Saudi Journal of Gastroenterology
Home About us Instructions Submission Subscribe Advertise Contact Login    Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
Users Online: 1892 


 
Table of Contents   
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 22  |  Issue : 1  |  Page : 37-42
Antiviral efficacy of entecavir versus entecavir plus adefovir for hepatitis B virus rtA181V/T mutants alone


1 Department of Internal Medicine, CHA University School of Medicine, CHA Gumi Medical Center, Gumi, South Korea
2 Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, South Korea

Click here for correspondence address and email

Date of Submission19-Mar-2015
Date of Acceptance12-Jun-2015
Date of Web Publication12-Jan-2016
 

   Abstract 

Background/Aims: Hepatitis B virus (HBV) rtA181V/T mutants developed by long-term nucleos(t) ide analogue therapy are known to present cross-resistance for other nucleos (t) ide analogues, except entecavir (ETV). Some studies reported that HBV rtA181V/T mutants could induce cross-resistance to ETV and showed incomplete response as well as persistence of HBV DNA, despite rescue therapy by ETV. This study aimed to investigate the antiviral efficacy of ETV monotherapy and ETV plus adefovir (ADV) as rescue therapy for HBV rtA181V/T single mutation. Patients and Methods: A total of 30 patients who received ETV alone (1.0 mg/day, n = 16) or ETV plus ADV (10.0 mg/day, n = 14) over 48 weeks between April 2008 and October 2011 were enrolled. Virological, biochemical, and serological response at 48 weeks of rescue therapy were investigated retrospectively. Results: No significant difference in baseline characteristics was observed between the ETV group and the ETV plus ADV group. Virological response showed complete response (62.5 vs. 42.9%), partial response (6.3 vs. 28.6%), non-response (25.0 vs. 28.6%), and virological breakthrough (6.3 vs. 0%) in the two groups, respectively. Virological response did not statistically differ between both groups (P = 0.278). No significant difference in the mean reduction of serum HBV DNA and biochemical response was observed between both groups (4.3 ± 2.9 vs. 4.1 ± 1.8 log 10 IU/ml; P = 0.294 and 88.9 vs. 100%; P = 1.000, respectively). In addition, no significant difference in HBeAg loss or seroconversion was observed between the two groups (26.7 vs. 28.6%; P = 1.000). Conclusions: ETV monotherapy and ETV plus ADV therapy were clinically effective and comparable as rescue therapy for HBV rtA181V/T mutants alone.

Keywords: Adefovir, entecavir, hepatitis B virus, rescue therapy, rtA181V/T mutants

How to cite this article:
Oh MJ, Lee HJ. Antiviral efficacy of entecavir versus entecavir plus adefovir for hepatitis B virus rtA181V/T mutants alone. Saudi J Gastroenterol 2016;22:37-42

How to cite this URL:
Oh MJ, Lee HJ. Antiviral efficacy of entecavir versus entecavir plus adefovir for hepatitis B virus rtA181V/T mutants alone. Saudi J Gastroenterol [serial online] 2016 [cited 2019 Nov 15];22:37-42. Available from: http://www.saudijgastro.com/text.asp?2016/22/1/37/173757


Treatment of hepatitis B virus (HBV) infection has improved significantly due to development of nucleos (t) ide analogues (NA), including lamivudine (LMV), adefovir (ADV), telbivudine (LdT), clevudine (CLV), entecavir (ETV), and tenofovir (TDF). [1],[2],[3] Durable suppression of serum HBV DNA through NA therapy can prevent progression of serious HBV-related liver diseases such as cirrhosis and hepatocellular carcinoma. [4],[5] However, treatment of HBV infection with NA has a fatal weakness in that NA cannot remove covalently closed circular DNA in the nucleus of infected hepatocytes and the rate of virological relapse is high when NA therapy is discontinued. [6] Consequently, an indefinite therapeutic duration is essential in NA therapy for chronic hepatitis B. Prolonged treatment with NA inevitably results in development of drug resistance mutation, although it is rare in ETV or TDF therapy. [7],[8]

