Factors associated with a reduction in the quality of life of patients with chronic hepatitis C treated by ledipasvir/sofosbuvir therapy

Abstract

Objective

We investigated factors associated with a reduction in the quality of life and their OR of patients with chronic hepatitis C who underwent ledipasvir/sofosbuvir therapy.

Methods

The subjects were 141 outpatients who had undergone ledipasvir/sofosbuvir therapy under a diagnosis of genotype I chronic hepatitis C or Child-Pugh A compensated cirrhosis at Hitachi General Hospital. The patient background before ledipasvir/sofosbuvir therapy, laboratory data and the Chronic Liver Disease Questionnaire scores during ledipasvir/sofosbuvir therapy were investigated. The Chronic Liver Disease Questionnaire consists of 29 questions, and the mean value is calculated as the overall score through a 7-step assessment by patients. Using two divisions: a Chronic Liver Disease Questionnaire score of <7 (symptoms are present) and that of 7 (no symptoms), as objective variables, patients with a Chronic Liver Disease Questionnaire score of <7 were defined as having a reduced quality of life. Independent factors significantly associated with a reduction in the quality of life were extracted using logistic regression analysis.

Results

Based on the multivariate analysis, an alanine aminotransferase level of ≥23 U/L (OR: 4.380, 95% CI: 1.394 to 13.756) was extracted as an independent factor associated with a reduction in the quality of life (p<0.05).

Conclusion

An increase in the baseline level of alanine aminotransferase was found to play a role in the reduction in the quality of life of patients with chronic hepatitis C who had undergone ledipasvir/sofosbuvir therapy.

Introduction

In the chronic phase of hepatitis C, fibrosis of the liver gradually progresses, deteriorating to liver cirrhosis or hepatocellular carcinoma during a period of 20–30 years. WHO estimates that in 2015, there were 71 million persons with chronic hepatitis C virus (HCV) infection worldwide, and that 399 000 people died from cirrhosis or hepatocellular carcinoma caused by HCV infection.¹ Therefore, early detection and treatment are important for HCV treatment. Direct-acting antivirals, such as ledipasvir (LDV) and sofosbuvir (SOF), are currently recommended as a drug category for chronic hepatitis C (CH-C). Adverse events to LDV/SOF therapy are less marked than those to conventional therapy with interferon (IFN) or ribavirin (RBV). A phase III clinical trial demonstrated the sustained virological response 12 weeks (SVR12) rate to be 100% in Japan.²

The treatment of CH-C primarily consists of outpatient care. The final goal of treatment is to improve the quality of life (QOL) and prognosis. For QOL assessment, comprehensive and disease-specific scales are used. The sensitivity of the former is lower than that of the latter because the volume of information on disease-specific complaints or symptoms is smaller. To evaluate the severity of specific diseases or disease-related symptoms, a disease-specific scale is useful. Younossi et al developed the Chronic Liver Disease Questionnaire (CLDQ) as a patient-reported outcome-based liver disease-specific QOL scale.³ The QOL of patients with CH-C is also assessed using the CLDQ in Japan.⁴

Younossi et al conducted 12 multicentre multinational clinical trials (phase III) of RBV±IFN (+SOF) and LDV/SOF therapies for CH-C, and measured the QOL using the CLDQ-HCV.⁵ The QOL of LDV/SOF-treated participants was better than that of RBV±IFN (+SOF)-treated participants, but there was a reduction in the QOL score in some participants.⁵ These suggested three factors associated with a reduction in the QOL after RBV±IFN (+SOF) administration: baseline depression, clinically overt fatigue and an HCV >6 log10 IU/mL. However, factors associated with a reduction in the QOL after LDV/SOF administration were not investigated. If patients who may have a reduction in QOL can be selected before the start of treatment, a QOL-emphasised interview may be carried out for them. The patient’s QOL may be improved by clarifying patient-side problems in the early phase through such an interview and promptly presenting countermeasures. In this study, we investigated factors associated with a reduction in the QOL and their OR of patients with CH-C who had undergone LDV/SOF therapy, to share QOL information on LDV/SOF therapy with healthcare professionals and use it.

