Gastroenterol Res
Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access
Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc
Journal website http://www.gastrores.org

Original Article

Volume 11, Number 2, April 2018, pages 138-144


Efficacy and Safety of Entecavir 0. 5 mg in Treating Naive Chronic Hepatitis B Virus Patients in Egypt: Five Years of Real Life Experience

Sahar Maklada, e, Ehab Mahfouz Reyadb, Emad Adel Williamc, Alaa Abouzeidd

aDepartment of Internal Medicine, Hepatology and Gastroenterology, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
bDepartment of Clinical Pathology, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
cDepartment of Internal Medicine, National Research Center, Cairo, Egypt
dDepartment of Public Health, Faculty of Medicine Cairo University, Cairo, Egypt
eCorresponding Author: Sahar Maklad, Department of Internal Medicine, Hepatology and Gastroenterology, National Hepatology and Tropical Medicine Research Institute (NHTMRI), 1st of Lebanon Square, Mohandessin, 12411 Cairo, Egypt

Manuscript submitted January 12, 2018, accepted March 6, 2018
Short title: Entecavir in Treating Naive Chronic HBV
doi: https://doi.org/10.14740/gr965w

Abstract▴Top 

Background: The aim of the study was to evaluate the efficacy and safety of entecavir (ETV) among chronic hepatitis B (CHB) nucleos(t)ide-naive Egyptian patients.

Methods: Forty-eight CHB patients on ETV were included. Males comprised 83.3% (40 cases), while females comprised 16.7% (eight cases). Minimum age was 19 years, while maximum age was 64 years. Hepatitis B envelope antigen (HBeAg)-negative cases were 60.4%. HBeAg-positive cases were 39.6%. Factors including sex, positive HBeAg, baseline hepatitis B virus (HBV) DNA level, baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were evaluated in terms of their predictive role in treatment response, which was defined as a serum HBV DNA decrease of < 10 IU/mL.

Results: Mean age of patients was 38.2 years; males were 83.3% and females were 16.7%. HBeAg-negative cases were 60.4%, while HBeAg-positive cases were 39.6%. Mean baseline DNA level was 44 × 106 IU/mL. Ultrasound results showed 14 cases had hepatomegaly, 10 cases had bright liver, seven cases had coarse liver, and eight cases had cirrhosis. Of the cases, 45.8% showed a negative PCR after the first 6 months of therapy to reach 64.6% by the end of the first year. HBV DNA undetectability reached 91.3% and 100% after 4 and 5 years, respectively for those who completed the study period. ALT reduction started after 6 months of treatment and reached 53.37% after 5 years. Similarly AST showed the same pattern of decline and reached 54.37% after 5 years. Only two cases achieved HBeAg seroconversion. Three patients experienced virological breakthrough and the three cases shared similar characteristics of being less than 40 years, with baseline HBV DNA of ≥ 105 IU/mL and positive HBeAg. None of the cases showed hepatitis B surface antigen (HBsAg) seroconversion.

Conclusion: ETV proved to have a potent antiviral efficacy and safety in nucleoside/tide-naive Egyptian patients. Rate of HBV DNA undetectability was higher in patients above 40 years of age and in patients who initially had a low viral load. ETV was well tolerated during the treatment period with a good overall safety profile.

Keywords: Hepatitis B; Entecavir; Egypt

Introduction▴Top 

The prevalence of chronic hepatitis B virus (HBV) infection is approximately 800,000 to 1.4 million people in the United States and 350 million worldwide. Serious morbidity occurs in approximately 15-25% of people with chronic HBV infection, including liver damage or liver failure, cirrhosis, or liver cancer, and HBV causes approximately 620,000 deaths annually worldwide [1]. Viral replication is now recognized as the key driver of liver injury and disease progression, and thus the primary aim of treatment for chronic HBV infection is long-term suppression of HBV replication to undetectable levels [2, 3]. Therefore, the goal of therapy for chronic hepatitis B (CHB) patients is to delay or prevent progression of liver disease by suppressing long-term HBV DNA replication [4]. Antiviral drugs available for HBV treatment include interferon-alpha (INF-α) and nucleos(t)ide analogue (NA) polymerase inhibitors (lamivudine (LAM), adefovir, entecavir (ETV), telbivudine and tenofovir). Treatments include individualized single-agent or combination therapies. Evidence-based medicine has demonstrated that effective antiviral treatment of CHB reduced the risk of long-term complications and improved patient survival [4, 5]. LAM was the first nucleoside analog inhibitor to be approved for treatment of CHB infection and has been used widely in the treatment of CHB patients. However, a major shortcoming of LAM-based therapies is the development of drug-resistant strains that develop with increasing frequency with treatment duration [6]. The rate of LAM resistance is 24% after 1 year and approximately 70% after 5 years. Furthermore, LAM resistance leads to the attenuation of HBV suppression and even causes hepatitis flare ups, hepatic decompensation and increased mortality rates, thereby posing a serious clinical challenge [7].

