Risk Factors for Liver-related and Non-liver-related Mortality Following a Sustained Virological Response After Direct-acting Antiviral Treatment for Hepatitis C Virus Infection in a Real-world Cohort

Ritsuzo Kozuka; Akihiro Tamori; Masaru Enomoto; Yoshimi Muto-Yukawa; Naoshi Odagiri; Kohei Kotani; Hiroyuki Motoyama; Etsushi Kawamura; Atsushi Hagihara; Hideki Fujii; Sawako Uchida-Kobayashi; Norifumi Kawada

Disclosures

J Viral Hepat. 2023;30(5):374-385.

Abstract and Introduction

Abstract

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84–2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m² (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m² at baseline (p = .012; HR, 3.407) and albumin–bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.

Introduction

An estimated 58 million people were chronically infected with hepatitis C virus (HCV) worldwide in 2019,^[1] and 10%–20% of HCV-infected individuals develop liver complications, including cirrhosis, liver failure and hepatocellular carcinoma (HCC).^[2] Thus, the ultimate goal of anti-HCV treatment is to prevent the development of cirrhosis and HCC and reduce mortality.

An all-oral direct-acting antiviral (DAA) regimen was approved in Japan in 2014. This regimen is used for a large number of patients with chronic HCV infection, and it results in a rapid elimination of the HCV RNA level and remission of liver inflammation in most patients without any adverse effects. This interferon (IFN)-free DAA treatment achieves a sustained virological response (SVR) in nearly 100% of patients with chronic HCV infection.^[3–6]

PEG-IFN and ribavirin had been the standard treatments for patients with chronic hepatitis C. Although SVR rates are lower in patients who received an IFN-based treatment compared with IFN-free DAA treatment, several long-term follow-up studies of patients who received IFN-based treatment showed that the HCC incidence and all-cause, liver-related, and non-liver-related mortality rates were significantly lower in patients who achieved a SVR than in those who did not.^[7–9]

Although the follow-up periods in studies of patients who received DAA treatment have been relatively short, several studies have reported that the HCC incidence^[10–14] as well as all-cause, liver-related, and non-liver-related mortality rates^[9,13–18] were significantly lower in patients who achieved a SVR than in those who did not or in untreated patients. Janjua, et al. evaluated the effect of a DAA-induced SVR on mortality risk in a large population-based cohort after more than 5 years of follow-up and found that achieving an SVR was associated with 81% and 78% reductions in all-cause and liver-related mortality rates, respectively, compared with no treatment. Achieving a SVR was associated with 81% and 87% reductions in all-cause and liver-related mortality rates, respectively, compared with not achieving a SVR.^[18] Furthermore, there was no significant effect of achieving a SVR induced by IFN-based or DAA treatment on HCC risk or mortality.^[19,20]

In addition, a DAA-induced SVR results in hepatic benefits, such as improved or reduced hepatic fibrosis,^[21,22] portal hypertension,^[23,24] hepatic decompensation^[9,13,25] and extrahepatic benefits, such as reduced risks of non-HCC malignancy,^[26] diabetes mellitus^[27] and cardiovascular disease.^[17,28]

A DAA-induced SVR reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality in patients with SVR following DAA treatment are unclear. Therefore, this study aimed to assess the incidence and risk factors of liver-related and non-liver-related mortality in patients who achieved SVR after DAA treatment in a real-world cohort.

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Abstract and Introduction
Patients and Methods
Results
Discussion
References

