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World J Hepatol. Oct 8, 2015; 7(22): 2404-2410
Published online Oct 8, 2015. doi: 10.4254/wjh.v7.i22.2404
Benefits of nucleos(t)ide analog treatments for hepatitis B virus-related cirrhosis
Koichi Honda, Masataka Seike, Kazunari Murakami, Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu-City, Oita 879-5593, Japan
Author contributions: Honda K, Seike M and Murakami K designed the review aricle; Honda K wrote the manuscript; Seike M and Murakami K revised the manuscript.
Conflict-of-interest statement: We declare that we have no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Koichi Honda, MD, PhD, Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-City, Oita 879-5593, Japan. hondak@oita-u.ac.jp
Telephone: +81-97-5866193 Fax: +81-97-5866194
Received: April 27, 2015
Peer-review started: May 4, 2015
First decision: July 17, 2015
Revised: August 2, 2015
Accepted: September 7, 2015
Article in press: September 8, 2015
Published online: October 8, 2015

Abstract

Chronic hepatitis B infection induces progressive liver disease. Before nucleos(t)ide analogs (NUCs) became established as a safe and effective treatment for hepatitis B, it was difficult to suppress the activity of the hepatitis B virus (HBV). Currently, many patients with hepatitis or cirrhosis associated with HBV are treated with NUCs for an extended period of time, and the effects, benefits, and limitations of these treatments have been apparent. This article reviews HBV-related cirrhosis, its natural course and survival, histological improvement after NUC treatments, treatment effects for decompensated cirrhosis, the incidence of hepatocellular carcinoma (HCC) after NUC treatments, and the efficacy of NUC treatments before and after the treatment of patients for HBV-related HCC. Of particular interest are the histological improvements, including regression of fibrosis, that have been achieved with NUC treatments. Liver function of patients with decompensated cirrhosis has significantly improved regardless of the type of NUC applied, and treatment with NUCs has reduced the incidence of HCC in cirrhotic patients. However, cirrhosis remains the strongest risk factor for HCC occurrence following NUC treatments, and the long-term cumulative incidence of HCC after NUC treatments remains high. When recurrence does occur, it is important to reconsider the treatment modality according to the degree of improved liver function that was achieved.

Key Words: Hepatitis B, Nucleos(t)ide analogue, Liver cirrhosis, Lamivudine, Entecavir

Core tip: We presented the benefits of nucleos(t)ide analogs (NUCs) treatments for HBV-related cirrhosis in this article. NUC treatments have been found to improve inflammation and fibrosis in the liver of cirrhotic patients. Moreover, even in patients with decompensated cirrhosis, liver function has improved in many cases. Furthermore, although NUC treatments can reduce the incidence of hepatocellular carcinoma (HCC), rates of HCC remain high in patients with cirrhosis. NUC treatments have been found to improve liver function and the survival of patients with HCC. Improved liver function was also achieved by providing NUC treatments for hepatitis B virus-related HCC when recurrent tumors developed. Therefore, it is important to select the most appropriate treatment method considering the alterations in liver function that may occur following NUC treatments.
INTRODUCTION

An estimated 400 million people worldwide are chronically infected with hepatitis B virus (HBV)[1]. Chronic hepatitis B infection induces a progressive liver disease that can lead to cirrhosis and hepatocellular carcinoma (HCC)[2]. Prior to establishing the antiviral drug, lamivudine, as an effective treatment for hepatitis B[3], it was difficult to prevent disease progression. Lamivudine was the first nucleos(t)ide analog (NUC) to be extensively characterized and it inhibits DNA synthesis. Subsequently, it has been found to rapidly reduce serum levels of HBV and to reduce inflammation in the liver[3]. Moreover, several NUCs, including adefovir dipivoxil, telbivudine, entecavir, and tenofovir disoproxil fumarate, have been developed. Initially, the indication of these drugs was limited to patients with chronic hepatitis or compensated cirrhosis, although they have gradually been applied to the treatment of decompensated cirrhosis. In this review article, we describe the effects, benefits, and limitations of using NUCs to treat cirrhotic patients.

