LIVER

477

riginal Paper

Comparison of the Efficacy of Entecavir and Tenofovir in Chronic Hepatitis B

Fatih Gzelbulut1, Aye Oya Kurda vn1, Zleyha Akkan etinkaya1, Ebubekir enate1, Yasemin Gkden1, Aya Gken Deirmenci Saltrk1, Mesut Sezikli1, Selvinaz zkara2 and Fuat etinkaya3
1

ABSTRACT

Corresponding author: Fatih Gzelbulut, Yukari Dudullu, Mehmet Akif Mah, Emir Sok, Alya Apt, No:17 Daire:10, Umraniye, Istanbul, Turkey; Tel: +905327428657; E-mail: fguzelbulut@hotmail.com

Department of Gastroenterology, 2Department of Pathology and 3Department of Microbiology, Haydarpaa Numune Education and Research Hospital, Istanbul, Turkey

Background/Aims: This study aimed to compare the efficacy of entecavir and tenofovir in nucleos(t)ide-naive chronic hepatitis B patients after 48 weeks of therapy. Methodology: We retrospectively reviewed our data of chronic hepatitis B patients. Nucleos(t)ide-naive patients who had received entecavir or tenofovir for at least 48 weeks were included. We compared entecavir and tenofovir after 48 weeks of therapy with respect to virological, biochemical, serological and histological responses. Results: Of the 44 patients, 24 received entecavir and 20 received tenofovir. Pretreatment characteristics of the patients were similar. After 48 weeks, serum HBV DNA levels decreased by 6.931.54log copy/ mL in the entecavir group and 6.891.22log copy/mL INTRODUCTION It is estimated that 400 million people worldwide are chronically infected with hepatitis B virus (HBV). Chronic HBV infection is an important cause of cirrhosis, end stage liver disease, hepatocellular carcinoma (HCC) and death from liver disease (1). The ultimate goal of therapy for chronic hepatitis B (CHB) is to prevent the development of cirrhosis, decompansation and HCC (2,3). Since high serum HBV DNA level is a risk factor for progression to cirrhosis and development of HCC (4), the goal of therapy is to suppress HBV DNA replication in a sustained manner (2,3). In HBeAgpositive and HBeAg-negative patients, long-term therapy with lamivudine is associated with histological and clinical improvement probably as a result of suppression of HBV DNA and hepatic necroinflammation (5,6). The ideal drug for the treatment of CHB must have potent antiviral activity. Since treatment of CHB is long-term, especially in HBeAg-negative patients, it also must have a high genetic barrier conferring with low antiviral resistance. Currently, there are 7 drugs approved for the treatment of CHB: interferon alfa, pegylated interferon alfa, lamivudine (LAM), adefovir (ADV), entecavir (ETV), tenofovir (TDF) and telbivudine (LdT) (2,3). Efficacy of pegylated interferons are limited, especially in genotype D infection (7,8). Although LAM is associated with effective HBV DNA suppression, resistance to LAM develops in up to 70% of patients through 4 years of therapy (9,10). ETV and TDF are potent inhibitors of HBV DNA polymerase. In phase 3 studies, both drugs have been shown to be more effective than LAM and ADV in both nucleoside naive HBeAg-positive and HBeAg-negative CHB patients with respect to virological, serological, biochemical and

the Liver (EASL); Entecavir (ETV); Histological Activity Index (HAI); Hepatitis B e histological responses at week 48 (11-13). Moreover, the Antigen (HBeAg); rate of antiviral resistance was low with long-term use of Hepatitis B Virus Deoxyribonucleithese drugs (14-16). According to the recently published EASL and AASLD cacid (HBV DNA); Hepatitis B Virus guidelines, ETV or TDF are the first-line therapies for CHB (HBV); Hepatocel(2,3). Although there are many studies evaluating the ef- lular Carcinoma ficacy of ETV and TDF, there is no study comparing the ef- (HCC); Lamivuficacy of these 2 potent antivirals with high genetic barri- dine (LAM); Telbivudine (LdT); er in compensated CHB. Tenofovir (TDF).

in the tenofovir group (p=0.65). A similar proportion of patients in entecavir and tenofovir groups achieved undetectable serum HBV DNA (87.5% vs. 95%, p=0.39) Abbreviations: and serum ALT normalization (79.2% vs. 85%, p=0.62). American AssociaThe mean histological activity index score improved by tion for the Study 3.833.51 points in the entecavir group and 2.201.91 of Liver Diseases Adefovir points in the tenofovir group (p=0.07), and the mean fi- (AASLD); (ADV); Alanine brosis scores improved by 0.381.61 points in the ente- Aminotransferase cavir group and 0.701.17 points in the tenofovir group (ALT); Body Mass after 48 weeks (p=0.44). Conclusions: Entecavir and Index (BMI); Hepatitis tenofovir are similarly effective in nucleos(t)ide-naive Chronic B (CHB); Eurochronic hepatitis B patients with high viral load and/or pean Association for the Study of high fibrosis scores after 48 weeks of therapy.