Table 1. Characteristics of the patients at baseline, EOT, and SVR ₁₂.
	Total (n = 1180)
Age (years)	68 (21–93)
Sex (male)	554 (46.9%)
Body mass index (kg/m²)	22.8 (11.7–40.0)
Cirrhosis	226 (19.2%)
HCC history (+)	142 (12.0%)
DAA treatment (AD/Sr/SL/POR/GE/GP/SV/SVr)	145/197/459/24/113/216/19/7
Alcohol consumption (+)	344 (29.2%)
Cigarette smoking (+)	446 (37.8%)
Diabetes mellitus (+)	231 (19.6%)
Hypertension (+)	599 (50.8%)
Baseline
White blood cells (/μl)	4800 (1400–11,700)
Haemoglobin (g/dl)	13.4 (7.5–18.2)
Platelet count (×10³/mm³)	165 (13–438)
Aspartate aminotransferase (U/L)	42 (4–275)
Alanine aminotransferase (U/L)	37 (3–610)
γ-Glutamyltransferase (U/L)	33 (4–827)
Total bilirubin (mg/dl)	0.6 (0.1–3.4)
Albumin (g/dl)	4.0 (2.0–5.0)
Albumin–bilirubin grade (1/2/3)	754/417/9
Estimated glomerular filtration rate (ml/min/1.73 m²)	73.0 (4.2–166.5)
Fibrosis-4 index	2.81 (0.18–49.75)
α-Fetoprotein (ng/ml)	4.5 (<2.0–661.9)
HCV genotype (1/2/3)	819/358/3
HCV RNA (log IU/ml)	6.2 (1.4–7.7)
EOT
Albumin–bilirubin grade (1/2/3)	773/389/4
Fibrosis-4 index	2.20 (0.13–24.77)
α-Fetoprotein (ng/ml)	3.6 (<2.0–2955.4)
SVR₁₂
Albumin–bilirubin grade (1/2/3)	935/218/5
Fibrosis-4 index	2.26 (0.27–54.60)
α-Fetoprotein (ng/ml)	3.3 (<2.0–188.1)
After the end of DAA treatment
Observation period (days)	1099 (84–2345)
HCC development (+)	144 (12.2%)

Note: The values are medians (with ranges) or numbers (with percentages).
Abbreviations: AD, asunaprevir plus daclatasvir; DAA, direct-acting antiviral; EOT, end of treatment; GE, grazoprevir plus elbasvir; GP, glecaprevir plus pibrentasvir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; POR, paritaprevir plus ombitasvir plus ritonavir; SL, sofosbuvir plus ledipasvir; Sr, sofosbuvir plus ribavirin; SV, sofosbuvir plus velpatasvir; SVr, sofosbuvir plus velpatasvir plus ribavirin; SVR, sustained virological response.

Table 2. Predictive factors associated with all-cause mortality after DAA treatment.
Factor	Category	Univariate analysis				Multivariate analysis
Factor	Category	HR	95 % CI		p-Value	HR	95 % CI		p-Value
Age (years)	≥71	2.187	1.255	3.813	.006*	0.918	0.472	1.785	.80
Sex	Male	1.512	0.880	2.598	.134
Body mass index (kg/m²)	≥23.0	1.763	1.011	3.072	.046*	1.358	0.746	2.472	.32
Cirrhosis	(+)	4.284	2.491	7.367	<.001*	1.219	0.523	2.841	.65
HCC history	(+)	4.135	2.371	7.211	<.001*	1.566	0.771	3.180	.22
Alcohol consumption	(+)	0.552	0.270	1.132	.105
Cigarette smoking	(+)	1.482	0.858	2.561	.159
Diabetes mellitus	(+)	1.442	0.783	2.656	.24
Hypertension	(+)	1.965	1.104	3.499	.022*	1.411	0.764	2.606	.27
Baseline
White blood cells (/μl)	≤4200	2.566	1.480	4.450	<.001*	1.858	0.967	3.570	.063
Haemoglobin (g/dl)	≤12.7	2.202	1.281	3.785	.004*	1.357	0.739	2.491	.32
Platelet count (×10³/mm³)	≤131	2.823	1.625	4.907	<.001*	1.208	0.451	3.234	.71
Aspartate aminotransferase (U/L)	≤44	1.353	0.780	2.347	.28
Alanine aminotransferase (U/L)	≤36	1.559	0.902	2.693	.112
γ-Glutamyltransferase (U/L)	≤33	1.289	0.744	2.235	.37
Total bilirubin (mg/dl)	≥0.7	1.048	0.610	1.801	.87
Albumin (g/dl)	≤3.8	2.775	1.581	4.870	<.001 *	0.726	0.268	1.964	.53
Albumin–bilirubin grade	≥2	3.016	1.706	5.331	<.001*	1.397	0.514	3.798	.51
Estimated glomerular filtration rate (ml/min/1.73 m²)	≤68.52	2.908	1.633	5.177	<.001*	2.035	1.112	3.725	.021*
Fibrosis-4 index	≥3.25	2.361	1.335	4.174	.003*	0.549	0.200	1.506	.24
α-Fetoprotein (ng/ml)	≥5.4	1.125	0.656	1.930	.67
HCV RNA (log IU/ml)	≤6.3	1.762	0.969	3.205	.063
EOT
Albumin–bilirubin grade	≥2	2.699	1.562	4.662	<.001*	0.980	0.459	2.092	.96
Fibrosis-4 index	≥3.25	3.275	1.893	5.665	<.001*	1.673	0.524	5.337	.38
α-Fetoprotein (ng/ml)	≥4.6	1.241	0.703	2.190	.46
SVR₁₂
Albumin–bilirubin grade	≥2	4.078	2.367	7.024	<.001*	2.413	1.142	5.098	.021*
Fibrosis-4 index	≥3.25	2.664	1.552	4.574	<.001*	0.790	0.287	2.174	.65
α-Fetoprotein (ng/ml)	≥4.7	1.515	0.873	2.627	.140
After the end of DAA treatment
HCC development	(+)	4.955	2.882	8.519	<.001*	2.502	1.229	5.094	.011*