ETV is a cyclopentyl guanosine analogue, and a potent and selective inhibitor of HBV replication in vitro [8]; its efficacy has been demonstrated in both patients with Hepatitis B envelope antigen (HBeAg)-positive and patients with HBeAg-negative chronic HBV infection. Treatment with the potent antiviral agent like ETV for periods ranging from 48 weeks to 3 years has shown superior virologic, histologic, and biochemical outcomes in nucleoside-naive patients, with minimal emergence of resistance [9]. Compared with LAM, 1 year of treatment with ETV 0.5 mg daily in nucleoside-naive patients with HBeAg-positive or HBeAg-negative chronic HBV infection was associated with significantly improved liver histology and virologic and biochemical endpoints [10].

Although proven international efficacy, yet efficacy and safety profile of widespread use of ETV (Baraclude 0.5 mg, BMS) was not evaluated in Egypt. The study aimed at evaluating the efficacy and safety of ETV among CHB nucleos(t)ide-naive Egyptian patients.

Patients and Methods▴Top 

The study evaluated 48 nucleoside-naive chronic HBV patients who were treated with ETV 0.5 mg (Baraclude 0.5 mg, Bristol Myers Squibb, BMS) monotherapy for a period of 1 - 5 years. Recruited patients were selected from patients regularly attending a specialized HBV outpatient clinic on twice weekly basis at National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo. Recruitment started in June 2009 and ended in June 2014. The medication was given to the patients as part of their routine medical care they are given at the clinic with no sponsorship whatsoever from the producing pharmaceutical company. A pre-designed pretested sheet was used to record clinical information from each recruited patient. Part of the data was obtained from patients’ files, which included all pre-enrolment data collected before the recruitment of patients. Other data were actively collected from each recruited patient during the follow-up visits. Basic data such as age, sex, and residency were recorded. All patients were over 18 years of age, positive for hepatitis B surface antigen (HBsAg) for at least 6 months, showing persistent elevation of transaminases for 6 months and both HBeAg-positive and HBeAg-negative patients were included. Exclusion criteria included co-infection with hepatitis C, D viruses, evidence of liver decompensation or hepatocellular carcinoma, history of alcohol or drug abuse within 1 year prior to enrollment in the study, other possible causes of chronic liver damage, or previous treatment for CHB. Females who were planning for pregnancy or nursing were also excluded. The study protocol conformed to the ethical guidelines and was approved by the Research Ethics Committee of the General Organization for Teaching Hospitals and Institutes, Cairo. Among 60 naive patients treated with ETV 0.5 mg/day, 12 were excluded because of poor compliance to treatment or interrupted treatment courses. A total of 48 patients were eligible for this analysis. All patients were subjected to pre-enrolment investigations in the form of HBsAg, HBeAg, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, complete blood picture (CBC), alpha-fetoprotein (AFP) testing, serum creatinine, serum albumin, hepatitis C virus antibody (HCV Ab) testing, hepatitis delta antibody testing, quantitative HBV-DNA assays and abdominal ultrasound. The diagnosis of cirrhosis was based on ultrasound examinations.

All patients were educated individually about the nature of the disease, the treatment regimen and the importance of adhering to the medication. Also were instructed that the drug should be administered on an empty stomach (at least 2 h before or after a meal and 2 h before the next meal).