NATURAL COURSE OF HBV INFECTION AND CIRRHOSIS IN PATIENTS

Several studies have documented the natural history of chronic hepatitis B prior to the availability of NUCs (Table 1). For example, Weissberg et al[4] studied 379 histologically confirmed chronic hepatitis B patients and reported the following estimated 5-year survival rates: 97% for chronic persistent patients, 86% for chronic active hepatitis patients, and 55% for chronic active hepatitis patients with cirrhosis. Liaw et al[5] also reported the natural history of chronic HBV infection following the recent development of histologically confirmed cirrhosis in a cohort of 76 patients. The annual incidences of hepatic decompensation and HCC development were calculated to be 2.3% and 2.8%, respectively. Furthermore, Liaw et al[5] estimated the 5-year survival rate to be 80%. de Jongh et al[6] conducted a follow-up study of 98 hepatitis B surface antigen - positive cirrhosis patients with histopathologically confirmed cirrhosis. The reported survival probability was 71% after 5 years. For the 21 patients with decompensated cirrhosis, the survival probability was only 14%. Consistent with these previous studies, Realdi et al[7] found that the 5-year survival rate for 366 patients with histologically confirmed cirrhosis was 84%. With the exception of the study by Liaw et al[5], these studies analyzed the factors affect their prognosis using multivariate analysis: Patient age, total bilirubin levels, albumin levels, platelet counts, hepatitis B e antigen (HBeAg) positivity, ascites, spider nevi, and splenomegaly were reported as significant prognostic factors. Patient age and total bilirubin were the factors that were included in each of the studies. Overall, the 5-year survival rates for HBV-related cirrhosis reported in these studies ranged from 55% to 84%, which may be due to differences in lead time bias, study design, country, ethnicity, HBV genotype, and/or HBeAg positivity.

Table 1 Studies characterizing the natural history of hepatitis B-related cirrhosis.
Ref.Publication yearCountryNumber of patients with cirrhosis5-yr survival for patients with compensated cirrhosis (%)Cause of death
Weissberg et al[4]1984United States13055Liver failure (70.3%)
Unrelated disease (18.9%)
Unknown causes (10.8%)
Liaw et al[5]1989Taiwan7680Hepatic failure or variceal bleeding (100%)
de Jongh et al[6]1992The Netherlands9871Hepatocellular carcinoma (38.5%)
Liver failure or fatal upper gastrointestinal bleeding (38.5%)
Unrelated disease (23.1%)
Realdi et al[7]1994Italy36684Liver failure (53.6%)
Hepatocellular carcinoma (27.4%)
Unrelated disease (19.0%)
HISTOLOGICAL IMPROVEMENT IN PATIENTS WITH CIRRHOSIS

Histologically, fibrosis has improved with long-term treatment with NUCs[8-17]. In early studies, lamivudine was administered for a short period of time (e.g., 6-12 mo)[3,8,9]. In 52%-95% of patients that received lamivudine treatment for at least one year, an improvement in necroinflammatory activity was observed [which was defined as at least a 2-point decrease in the histologic activity index (HAI) score][3,9-11]. In contrast, the rate of hepatic fibrosis improvement (defined as at least a 1-point decrease in the HAI fibrosis score) associated with short-term lamivudine treatments were not as high[3,9] and ranged from < 10% to 35%. Since then, long-term use of NUCs has led to improvements in liver fibrosis, even in cases of advanced fibrosis or cirrhosis[11,13,14]. For example, Chang et al[13] followed 57 hepatitis B patients that were treated with entecavir for 3-7 years (median, 6 years) and underwent repeated histological examinations. Improved Ishak fibrosis scores (≥ a 1-point decrease) were reported for 88% of these patients. In addition, four patients with cirrhosis also demonstrated an improvement in their Ishak fibrosis scores (median decrease: 3 points, range: 1-4). Table 2 summarizes the primary studies that have described histological changes after an initial NUC treatment. Dienstag et al[11] reported that fibrosis improved (defined as a decrease in the HAI fibrosis score of at least 1-point) in 45.5% of patients treated with lamivudine (n = 11) after 1 year, and this rate increased to 72.7% after an additional 2 years of treatment. Marcellin et al[14] reported that 51% of patients with hepatitis B that were treated with tenofovir (n = 348) showed improvement in fibrosis (defined as a decreased in the Ishak fibrosis score of at least 1-point). In addition, fibrosis improved in 74% of patients with cirrhosis (n = 97) at 5 years. Taken together, these results demonstrate that long-term treatment with NUCs can potentially lead to histological improvements in patients with cirrhosis.

