Fibrosis regression following hepatitis C antiviral therapy

Table 1 Studies illustrating outcome of liver fibrosis following hepatitis C virus clearance with direct-acting antivirals therapy

Ref.	Therapy	n	Follow-Up	Method of fibrosis assessment	Outcome
Knop et al[14], 2016	DAA	54	24 wk	TE, ARFI	- 88% achieved an improvement of LS values at FU24; - 46% showed reduction in liver stiffness higher than 30% at FU24
Bachofner et al[15], 2016	DAA	392	18 mo	TE, FIB-4 and APRI scores, histopathological results were recorded if available	- Overall TE values of the included patients significantly decreased (regression of 32.4%); - Median FIB-4 and APRI values significantly decreased from 2.54 and 1.10 to 1.80 and 0.43
Dolmazashvili et al[16], 2017	INF-based/DAA	304	24 wk	TE	- 65.1% achieved at least a 20% reduction in LS; - Overall proportion of patients with stage F4 decreased from 56.6% to 36.5%
Pietsch et al[17], 2018	DAA	143	24 and 96 wk	TE, FIB-4 and APRI	-A short-term reduction in LS until FU24 was seen in almost every patient regardless of stage of liver disease; -Further regression was seen in patients with early cirrhosis but not in individuals with cirrhosis and impaired liver function; -Progression of LS values occurred despite viral clearance in about one-sixth of the patients (17%)
Hedenstierna et al[18], 2018	DAA	269	7.7 yr	TE	- A majority improved their fibrosis stage after SVR; - 24% had persisting advanced fibrosis with a LS level of ≥ 9.5 kPa
Lledó et al[19], 2018	DAA	260	SVR12	TE	Significant fibrosis regression in 40% of the cohort patients more pronounced in patients with baseline advanced fibrosis and cirrhosis
Soliman et al[20], 2020	DAA/ INF-based	180 DAA/ 180 INF-based	at SVR12, 6 mo and 1 yr	TE	Reduction in fibrosis was reported in; 46.7% and 49.3% of patients with moderate fibrosis, and 89% and 78.7% of patients with advanced fibrosis after one yr of INF containing and INF free DAAs regimens respectively
Shiha et al[21], 2020	DAA	2326	12-45 mo	TE, and (FIB-4, FIB-5 and APRI)	- In cirrhotic patients, 21.8% showed reversal of cirrhosis, 27.4% showed fibrosis regression while 50.8% remained stationary; - About 26.5% of F3 patients showed reversal of fibrosis, 31.5% showed fibrosis regression and 30.6% remained stationary while 11.4% progressed to F4
Hablass et al[22], 2021	DAA	137	12 mo	TE, and FIB-4	In all patients, the FIB-4 and TE values after HCV elimination was significantly lower than its mean values at baseline
El-Kady et al[23], 2021	DAA	300	2 yr	TE	Both HCV treatment regimens showed improvement in liver fibrosis
Zakareya et al[13], 2021	DAA	655	1, 3, and 5 yr	TE	There was an overall significant regression of liver stiffness in all patients after sustained HCV eradication
Agwa et al[24], 2022	DAA	1230	12 and 48 wk	TE, FIB-4	- 42.7% F4 patients improved and became (190) F3, (90) F2, and (220) F1; - 40 of 60 F3 patients improved and became (10) F2 and (30) F1; - 28.4% off the treated patients transited from significant fibrosis (≥ F3) to non-significant fibrosis (≤ F2)
Hassanin et al[25], 2022	DAA	162	48 wk	TIMP-1, FIB-4 and TE	Liver ‎fibrosis was improved as evidenced by significant decline in serum level of ‎TIMP-1, significant improvement in Fib-4 score, and significant decline in LSM
Thanapirom et al[26], 2022	DAA	89	1 yr	TE, SWE, and MRE	Viral eradication resulted in the reduction of LS values as evaluated by three elastography techniques
Rosato et al[27], 2022	DAA	516	24 mo	TE	- LS significantly decreased till SVR with a progressive reduction until 24 mo; - Only patients with steatosis and those who developed HCC did not experience a late improvement in LS
Yoo et al[28], 2022	DAA	112	48, 96 and 144 wk	TE, FIB-4 and APRI	LS value in patients achieving SVR signifcantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 wk], 11.7 ± 8.2 kPa [96 wk], 10.09 ± 6.23 [144 wk]

