Fibroscan Liver Stiffness After Anti-viral Treatment for Hepatitis C Is Independently Associated With Adverse Outcomes

Philip Vutien; Nicole J. Kim; Andrew M. Moon; Meredith Pearson; Feng Su; Kristin Berry; Hannah Gelman; George N. Ioannou

Disclosures

Aliment Pharmacol Ther. 2020;52(11-12):1717-1727.

Abstract and Introduction

Abstract

Background: Fibroscan-derived liver stiffness decreases after anti-viral treatment for hepatitis C virus (HCV) infection, which may affect the associations and interpretation of liver stiffness.

Aims: To assess whether liver stiffness pre- or post-anti-viral therapy is associated with the development of decompensated cirrhosis, hepatocellular carcinoma (HCC) or death.

Methods: In this retrospective cohort study, we identified US veterans who initiated HCV treatment and had at least one liver stiffness before (n = 492) or after (n = 877) HCV therapy. We used Cox proportional hazards regression (adjusting for age, race/ethnicity, history of cirrhosis, body mass index, diabetes, FIB-4 score, Charlson comorbidity index, alcohol use disorder, Model for end-stage liver disease score and sustained virological response status) to determine the associations between pre- or post-treatment liver stiffness values and the development of decompensated cirrhosis, HCC, death or liver transplant.

Results: In the post-treatment liver stiffness cohort, during a mean follow-up of 27.3 months, 21 (2.4%) developed decompensated cirrhosis, 26 (3.0%) developed HCC and 57 (6.5%) died or underwent liver transplant. Compared to patients with post-treatment liver stiffness ≤12.5 kPa, those with post-treatment liver stiffness >20 kPa, had higher rates of developing decompensated cirrhosis (adjusted HR 3.85, 95% CI 1.29–11.50) and the composite outcome of death, liver transplant, decompensated cirrhosis or HCC (adjusted HR 1.95, 95% CI: 1.07–3.56). There were no significant associations between pre-treatment liver stiffness and any outcomes on multivariable analysis.

Conclusions: Post-treatment liver stiffness >20 kPa, but not pre-treatment liver stiffness, was independently associated with the development of decompensated cirrhosis and the composite outcome in multivariable analyses. Measuring liver stiffness should be considered after anti-viral treatment because it predicts adverse outcomes even beyond routinely available clinical predictors.

Introduction

Fibroscan-derived liver stiffness is a non-invasive test that correlates well with the presence of advanced liver fibrosis and clinically significant portal hypertension in patients with hepatitis C virus (HCV) infection.^[1–3] It has been suggested that liver stiffness, measured either before or after anti-viral treatment, is associated with the development of hepatocellular carcinoma (HCC), decompensated liver disease and death.^[4–11]

Liver stiffness can decrease up to 3–5 kPa within months after initiating anti-viral therapy due to the resolution of hepatic inflammation from viral suppression and also over years after viral eradication due to a regression of fibrosis.^[12] The implications of liver stiffness values are therefore likely to be different for those measured before vs after anti-viral treatment. It is therefore imperative to study and clearly distinguish the associations of liver stiffness before or after anti-viral treatment with liver-related complications.

There are many routinely available clinical and laboratory predictors of the development of liver-related complications after anti-viral treatment, including age, a clinical diagnosis of cirrhosis, fibrosis-4 (FIB-4) score, model for end-stage liver disease (MELD) score and viral clearance by sustained virological response (SVR).^[13,14] It is unclear if liver stiffness before or after treatment is independently associated with adverse liver outcomes even after adjustment for these predictors. These predictors are routinely available at no extra cost to healthcare providers, whereas liver stiffness measurement requires costly, specialised equipment and dedicated healthcare personnel. Therefore, for the purposes of predicting long-term outcomes, fibroscan-derived liver stiffness measurement should only be performed if it adds prognostic information above and beyond these routinely available predictors.

We aimed to determine whether liver stiffness before or after anti-viral treatment is associated with the development of decompensated cirrhosis (Figure 1), HCC or death even after adjusting for readily available clinical and laboratory characteristics.

(Enlarge Image)

Figure 1.