Table 2 Rates of fibrosis improvement in patients with chronic hepatitis or cirrhosis treated with lamivudine, entecavir, or tenofovir.
Ref.Publication yearNucleos(t)ideNo. of patientsTreatment durationCirrhosis percentageImprovement ratio of fibrosis
Honkoop et al[8]1997LAM (25 mg, 100 mg, 300 mg)136 moNot describedNo difference in fibrosis was observed
Lai et al[3]1998LAM (25 mg, 100 mg, placebo)35852 wk5%25 mg (n = 72) 5%14
100 mg (n = 142) 2.5%14
Placebo (n = 143) 0%14
Suzuki et al[9]1999LAM (100 mg)2052 wk0%All patients (n = 20) 35%1
Dienstag et al[10]2003LAM (100 mg, placebo)631 yr + additional 2 yr17%Bridging fibrosis (HAI fibrosis score of 3; n = 19)
63% (1 yr + additional 2 yr)2
Cirrhosis (HAI fibrosis score of 4; n = 11) 45.5% (1 yr)2; 72.7% (1 yr + additional 2 yr)2
Schiff et al[12]2008LAM (100 mg)24548 wkNot described5ETV (n = 120) HBeAg+ 57%3
Entecavir (0.5 mg)HBeAg- 59%3
LAM (n = 125)
HBeAg+ 49%3
HBeAg- 53%3
Chang et al[13]2010ETV (0.5 mg)5748 wk, long-term (range: 3-7 yr, median: 6 yr)7%All patients (n = 57) 32% (48 wk)3
88% (long-term)3
Cirrhosis (n = 4)
100% (long-term)3
Marcellin et al[14]2012TDF3485 yr28%All patients (n = 348)
51% (5 yr)3
Cirrhosis (n = 97) 74% (5 yr)3
1Fibrosis improvement was defined as an HAI fibrosis score decrease of at least 1-point;
2Bridging fibrosis improvement was defined as achieving an HAI fibrosis score of 0 or 1. Cirrhosis improvement was defined as achieving an HAI fibrosis score of 0, 1, or 3;
3Fibrosis improvement was defined as a decrease in the Ishak fibrosis score of at least 1-point;
4Approximate value estimated from the published graph;
5All patients had advanced fibrosis or cirrhosis (Ishak fibrosis scores of 4-6). LAM: Lamibudine; ETV: Entecavir; TDF: Tenofovir; HBeAg: Hepatitis B e antigen; HAI: Histologic activity index.
NUC TREATMENT FOR DECOMPENSATED CIRRHOSIS

Once lamivudine treatment was established as an effective and safe drug for the treatment of chronic hepatitis B or compensated cirrhosis[3,10], it was gradually applied to the treatment of decompensated cirrhosis[18-30]. The 1-year, 3-year, and 5-year survival probabilities for patients with decompensated cirrhosis without NUC treatment were: 70%-71%[6,31], 35%-40%[6,31] and 14%-35%[6,31,32], respectively. These survival rates increased dramatically following the use of NUC treatments to: 70%-94%, 63%-87%, and 55%-86%, respectively[18,23,26,29] (Table 3). The liver function of the latter patients also significantly improved regardless of the type of NUC administered[18-30]. In addition, NUC treatment led to a reduction in the Child-Pugh class or a decrease in the Child-Pugh score (≥ 2-points or ≥ 3-points decrease), in a substantial number of cases[18-28,30]. However, there were a small number of patients that were treated with NUCs who progressed to death or required a liver transplant[18-30]. Studies that analyzed the determinants of early mortality in patients with decompensated cirrhosis B treated with NUCs found that poor baseline liver function was associated with poor prognosis[23,26,30]. Furthermore, most of the deaths occurred within 1 year after NUC treatment, and the most common causes of death were liver failure or complications from liver failure[23,26,30]. In work by Hyun et al[26], Child-Turcotte-Pugh scores at baseline and the Model for End-stage Liver Disease score at 3 mo after beginning a NUC treatment were found to be significant predictors of early mortality.