Methods

Subjects

A total of 141 outpatients, who consented to participate in this study, were selected from patients who had undergone LDV/SOF therapy under a diagnosis of genotype I CH-C or compensated cirrhosis (Child-Pugh A) at Hitachi General Hospital, Japan, between 1 September 2015 and 30 November 2017.⁶

Survey method

Based on medical records, we investigated the background factors, hepatitis-associated factors and haematological data at the start of LDV/SOF therapy: age, sex, body weight, period after the diagnosis of hepatitis C was made, compensated cirrhosis, presence of hepatocellular carcinoma, presence of diabetes mellitus, previous treatment for CH-C, presence of combined drugs (choleretics, antihypertensive drugs, diuretics, antidiabetic agents, gastrointestinal medicines, sleeping pills and antihyperlipidemic drugs), HCV-RNA level, alanine aminotransferase (ALT), albumin (Alb), haemoglobin (Hb), bilirubin (Bil), platelet (PLT) and creatinine clearance (Ccr). Regarding combined drugs, we surveyed hepatitis-associated drugs, drugs that interact with LDV/SOF and drugs that may influence the QOL.

The QOL was assessed at a point during the administration period ≥2 weeks after the start of administration. For measurement, we used the Japanese version of the CLDQ⁷ obtained permission from Younossi et al. CLDQ evaluates six domains, namely: abdominal symptom, fatigue, systematic symptom, activity, emotional function, worry) and including 29 items (dealing with physical and psychological symptoms associated with liver disease), using a rating scale of 1–7 (where 7 denotes the best possible). These scores range from 1 (worst) to 7 (least severe), wherein higher scores indicate a minimum frequency of symptoms and, consequently, a better QOL: (1) all of the time, (2) most of the time, (3) a good bit of the time, (4) some of the time, (5) a little of the time, (6) hardly any of the time, (7) none of the time. Concerning adverse events, the presence of pruritus, nausea or stomatitis was confirmed on the day of CLDQ measurement. The other adverse reactions were voluntarily reported by the patients.

Outcome

For the outcome, the median of the 29 CLDQ items was regarded as the overall score, and the domain-based score was calculated by adding the scores of the question items in each domain and dividing the overall score by the number of items. Using two divisions: a CLDQ score of <7 (symptoms are present) and that of 7 (no symptoms), as objective variables, patients with a CLDQ score of <7 were defined as having a reduced QOL.

Statistical analysis

Two age categories: ≥75 years and <75 years were divided. The ≥75 years of age group was defined as the late elderly in Japan. The other continuous scales were classified into two categories based on the mean value.

The subjects were divided into two groups based on the presence of each background factor. The results were compared using the χ² test between two groups: a group with a CLDQ score of <7 (symptoms are present) and a group with a score of ≥7 (no symptoms). When the expected frequency was <5, Fisher’s exact test was used. The age, ALT and Ccr ranged widely, and were therefore divided into 5-year age (ie, 25–29, 30–34, 40–44 and so on), 10 U/L (ie, 10–19, 20–29, 30–39 and so on) and 10 mL/min (ie, 40–49.9, 50–59.9, 60–69.9 and so on) groups, respectively, to examine their associations with the overall score using Spearman’s rank correlation coefficient (rs).

In addition, multivariate analysis (logistic regression analysis, stepwise selection methods) of factors with p<0.5 on univariate analysis was performed, and significant factors independently contributing to a CLDQ score of <7 (symptoms are present) were extracted. The degree of contribution (OR) and 95% CI were calculated. The multivariate analysis was a two-sided test, and p values <0.05 were considered to be statistically significant. Statistical analyses were performed using SPSS V.22 statistical software package (SPSS, Tokyo, Japan).

Ethical matters

Informed consent was obtained from each patient, and CLDQ measurement was performed.

Results

Patient background

The patient background of the 141 patients is shown in table 1. Males accounted for approximately 40%. The median age was 69 years (range: 28–87 years). Patients with compensated cirrhosis accounted for 14.2%. Hepatocellular carcinoma was present in 3.5%, and diabetes mellitus (type 2) was present in 10.6%. At the start of LDV/SOF therapy, the median HCV-RNA level was 6.1 log IU/mL (range: 1.2–8.1 log IU/mL).

Table 1.