Chronic hepatitis B; Entecavir; Tenofovir.

Key Words:

Hepato-Gastroenterology 2012; 59:477-480 doi 10.5754/hge11426 H.G.E. Update Medical Publishing S.A., Athens

METHODOLOGY We retrospectively reviewed our data of CHB patients who had received ETV 0.5mg or TDF 245mg for at least 48 weeks. Those patients with the following criteria were included in this study: 1) adequate liver biopsy 6 months prior to and after week 48 of therapy, 2) pretreatment fibrosis scores 3 (Ishak) with any serum HBV DNA levels, 3) serum HBV DNA levels 6 log copy/mL (HBeAg-positive) or 5 log copy/mL (HBeAg-negative) with any fibrosis scores. Exclusion criteria included: 1) coinfection with hepatitis C virus, hepatitis D virus or human immunodeficiency virus, 2) the presence of other liver diseases, 3) a history of hepatocellular carcinoma, 4) a history of liver transplantation, 5) absence of adequate liver biopsy prior to or after week 48 of therapy, 6) low fibrosis scores <3 (Ishak) with low serum HBV DNA levels (<6log copy/mL for HBeAg-positive and <5log copy/mL for HBeAg-negative) at the beginning of therapy, 7) previous treatment

In the present study, we aimed to compare the efficacy of ETV and TDF in nucleos(t)ide-naive CHB patients with high viral load and/or high fibrosis scores at week 48 of therapy with respect to virological, serological, biochemical and histological responses.

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Hepato-Gastroenterology 59 (2012) with any other agent with activity against HBV, 8) previous treatment with interferon alfa or pegylated interferon alfa within 1 year before therapy. Serum HBV DNA levels, alanine aminotransferase (ALT) levels, and HBeAg status of the eligible patients at baseline, week 4, week 12, week 24 and week 48 of therapy were recorded. Serum HBV DNA levels had been measured by polymerase chain reaction (PCR) and <400 copy/mL was considered negative. All liver biopsy specimens prior to and after week 48 of therapy were reevaluated by a single pathologist. Histological activity index (HAI) (grade) and fibrosis (stage) were scored according to the Ishak system. Histological improvement was defined as a decrease by at least 2 points in the histological activity index, without worsening fibrosis. We compared the efficacy of ETV and TDF at week 4, week 12, week 24 and week 48 of therapy with respect
TABLE 1. Pretreatment characteristics of patients. ETV (n=24 ) 43.68.9 17 5 37.810.1 14 6 TDF (n=20 ) p-value 0.06 0.95

F Gzelbulut, AOK vn, ZA etinkaya, et al. to declines in serum HBV DNA levels from baseline, undetectable HBV DNA, normalization of serum ALT levels, and improvements in HAI and fibrosis scores. In addition, HBeAg seroconversion rates in HBeAg positive patients were evaluated following week 48 of therapy. Statistical analyses were made using SPSS (SPSS, Inc, Chicago, IL, USA) for Windows 15.0. For the evaluation of the study data, in addition to descriptive statistical methods (meanSD), the Students t-test and the Mann-Whitney U Test were used to establish potential differences between the averages of two independent groups for parameters with and without normal distributions, respectively. Variance analysis of intergroup values was performed using the Kruskal-Wallis test. The one-way ANOVA test was used for normal distribution, one-way variance analysis. Tukey/Bonferroni correction was applied to obtain the right group making the difference. Statistically significant differences were also analyzed with the Dunnett test. For comparisons of qualitative data, the chi-squared test was used. The results in the 95% confidence interval and p values <0.05 were considered to be significant. This study was carried out in accordance with the Helsinki Declaration and approved by the local ethics commitee.