Table 3 Effects of treatment with nucleos(t)ide analogs in patients with decompensated cirrhosis.
Ref.Nucleos(t)idePatient numberTreatment durationImprovement ratio of Child-Pugh scoreCumulative survival rate3
Villeneuve et al[18]LAM (100 mg or 150 mg)35 (CPB: 10, CPC: 25)Mean: 19 mo62.9% (22/35)11 yr: 78%4
2 yr: 63%4
Kapoor et al[19]LAM (150 mg)18 (CPB: 14, CPC: 4)Mean: 17.9 mo (range: 9-31 mo)CPB to CPA: 50% (4/14)No deaths attributed to liver disease
CBC to CPB: 50% (2/4)
Yao et al[20]LAM (150 mg)13 (CPB: 0, CPC: 13)Mean: 17.5 mo (range: 3-39 mo)69% (9/13)2Not described
Hann et al[22]LAM (100 mg)75 (CPA: 4, CPB: 28, CPB: 43)Mean: 12.7 mo (range: 0.5-33 mo)31% (23/75)1Not described
Tseng et al[23]LAM (100 mg)30 (CPB: 16, CPC: 14)Mean: 39.7 mo (range: 3-128 mo)CPB to CPA: 62.5% (10/16)1 yr 70%4
CBC to CPB: 35.7% (5/14)2 yr 66%4
3 yr 55%4
5 yr 55%4
Bae et al[24]LAM (100 mg)17 (CPB: 12, CPC: 5)Mean: 28 mo (range: 14-42 mo)CPB to CPA: 83% (10/12)Not described
CBC to CPB (1/5) or CPA (3/5): 80% (4/5)
Shim et al[25]ETV (0.5 mg)55 (mean CP score 8.1 ± 1.7)12 mo49% (27/55)112 mo: 87.1%
24 mo: 83.0%
Hyun et al[26]LAM (100 mg)86 (CPB: 45, CPC: 41)Mean: 2 yrMean Child-Pugh score1 yr
ETV (0.5 mg)BaselineLAM: 92.4%
LAM: 9.5, ETV: 9.6ETV: 90.7%
12 mo3 yr
LAM: 6.7, ETV: 6.6LAM: 86%4
ETV: 76%4
Liaw et al[27]TDF (300 mg)/FTC (200 mg) + TDV (300 mg)/ETV (0.5 mg or 1 mg)112 (median CP score: 7, range: 6-9)48 wkTDF: 25.9% (7/27)1Not described
FTC/TDF: 48.0% (12/25)1
ETV: 41.7% (5/12)1
Chan et al[29]LAM (100 mg), TdT (600 mg)228 (CPS < 7: 18, CPS 7-9: 155, CPS 9 <: 55)52-104 wk52 wk52 wk
LAM: 38.6% (44/114), TdT: 31.6% (36/114)1LAM: 88%, TdT: 94%
104 wk104 wk
LAM: 40.4% (46/114 ), TdT: 38.6% (44/114)1LAM: 79%, TdT: 87%
1Improvement of Child-Pugh score was defined as a decrease in the CPS greater than or equal to 2-points;
2Improvement of Child-Pugh score was defined as a decrease in the CPS greater than or equal to 3-points;
3Cumulative survival rates calculated by Kaplan-Meier method;
4Approximate value from the published graph. LAM: Lamibudine; ETV: Entecavir; TDF: Tenofovir; FTC: Emtricitabine; TdT: Telbivudine; CPB: Child-Pugh class B; CBC: Child-Pugh class C; CPS: Child Pugh score; CPA: Child-Pugh class A.
INCIDENCE OF HCC IN PATIENTS WITH CIRRHOSIS THAT RECEIVED NUC TREATMENT