Baseline demographic and clinical characteristics

	Median (range), n (%)
Age (years)	69	(28–87)
Male	61	(42.9)
Weight (kg)	58	(37–85)
Duration of the chronic hepatitis C (years)	15	(0.1–60)
Liver cirrhosis Child-Pugh A	20	(14.2)
Hepatocellular carcinoma	5	(3.5)
Type 2 diabetes	15	(10.6)
Pretreatment history of chronic hepatitis C	63	(44.7)
Concomitant medication	117	(83.0)
HCV-RNA (log IU/mL)	6.1	(1.2–8.1)
ALT (U/L)	18	(12–116)
Albumin (g/dL)	4.2	(2.8–4.9)
Haemoglobin (g/L)	135	(79-175)
Bilirubin (mg/dL)	0.8	(0.4–2.4)
Platelet ×104 (/μL)	15.3	(2.8–34.6)
Ccr (mL/min)	80.4	(38.7–149.0)

n=141.

ALT, alanine aminotransferase; Ccr, creatinine clearance; HCV-RNA, hepatitis C virus-RNA.

Outcome

The median overall CLDQ score was 6.59 (range: 3.5–7.0). With respect to the domains, the median CLDQ score for abdominal symptoms was 7.00 (range: 3.0–7.0). Those for fatigue, systemic symptoms, activity, emotional function and worry were 6.60 (range: 2.2–7.0), 6.80 (range: 3.4–7.0), 7.00 (range: 3.0–7.0), 6.75 (range: 2.6–7.0) and 6.80 (range: 1.0–7.0), respectively (table 2). Adverse events were noted in 53 (37.6%) of the 141 patients. The most frequent adverse events were stomatitis (14/53, 26.4%), followed by pruritus (13/53, 24.5%), headache (9/53, 17.0%), fatigue (6/53, 11.3%) and nausea (2/53, 3.8%).

Table 2.

CLDQ scores in patients with chronic hepatitis C infection during treatment with LDV/SOF

Domains	Median (range)
Overall	6.59 (3.5–7.0)
Abdominal symptoms	7.00 (3.0–7.0)
Fatigue	6.60 (2.2–7.0)
Systemic symptoms	6.80 (3.4–7.0)
Activity	7.00 (3.0–7.0)
Emotional function	6.75 (2.6–7.0)
Worry	6.80 (1.0–7.0)

n=141.

CLDQ, Chronic Liver Disease Questionnaire; LDV/SOF, ledipasvir and sofosbuvir.

Furthermore, the median interval from the start of administration until CLDQ measurement was 35 days (range: 21–70 days).

Univariate analysis

There were significantly more patients with an overall CLDQ score of <7 (symptoms are present) among those with an ALT level of ≥23 U/L at the start of LDV/SOF therapy (38.9% vs 14.3%, respectively, p=0.014) (table 3). With respect to the domains, the rate of patients with a fatigue score of <7 was significantly higher among those with an ALT level of ≥23 U/L (39.0% vs 19.4%, respectively, p=0.032). The rate of patients with a systemic symptom score of <7 was significantly higher among those with an Alb level of <4.1 g/dL (55.2% vs 72.2%, respectively, p=0.043) and those with an Hb level of <136 g/L (39.1% vs 64.8%, respectively, p=0.003). The rate of patients with an activity score of <7 was significantly higher among those aged ≥75 years (41.7% vs 19.4%, respectively, p=0.005) and those with an Hb level of <136 g/L (29.2% vs 59.1%, respectively, p=0.001). The rate of patients with an emotional functional score of <7 was significantly higher among those with a body weight of <58 kg (42.5% vs 60.7%, respectively, p=0.033) and those with an Hb level of <136 g/L (38.8% vs 62.3%, respectively, p=0.006) (table 3). Correlations between the age, ALT and Ccr, and the overall score were examined, revealing no significant correlation (age: rs=0.016, p=0.848; ALT: rs=−0.139, p=0.101; Ccr: rs=0.002, p=0.980).

Table 3.

The association between CLDQ scores and characteristic in patients with chronic hepatitis C infection during treatment with LDV/SOF