The patients were monitored on a monthly basis to supply the medication, follow-up on the treatment compliance and to ensure there were no complications or side effects. Every 3 months, our patients were subjected to investigations for ALT, AST, total bilirubin, CBC and serum creatinine and every 6 months to HBeAg, hepatitis B envelope antibody (HBeAb), ALT, AST, total bilirubin, CBC, AFP, serum creatinine in addition to quantitative HBV-DNA testing and abdominal ultrasound. All patients were subjected to HBsAg and hepatitis B surface antibody (HBsAb) testing annually during treatment. The patients were carefully examined at each follow-up visit and asked to report any incidence of adverse events.

Statistical methods

Statistical Package for Social Science (SPSS) program version 17.0 was used for data analysis. Mean and standard deviation (SD) and median and interquartile range (IQR) were estimates of quantitative data while frequency and percentage were estimates of qualitative data. Student’s t-test was used to compare the responses over time.

Results▴Top 

The study included 48 patients, where males comprised 83.3% (40 cases) and females comprised 16.7% (eight cases). The mean age of our patients was 38.2 years, where the minimum age was 19 years and the maximum age was 64 years. HBeAg-negative cases were 26 (60.4%), while HBeAg-positive cases were 19 (39.6%) (Table 1).

Table 1.
Click to view
Table 1. Patients and Ultrasound Results
 

Ultrasound results showed that 14 cases (29.2%) had hepatomegaly, 10 cases (20.8%) had bright liver, seven cases (14.6%) had coarse liver, and eight cases (16.7%) had liver cirrhosis (Table 1).

The mean starting ALT level is 98.5 (32 - 385), while the mean for AST is 68.3 (21 - 239) (Table 2).

Table 2.
Click to view
Table 2. Percent Change in Levels of ALT, AST and Serum Creatinine Over Study Period as Compared to Baselines Among Study Subjects
 

Results proved that HBV DNA undetectability started from the first 6 months of treatment, where 22 cases showed a negative PCR after the first 6 months of therapy. Nine more cases had a negative PCR after 1 year of treatment to be a total of 31 cases out of 48 (64.6%) by the end of the first year. HBV DNA undetectability reached 91.3% and 100% after 4 and 5 years, respectively (Table 3).

Table 3.
Click to view
Table 3. Relation of Age Group to Different Parameters at Different Intervals of Study Period
 

ALT showed 43.2% reduction on average comparing its level from baseline to 6 months and 48.14% reduction after 1 year of treatment from baseline and reached 53.37% after 5 years. AST showed 36.15% reduction on average comparing its level from baseline to 6 months and 44.57% reduction after 1 year of treatment from baseline and reached 54.37% after 5 years of continuous (Table 4).

Table 4.
Click to view
Table 4. ALT and AST Change Reduction Over Study Period
 

Only two cases (4.16%) out of 19 cases (39.6%) managed to achieve HBeAg seroconversion. The first case achieved seroconversion after 36 months of treatment. The second case achieved seroconversion at 12 months of treatment.

Three patients (6.25%) experienced virological breakthrough and the three cases shared similar characteristics of being less than 40 years of age, with a starting HBV DNA of ≥ 105 IU/mL and positive HBeAg.

Serum creatinine levels showed an increase by 41.85% on average after 1 year of treatment versus 34.07% after 5 years of treatment and both results showed statistical significance (Table 5).

Table 5.
Click to view
Table 5. Serum Creatinine Levels Showed an Increase by 41.85% on Average After 1 Year of Treatment Versus 34.07% After 5 Years of Treatment
 

Table 3 shows the correlation between age (classified as below or above 40 years of age) and different parameters as HBV DNA, ALT levels and serum creatinine. HBV DNA levels were found significantly less in those above 40 years of age. This finding was found statistically significant at baseline and at 24 months of therapy. None of our cases cleared HBsAg during their treatment course.