Worldwide, HBV infection has been identified as an important risk factor for the development of HCC[31]. Longitudinal studies of patients with chronic hepatitis B infection have described the cumulative incidence of HCC[5,31-35]. Incidence of HCC has been found to vary by region and is influenced by the underlying stage or condition of the liver disease present. For patients with compensated cirrhosis that were not treated with NUCs, the annual incidence of HCC has been reported to range from 2.2%-2.8%[5,31,36,37]. In a comparison of cumulative HCC incidence for patients with and without lamivudine treatment, the former had a significantly lower incidence than the latter in a randomized study[38]. Non-randomized studies have also demonstrated that NUCs reduce the incidence of HCC[39-41]. Furthermore, in three meta-analyses[42-44] and a systematic review[45], NUC treatments were found to consistently reduce the risk of HCC compared with an absence of NUC treatment. In addition, two Asian studies reported that entecavir-treated patients had a reduced risk of HCC compared with treatment-naïve patients with cirrhosis[40,46], and Wong et al[46] reported that the 5-year cumulative probability of HCC development among cirrhotic patients was 13.8% in an entecavir cohort vs 26.4% in a control treatment-naïve cohort (P = 0.036). Hosaka et al[40] conducted a propensity score-matched control study and found that the cumulative 5-year incidence of HCC among cirrhotic patients treated with entecavir (7.0%) was lower than that of a control non-treated group (38.9%) (P < 0.001). Furthermore, the entecavir-treated group had a significantly lower incidence of HCC than a lamivudine-treated group of cirrhotic patients (P = 0.043)[40]. Liver cirrhosis has been found to be the strongest risk factor for the occurrence of HCC after NUC treatment[40,47,48], and the long-term cumulative incidence of HCC after NUC treatment remains high in cirrhotic patients[40,45,46].

EFFICACY OF NUC TREATMENTS FOR PATIENTS WITH HBV-RELATED HCC

Several studies have documented that antiviral therapy with NUCs is beneficial after the treatment of HBV-related HCC[49-52]. For example, improved liver function has been observed following curative liver resection and following radiofrequency ablation for the treatment of HCC[48-50]. Moreover, in a longitudinal randomized clinical trial conducted by Yin et al[49] to evaluate the effects of NUC treatments following radical hepatectomy, patients who received NUCs exhibited significantly improved liver function and decreased HCC recurrence. NUC treatment following curative therapy for HCC has also improved overall survival[49-52]. In a study by Kuzuya et al[50], NUC treatment improved liver function in patients with recurrent HCC, and allowed all of the treated patients to be eligible for curative treatment for recurrent HCC. In contrast, two-thirds of the untreated group were not eligible for curative therapy for recurrent HCC due to deterioration of remnant liver function[50]. Furthermore, an increasing number of treatment options have become available for recurrent tumors[53,54]. We previously reported that a patient with decompensated cirrhosis was able to undergo a right hepatectomy four years after starting a lamivudine treatment regimen[54].

CONCLUSION

Here, the benefits of NUC treatments for patients with HBV-related cirrhosis have been presented. NUC treatments have been found to improve inflammation and fibrosis in the liver of cirrhotic patients. Moreover, even in patients with decompensated cirrhosis, liver function has improved in many cases. Given that hepatitis B can occasionally lead to death, or the need for a liver transplant, in patients with highly deteriorated liver function even after NUC treatment, it is recommended that a NUC treatment be started as early as possible. Furthermore, although NUC treatments can reduce the incidence of HCC, rates of HCC remain high in patients with cirrhosis. However, NUC treatments have been found to improve liver function and the survival of patients with HCC. Improved liver function was also achieved by providing NUC treatments for HBV-related HCC when recurrent tumors developed. Therefore, it is important to select the most appropriate treatment method considering the alterations in liver function that may occur following NUC treatments.