	Overall					Abdominal symptoms					Fatigue					Systemic symptoms
	<7 n=113		7 n=28		P value	<7 n=53		7 n=88		P value	<7 n=105		7 n=36		P value	<7 n=87		7 n=54		P value
Age ≥75 years	32	(28.3)	6	(21.4)	0.462	18	(34.0)	20	(22.7)	0.145	52	(49.5)	18	(50.0)	0.961	47	(54.0)	23	(42.6)	0.187
Female	64	(56.6)	16	(57.1)	0.961	32	(60.4)	48	(54.5)	0.498	59	(56.2)	21	(58.3)	0.823	53	(60.9)	27	(50.0)	0.203
Weight ≥58 kg	56	(49.6)	15	(53.6)	0.704	25	(48.2)	46	(52.3)	0.557	54	(51.4)	17	(47.2)	0.663	41	(47.1)	30	(55.6)	0.330
Duration of the CH-C ≥15 years	62	(54.9)	20	(71.4)	0.112	27	(51.9)	55	(62.5)	0.178	60	(57.1)	22	(61.1)	0.677	51	(58.6)	31	(57.4)	0.887
Liver cirrhosis Child-Pugh A	18	(15.9)	2	(7.1)	0.365	9	(17.0)	11	(12.5)	0.460	16	(15.2)	4	(11.1)	0.540	16	(18.4)	4	(7.4)	0.069
Hepatocellular carcinoma	3	(2.7)	2	(7.1)	0.258	2	(3.8)	2	(3.4)	0.623	4	(3.8)	1	(2.8)	0.621	3	(3.4)	2	(3.7)	0.636
Type 2 diabetes	13	(11.5)	2	(7.1)	0.392	6	(11.3)	9	(10.2)	0.838	12	(11.4)	3	(8.3)	0.435	12	(13.8)	3	(5.6)	0.123
Pretreatment history of CH-C	53	(46.9)	10	(35.7)	0.286	26	(49.1)	37	(42.0)	0.417	48	(45.7)	15	(41.7)	0.673	44	(50.6)	19	(35.2)	0.074
Concomitant medication received	93	(82.3)	24	(85.7)	0.456	42	(79.2)	75	(85.2)	0.360	86	(81.9)	31	(86.1)	0.562	73	(83.9)	44	(81.5)	0.709
HCV-RNA ≥6.1 log/IU/mL	66	(58.4)	17	(60.7)	0.824	28	(52.8)	55	(62.5)	0.258	62	(59.0)	21	(58.3)	0.940	49	(56.3)	34	(63.0)	0.436
ALT ≥23 U/L	44	(38.9)	4	(14.3)	0.014	23	(43.4)	25	(28.4)	0.069	41	(39.0)	7	(19.4)	0.032	34	(39.1)	14	(25.9)	0.109
Alb ≥4.1 g/dL	67	(59.3)	20	(71.4)	0.237	30	(56.6)	57	(64.8)	0.334	62	(59.0)	25	(69.4)	0.268	48	(55.2)	39	(72.2)	0.043
Hb ≥136 g/L	52	(46.0)	17	(60.7)	0.164	21	(39.6)	48	(54.5)	0.086	50	(47.6)	19	(52.8)	0.593	34	(39.1)	35	(64.8)	0.003
Bil ≥0.9 g/dL	44	(38.9)	14	(50.0)	0.287	23	(43.4)	35	(39.8)	0.672	43	(41.0)	15	(41.7)	0.940	31	(35.6)	27	(50.0)	0.092
PLT ≥15.7×104 (/μL)	54	(47.8)	15	(53.6)	0.584	24	(45.3)	45	(51.1)	0.501	50	(47.6)	19	(52.8)	0.593	37	(42.5)	32	(59.3)	0.053
Ccr ≥78.8 mL/min	72	(63.7)	15	(53.6)	0.323	33	(62.3)	54	(61.4)	0.915	66	(62.9)	21	(58.3)	0.630	56	(64.4)	31	(57.4)	0.409
Treatment-related adverse events	46	(40.7)	7	(25.0)	0.124	33	(62.3)	54	(61.4)	0.915	42	(40.0)	11	(30.6)	0.313	36	(41.4)	17	(31.5)	0.238

