Antiviral Effects of Different Nucleos(t)ide Antiviral Drugs in Patients with Decompensated Hepatitis B Virus-Related Cirrhosis
CAI Lei*, WENG Jun, FENG Lei
Second Department of Hepatobiliary Surgery, Zhujiang Hospital, State Key Laboratory of Organ Failure Research, Co-Innovation Center for Organ Failure Research, Southern Medical University, Guangzhou, 510280, China
*Corresponding Author:CAI Lei, E-mail: cailei_427@163.com
Abstract

Objective: To explore antiviral effects of different nucleos(t)ide antiviral drugs in patients with decompensated hepatitis B virus (HBV)-related cirrhosis. Methods: A total of 126 patients with decompensated HBV-related cirrhosis were selected and randomly divided into Group A, 42 cases, Group B, 42 cases, and Group C, 42 cases. All groups were treated with liver protection and symptomatic supportive treatment. Group A was added with lamivudine (LAM), Group B with adefovir dipivoxil (ADV), Group C with LAM and ADV. After 48-week treatment, changes of the liver function indexes, liver fibrosis indexes, and the conditions of virus replication and kidney damage were observed and compared among three groups. Results: Compared with pretreatment, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) showed a significant reduction (P<0.05), and were lower in Group C than Groups A and B (P<0.05), the levels of albumin (ALB) and cholinesterase (CHE) showed a marked increase in all groups after 48-week treatment (P<0.05), and were higher in Group C than Groups A and B (P<0.05). The HBV DNA copy number reduced significantly in all groups compared with pretreatment, and was the lowest in Group C, followed by Group A and Group B after treatment (P<0.05). The levels of hyaluronidase (HA), procollagen III (PCIII) and laminin (LN) showed a significant decrease after treatment (P<0.05), but there was no difference among three groups (P>0.05). The level of creatinine (Cr) was raised significantly in Group B after treatment, but the levels of Cr, BUN and eGFR in the other two groups didn’t change much after treatment (P>0.05). The normalizing rate of ALT, HBV-DNA negative conversion rate, and drug resistance were better in Group C than Groups A and B (P<0.05), but with no difference between Group A and Group B (P>0.05). Conclusion: Use of different nucleos(t)ide antiviral drugs can improve the liver function and degree of the liver cirrhosis in patients with decompensated HBV-related cirrhosis to various extents, and the combined use of antiviral drugs has better antiviral effects.

Key words: HBV-related cirrhosis; Liver function; Kidney damage Decompensated stage Nucleos(t)ide antiviral drugs
Introduction

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, especially in Asia-Pacific countries [1]. HBV infection is recognized as a global public health problem [2]. According to the survey data, 7.18% of general population, about 93 000 000 are hepatitis B surface antigen (HBsAg) carrier in our country [3]. The number of patients with HBV new infections is up to 100 000 annually, and about half of Hepatitis B-related death worldwide each year are from Chinese [4]. Hepatitis B is complex in decompensated stage, with many complications. Patients often die of portal hypertension complicated with hemorrhage due to cirrhosis with esophageal-gastro varices, hepatorenal syndrome, hepatic encephalopathy, abdominal infection and pulmonary infection [5]. The study made by Calvaruso et al.[6] showed that there were 3% of untreated patients with chronic hepatitis B (CHB) who had been developing into decompensated cirrhosis, with 5-year cumulative survival rate of 14%-35%. As for patients with decompensated HBV-related cirrhosis, inhibiting the replication of HBV is the key to the treatment, and an early long-term lifetime treatment is required [7]. Therefore, this study used nucleos(t)ide antiviral drugs to treat patients with decompensated HBV-related cirrhosis and aimed to explore the influence of them on liver and kidney functions of patients.

Materials and Methods
General data

This study was approved by the Ethics Committees of Zhujiang Hospital, and patients agreed the study protocol and signed the informed consent. Inclusion criteria: (1) patients who confirmed to the diagnostic criteria of decompensated HBV-related cirrhosis in Guideline on Prevention and Treatment of Chronic Hepatitis B[8] formulated by Chinese Society of Hepatology and Society of Infectious Diseases, CMA; (2) patients who received nucleoside antiviral drugs initially or never. Exclusion criteria: (1) patients who were complicated with hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), and human immunodeficiency virus (HIV) infections. (2) patients who were complicated with other liver diseases such as alcoholic liver disease, autoimmune liver disease, and primary hepatic carcinoma. (3) patients with severe heart and kidney dysfunction. (4) patients with cytomegalovirus and epstein-barr (EB) virus infections. (5) patients with acquired immune deficiency syndrome (AIDS) virus infection. (6) pregnant or breast-feeding women.