Footnotes

P- Reviewer: Bakulin IG S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ

References
1.  Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. 2003;362:2089-2094.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 595]  [Cited by in F6Publishing: 582]  [Article Influence: 27.7]  [Reference Citation Analysis (0)]
2.  Park BK, Park YN, Ahn SH, Lee KS, Chon CY, Moon YM, Park C, Han KH. Long-term outcome of chronic hepatitis B based on histological grade and stage. J Gastroenterol Hepatol. 2007;22:383-388.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 61]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
3.  Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339:61-68.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1346]  [Cited by in F6Publishing: 1288]  [Article Influence: 49.5]  [Reference Citation Analysis (0)]
4.  Weissberg JI, Andres LL, Smith CI, Weick S, Nichols JE, Garcia G, Robinson WS, Merigan TC, Gregory PB. Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med. 1984;101:613-616.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 194]  [Cited by in F6Publishing: 198]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
5.  Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver. 1989;9:235-241.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology. 1992;103:1630-1635.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Realdi G, Fattovich G, Hadziyannis S, Schalm SW, Almasio P, Sanchez-Tapias J, Christensen E, Giustina G, Noventa F. Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol. 1994;21:656-666.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 207]  [Cited by in F6Publishing: 213]  [Article Influence: 7.1]  [Reference Citation Analysis (0)]
8.  Honkoop P, de Man RA, Zondervan PE, Schalm SW. Histological improvement in patients with chronic hepatitis B virus infection treated with lamivudine. Liver. 1997;17:103-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 50]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
9.  Suzuki Y, Kumada H, Ikeda K, Chayama K, Arase Y, Saitoh S, Tsubota A, Kobayashi M, Koike M, Ogawa N. Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection. J Hepatol. 1999;30:743-748.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 106]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
10.  Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1020]  [Cited by in F6Publishing: 1066]  [Article Influence: 42.6]  [Reference Citation Analysis (0)]
11.  Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, Gardner S, Gray DF, Schiff ER. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105-117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 573]  [Cited by in F6Publishing: 549]  [Article Influence: 26.1]  [Reference Citation Analysis (0)]
12.  Schiff E, Simsek H, Lee WM, Chao YC, Sette H, Janssen HL, Han SH, Goodman Z, Yang J, Brett-Smith H. Efficacy and safety of entecavir in patients with chronic hepatitis B and advanced hepatic fibrosis or cirrhosis. Am J Gastroenterol. 2008;103:2776-2783.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 91]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
13.  Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886-893.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 721]  [Cited by in F6Publishing: 717]  [Article Influence: 51.2]  [Reference Citation Analysis (0)]
14.  Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468-475.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1228]  [Cited by in F6Publishing: 1226]  [Article Influence: 111.5]  [Reference Citation Analysis (0)]
15.  Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Ma J. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743-1751.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 674]  [Cited by in F6Publishing: 639]  [Article Influence: 35.5]  [Reference Citation Analysis (0)]
16.  Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, Frederick D, Rousseau F. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48:750-758.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 247]  [Cited by in F6Publishing: 259]  [Article Influence: 16.2]  [Reference Citation Analysis (0)]
17.  Schiff ER, Lee SS, Chao YC, Kew Yoon S, Bessone F, Wu SS, Kryczka W, Lurie Y, Gadano A, Kitis G. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2011;9:274-276.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 125]  [Cited by in F6Publishing: 129]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
18.  Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology. 2000;31:207-210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 312]  [Cited by in F6Publishing: 285]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
19.  Kapoor D, Guptan RC, Wakil SM, Kazim SN, Kaul R, Agarwal SR, Raisuddin S, Hasnain SE, Sarin SK. Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2000;33:308-312.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 111]  [Cited by in F6Publishing: 121]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
20.  Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol. 2000;33:301-307.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 149]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
21.  Yao FY, Terrault NA, Freise C, Maslow L, Bass NM. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology. 2001;34:411-416.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 210]  [Cited by in F6Publishing: 214]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
22.  Hann HW, Fontana RJ, Wright T, Everson G, Baker A, Schiff ER, Riely C, Anschuetz G, Gardner SD, Brown N. A United States compassionate use study of lamivudine treatment in nontransplantation candidates with decompensated hepatitis B virus-related cirrhosis. Liver Transpl. 2003;9:49-56.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 54]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
23.  Tseng PL, Lu SN, Tung HD, Wang JH, Changchien CS, Lee CM. Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus-related decompensated liver cirrhosis. J Viral Hepat. 2005;12:386-392.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 21]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