Age (years)

Gender (male) BMI (kg/m )

2

ALT

HBV DNA (log copy/mL) HAI (mean)

HBeAg positivity

25.673.27 7.40 1.31 6.333.50 3.712.16

25.814.83 7.44 1.20 6.202.09 3.102.15

0.48 0.18

0.60

Week 4

TABLE 2. Changes in serum HBV DNA levels, ALT levels, and HAI and fibrosis scores during therapy. ETV (n/N) (%) TDF (n/N) (%) 4.191.87 3.621.21

Fibrosis (mean)

143.54113.87 126.16156.08

0.96

0.34

0.63

p-value 0.62

RESULTS In total, 44 Caucasian patients with a mean age of 419.8 years were included in the present study. Twenty-four patients received ETV and 20 received TDF. There were no statistically significant differences between patients who received ETV and those who received TDF in terms of age, gender, body mass index (BMI), HBeAg status, serum HBV DNA levels, ALT levels, histological activity index (HAI) and fibrosis scores at the beginning of therapy (Table 1). Declines in serum HBV DNA levels, rate of undetectable HBV DNA and normalization of serum ALT levels were similar in patients who received ETV and TDF at

ALT normalization Week 12

Undetectable HBV DNA

Decline in serum HBV DNA

2/12 (16.67) 4.331.60

ALT normalization Week 24

Undetectable HBV DNA

Decline in serum HBV DNA

5/14 (35.71)

4/19 (21.05) 4.761.31 6/20 (30)

2/13 (15.39) 11/20 (55) 5.302.05 9/18 (50)

ALT normalization Week 48

Undetectable HBV DNA

Decline in serum HBV DNA

13/18 (72.22) 13/20 (65) 6.891.22 3/6 (50) 6.241.54

6/19 (31.58)

0.68

0.73

0.76

0.30

0.27

ALT normalization Liver histology

Undetectable HBV DNA HBeAg seroconversion

Decline in serum HBV DNA

17/22 (77.27) 21/24 (87.5) 1/5 (20) 6.931.54

17/20 (85) 19/20 (95) 17/20 (85) 2.201.91

0.52 0.39

0.35

0.21

FIGURE 1. Percentage of patients who achieved undetectable serum HBV DNA through 48 weeks.

19/24 (79.17) 3.833.51

Regression of fibrosis

Histological improvement Improvement in fibrosis

Improvement in HAI

0.30 0.08

0.62

0.65

20/24 (83.3) 9/22 (40.9) 0.381.61

10/17 (58.8)

12/20 (60) 0.701.17

0.44

0.07
FIGURE 2. Mean HBV DNA levels through 48 weeks. The horizontal line represents the lower limit of detection of HBV DNA (400 copy/mL).

0.27

Entecavir versus Tenofovir week 4, week 12, week 24 and week 48 of therapy (Table 2). At week 48 of therapy, 21 out of 24 (87.5%) patients in the ETV group and 19 out of 20 (95%) patients in the TDF group achieved undetectable HBV DNA (p=0.39) (Figure 1). Serum HBV DNA levels decreased by 6.931.54log copy/mL in the ETV group and 6.891.22log copy/mL in the TDF group from baseline at week 48 of therapy (p=0.65) (Figure 2). At week 48 of therapy, serum ALT levels were normalized in 19 out of 24 (79.2%) patients in the ETV group and in 17 out of 20 (85%) patients in the TDF group (p=0.62). The mean HAI score improved by 3.833.51 points in the ETV group and 2.201.91 points in the TDF group after 48 weeks of therapy (p=0.07). Histological improvement occurred in 20 patients (83.3%) in the ETV group and in 12 patients (60%) in the TDF group (p=0.08). Mean fibrosis scores improved by 0.381.61 points in the ETV group and 0.701.17 points in the TDF group at week 48 of therapy (p=0.44). Fibrosis scores regressed in 9 out of 22 patients with fibrosis (40.9%) in the ETV group and in 10 out of 17 patients with fibrosis (58.8%) in the TDF group (p=0.27). Among the HBeAg-positive patients, all of the 6 patients in the TDF group (100%) and 2 out of the 5 patients in the ETV group (60%) achieved undetectable HBV DNA levels at week 48. HBeAg seroconversion was achieved in 1 out of 5 patients in the ETV group and in 3 out of 6 patients in the TDF group (p=0.30). Serum ALT levels were normalized in all patients except for 1 patient in the ETV group. Changes in serum HBV DNA levels, serum ALT levels and HAI and fibrosis scores during therapy are shown in Table 2. DISCUSSION The ultimate goal of therapy for CHB is to prevent life threatening complications such as cirrhosis, decompansation and HCC (2,3). It was shown that long-term therapy with LAM reduced the degree of liver fibrosis and the development of HCC (5,6). Furthermore, LAM decreased the rate of decompansation and Child-Pugh score in cirrhotic patients (6). However, developing in up to 70% of patients after 4 years of therapy, the emergence of LAM resistant mutations with long-term therapy is an important problem and results in loss of histological benefit and hepatic decompansation (5,6). In the present study, the proportions of patients who had achieved undetectable HBV DNA in ETV and TDF groups were 87.5% and 95%, respectively. Although a higher proportion of patients who had received TDF achieved undetectable HBV DNA than did those who had received ETV, the difference was not statistically significant. The mean reductions in HBV DNA from baseline with ETV and TDF were similar. In phase 3 studies evaluating the efficacy of ETV as compared to lamivudin, 67% of patients with HBeAg-positive CHB and 90% of those with HBeAg-negative CHB achieved undetectable HBV DNA after 1-year of therapy (11,12). In a recently published meta-analysis, ETV was shown to be superior to ADV in HBeAg-positive CHB with respect to undetectable serum HBV DNA and ALT normalization (17). In another phase 3 study, undetectable HBV DNA was achieved in 76% of patients with HBeAg-positive CHB and in 93% of those with HBeAg-negative patients after 48 weeks of TDF therapy and TDF was superior to ADV (13). Improvements in mean fibrosis scores and the proportion of patients who achieved regression of fibrosis were