Discussion▴Top 

The present cohort study represents to our knowledge the first study to assess the efficacy and safety of ETV among Egyptian patients. Egypt although classified by the World Health Organization (WHO) to be an area of intermediate prevalence of 4-8%, yet CHB is still considered a major health problem due to the long duration of treatment, associated co-morbidities and the potential high cost of therapy. HBV chronically infects more than 400 million people worldwide. Major breakthroughs have been achieved in diagnosis and treatment of this virus [9, 11]. Ultimately, the treatment for CHB aims to suppress HBV replication, relieve inflammation, prevent fibrosis and hepatocellular carcinoma (HCC), and increase the survival rate [12, 13]. However, chronic HBV infection is not completely eradicated due to persistence of covalently closed circular DNA (cccDNA) of nucleus in the infected hepatocytes, and this can result in HBV reactivation [14-16]. So it is important to decrease and maintain serum HBV DNA level to the undetectable level as the actual purpose of treatment for CHB [17-19]. ETV is a cyclopentyl guanosine analogue that undergoes intracellular phosphorylation to its active 5-triphosphate metabolite. This form competes with the natural substrate deoxyguanosine triphosohate to inhibit HBV DNA polymerase, which is essential for viral replication. Hence, the drug is considered a potent and selective inhibitor of HBV replication in vitro [20]. The rates of histologic improvement, virologic response, and normalization of ALT levels were significantly higher with ETV than with LAM and adefovir dipivoxil (ADV) [21]. ETV is considered effective in the suppression of HBV replication, inducing HBeAg seroclearance, and reduces cirrhosis and HCC development [22].

ETV in general has a good safety profile and tolerability [23]. Most of our patients did not experience serious adverse event during the study time while receiving ETV treatment. Only few reports on mild dizziness, transient abdominal discomfort at the beginning of the treatment course. None of our patients stopped medication because of adverse events. One patient 31 years old experienced the development of multiple pancreatic cysts, which were not preceded by acute pancreatitis, ERCP maneuver or any other related cofactors. The patient experienced reaccumilation of the cysts after drainage and repeated cytology examinations proved no malignancy. No direct correlation with the drug could be proved. Very few reports in literature were found regarding the association of ETV with acute pancreatitis. Kim and colleagues stated the possibility of adverse drug reactions (ADRs) related to ETV therapy in patients with advanced cirrhosis including lactic acidosis, myalgia, neuropathy, azotemia, hypophosphatemia, muscular weakness, and pancreatitis, as well as immune-mediated responses [24]. Moreover, in another study, a possible role of antiretroviral therapy with ETV was suggested in cases with hyperlipidemic pancreatitis [25].

In our study, all patients were fulfilling the criteria of eligibility to treatment with HBV DNA > 2,000 with successive persistent elevation of transaminases. According to EASL practice guidelines 2012, a liver biopsy is not required in patients with clinical evidence of cirrhosis or in those in whom treatment is indicated irrespective of the grade of activity or the stage of fibrosis.

Abdominal ultrasound was repeatedly done every 6 months during our treatment course but results were almost the same with no significant change observed.

ETV treatment was associated with significant improvement in the biochemical profile of the patients during the study period. ALT showed 43.2% reduction on average comparing its level from baseline to 6 months and 48.14% reduction after 1 year of treatment from baseline and reached 53.37% after 5 years. Similarly AST levels showed significant reduction, which reached 54.37% after 5 years of continuous treatment. Shin and colleagues in 2015 found similar results in their study that detected that ETV improves liver function and also non-invasive fibrosis markers in patients with HBV-associated cirrhosis [26].

ETV as a potent and safe agent leading to continuous viral suppression proved to be safe and well tolerated therapy [27]. Our results also showed that HBV DNA undetectability started from the first 6 months of treatment, where 22 cases showed a negative PCR after the first 6 months of therapy. Nine more cases had a negative PCR after 1 year of treatment to be a total of 31 cases by the end of the first year.

One of the aims of the study was to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion. Only two cases (4.16%) managed to achieve HBeAg seroconversion. The first case had a starting PCR of 95 × 103 IU/mL and achieved early HBV DNA undetectability after the first 3 months of treatment and HBeAg seroconversion at 36 months of treatment. The second case had a higher starting PCR of 20 × 106 IU/mL, and achieved both HBV DNA undetectability and HBeAg seroconversion after 12 months of treatment. None of the cases who failed to clear HBV DNA after 1 year of treatment achieved HBeAg seroconversion. Similarly, in an earlier study prolonged ETV therapy was not found very effective in achieving HBeAg seroconversion in treatment-naive CHB patients with a partial virological response. In their study partial virological response was defined as detectable HBV DNA (> 116 copies/mL) at year one [28]. The two cases received consolidation treatment for 1 year after confirming HBeAg seroconversion on two different occasions 3 months apart.