Cumulative incidence rates of death or liver transplant (P < 0.01), decompensated cirrhosis (P < 0.001), HCC (P < 0.001) and the composite event (P < 0.001) increased sequentially across higher post-treatment liver stiffness groups

1 2 3 4 5

Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Baseline characteristics of HCV-infected Veterans who had liver stiffness measured after anti-viral therapy
Baseline characteristics prior to liver stiffness date	Post-treatment liver stiffness (kPa)
Baseline characteristics prior to liver stiffness date	≤12.5 N = 670	12.6–20 N = 103	>20 N = 104	P value
Age, years (mean ± SD)	63.3 ± 5.7	64.2 ± 5.6	62.8 ± 4.9	0.2
Male (%)	100	100	100	N/A
Race/ethnicity (%)
White, non-Hispanic	42.7	41.7	46.2	0.01
Black, non-Hispanic	39.7	29.1	33.7
Hispanic, Asian, Pacific Islander	8.5	20.4	12.5
Declined/missing	9.1	8.7	7.7
BMI, kg/m² (mean ± SD)	27.7 ± 4.7	29.1 ± 4.9	28.0 ± 4.7	0.03
Diabetes (%)	24	33	31.7	0.06
Alcohol use disorder (%)	39.9	40.8	43.3	0.8
HBV co-infection (%)	0.9	0	1.9	0.35
HIV co-infection (%)	6.3	6.8	5.8	0.95
Charlson comorbidity index (%)
0	28.8	28.6	26.7	0.1
1	20.3	25.7	13.3
2	25.4	11.4	6.7
>2	25.4	34.3	53.3
Cirrhosis (%)	32.7	53.4	70.2	<0.001
Decompensated cirrhosis (%)	3.9	7.8	16.3	<0.001
HCC (%)	1.2	4.9	5.8	<0.01
HCV genotype (%)
1	82.8	75.7	83.7	0.05
2	9.3	11.7	4.8
3	5.8	9.7	5.8
4	1.3	2.9	1.9
Missing	0.7	0.0	3.8
Type of therapy
IFN	34.3	37.9	36.5	0.13
DAA	55.7	62.1	73.5	0.13
MELD Score ≥ 9 (%)	28.1	28.7	39.6	0.06
Fibrosis-4 Score ≥ 3.25 (%)	9	27.2	49	<0.001
SVR (%)	60.1	54.4	57.7	0.51
Length of follow up, months (mean ± SD)	27.4 ± 11.2	26.0 ± 9.9	28.2 ± 11.5	0.35
More than one treatment course (%)	25.2	28.2	32.7	0.25

Abbreviations: BMI, body mass index; DAA, direct-acting anti-viral; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; IFN, interferon MELD: model for end-stage liver disease.

Table 2. Baseline characteristics of HCV-infected Veterans who had liver stiffness measured before anti-viral treatment
Baseline characteristics prior to anti-viral treatment	Pre-treatment liver stiffness (kPa)
Baseline characteristics prior to anti-viral treatment	≤12.5 N = 273	12.6–20 N = 104	>20 N = 115	P value
Age, years (mean ± SD)	61.9 ± 6.2	63.2 ± 5.2	62.6 ± 4.8	0.11
Male (%)	100	100	100	N/A
Race/ethnicity (%)
White, non-Hispanic	39.6	45.2	57.4	<0.001
Black, non-Hispanic	45.1	31.7	17.4
Hispanic, Asian, Pacific Islander	7	14.4	16.5
Declined/missing	8.4	8.7	8.7
BMI, kg/m² (mean ± SD)	27.6 ± 5.2	28.2 ± 5.6	28.5 ± 5.4	0.22
Diabetes (%)	24.2	41.3	33.9	<0.01
Alcohol use disorder (%)	45.8	40.4	42.6	0.61
HBV co-infection (%)	0	0	0	N/A
HIV co-infection (%)	9.5	6.7	8.7	0.69
Charlson comorbidity index (%)
0	19.4	19.2	15.7	<0.01
1	34.4	21.2	26.1
2	19.8	21.2	13
>2	26.4	38.5	45.2
Cirrhosis (%)	17.2	58.7	84.3	<0.001
Decompensated cirrhosis (%)	2.9	7.7	15.7	<0.001
HCC (%)	0.7	3.8	6.1	<0.01
HCV genotype (%)
1	89.7	86.5	79.1	0.09
2	4.4	2.9	10.4
3	4	8.7	8.7
4	1.1	1	1.7
Missing	0.7	1	0.0
DAA therapy	100	100	100	N/A
MELD Score ≥ 9 (%)	20.9	24	36	<0.01
Fibrosis-4 Score ≥ 3.25 (%)	14.7	44.2	71.3	<0.001
SVR (%)	94.1	93.3	83.5	<0.01
Length of follow-up, months (mean ± SD)	34.2 ± 6.8	35.0 ± 6.2	35.3 ± 6.3	0.27
More than one treatment course (%)	21.6	22.1	22.6	0.98

