 2016	HD or HCC, whichever occurred first	TE (Post-Rx)	37.76 (17.87–79.80)	< 0.001
Macías et al[21], 2015	HD (HCC included)	TE	39.90 (5.50–291.00)	< 0.0001
Adjusted hazard ratio (aHR)
Ref.	Outcomes	NIT1	aHR (95%CI)	P value	Adjustment variables
Hansen et al[20], 2019	HD (HCC included)	TE	9.00 (2.49-32.20)	0.001	Age, SVR, hyaluronic acid
Ogasawara et al[38], 2019	HD	TE (Pre-Rx)	4.85 (0.80–29.40)	0.086	Platelet count, albumin
		TE (Post-Rx)	14.90 (1.45-152.10)	0.023	Platelet count, albumin
Peleg et al[23], 2019	OM or HCC	TE (Post-Rx)	2.32 (0.97-6.59)	0.062	liver steatosis, baseline serum platelets
Gomez-Moreno et al[19], 2017	LRE (HD, HCC and OM)	TE	30.97 (6.73-142.51)	< 0.001	Age, gender, time since HCV diagnosis, HCV genotype, injection drug use, high alcohol intake, HCV antiviral therapy
Merchante et al[26], 2017	HD	TE	1.90 (1.04–3.64)	< 0.001	Age, gender, SVR during follow-up
Lee et al[46], 2016	HD, HCC, and/or LRM	TE (Post-Rx)	9.47 (1.02-88.13)	0.048	Age, AFP
Macías et al[21], 2015	HD (HCC included)	TE	59.50 (8.30-427.00)	< 0.001	Age, gender, platelet counts, AIDS at baseline, alcohol use, treatment against HCV, time-varying CD4 cell counts and undetectable HIV RNA.
Berenguer et al[12], 2015	OM/LRE (HD or HCC), whichever occurred first.	FIB-4 (Pre-Rx)	3.90 (2.46-6.16)	< 0.001	Age, gender, HIV transmission category, Centers for Disease Control and Prevention HIV clinical category, CD4 cell nadir, HCV genotype, HCV RNA, alcohol intake, methadone use, SVR

¹Non-invasive tests are not classified as either pre-treatment or post-treatment if the study did not specify when the NIT measurement was done with regards to the initiation of hepatitis C virus therapy. APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fibrosis-4 index; HCC: Hepatocellular carcinoma; HD: Hepatic decompensation; LSM: Liver stiffness measurement; LRM: Liver-related mortality; LRE: Liver-related event; NIT: Non-invasive test; OM: Overall mortality; pre-Rx: Pre-treatment; post-Rx: Post-treatment; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; SVR: Sustained virologic response; TE: Transient elastography.