Of NA-related HBV mutants, HBV rtA181V/T mutants develop as a result of mutation of the HBV reverse transcriptase gene at position 181, where an alanine (A) is substituted with a valine (V) or threonine (T). HBV rtA181V/T mutants have been reported in chronic hepatitis B patients who received antiviral treatment with LMV, ADV, LdT, or CLV, and have been known to present cross-resistance against other NA, except ETV. [9],[10],[11] Thus, ETV with high susceptibility in vitro has been used primarily as rescue therapy for HBV rtA181V/T mutants. [12] However, some studies reported that HBV rtA181V/T mutants could even induce cross-resistance to ETV. [13],[14] In practice, a clinical investigation reported that HBV rtA181V/T mutants might present persistence of HBV DNA and showed an association with incomplete response, despite rescue therapy by ETV. [15]

In general, the majority of HBV rtA181V/T mutants are known to be induced after ADV therapy, along with the rtN236T mutant. Many guidelines published in Korea, the United States, and Europe recommend ETV plus TDF (or ADV if TDF is unavailable) as rescue therapy for HBV rtA181V/T mutants. [1],[2],[3] However, there is no specific therapeutic recommendation or clinical study on HBV rtA181V/T single mutation. Thus, antiviral therapy should be determined to support the decision on which rescue therapy, add-on therapy with ETV or switch to ETV monotherapy, is to be applied in patients who received prior ADV therapy for HBV rtA181V/T mutants alone. In other words, the aim of this study is to investigate the antiviral efficacy of ETV alone and in combination with ADV for HBV rtA181V/T single mutation.


   Patients and Methods Top


Study subjects

This research was conducted as a retrospective cohort study. Sequencing analysis of the HBV reverse transcriptase genome was performed in 797 adult patients (≥18 years in age) with virological breakthrough during antiviral therapy for chronic hepatitis B, from April 2008 to October 2011. Among the 797 patients, mutations of the HBV reverse transcriptase genome were detected in 557 patients. Of the 557 patients, HBV rtA181T/V mutants were found in 136 patients. Of these, a total of 30 patients who received ETV (1.0 mg/day) monotherapy or ETV plus ADV (10.0 mg/day) therapy over 48 weeks as rescue therapy against HBV rtA181V/T mutants only without other concomitant mutations were enrolled in this study. The enrolled subjects were divided into the ETV group (n = 16) and the ETV plus ADV group (n = 14) [Figure 1].
Figure 1: Flow chart of the enrolled patients

Click here to view


The study was conducted according to the principles of the Declaration of Helsinki of 1975. All patients submitted their written informed consent prior to enrollment in the study. Details of this study were approved by the Institutional Review Board of Yeungnam University Hospital (YUH-13-0319-O9).

Study assessments

Serum HBV DNA levels, alanine aminotransferase (ALT) levels, and the status of HBeAg at baseline and at 48 weeks of rescue therapy for HBV rtA181V/T mutants were investigated through review of medical records. Assessments of virological, biochemical, and serological responses as well as reduction of serum HBV DNA were performed at 48 weeks. In addition, reduction of serum HBV DNA was analyzed at week 24 of rescue therapy in order to investigate the trend of change. Sequencing analysis of the HBV reverse transcriptase polymerase gene was performed using polymerase chain reaction (PCR) and direct sequencing of HBV isolated from all individuals [Applied Biosystems (ABI) 3730 DNA Analyzer; Applied Biosystems, Foster City, CA, USA]. The HBV DNA load was tested using a commercially available quantitative real-time PCR assay (Cobas Taqman HBV-DNA Test; Roche Diagnostics Systems, Pleasanton, CA, USA) with a linear dynamic detection range of 20-1.7 × 10 8 IU/ml. Serological markers, including HBsAg, HBeAg, and anti-HBe, were determined using routine commercially available enzyme immunoassays (Architect i2000SR; Abbott Diagnostics, Abbott Park, IL, USA). Serum ALT, albumin, total bilirubin, platelet levels, and prothrombin time were measured using standard laboratory procedures.