The high potency of ETV is mainly attributed to its structural formula and mechanism of action which requires the occurrence of both LAM mutations and a specific “signature” ETV mutation, therefore, ETV is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients [29]. In our study, three patients (6.25%) experienced virological breakthrough and the three cases shared similar characteristics of being less than 40 years of age, with a starting HBV DNA of ≥ 105 IU/mL and HBeAg-positive virological breakthrough started after 2 years of continuous treatment in one case and after 3 years in two cases. Tenofovir was only launched in Egypt in 2012 so for the first two cases, ADV 10 mg was added to ongoing ETV 0.5 mg and the third case received tenofovir disoproxil fumarate (TDF) 300 mg.

These data support the conclusion that ETV 0.5 mg naive patients leads to potent suppression of HBV DNA, normalization of ALT, long-term ETV therapy for up to 5 years in our study was generally well tolerated, including those with cirrhosis at baseline. Substantially patients demonstrated biochemical improvement regarding normalization of both ALT and AST levels after few months of treatment and during long-term follow-up. The safety profile, potent suppression of HBV replication, and low potential for antiviral drug resistance in nucleoside-naive patients make long-term treatment of CHB with ETV monotherapy is greatly favored if compared to other lines of treatment. Closer follow-up of is required in HBeAg-positive cases with high baseline levels.

Abbreviations

HBV: hepatitis B virus; HCC: hepatocellular carcinoma; CHB: chronic hepatitis B; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NA: nucleos(t)ide analogue; LAM: lamivudine; ADV: adefovir dipivoxil; ETV: entecavir; CBC: complete blood picture; cccDNA: covalently closed circular DNA; TDF: tenofovir disoproxil fumarate; BMS: Bristol-Myers Squibb; NHTMRI: National Hepatology and Tropical Medicine Research Institute


References▴Top 
  1. Cao GW. Clinical relevance and public health significance of hepatitis B virus genomic variations. World J Gastroenterol. 2009;15(46):5761-5769.
    doi pubmed
  2. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65-73.
    doi pubmed
  3. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, Risk Evaluation of Viral Load E, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130(3):678-686.
    doi pubmed
  4. Pawlotsky JM, Dusheiko G, Hatzakis A, Lau D, Lau G, Liang TJ, Locarnini S, et al. Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach. Gastroenterology. 2008;134(2):405-415.
    doi pubmed
  5. Zhang QQ, An X, Liu YH, Li SY, Zhong Q, Wang J, Hu HD, et al. Long-term nucleos(t)ide analogues therapy for adults with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis. Virol J. 2011;8:72.
    doi pubmed
  6. Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, Brown N, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36(6):687-696.
    doi pubmed
  7. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45(2):507-539.
    doi pubmed
  8. Rosmawati M, 2009. 55th Annual Meeting of the AASLD; Oct 29- Nov 2, 2004; Boston, USA. Poster 2009.
  9. Bicer KC, Ari A, Genc VE, Ozsu Caymaz S, Avci M, Bal F. Efficacy of entecavir treatment among chronic hepatitis B nucleos(t)ide-naive and -experienced patients. Turk J Med Sci. 2015;45(1):99-104.
    doi pubmed
  10. Choi HN, Song JE, Lee HC, Jo HH, Lee CH, Kim BS. Efficacy of prolonged entecavir monotherapy in treatment-naive chronic hepatitis B patients exhibiting a partial virologic response to entecavir. Clin Mol Hepatol. 2015;21(1):24-31.
    doi pubmed
  11. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. 2003;362(9401):2089-2094.
    doi
  12. European Association for the Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-185.
    doi pubmed
  13. Korean Association for the Study of the Liver. KASL Clinical Practice Guidelines: Management of chronic hepatitis B. Clin Mol Hepatol. 2012;18(2):109-162.
    doi pubmed
  14. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxi A, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008;49(4):652-657.
    doi pubmed
  15. Brechot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, Tiollais P. State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases. Proc Natl Acad Sci U S A. 1981;78(6):3906-3910.
    doi pubmed
  16. Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Brechot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely "occult"? Hepatology. 2001;34(1):194-203.
    doi pubmed
  17. Liaw YF. Hepatitis B virus replication and liver disease progression: the impact of antiviral therapy. Antivir Ther. 2006;11(6):669-679.
    pubmed
  18. Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003;37(6):1309-1319.
    doi pubmed
  19. Yuan HJ, Yuen MF, Ka-Ho Wong D, Sablon E, Lai CL. The relationship between HBV-DNA levels and cirrhosis-related complications in Chinese with chronic hepatitis B. J Viral Hepat. 2005;12(4):373-379.
    doi pubmed
  20. Ke W, Liu L, Zhang C, Ye X, Gao Y, Zhou S, Yang Y. Comparison of efficacy and safety of tenofovir and entecavir in chronic hepatitis B virus infection: a systematic review and meta-analysis. PLoS One. 2014;9(6):e98865.
    doi pubmed
  21. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354(10):1001-1010.
    doi pubmed
  22. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354(10):1011-1020.
    doi pubmed
  23. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008;2(3):263-283.
    doi pubmed
  24. Kim JT, Jeong HW, Choi KH, Yoon TY, Sung N, Choi YK, Kim EH, et al. Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B. World J Gastroenterol. 2014;20(42):15931-15936.
    doi pubmed
  25. Durval A, Zamidei L, Bettocchi D, Luzzio MG, Consales G. Hyperlipidemic acute pancreatitis: a possible role of antiretroviral therapy with entecavir. Minerva Anestesiol. 2011;77(10):1018-1021.
    pubmed
  26. Shin SK, Kim JH, Park H, Kwon OS, Lee HJ, Yeon JE, Byun KS, et al. Improvement of liver function and non-invasive fibrosis markers in hepatitis B virus-associated cirrhosis: 2 years of entecavir treatment. J Gastroenterol Hepatol. 2015;30(12):1775-1781.
    doi pubmed
  27. Celen MK, Dal T, Ayaz C, Bayan K, Mert D, Devecil O, Oruc EK. Four-year study of entecavir efficacy and safety in nucleos(t)ide-naive HBeAg positive chronic hepatitis B patients. Acta Clin Croat. 2014;53(1):31-36.
    pubmed
  28. Lee HW, Kwon JC, Oh IS, Chang HY, Cha YJ, Choi IS, Kim HJ. Prolonged Entecavir therapy is not effective for HBeAg Seroconversion in treatment-naive chronic hepatitis B patients with a partial virological response. Antimicrob Agents Chemother. 2015;59(9):5348-5356.
    doi
  29. Cheng PN, Chang TT. Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients. Expert Rev Anti Infect Ther. 2008;6(5):569-579.
    doi pubmed