	Activity					Emotional function					Worry
	<7 n=48		7 n=93		P value	<7 n=80		7 n=61		P value	<7 n=75		7 n=66		P value
Age ≥75 years	20	(41.7)	18	(19.4)	0.005	19	(23.8)	19	(31.1)	0.327	20	(26.7)	18	(27.3)	0.935
Female	31	(64.6)	49	(52.7)	0.177	50	(62.5)	30	(49.2)	0.114	47	(62.7)	33	(50.0)	0.130
Weight ≥58 kg	22	(45.8)	49	(52.7)	0.440	34	(42.5)	37	(60.7)	0.033	33	(44.0)	38	(57.6)	0.108
Duration of the CH-C ≥15 years	24	(50.0)	58	(62.4)	0.158	44	(55.0)	38	(62.3)	0.384	41	(54.7)	41	(62.1)	0.371
Liver cirrhosis Child-Pugh A	8	(16.7)	12	(12.9)	0.544	11	(13.8)	9	(14.8)	0.866	10	(13.3)	10	(15.2)	0.757
Hepatocellular carcinoma	1	(2.1)	4	(4.3)	0.444	1	(1.3)	4	(6.6)	0.110	1	(1.3)	4	(6.1)	0.146
Type 2 diabetes	7	(14.6)	8	(8.6)	0.275	8	(10.0)	7	(11.5)	0.778	10	(13.3)	5	(7.6)	0.269
Pretreatment history of CH-C	23	(47.9)	40	(43.0)	0.579	35	(43.8)	28	(45.9)	0.799	36	(48.0)	27	(40.9)	0.398
Concomitant medication received	41	(85.4)	76	(81.7)	0.580	64	(80.0)	53	(86.9)	0.281	63	(84.0)	54	(81.8)	0.731
HCV-RNA ≥6.1 log/IU/mL	25	(52.1)	58	(62.4)	0.240	47	(58.8)	36	(59.0)	0.975	42	(56.0)	41	(62.1)	0.461
ALT ≥23 U/L	28	(58.3)	28	(30.1)	0.170	32	(40.0)	16	(26.2)	0.087	30	(40.0)	18	(27.3)	0.112
Alb ≥4.1 g/dL	26	(54.2)	61	(65.6)	0.186	45	(56.3)	42	(68.9)	0.127	44	(58.7)	42	(65.2)	0.429
Hb ≥136 g/L	14	(29.2)	55	(59.1)	0.001	31	(38.8)	38	(62.3)	0.006	31	(41.3)	38	(57.6)	0.054
Bil ≥0.9 g/dL	21	(43.8)	37	(39.8)	0.650	31	(38.8)	27	(44.3)	0.510	32	(42.7)	26	(39.4)	0.694
PLT ≥15.7×104 (/μL)	21	(43.7)	48	(51.6)	0.376	41	(51.2)	28	(45.9)	0.529	32	(42.7)	37	(56.1)	0.112
Ccr ≥78.8 mL/min	27	(56.3)	60	(64.5)	0.339	50	(62.5)	37	(60.7)	0.823	45	(60.0)	42	(63.6)	0.658
Treatment-related adverse events	19	(39.6)	34	(36.6)	0.263	35	(43.8)	18	(29.5)	0.084	31	(41.3)	22	(33.3)	0.328

n (%).

Alb, albumin; ALT, alanine aminotransferase; Bil, bilirubin; Ccr, creatinine clearance; CH-C, chronic hepatitis C; CLDQ, Chronic Liver Disease Questionnaire; Hb, haemoglobin; HCV-RNA, hepatitis C virus-RNA; LDV/SOF, ledipasvir and sofosbuvir; PLT, platelet.

Multivariate analysis

The adjusted OR and its 95% CI are presented in table 4. As a significant independent factor associated with a reduction in the QOL of patients with CH-C who had undergone LDV/SOF therapy, an ALT level of ≥23 U/L (OR: 4.380, 95% CI: 1.394 to 13.759) was extracted based on the total CLDQ score. With respect to the domains, an ALT level of ≥23 U/L (OR: 2.192, 95% CI: 1.046 to 4.595) and an Hb level of ≥136 g/L (OR: 0.482, 95% CI: 0.235 to 0.989) were extracted as significant independent factors for abdominal symptoms. Regarding fatigue, an ALT level of ≥23 U/L (OR: 2.654, 95% CI: 1.064 to 6.618) was extracted. Regarding systemic symptoms, an Hb level of ≥136 g/L (OR: 0.346, 95% CI: 0.163 to 0.733) was extracted. Regarding activity, an age of ≥75 years (OR: 2.988, 95% CI: 1.283 to 6.955) and an Hb level of ≥136 g/L (OR: 0.307, 95% CI: 0.141 to 0.670) were extracted. Regarding emotional function, an ALT level of ≥23 U/L (OR: 2.575, 95% CI: 1.164 to 5.699) and an Hb level of ≥136 g/L (OR: 0.267, 95% CI: 0.124 to 0.575) were extracted. Regarding worry, an Hb level of ≥136 g/L (OR: 0.449, 95% CI: 0.223 to 0.904) was extracted.

Table 4.