Definitions

Virological responses to NA therapy were divided into complete virological response, partial virological response, non-response, and virological breakthrough, according to the guidelines of the Korean Association for the Study of the Liver for treatment of chronic hepatitis B. [3] Complete virological response was defined as HBV DNA undetectable by quantitative real-time PCR at 48 weeks of rescue therapy (serum HBV DNA level <20 IU/ml). Partial virological response was defined as a decrease of HBV DNA of ≥2 log 10 IU/ml, but detected by real-time PCR assay. Virological breakthrough was defined as rebound of HBV DNA greater than 1 log 10 IU/ml, compared to the on-treatment nadir (the lowest value). Non-response was defined as a decrease in HBV DNA of <2 log 10 IU/ml at 48 weeks of rescue therapy. Biochemical response was defined as normalization of serum ALT level. The upper limit of normal ALT was defined as 40 IU/l. Serological response was defined as HBeAg loss or seroconversion. Liver cirrhosis was defined by means of histologic, clinical, or radiologic modalities. Clinical diagnosis of liver cirrhosis included lower platelet level (<1.4 × 10 5 cell/μl) with splenomegaly, existence of ascites or varices, or hepatic encephalopathy.

Evaluation of antiviral efficacy

The primary endpoint was virological response after 48 weeks of rescue therapy. The secondary endpoints included reduction of serum HBV DNA, normalization of serum ALT levels, HBeAg loss or seroconversion, and complications, including mortality and morbidity, after 48 weeks of rescue treatment.

Statistical analysis

Categorical data or frequency data were presented as absolute values and percentages, whereas continuous variables were summarized as mean ± standard deviation (SD) or median including range. Between-group comparisons were performed using the Mann-Whitney U test for continuous variables, and the Chi-square test or Fisher's exact test for categorized variables, as appropriate. A two-sided P value of less than 0.05 was considered statistically significant. Microsoft Excel 2007 (Microsoft Corp., Redmond, WA, USA) was used for organization of all data, and PASW statistics version 18.0 for Windows (SPSS Inc., Chicago, IL, USA) was used in performance of data analysis.


   Results Top


The baseline characteristics of the ETV group and the ETV plus ADV group are shown in [Table 1]. Most parameters of demographic and laboratory characteristics, including age; gender; cirrhosis; Child-Pugh class; serum ALT, total bilirubin, albumin, and platelet level; prothrombin time; and the rates of HBeAg positivity, did not differ significantly between the two groups (P > 0.05). Baseline serum HBV DNA levels in the ETV and ETV plus ADV groups were 4.8 ± 1.7 log 10 IU/ml and 4.1 ± 1.8 log 10 IU/ml, respectively (P = 0.193). Previous history of NA therapy prior to rescue therapy with ETV monotherapy or combination therapy of ETV plus ADV was analyzed. Of the enrolled total patients, 14 patients had no experience of ADV therapy (14/30, 46.7%). The 14 patients had received prior LMV monotherapy (n = 6), CLV monotherapy (n = 6), and sequential therapy with CLV after LMV therapy (n = 2). The ADV-experienced patients in the ETV group and the ETV plus ADV group numbered 6 and 10, respectively. Statistically, there was no difference in experience of ADV therapy (P = 0.081). Duration of prior antiviral therapy in the ETV plus ADV group was relatively longer compared with the ETV group (307.1 ± 180.8 vs. 188.6 ± 157.3 weeks); however, no statistical difference was observed (P = 0.064).
Table 1: Baseline characteristics of patients