Hepato-Gastroenterology 59 (2012) similar in the ETV and TDF groups in our study. On the other hand, improvements in mean HAI scores and proportion of patients who achieved histological improvement were greater in the ETV group than in the TDF group, although the differences were not statistically significant. These similar results may be due to the fact that both drugs suppressed HBV DNA effectively in a similar manner. However, it should be noted that the mean time between the beginning of therapy and the second biopsy was longer in the ETV group than in the TDF group. In phase 3 studies, ETV therapy resulted in a higher rate of histological improvement than lamivudin did, probably as a result of a higher rate of undetectable HBV DNA with ETV than with LAM (11,12). The superiority of ETV over LAM in terms of histological improvement and improvement in fibrosis scores was also demonstrated in patients with advanced fibrosis/cirrhosis in other studies (18,19). Moreover, long-term ETV therapy resulted in histological improvement and regression of fibrosis in 96% and 88% of patients, respectively (20). In the studies by Schiff et al. and Chang et al., all the patients were negative for HBV DNA at the time of second biopsy supporting that maintenance of HBV DNA suppression is necessary for histological improvement (19,20). However, histological improvement was similar in TDF and ADV groups at week 48, despite the superior efficacy of TDF with respect to virological and biochemical responses (13). Because the emergence of antiviral resistance is associated with loss of histological benefit and hepatic decompansation, the ideal drug should have a high genetic barrier conferring with low antiviral resistance (5,6). Maintenance of HBV DNA suppression is important for reducing the risk of development of a resistant virus (21). In longterm studies evaluating the efficacies of ETV and TDF, resistance to ETV was rare in nucleoside naive patients, whereas none of the patients developed resistance to TDF (14-16). But it should be kept in mind that emtricitabine was added to TDF therapy following week 48. Compatible with the previous studies, none of the patients in both groups experienced virological breakthrough and developed antiviral resistance through 48 weeks in our study. In a recently published study, ETV and TDF showed similar efficacy in decompansated HBV related cirrhosis. Approximately 70% of patients who received either ETV or TDF achieved undetectable HBV DNA (22). However, there is no study comparing the efficacy of these drugs in compansated CHB especially with high viral load and/or high fibrosis scores to date. In conclusion, both ETV and TDF are effective for CHB with respect to HBV DNA suppression, ALT normalization, and regression of histological activity index and fibrosis scores through 48 weeks of therapy. Resistance did not develope in patients who had received either ETV or TDF. Both ETV and TDF seem to be similarly effective in patients with compansated CHB. However, the number of patients was not very large in our study. There is a need for further randomized studies in large patient populations.

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ACKNOWLEDGEMENTS Abstract of this study was presented as poster presentation in Digestive Disease Week 2011, 7-10 May 2011, Chicago, IL, USA.

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