Abbreviations: DAA, direct-acting antiviral; EOT, end of treatment; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SVR, sustained virological response.
*p < .05 indicates statistical significance.
The bold values indicate statistical significance.

Table 3. Predictive factors associated with liver-related mortality after DAA treatment.
Factor	Category	Univariate analysis				Multivariate analysis
Factor	Category	HR	95 % CI		p-Value	HR	95 % CI		p-Value
Age (years)	≥74	4.450	1.521	13.022	.006*	1.767	0.351	8.898	.49
Sex	Male	1.467	0.532	4.047	.46
Body mass index (kg/m²)	≥23.3	2.592	0.886	7.585	.082
Cirrhosis	(+)	13.373	3.761	47.548	<.001*	0.989	0.125	7.854	.99
HCC history	(+)	26.707	7.519	94.859	<.001*	3.887	0.735	20.560	.110
Alcohol consumption	(+)	0.430	0.097	1.907	.27
Cigarette smoking	(+)	1.471	0.523	4.140	.46
Diabetes mellitus	(+)	3.504	1.269	9.674	.016*	2.146	0.614	7.503	.23
Hypertension	(+)	2.509	0.799	7.882	.115
Baseline
White blood cells (/μl)	≤4000	8.587	2.423	30.437	<.001*	3.253	0.566	18.710	.186
Haemoglobin (g/dl)	≤12.4	3.849	1.367	10.835	.011*	1.559	0.443	5.487	.49
Platelet count (×10³/mm³)	≤111	11.521	3.238	40.997	<.001*	2.235	0.159	31.349	.55
Aspartate aminotransferase (U/L)	≥39	2.009	0.639	6.314	.23
Alanine aminotransferase (U/L)	≥53	1.722	0.624	4.752	.29
γ-Glutamyltransferase (U/L)	≥40	1.551	0.562	4.278	.40
Total bilirubin (mg/dl)	≥0.7	1.659	0.587	4.691	.34
Albumin (g/dl)	≤3.7	4.293	1.460	12.623	.008*	0.813	0.097	6.808	.85
Albumin–bilirubin grade	≥2	5.897	1.658	20.974	.006*	0.962	0.078	11.871	.98
Estimated glomerular filtration rate (ml/min/1.73 m²)	≤61.68	3.929	1.397	11.049	.009*	6.607	1.436	30.395	.015*
Fibrosis-4 index	≥3.25	7.372	1.658	32.778	.009*	0.058	0.001	2.278	.128
α-Fetoprotein (ng/ml)	≥7.2	2.911	1.033	8.198	.043*	0.060	0.002	1.612	.094
HCV RNA (log IU/ml)	≤6.3	2.645	0.746	9.382	.132
EOT
Albumin–bilirubin grade	≥2	5.245	1.668	16.488	.005*	0.696	0.106	4.569	.71
Fibrosis-4 index	≥3.25	14.259	3.207	63.408	<.001*	2.459	0.047	128.327	.66
α-Fetoprotein (ng/ml)	≥7.6	6.394	2.211	18.492	<.001*	18.490	1.130	302.667	.041*
SVR₁₂
Albumin–bilirubin grade	≥2	6.272	2.230	17.637	<.001*	0.713	0.078	6.544	.77
Fibrosis-4 index	≥3.25	14.589	3.285	64.803	<.001*	5.702	0.115	281.768	.38
α-Fetoprotein (ng/ml)	≥5.7	5.131	1.825	14.429	.002*	1.993	0.207	19.155	.55
After the end of DAA treatment
HCC development	(+)	71.957	9.433	548.907	<.001*	31.484	2.411	411.207	.009*