A total of 126 patients with decompensated HBV-related cirrhosis in Zhujiang Hospital from Jan., 2013 to Jan., 2014 were enrolled and randomly divided into Groups A, B, and C, 42 cases for each group. All groups with no statistical difference in age, gender, HBV DNA copy number and Child-Turcotte-Pugh (CTP) scores were comparative. The baseline data of each group were shown in Table 1.

Table 1 Baseline Data of Patients in Three Groups (ヌ± S)
Methods

All groups were treated with liver protection, lowering transaminase, removing jaundice, and symptomatic supportive treatment, based on which, Group A was added with oral lamivudine (LAM), 100 mg/d, once daily; Group B was added with oral adefovir dipivoxil (ADV), 10 mg/d, once daily; Group C was treated with LAM, 100 mg/d, and ADV, 10 mg/d, once daily. The therapeutic effects among three groups were observed after 48-week treatment.

Fluorescence quantitative polymerase chain reaction (FQ-PCR) was used for detecting the quantitation of HBV DNA. AU 5400 automatic biochemical analyzer produced by Japan Olympus Company was used for detecting the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), total bilirubin (TBIL), cholinesterase (CHE), blood urea nitrogen (BUN), and creatinine (Cr).

Observational indexes

Liver function was reviewed every three months. The following indexes were observed: (1) liver function indexes: AST, ALT, ALB, CHE, and TBIL; (2) liver fibrosis indexes: HA, PCⅢ , LN. (3) virus replication, liver function recovery and kidney damage.

Statistical analysis

All the data were processed using SPSS15.0 statistical software package. The measurement data were presented as the mean ± standard deviation (ヌ± S), comparison among groups was analyzed using t test. The enumeration data were analyzed using Chi-squared test. P< 0.05 was considered statistically different.

Results
Biochemical index changes of liver function among three groups

Compared with pretreatment, the levels of AST, ALT, and TBIL showed a significant reduction (P< 0.05), and were lower in Group C than Groups A and B (P< 0.05). The levels of ALB and CHE showed a marked increase in all groups after 48-week treatment (P< 0.05), and were higher in Group C than Groups A and B (P< 0.05). However, there was no difference between Group A and Group B in AST, ALT, TBIL, ALB, and CHE (P> 0.05) (Table 2).

Table 2 Biochemical Index Changes of Liver Function Among Three Groups (ヌ± S)
Comparison of HBV DNA copy number and liver fibrosis among three groups

There was no difference among three groups in HBV DNA copy number and liver fibrosis indexes prior to treatment (P> 0.05). HBV DNA copy number decreased in three groups after 48-week treatment, and was lowest in Group C, followed by Group A and Group B (P< 0.05). The levels of HA, PCⅢ and LN reduced obviously after treatment (P< 0.05), but with no difference among three groups (P> 0.05).

Table 3 Comparison of HBV DNA Copy Number and Liver Fibrosis Among Three Groups (ヌ± S)
Changes of renal function indexes among three groups

There was no difference among three groups in Cr, BUN, and eGFR (P> 0.05). However, the level of Cr showed an obvious increase in Group B after treatment (P< 0.05), but the levels of Cr, BUN, and eGFR showed no difference in the other two groups compared with pretreatment (P> 0.05). There was no difference among there groups in above three indexes (P> 0.05) (Table 4).

Table 4 Changes of Renal Function Indexes Among Three Groups (ヌ± S)
Nomalization rate of ALT, HBV-DNA negative conversion rate, and drug resistance among three groups

The normalization of ALT, HBV-DNA negative conversion rate, and drug resistance in Group C had significant difference compared with Group A and Group B (P< 0.05). However, there was no difference between Group A and Group B in the normalizing rate of ALT, HBV-DNA negative conversion rate, and drug resistance (P> 0.05) (Table 5).