Table 3. Association of post-treatment liver stiffness with mortality and liver-related outcomes
Post-treatment liver stiffness (kPa)	Number of patients (%)	Patient-years (P-Y)	Number w/outcome (%)	Incidence (per 100 P-Y)	Hazard ratio	Adjusted hazard ratio^a	Test for trend^b (P value)	Departure from linearity^c (P value)
A. Mortality or liver transplant
≤12.5	667 (76.4)	1522	36 (5.4)	2.37	1	1	<0.01	0.34
12.6–20	102 (11.7)	221	7 (6.8)	3.18	1.35 (0.60–3.04)	1.55 (0.65–3.73)
>20	104 (11.9)	244	14 (13.5)	5.78	2.40 (1.29–4.45)	1.68 (0.80–3.53)
B. Decompensated cirrhosis
≤12.5	667 (76.6)	1512	9 (1.3)	0.6	1	1	<0.001	<0.01
12.6–20	101 (11.6)	216	1 (1.0)	0.46	0.76 (0.10–6.01)	0.96 (0.11–8.32)
>20	103 (11.8)	231	11 (10.7)	4.77	8.04 (3.33–19.41)	3.85 (1.29–11.50)
C. HCC
≤12.5	661 (77.1)	1490	13 (2.0)	0.87	1	1	<0.001	0.12
12.6–20	98 (11.4)	206	3 (3.1)	1.45	1.69 (0.48–5.92)	1.17 (0.30–4.56)
>20	98 (11.4)	225	10 (10.2)	4.44	5.03 (2.20–11.47)	2.49 (0.89–6.97)
D. Mortality, liver transplant, decompensated cirrhosis or HCC
≤12.5	667 (76.4)	1497	48 (7.2)	3.21	1	1	<0.001	0.03
12.6–20	102 (11.7)	216	9 (8.7)	4.18	1.30 (0.64–2.65)	1.34 (0.63–2.85)
>20	104 (11.9)	225	25 (24.0)	11.1	3.43 (2.12–5.57)	1.95 (1.07–3.56)

^aAdjusted for baseline age, race/ethnicity, body mass index, MELD score, Charlson comorbidity index, diabetes, SVR, history of cirrhosis, FIB-4 score, and alcohol use disorder.
^bA P < 0.05 suggests a significant trend in outcomes across increasing post-treatment liver stiffness categories.
^cA P < 0.05 suggests a significant departure from a linear relationship between the outcome and increasing post-treatment liver stiffness categories.

Table 4. Association of pre-treatment liver stiffness with mortality and liver-related outcomes
Pre-treatment liver stiffness (kPa)	Number of patients (%)	Patient-years (P-Y)	Number w/outcome (%)	Incidence (per 100 P-Y)	Hazard ratio	Adjusted hazard ratio^a	Test for trend^b (P-value)	Departure from linearity^c (P-value)
A. Mortality or liver transplant
>≤12.5	273(55.5)	777	13(4.8)	1.67	1	1	0.04	0.97
>12.6–20	104(21.1)	303	8(7.7)	2.64	1.60 (0.66–3.85)	0.97 (0.34–2.78)
>20	115(23.4)	338	12(10.4)	3.55	2.15 (0.98–4.71)	0.79 (0.25–2.49)
B. Decompensated cirrhosis
≤12.5	273(55.5)	776	1(0.4)	0.13	NA	NA	NA	NA
12.6–20	104(21.1)	300	5(4.8)	1.66	NA	NA
>20	115(23.4)	324	8(7.0)	2.47	NA	NA
C. HCC
≤12.5	271(56.6)	764	4(1.5)	0.52	1	1	<0.01	0.07
12.6–20	100(20.9)	284	8(8.0)	2.82	5.43 (1.64–18.03)	2.64 (0.65–10.80)
>20	108(22.5)	309	7(6.5)	2.26	4.40 (1.29–15.02)	0.68 (0.12–3.74)
D. Mortality, liver transplant, decompensated cirrhosis, or HCC
≤12.5	273(55.5)	770	16(5.9)	2.08	1	1	<0.001	0.88
12.6–20	104(21.1)	294	12(11.5)	4.08	1.99 (0.94–4.21)	1.13 (0.48–2.69)
>20	115(23.4)	319	21(18.3)	6.58	3.22 (1.68–6.17)	1.04 (0.40–2.70)