Multivariate analysis of the risk factors for low CLDQ scores in patients with chronic hepatitis C infection during treatment with LDV/SOF

	Overall			Abdominal symptoms			Fatigue			Systemic symptoms
	β	OR (95% CI)	P value	β	OR (95% CI)	P value	β	OR (95% CI)	P value	β	OR (95% CI)	P value
Age ≥75 years	–	–	–	–	–	–	–	–	–	–	–	–
Hb ≥136 g/L	–	–	–	−0.729	0.482 (0.235 to 0.989)	0.047	–	–	–	−1.061	0.346 (0.163 to 0.733)	0.006
ALT ≥23 U/L	1.477	4.380 (1.394 to 13.756)	0.011	0.785	2.192 (1.046 to 4.595)	0.038	0.976	2.654 (1.064 to 6.618)	0.036	–	–	–

	Activity			Emotional function			Worry
	β	OR (95% CI)	P value	β	OR (95% CI)	P value	β	OR (95% CI)	P value
Age ≥75 years	1.094	2.988 (1.283 to 6.955)	0.011	–	–	–	–	–	–
Hb ≥136 g/L	−1.181	0.307 (0.141 to 0.670)	0.003	−1.320	0.267 (0.124 to 0.575)	0.001	−0.802	0.449 (0.223 to 0.904)	0.025
ALT ≥23 U/L	–	–	–	0.946	2.575 (1.164 to 5.699)	0.020	–	–	–

ALT, alanine aminotransferase; CLDQ, Chronic Liver Disease Questionnaire; Hb, haemoglobin; LDV/SOF, ledipasvir and sofosbuvir.

Discussion

As a factor associated with a reduction in the QOL of patients with CH-C who had undergone LDV/SOF therapy, a baseline ALT level of ≥23 U/L was extracted based on the overall CLDQ score. The risk of having a CLDQ score of <7 (symptoms are present) for patients with an ALT level of ≥23 U/L was 4.4-times higher than for those with an ALT level of <23 U/L. No study has reported factors associated with a reduction in the QOL of patients with CH-C who underwent LDV/SOF therapy; therefore, our results clarifying the relationship between an increase in the baseline ALT level and a reduction in the QOL are of interest. By using these parameters, it could be possible for healthcare professionals to conduct QOL-conscious interviews in patients with CH-C during LDV/SOF therapy, especially in patients being on elevated ALT in advance. Furthermore, information related to these QOLs is considered to be useful information for healthcare workers.

Sabina et al reported that the overall CLDQ score in untreated patients with CH-C with an ALT level of ≥40 U/L was significantly lower than in those with an ALT level of <40 U/L.⁸ In this study, among the LDV/SOF-treated patients, the overall CLDQ score in high ALT patients was also significantly lower than in low ALT patients. Patients with higher ALT levels had a consistently lower QOL regardless of differences in the patient background.

Taken together with the report of Sabina et al and the results of this study, the baseline ALT value and CLDQ score were considered to be related in CH-C or relatively mild compensated cirrhosis.

On the other hand, Younossi et al found no correlation between the overall CLDQ score and ALT level.⁹ In their study, the patient background included chronic liver diseases, such as chronic hepatitis B, alcoholic liver disease, non-alcoholic fatty liver disease, primary biliary cirrhosis and primary sclerosing cholangitis, in addition to CH-C. As no data on ALT were presented, the grade of hepatocellular damage was unclear, but patients with non-compensated cirrhosis other than Child-Pugh A cirrhosis were also included. Non-compensated cirrhosis causes jaundice, ascites, oedema, consciousness disorder, such as hepatic encephalopathy and gastrointestinal haemorrhage, such as hematemesis/melena, influencing daily living. The level of ALT increases with progression of CH-C status. However, if CH-C progresses to liver cirrhosis, the levels of deviation enzymes may decrease, and the ALT level may be within the reference range. Therefore, the CLDQ score was associated with the ALT in patients with CH-C or relatively mild decompensated cirrhosis, but not in those with decompensated cirrhosis.