Table 5 The Normalization of ALT, HBV-DNA Negative Conversion Rate, and Drug Resistance Among Three Groups After Treatment
Discussion

Patients with CHB are prone to develop into liver cirrhosis, accounting for 6%-20%, and the incidence rate, progression and prognosis of liver cirrhosis are closely associated with the level of serum HBV DNA[9]. Guideline on Prevention and Treatment of Chronic Hepatitis B points out that the aim of CHB treatment is to maximally inhibit the replication of HBV for a long term, reduce the inflammatory necrosis of liver cells and liver fibrosis, and lower the incidence of liver decompensation, liver cirrhosis, hepatocellular carcinoma and complications, thus improving the quality of life and prolonging the survival time of patients. In patients with decompensated HBV-related cirrhosis, continuous replication of HBV in the body can lead to hepatocellular injury, the deterioration of liver function, esophageal-gastro varices, infections, hepatic encephalopathy, electrolyte, acid-base disturbance, hepatopulmonary syndrome, hepatorenal syndrome, pylethrombosis, and primary hepatocellular carcinoma, consequently lowering the quality of life of patients, with poor prognosis [10]. Therefore, it is vitally important for patients to receive antiviral therapy in clinic [11]. Nucleoside drugs can postpone disease progression of patients with cirrhosis, for ncleoside drugs can action on HBV-infected cells and inhibit the activity of HBV polymerase and block the synthesis of HBV DNA[12, 13].

At present, nucleoside analogues include LAM, clevudine, telbivudine (LdT) and entecavir (ETV), while nucleotide analogues include ADV and tenofovir dipivoxil fumarate (TDF) [14]. Wei et al. [15] conducted a survey of Chinese physicians’ awareness of the 2010 guidelines on the treatment of chronic HBV infection, and found that most Chinese physicians often adhere to Chinese 2010 CHB guidelines and are very aware of the use of antiviral medications for hepatitis B. Lian et al. [16] selected 120 patients with naï ve patients with HBV-related decompensated cirrhosis who were divided into two groups, one (LAM + ADV group, 60 cases) was treated with LAM combined with ADV therapy, another (ETV group, 60 cases) with ETV monotherapy. They concluded that LAM + ADV combination therapy and ETV monotherapy could effectively inhibit HBV replication, improve liver function, and decrease mortality. Zhao [17] used LAM and ADV to treat patients with decompensated HBV-related cirrhosis, and the results showed that the levels of liver function indexes (ALT, AST, ALB and TBIL) had been improved in combined group, superior to those of control group treated with ADV. In this study, after patients were treated with nucleos(t)ide antiviral drugs for 48 weeks, the levels of ALT, AST, and TBIL decreased, the levels of ALB and CHE increased significantly compared with pretreatment, which showed that coagulation function had been improved, with optimal effects in the combined therapy (Group C), indicating that after antiviral therapy, cell inflammatory reaction was relieved, the liver function improved obviously, and the exogenous infusion of ALB was not required. The levels of HA, PCⅢ and LN had improved in three groups after treatment, indicating that nucleos(t)ide antiviral drugs could suppress the replication of HBV virus and postpone the progression of liver fibrosis, which is consistent with the research results of Yanet al.[18].

Kidney damage is a common complication in patients with decompensated HBV-related cirrhosis [19]. In this study, the level of Cr showed an obvious increase in Group B after treatment compared with pretreatment, showing that ADV might increase the risk of kidney damage in patients with decompensated cirrhosis. Zeng et al.[20] reported that LdT had direct protective effects on the kidney, and also could improve the kidney function when combined with ADV. Use of one nucleos(t)ide analogue monotherapy is susceptible to drug resistance and long-term use caused virus variation to different degrees, so combined use of drugs with no cross resistance loci is preferred for such patients after antiviral therapy. Wang et al. [21] assessed the cost-effectiveness of LMV, LdT, ADV, ETV and LMV+ADV on decompensated HBV-related cirrhosis. They found those therapies were all effective in the treatment of decompensated HBV-related cirrhosis, with slight side effects being controlled, and of them, ETV and LMV+ADV were recommended from the perspective of cost-effectiveness. Additionally, the normalization rate of ALT, HBV-DNA negative conversion rate, and drug resistance were better in Group C than Groups A and B, but with no statistical difference between Group A and Group B, which showed that LAM combined with ADV could postpone the disease progression, reduce the occurrence of drug resistant strain, as well as the efficacy of patients with decompensated HBV-related cirrhosis.

In conclusion, use of different nucleos(t)ide antiviral drugs can improve the liver function and degree of the liver cirrhosis in patients with decompensated HBV-related cirrhosis to various extents, and the combined use of antiviral drugs has better antiviral effects.

Declaration

The authors of this manuscript declare that they have no conflict of interest.

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