Table 4. Predictive factors associated with non-liver-related mortality after DAA treatment.
Factor	Category	Univariate analysis				Multivariate analysis
Factor	Category	HR	95 % CI		p-Value	HR	95 % CI		p-Value
Age (years)	≥71	1.997	0.897	4.446	.090
Sex	Male	1.147	0.523	2.515	.73
Body mass index (kg/m²)	≤21.7	1.409	0.639	3.104	.40
Cirrhosis	(+)	3.889	1.772	8.535	<.001*	1.477	0.435	5.009	.53
HCC history	(+)	2.167	0.865	5.427	.099
Alcohol consumption	(+)	0.364	0.109	1.218	.101
Cigarette smoking	(+)	1.154	0.510	2.612	.73
Diabetes mellitus	(+)	0.551	0.165	1.843	.33
Hypertension	(+)	1.401	0.629	3.118	.41
Baseline
White blood cells (/μl)	≤4200	2.536	1.139	5.646	.023*	1.765	0.693	4.498	.23
Haemoglobin (g/dl)	≤12.7	3.198	1.412	7.242	.005*	2.073	0.849	5.062	.110
Platelet count (×10³/mm³)	≤126	2.668	1.208	5.890	.015 *	1.028	0.290	3.648	.97
Aspartate aminotransferase (U/L)	≥40	1.243	0.558	2.768	.59
Alanine aminotransferase (U/L)	≤33	1.457	0.665	3.196	.35
γ-Glutamyltransferase (U/L)	≤33	1.892	0.810	4.422	.141
Total bilirubin (mg/dl)	≤0.5	1.827	0.832	4.014	.133
Albumin (g/dl)	≤3.8	3.308	1.426	7.669	.005*	1.378	0.331	5.741	.66
Albumin–bilirubin grade	≥2	2.787	1.230	6.314	.014*	0.835	0.212	3.287	.80
Estimated glomerular filtration rate (ml/min/1.73 m²)	≤67.94	4.590	1.833	11.494	.001*	3.407	1.315	8.825	.012*
Fibrosis-4 index	≥3.25	2.204	0.973	4.994	.058
α-Fetoprotein (ng/ml)	≥5.8	1.715	0.777	3.783	.182
HCV RNA (log IU/ml)	≤6.0	2.107	0.956	4.641	.064
EOT
Albumin–bilirubin grade	≥2	2.436	1.106	5.367	.027*	0.617	0.211	1.803	.38
Fibrosis-4 index	≥3.25	3.003	1.361	6.625	.006*	0.842	0.254	2.793	.78
α-Fetoprotein (ng/ml)	≥4.9	1.418	0.612	3.285	.42
SVR₁₂
Albumin–bilirubin grade	≥2	4.746	2.125	10.598	<.001*	3.449	1.181	10.072	.024*
Fibrosis-4 index	≥3.25	1.898	0.861	4.187	.112
α-Fetoprotein (ng/ml)	≥4.1	1.379	0.619	3.073	.43
After the end of DAA treatment
HCC development	(+)	3.797	1.702	8.469	.001*	2.077	0.823	5.241	.122