Click here to view


Data on the mean changes in serum HBV DNA at 24 weeks and 48 weeks are shown in [Figure 2] and [Table 2]. The mean reduction of serum HBV DNA at 24 weeks did not differ significantly between the ETV group (4.0 ± 3.4 log 10 IU/ml) and the ETV plus ADV group (3.7 ± 2.5 log 10 IU/ml) (P = 0.400). In addition, no statistical difference in the mean decline of serum HBV DNA at 48 weeks was observed between the two groups (4.3 ± 2.8 vs. 4.1 ± 1.8 log 10 IU/ml; P = 0.294).
Figure 2: Comparison of the mean reduction of serum HBV DNA at 24 weeks and 48 weeks between ETV monotherapy and ETV plus ADV therapy

Click here to view
Table 2: Summary of efficacy measures after rescue therapy


Click here to view


Virological response at 48 weeks of rescue therapy showed complete virological response (62.5 vs. 42.9%), partial virological response (6.3 vs. 28.6%), non-response (25.0 vs. 28.6%), and virological breakthrough (6.3 vs. 0%) in the ETV group and the ETV plus ADV group, respectively. No significant difference in virological response was observed between the two groups (P = 0.278).

At baseline, serum ALT levels over the upper limit of normal were detected in nine patients and four patients in the ETV group and the ETV plus ADV group, respectively. Normalization of serum ALT level occurred after 48 weeks of rescue therapy in eight patients (8/9, 88.9%) in the ETV group and four patients (4/4, 100%) in the ETV plus ADV group. Biochemical response did not differ significantly between the two groups (P = 1.000).

Among the patients who were HBeAg-positive at baseline, 26.7% (4/15) in the ETV group and 28.6% (4/14) in the ETV plus ADV group achieved HBeAg loss at 48 weeks. No significant difference was observed in the rates of HBeAg loss (P = 1.000). In addition, the rates of HBeAg seroconversion at 48 weeks did not differ statistically between the two groups (13.3 vs. 28.6%; P = 0.401). There was no occurrence of complications, including mortality and morbidity, related to HBV with rtA181T/V mutants during the 48 weeks of rescue therapy. In addition, newly developed hepatocellular carcinoma was not observed among these subjects.


   Discussion Top


Development of NA with a high genetic barrier, such as ETV and TDF, has revolutionized our ideas regarding treatment of HBV. The optimal therapeutic goal or complete suppression of HBV DNA can be achieved in many CHB patients through ETV or TDF therapy. However, NA used prior to the introduction of ETV or TDF can hardly be free from the problem of development of drug resistance related to long-term medication. Above all, the emergence of cross-resistance or multidrug resistance of HBV can be more problematic due to sequential monotherapy for treatment of chronic hepatitis B. [11],[16],[17] Cross-resistance of HBV, including HBV rtA181V/T mutants, can result in development of serious liver-related diseases such as hepatic failure or progression to liver disease. [11],[15],[18],[19] HBV rtA181V/T mutants are more important in practice because a single mutation can confer multidrug resistance against the L-nucleoside LMV, CLV, and LdT, as well as the alkyl phosphonates ADV and TDF. [10],[11],[12] As a result, the standard of care for HBV rtA181V/T mutants has not been established and clinical evidence of optimal treatment for HBV rtA181V/T mutants is also lacking. Although many authorized guidelines have recommended the combination therapy of a nucleoside and a nucleotide analogue for multidrug resistance of HBV, the efficacy has not been confirmed in practice. [1],[2],[3] Thus, to the best of our knowledge, this research appears to be valuable as it provides rare clinical evidence of treatment of HBV rtA181V/T mutants alone.

In this study, all therapeutic responses of HBV rtA181V/T mutants alone, including decline of serum HBV DNA, virological, biochemical, and serological responses did not differ significantly between the ETV monotherapy group and the ETV plus ADV group (P > 0.05). In addition, a study on multidrug resistance of HBV reported a similar result showing that antiviral efficacy of ETV plus ADV combination therapy was not clinically superior to that of ETV monotherapy. [20]