DAA: Direct acting antiviral; INF: Interferon; TE: Transient elastography; ARFI: Acoustic Radiation Force Impulse; LSM: Liver stiffness measurement; SWE: Shear wave elastography; MRE: Magnetic resonance elastography; SVR: Sustained virological response; HCC: Hepatocellular carcinoma; TIMP-1: Tissue inhibitor of metalloproteinases-1.

Table 2 Studies illustrating hepatic histological changes following hepatitis C virus clearance with direct acting antiviral therapy

Ref.	Therapy	n	Follow-up	Scores utilized	Outcome
Shiratori et al[29], 2000	INF-based	487	Median of 3.7 yr apart (range, 1 to 10 yr)	Criteria of Desmet and colleagues (F0 to F4) and those of the French METAVIR Cooperative Study Group (A0 to A3)	- A mean reduction in fibrosis score of -0.60+/-0.07 at less than 3 yr of follow-up and -0.88+/-0.08 at 3 yr or more of follow-up; - Reversal of cirrhosis among 11 CHC patients; - Seven patients decreased their level of fibrosis from F4 to F2 and four from F4 to F3
Poynard et al[30], 2002	INF-based	1030	20 mo mean duration between the biopsies	METAVIR scoring system	- Reversal and/or regression of cirrhosis occurred in 49% of patients where 15% regressed to stage 3, 16% reversed to stage 2, 15% reversed to stage 1 and 2% reversed to stage 0; - Fibrosis worsened in 15%
Maylin et al[31], 2008	INF-based	126	3.27 yr	METAVIR scoring system	- Fibrosis stage was improved in 56%, stable in 32%, progressed in 12%; - Regression of cirrhosis was observed in 64% patients; - No cirrhosis decompensation was observed, and 3 patients developed HCC
George et al[32], 2009	INF-based	49	5 yr	METAVIR scoring system	- 82% had a decrease in fibrosis score, and 92% had a decrease in combined inflammation score; - Two patients with pretreatment cirrhosis developed HCC and one died; - All the other patients with pretreatment cirrhosis or advanced fibrosis had improved fibrosis scores on long-term follow-up biopsy
D’Ambrosio et al[33], 2012	INF-based	38	61 mo	METAVIR scoring system, and the area of fibrosis was measured using morphometry	- Reversal of cirrhosis in 23.6% of the patients, regression of cirrhosis in 61%; regression of fibrosis in 36% of CHC patients
Enomoto et al[34], 2018	DAA	20 paired biopsy specimen	41 ± 20 wk	Knodell scoring system and the METAVIR scoring system	- The inflammation grade significantly regressed, but the fibrosis stage did not; - Histological improvement, defined as a ≥ 2-point decrease in the Knodell inflammatory score and no worsening of the fibrosis, was found 55% patients.
Pan et al[35], 2018	INF-based/DAA	15	3 yr	METAVIR and Batts - Ludwig grading systems	- 13 of patients had improved liver stiffness (to < 9.5 kPa)
Chu et al[36], 2019	INF-based	31	93 mo	METAVIR scoring system and HAI	- Fibrosis regression, stable, and progression were 19%, 45%, and 36%; - A total of 71% of patients achieved inflammation improvement, whereas 6% and 23% of patients had stable disease and disease-progression, respectively
Cheng et al[37], 2021	DAA	21	6 mo	METAVIR fibrosis score and HAI	- Fibrosis scores improved in 61.9% of the patients; - 24.8% stable course; - 14.3% progression of fibrosis

DAA: Direct acting antiviral; INF: Interferon; HAI: Histological Activity Index; HCC: Hepatocellular carcinoma; CHC: Chronic hepatitis C.