This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Gastroenterology Research is published by Elmer Press Inc.

 
Home     |     Log In     |      About     |      Search     |      Current     |      Archives     |      Submit      |     Subscribe


 

     

Aims and Scope

Current Issues

Conflict of Interest

About Publisher

Editorial Board

Archives

Copyright

Company Profile

Editorial Office

Misconduct and Retraction

Permissions

Company Registration

Contact Us

Abstracting and Indexing

ICMJE

Ownership

Instructions to Authors

Access

Declaration of Helsinki

Contact Publisher

Submission Checklist

Reprints

Terms of Use

Company Address

Submit a Manuscript

Open Access Policy

Privacy Policy

Browse Journals

Publishing Fee

Publishing Policy

Disclaimer

Recent Highlights

Peer-Review Process

Publishing Quality

Code of Ethics

Advertising Policy

Manuscript Tracking

Advanced Search

For Librarians

Careers

Publishing Process

Publication Frequency

For Reviewers

Propose a New Journal

       
       

Gastroenterology Research, bimonthly, ISSN 1918-2805 (print), 1918-2813 (online), published by Elmer Press Inc.     
The content of this site is intended for health care professionals.

This is an open-access journal distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons Attribution license (Attribution-NonCommercial 4.0 International CC-BY-NC 4.0)


This journal follows the International Committee of Medical Journal Editors (ICMJE) recommendations for manuscripts submitted to biomedical journals,
the Committee on Publication Ethics (COPE) guidelines, and the Principles of Transparency and Best Practice in Scholarly Publishing.

website: www.gastrores.org   editorial contact: editor@gastrores.org
Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada

© Elmer Press Inc. All Rights Reserved.

DECLARATION: THIS JOURNAL SITE OUTLOOK IS DESIGNED BY THE PUBLISHER AND COPYRIGHT PROTECTED. DO NOT COPY!