In our study, virological breakthrough occurred in one patient belonging to the ETV monotherapy group. The patient had received CLV therapy prior to detection of the HBV rtA181V mutant. ETV alone was administered as rescue therapy for the HBV rtA181V mutant. Reduction of serum HBV DNA by more than 2 log 10 IU/ml was observed at 24 weeks. However, virological breakthrough occurred at 48 weeks. At 48 weeks, sequencing analysis for the reverse transcriptase gene of HBV was performed in order to detect the cause of the virological breakthrough. Newly developed HBV rtM204I and rtP237H mutants were detected, and the pre-existing HBV rtA181V mutant disappeared completely through rescue therapy. The patient received ETV plus TDF combination therapy after the introduction of TDF in Korea, and partial virological response has been shown. Although liver failure or serious complications related to HBV did not happen, occurrence of virological breakthrough by ETV monotherapy might be problematic. The appearance of mutations other than HBV rtA181V/T mutants in this case may be associated with sequential antiviral monotherapy, as mentioned above, and is a problem to be solved before agreement on use of ETV monotherapy for HBV rtA181V/T mutants.

In our study, the mean duration of previous antiviral therapy prior to rescue therapy was longer in patients of the ETV plus ADV group. The reason may be associated with the fact that physicians are concerned about the increased risk of development of drug resistance to HBV according to therapeutic duration. [2] Therefore, there was a high probability of intentional selection of ADV combination therapy. However, no statistically significant difference in therapeutic results was observed between the methods of rescue therapy. In addition, although there was no statistical significance, more ADV-experienced patients were recruited in the ETV plus ADV group. It seemed that more add-on therapy with ETV was intentionally selected in the patients who received prior ADV therapy.

Response to antiviral therapy differed according to genotype. [21] A recent study reported that drug susceptibility of HBV rtA181V/T mutants was different, and the difference might be explained by a difference in HBV genotypes. [12] In addition, an investigation conducted in China reported that the genotype-dependent polymorphism feature of HBV reverse transcriptase sequences in treatment-naïve chronic hepatitis B patients would be an important basis for understanding evolution of NA resistance. [22] As a result, the antiviral efficacy of ETV or ETV plus ADV as rescue therapy for HBV rtA181V/T mutants may be related to the genotypes of HBV. However, the genotypes of HBV in most Korean patients were known to be genotype C2; therefore, in this study, HBV genotypes of the enrolled patients were not investigated. [23] Consequently, there is a limitation to application of our results for other genotypes of HBV, except for the predominant genotype C in Korea. Clinical researches for rescue therapy for HBV rtA181V/T mutants should be performed considering the discrepancy in genotypes of HBV.

There were some limitations in this study. This research was conducted retrospectively, with an insufficient number of subjects. Thus, there might be a limitation of selection bias. In addition, the duration of rescue therapy was relatively short term. The outcomes can change through a longer follow-up period. After rescue therapy for rtA181V/T mutants alone, newly developed mutants or disappearance of HBV rtA181V/T mutants were not evaluated in total. Finally, TDF, which is known to be a potent HBV inhibitor with a higher barrier to resistance, has recently been used in Korea. [24],[25] As a substitute of ADV, antiviral efficacy of TDF for HBV rtA181V/T mutants is still unclear in practice. Further investigation of rescue therapy, including TDF, for HBV rtA181V/T mutants alone will be necessary.


   Conclusion Top


In conclusion, findings of this study demonstrated that ETV monotherapy and ETV plus ADV therapy were clinically effective and comparable as rescue therapy for HBV rtA181V/T mutants alone. However, occurrence of virological breakthrough by ETV monotherapy may be problematic. Large-scale, long-term studies of rescue therapy for HBV rtA181V/T mutants alone should be conducted, and therapeutic plans for achievement of further antiviral efficacy for HBV rtA181V/T mutants alone should be established and recommended.

