Increase in albumin by daclatasvir/asunaprevir therapy is correlated with decrease in aspartate transaminase

Introduction

Chronic hepatitis C virus (HCV) infection affects approximately 180 million people worldwide. HCV usually causes a chronic infection, which can result in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC).[1,2] In Japan, approximately 1.5 million patients with hepatitis are infected with HCV; approximately 70% of them have HCV genotype 1b, which is resistant to interferon (IFN)-based therapy.

On September 2014, Japan authorized IFN-free therapy with oral direct-acting antivirals (DAAs), daclatasvir (DCV; NS5A inhibitor) and asunaprevir (ASV; NS3/4A protease inhibitor) for patients with HCV genotype 1b. DCV/ASV therapy increased the sustained virological response (SVR) rate to about 90% and caused less adverse effects than IFN-based therapy.[3–7]

In Japan, DCV/ASV therapy can be administered to patients with chronic hepatitis or compensated cirrhosis with a Child-Pugh score of 6 or less, but not to those with decompensated cirrhosis with a Child-Pugh score of 7 or more. In some other countries, IFN-free therapy is authorized for patients with decompensated cirrhosis, and high SVR rates are reported with it.[8,9]

Albumin levels are one of the factors constituting the Child-Pugh score formula; they are also one of the outcome predictors of compensated HCV-related cirrhosis.[10] It has been reported that IFN-free therapies can reverse liver dysfunction in decompensated patients.[11–14] Although IFN-free therapies reportedly increase albumin levels, the mechanism of an increase in albumin levels has not been elucidated.

Here, we retrospectively assessed whether DCV/ ASV therapy improved albumin levels, and we aimed to elucidate the factors associated with an increase in albumin levels.

Materials and methods

Results

Increase in albumin levels

Albumin levels significantly increased from 4.0 ± 0.4 g/ dL at baseline to 4.1 ± 0.5 g/dL at EOT (P = 0.0152) and to 4.2 ± 0.4 g/dL at 24 weeks after EOT (P < 0.0001) in patients with SVR. However, the albumin levels did not significantly increase in patients who did not achieve SVR (from 4.1 ± 0.4 g/dL at baseline to 4.2 ± 0.2 g/dL at EOT and to 4.2 ± 0.3 g/dL at 24 weeks after EOT) (Figure 1).

Figure 1

(a) Albumin levels significantly increased from 4.0 ± 0.4 g/dL at baseline to 4.1 ± 0.5 g/dL at the end of treatment (EOT) (P = 0.0152) and to 4.2 ± 0.4 g/dL at 24 weeks after EOT (P < 0.0001) in patients who achieved sustained virological response (SVR). (b) Albumin levels did not significantly increase in patients who did not achieve SVR (from 4.1 ± 0.4 g/dL at baseline to 4.2 ± 0.2 g/dL at EOT and to 4.2 ± 0.3 g/dL at 24 weeks after EOT).

Baseline albumin levels were significantly higher in group A than in groups B and C (P < 0.0001). They were also significantly higher in group B than in group C (P < 0.0001). In group A, the albumin levels did not increase significantly after DCV/ASV therapy, from 4.4 ± 0.2 g/dL at baseline to 4.4 ± 0.3 g/dL at 24 weeks after EOT. In group B, the albumin levels significantly increased from 3.8 ± 0.1 g/ dL at baseline to 4.0 ± 0.4 g/dL at 24 weeks after EOT (P = 0.0039). In group C, the albumin levels significantly increased from 3.3 ± 0.2 g/dL at baseline to 3.7 ± 0.5 g/ dL at 24 weeks after EOT (P = 0.0026) (Figure 2a).