Regarding activity in the CLDQ, an age of ≥75 years was extracted as a factor associated with a reduction in the QOL of patients with CH-C who underwent LDV/SOF therapy. In patients aged ≥75 years, the risk of having a CLDQ activity score of <7 (symptoms are present) was 3.0-times higher than in those aged <75 years. Younossi et al reported that the activity score markedly decreased with age in patients with liver disease, including those with CH-C.⁹ Similarly, Sabina et al also noted a reduction in the activity score in Japanese patients aged ≥70 years with CH-C. ⁸ The homeostasis maintaining physical and motor functions decline with age through complications or muscle weakness of the lower limbs or trunk. This study yielded similar results. Thus, to maintain the QOL, the ageing-related reduction in physical and motor functions must be minimised, and exercise to maintain muscles is recommended for elderly patients with CH-C. On the other hand, Ozono et al and Tsujii et al reported that there were no differences in the efficacy or safety of LDV/SOF therapy between Japanese patients aged ≥75 years and those aged <75 years.^{10 11} However, in their studies, information on the QOL was not reviewed, and this is the first report to demonstrate that an age of ≥75 years is a factor contributing to a reduction in the QOL regarding activity.

In a previous clinical trial of LDV/SOF, the median age was 52 years.¹² On the other hand, the median age in clinical practice in Japan is 69 years.^{10 11} Of Japanese patients with CH-C, those aged ≥75 years account for ≥50%,¹³ and the rate of elderly patients is higher than that in other countries. Therefore, when performing LDV/SOF therapy, a reduction in the QOL must be considered in patients aged ≥75 years.

In addition, as a factor associated with a reduction in the QOL of patients with CH-C who underwent LDV/SOF therapy, an Hb level of <136 g/L was extracted with respect to activity. In patients with an Hb level of <136 g/L, the risk of having a activity score of <7 (symptoms are present) was 3.3-times higher than in those with an Hb level of ≥136 g/L. An association between anaemia and the CLDQ score was reported during peg-IFN and RBV treatment for CH-C.¹⁴ In this study, similar results were also obtained, and symptoms of anaemia, such as dizziness, vertigo and fatigue, may have led to a reduction in the QOL regarding activity. On the other hand, the rate of having an emotional function score of <7 (symptoms are present) in patients with an Hb level of <136 g/L was 3.3-times higher than that in those with an Hb level of ≥136 g/L. However, in this study, the mechanism by which a reduced Hb level influenced anxiety or anger was unclear.

We examined the relationship between treatment-associated adverse events and a CLDQ score of <7 (symptoms are present). However, there was no association between an overall or domain-based CLDQ score of <7 (symptoms are present) and adverse events. This was possibly because the frequency of events during the past 2 weeks was investigated in the CLDQ and because most adverse events to LDV/SOF were mild. Thus, adverse events may not have markedly influenced the CLDQ score. Furthermore, the presence of hepatocellular carcinoma was not extracted as a factor associated with a reduction in the QOL. However, recent studies have reported that the QOL influences the prognosis of patients with cancer^15–17; therefore, QOL follow-up for patients with hepatocellular carcinoma may be important in the future.

As the limitation of this study, CLDQ measurement was performed at a point during LDV/SOF administration. If the CLDQ had been measured several times during the 12-week administration period, a high-accuracy outcome may have been obtained. Furthermore, to apply the finding that the ALT level at the start of treatment is a factor influence to a reduction in the QOL in clinical practice, its external validity should be verified by conducting a prospective study in the future.

Conclusions

This study demonstrated the baseline level of ALT to be a factor associated with a reduction in the QOL of patients with CH-C who underwent LDV/SOF therapy. This may facilitate the implementation of QOL-based interviews by healthcare professionals for patients with an increase in the baseline ALT level among LDV/SOF-treated patients with CH-C. Furthermore, the prompt management of patient-side problems may improve the patient’s QOL.

What this paper adds.

What is already known on this subject

• The quality of life (QOL) of ledipasvir/sofosbuvir (LDV/SOF)-treated participants was better than that of ribavirin±interferon (+SOF)-treated participants, but there was a reduction in the QOL score in some participants.

• Factors associated with a reduction in the QOL after LDV/SOF administration were not investigated.

• If patients who may have a reduction in QOL can be selected before the start of treatment, a QOL-emphasised interview may be carried out for them.

What this study adds

• An increase in the baseline level of alanine aminotransferase (ALT) was found to play a role in the reduction in the QOL of patients with chronic hepatitis C (CH-C) who had undergone LDV/SOF therapy.

• This may facilitate the implementation of QOL-based interviews by healthcare professionals for patients with an increase in the baseline ALT level among LDV/SOF-treated patients with CH-C.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Obtained.

Ethics approval

This study was approved by the ethics review board of Hitachi General Hospital.