 
   References Top

1.
Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50:661-2.  Back to cited text no. 1
    
2.
European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.  Back to cited text no. 2
    
3.
Korean Association for the Study of the Liver. KASL clinical practice guidelines: Management of chronic hepatitis B. Clin Mol Hepatol 2012;18:109-62.  Back to cited text no. 3
    
4.
Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al. Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-86.  Back to cited text no. 4
    
5.
Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65-73.  Back to cited text no. 5
    
6.
Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32:803-6.  Back to cited text no. 6
    
7.
Si Ahmed SN, Zoulim F. Pathobiology of HBV mutants and clinical impact for treatment monitoring. Expert Rev Anti Infect Ther 2009;7:309-20.  Back to cited text no. 7
    
8.
Song ZL, Cui YJ, Zheng WP, Teng DH, Zheng H. Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos (t) ide analogues. World J Gastroenterol 2012;18:7149-57.  Back to cited text no. 8
    
9.
Locarnini S. Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure. Hepatol Int 2008;2:147-51.  Back to cited text no. 9
    
10.
Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rtA181T/sW172FNx01 mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology 2008;48:88-98.  Back to cited text no. 10
    
11.
Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos (t) ide analogues. Gastroenterology 2009;137:1593-608. e1-2.  Back to cited text no. 11
    
12.
Villet S, Pichoud C, Billioud G, Barraud L, Durantel S, Trépo C, et al. Impact of hepatitis B virus rtA181V/T mutants on hepatitis B treatment failure. J Hepatol 2008;48:747-55.  Back to cited text no. 12
    
13.
Qi X, Xiong S, Yang H, Miller M, Delaney WE 4 th . In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther 2007;12:355-62.  Back to cited text no. 13
    
14.
Heo NY, Lim YS, Lee HC, Chung YH, Lee YS, Suh DJ. Lamivudine plus adefovir or entecavir for patients with chronic hepatitis B resistant to lamivudine and adefovir. J Hepatol 2010;53:449-54.  Back to cited text no. 14
    
15.
Fung SK, Andreone P, Han SH, Rajender Reddy K, Regev A, Keeffe EB, et al. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol 2005;43:937-43.  Back to cited text no. 15
    
16.
Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44:283-90.  Back to cited text no. 16
    
17.
Yim HJ, Hussain M, Liu Y, Wong SN, Fung SK, Lok AS. Evolution of multi-drug resistant hepatitis B virus during sequential therapy. Hepatology 2006;44:703-12.  Back to cited text no. 17
    
18.
Borroto-Esoda K, Miller MD, Arterburn S. Pooled analysis of amino acid changes in the HBV polymerase in patients from four major adefovir dipivoxil clinical trials. J Hepatol 2007;47:492-8.  Back to cited text no. 18
    
19.
Gaia S, Barbon V, Smedile A, Olivero A, Carenzi S, Lagget M, et al. Lamivudine-resistant chronic hepatitis B: An observational study on adefovir in monotherapy or in combination with lamivudine. J Hepatol 2008;48:540-7.  Back to cited text no. 19
    
20.
Park MS, Kim BK, Kim KS, Kim JK, Kim SU, Park JY, et al. Antiviral efficacies of currently available rescue therapies for multidrug-resistant chronic hepatitis B. Clin Mol Hepatol 2013;19:29-35.  Back to cited text no. 20
    
21.
Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008;359:1486-500.  Back to cited text no. 21
    
22.
Liu BM, Li T, Xu J, Li XG, Dong JP, Yan P, et al. Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-naive Chinese patients. Antiviral Res 2010;85:512-9.  Back to cited text no. 22
    
23.
Kim H, Jee YM, Song BC, Hyun JW, Mun HS, Kim HJ, et al. Analysis of hepatitis B virus quasispecies distribution in a Korean chronic patient based on the full genome sequences. J Med Virol 2007;79:212-9.  Back to cited text no. 23
    
24.
Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442-55.  Back to cited text no. 24
    
25.
Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011;140:132-43.  Back to cited text no. 25
    

Top
Correspondence Address:
Prof. Heon Ju Lee
Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchungro, Nam-gu, Daegu - 705-717
South Korea
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.173757

Rights and Permissions


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
  
 
  Search
 
  
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
   Patients and Methods
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed1531    
    Printed23    
    Emailed0    
    PDF Downloaded250    
    Comments [Add]    

Recommend this journal