Figure 2

(a) Baseline albumin levels were significantly higher in group A than in group B (P < 0.0001) and in group C (P < 0.0001). Baseline albumin levels were significantly higher in group B than in group C (P < 0.0001). In group A, albumin levels did not increase significantly after daclatasvir/asunaprevir treatment, from 4.4 ± 0.2 g/dL at baseline to 4.4 ± 0.3 g/dL at 24 weeks after the end of treatment (EOT). In group B, albumin levels significantly increased from 3.8 ± 0.1 g/dL at baseline to 4.0 ± 0.4 g/dL at 24 weeks after EOT (P = 0.0039). In group C, albumin levels significantly increased from 3.3 ± 0.2 g/dL at baseline to 3.7 ± 0.5 g/dL at 24 weeks after EOT (P = 0.0026). At 24 weeks after EOT, albumin levels in group A (4.4 ± 0.3 g/dL) were significantly higher than those in group B (4.0 ± 0.4 g/dL; P < 0.0001) and in group C (3.7 ± 0.5 g/dL; P < 0.0001). They were significantly higher in group B than in group C (P = 0.0293). (b) The increase in albumin levels from baseline to at 24 weeks after EOT was significantly greater in group C (0.5 ± 0.5 g/dL; P < 0.0001) and group B (0.2 ± 0.4 g/dL; P = 0.0059) than in group A (0.0 ± 0.3 g/dL).

Twenty-four weeks after EOT, the albumin levels in group A (4.4 ± 0.3 g/dL) remained significantly higher than those in groups B (4.0 ± 0.4 g/dL; P < 0.0001) and C (3.7 ± 0.5 g/dL; P < 0.0001) (Figure 2a). The levels were significantly higher in group B than in group C (P = 0.0293). The increase in albumin levels from baseline to at 24 weeks after EOT was significantly greater in groups C (0.5 ± 0.5 g/dL; P < 0.0001) and B (0.2 ± 0.4 g/dL; P = 0.0059) than in group A (0.0 ± 0.3 g/dL)(Figure 2b).

The factors associated with ≥0.3 g/dL increase in albumin levels were assessed in groups B and C using univariate analysis. Higher aspartate transaminase (AST) levels (P = 0.0140), alanine transaminase levels (P = 0.0301), and Vs values measured using ARFI (P = 0.0423) were significantly associated with ≥0.3 g/dL increase in albumin levels. Multivariate analysis showed that AST levels were the only significant factor associated with albumin elevation (β = 0.03546, SE = 0.01649, P = 0.0305) (Table 2).

A decrease in AST levels was significantly associated with an increase in albumin levels (r = 0.4729, P = 0.0119) (Figure 3).

Figure 3

The decrease in aspartate transaminase (AST) levels is significantly associated with the increase in albumin levels (r = 0.4729, P = 0.0119).

Table 2

Univariate analysis and multivariate analysis for factors associated with albumin elevation of 0.3 g/dl or more in group B and C.

	Univariate analysis			Multivariate analysis
	Patients with albumin elevation of 0.3 g/dL or more (n = 24)	Patients without albumin elevation of 0.3 g/dL or more (n = 20)	P -Value	β	SE (β)	P -Value
Gender (male : female)	11:13	9:11	NS
Age (years)	70.0 ± 4.9	69.8 ± 9.9	NS
History of past IFN-based therapy (none : relapse : breakthrough : nonvirological response : discontinuation)	12 : 2 : 2 : 7 : 1	9 : 1 : 1 : 8 : 1	NS
Platelets (104/µL)	11.0 ± 4.3	13.3 ± 5.9	NS
Albumin (g/dL)	3.6 ± 0.3	3.6 ± 0.3	NS
Total bilirubin (mg/dL)	1.0 ± 0.3	0.9 ± 0.4	NS
AST (IU/L)	62.2 ± 33.2	41.0 ± 17.6	0.014	0.03546	0.01649	0.0305
ALT (IU/L)	52.0 ± 33.3	33.1 ± 19.6	0.0301	-	-	-
Hyaluronic acid (ng/mL)	471.9 ± 346.6	381.3 ± 375.8	NS
α-fetoprotein (ng/mL)	27.2 ± 35.7	19.5 ± 35.0	NS
PIVKA-2 (mAU/mL)	18.0 ± 6.8	28.4 ± 33.7	NS
Vs by ARFI (m/s)	2.55 ± 0.65	2.04 ± 0.82	0.0423	0.84931	0.51791	0.101
HCV RNA (Log IU/mL)	6.2 ± 0.5	5.9 ± 1.1	NS
Presence of liver cirrhosis (positive : negative)	12:12	10:10	NS
History of hepatocellular carcinoma (positive : negative)	7:17	5:15	NS
RAS of Y93 (positive : negative)	0:24	1:19	NS

Data are expressed as mean ± SD. NS: not significant. SE: standard error. AST: aspartate aminotransferase. ALT: alanine aminotransferase. PIVKA-2: protein induced by vitamin K absence or antagonist- 2. Vs: velocity of shear wave. ARFI: acoustic radiation force impulse. RAS: resistance associated substitutions.

Discussion

The present study confirmed that DCV/ASV therapy yielded a high SVR rate (86.4%) as previously reported.[3–7]

It has been reported that IFN-free therapy significantly increases albumin levels [11–14]. One study reported that albumin levels significantly increased only in patients with SVR, while there was no change in patients who did not achieve SVR.[13]. The present study also showed that albumin levels significantly increased in patients with SVR, but not in patients who did not achieve SVR.

Although albumin levels at 24 weeks after EOT were significantly higher in group A than in groups B and C, the increase in albumin levels from baseline to at 24 weeks after EOT was significantly greater in groups B and C than in group A. In group A, the baseline albumin levels were within normal range and the levels remained unchanged after achieving SVR, probably due to homeostasis, which maintains normal albumin levels. In contrast, the baseline albumin levels were lower than the normal limit in groups B and C, and after achieving SVR, the levels increased, approaching the normal levels. Deterding et al. also observed that after achieving SVR, there was a marked increase in the albumin levels in patients with albumin levels below 3.5 g/dL.[12]

Deterding et al. showed that mean albumin levels increased by 0.3 g/dL, from 3.0 g/dL at baseline to 3.3 g/dL at 12 weeks after EOT, in the patients with baseline albumin levels of below 3.5 g/dL.[12] In the present study, mean increases of albumin levels were 0.2 g/dL in group B and 0.5 g/dL in group C. Thus, we assessed the factors associated with ≥ 0.3 g/dL increase in albumin levels in groups B and C. The only factor associated with ≥ 0.3 g/dL increase in albumin levels was the baseline AST level. We also showed that a decrease in AST levels was significantly associated with an increase in albumin levels.

In healthy subjects, the albumin turnover time is approximately 25 days, and it reflects a liver albumin synthesis rate of approximately 10.5 g/day, balanced by renal (6%), gastrointestinal (10%), and catabolic (84%) clearances.[17] Since only 20-30% of hepatocytes are committed to the production of albumin in healthy subjects, liver has a large functional reserve to increase the synthesis of albumin by 3–4 times. In cirrhosis, liver has lost this capacity. The production of albumin is mainly regulated by the osmolality and oncotic pressure, induced by hormonal factors (insulin, cortisol and growth hormone) and inhibited by acute phase cytokines, such as interleukin 6 and tumor necrosis factor α.[18] Inflammation increases catabolic rate and results in hypoalbuminemia.[19]

Hypoalbuminemia in cirrhosis can be attributed mainly to the dysfunction of hepatocytes caused by fibrosis and partially to the suppression of albumin synthesis by inflammatory cytokines and increase in the catabolic rate of albumin caused by liver inflammation, which was reflected as increased AST levels. The amelioration of inflammation that suppresses albumin synthesis and increases catabolism of albumin is a reason for the association between a decrease in AST levels and an increase in the albumin levels after SVR. In groups B and C, the albumin levels at 24 weeks after EOT were still lower than those in group A. This indicates that the recovery of liver function depressed by fibrosis and destruction of functional structure may take a longer period after achieving SVR.

In conclusion, DCV/ASV therapy yielded a high SVR rate and increased albumin levels in patients with SVR. An increase in albumin levels was significantly associated with a decrease in AST levels. Thus, an increase in the albumin levels can be attributed to amelioration of inflammation that suppresses liver albumin synthesis and increases the catabolic rate of albumin. However, albumin levels did not recover to within the normal range, probably because liver function is largely suppressed by fibrosis and destruction of functional structure. Recovery of albumin levels to within the normal range may take a longer period, which enables the reduction of fibrosis and recovery of functional structure.