24.  Bae SH, Yoon SK, Choi JY, Jang JW, Cho SH, Yang JM, Han NI, Ahn BM, Chung KW, Sun HS. Timing of lamivudine administration according to Child class in patients with decompensated cirrhosis. J Gastroenterol Hepatol. 2005;20:1527-1532.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 9]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
25.  Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ. Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2010;52:176-182.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 203]  [Cited by in F6Publishing: 214]  [Article Influence: 15.3]  [Reference Citation Analysis (0)]
26.  Hyun JJ, Seo YS, Yoon E, Kim TH, Kim DJ, Kang HS, Jung ES, Kim JH, An H, Kim JH. Comparison of the efficacies of lamivudine versus entecavir in patients with hepatitis B virus-related decompensated cirrhosis. Liver Int. 2012;32:656-664.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 29]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
27.  Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, Chang TT, Horban A, Wang C, Kwan P, Buti M, Prieto M, Berg T, Kitrinos K, Peschell K, Mondou E, Frederick D, Rousseau F, Schiff ER. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 235]  [Cited by in F6Publishing: 252]  [Article Influence: 19.4]  [Reference Citation Analysis (0)]
28.  Hsu YC, Mo LR, Chang CY, Perng DS, Tseng CH, Lo GH, Tai CM, Lin CW, Hsu CC, Hsu CY. Entecavir versus lamivudine in the treatment of chronic hepatitis B patients with hepatic decompensation. Antivir Ther. 2012;17:605-612.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 12]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
29.  Chan HL, Chen YC, Gane EJ, Sarin SK, Suh DJ, Piratvisuth T, Prabhakar B, Hwang SG, Choudhuri G, Safadi R. Randomized clinical trial: efficacy and safety of telbivudine and lamivudine in treatment-naïve patients with HBV-related decompensated cirrhosis. J Viral Hepat. 2012;19:732-743.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 65]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
30.  Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, Anschuetz G, Davis R, Gardner SD, Brown NA. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002;123:719-727.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Fattovich G, Pantalena M, Zagni I, Realdi G, Schalm SW, Christensen E. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol. 2002;97:2886-2895.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 239]  [Cited by in F6Publishing: 234]  [Article Influence: 10.6]  [Reference Citation Analysis (0)]
32.  Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, Christensen E, Krogsgaard K, Degos F, Carneiro de Moura M. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology. 1995;21:77-82.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264-1273.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2183]  [Cited by in F6Publishing: 2337]  [Article Influence: 194.8]  [Reference Citation Analysis (0)]
34.  Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol. 1998;28:930-938.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 316]  [Cited by in F6Publishing: 309]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
35.  Yu MW, Hsu FC, Sheen IS, Chu CM, Lin DY, Chen CJ, Liaw YF. Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers. Am J Epidemiol. 1997;145:1039-1047.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48:335-352.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 909]  [Cited by in F6Publishing: 902]  [Article Influence: 56.4]  [Reference Citation Analysis (0)]
37.  Chen YC, Chu CM, Yeh CT, Liaw YF. Natural course following the onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study. Hepatol Int. 2007;1:267-273.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 82]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
38.  Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1739]  [Cited by in F6Publishing: 1648]  [Article Influence: 82.4]  [Reference Citation Analysis (0)]
39.  Matsumoto A, Tanaka E, Rokuhara A, Kiyosawa K, Kumada H, Omata M, Okita K, Hayashi N, Okanoue T, Iino S. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients. Hepatol Res. 2005;32:173-184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 151]  [Cited by in F6Publishing: 161]  [Article Influence: 8.5]  [Reference Citation Analysis (0)]
40.  Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, Akuta N, Suzuki Y, Saitoh S, Arase Y. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98-107.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 519]  [Cited by in F6Publishing: 502]  [Article Influence: 45.6]  [Reference Citation Analysis (0)]
41.  Eun JR, Lee HJ, Kim TN, Lee KS. Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease. J Hepatol. 2010;53:118-125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 93]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
42.  Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008;28:1067-1077.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 283]  [Cited by in F6Publishing: 226]  [Article Influence: 14.1]  [Reference Citation Analysis (0)]
43.  Zhang QQ, An X, Liu YH, Li SY, Zhong Q, Wang J, Hu HD, Zhang DZ, Ren H, Hu P. 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.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 48]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
44.  Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther. 2013;38:98-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 118]  [Article Influence: 10.7]  [Reference Citation Analysis (0)]
45.  Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010;53:348-356.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 328]  [Cited by in F6Publishing: 321]  [Article Influence: 22.9]  [Reference Citation Analysis (0)]
46.  Wong GL, Chan HL, Mak CW, Lee SK, Ip ZM, Lam AT, Iu HW, Leung JM, Lai JW, Lo AO. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58:1537-1547.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 347]  [Cited by in F6Publishing: 365]  [Article Influence: 33.2]  [Reference Citation Analysis (0)]
47.  Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol. 2015;62:956-967.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 320]  [Cited by in F6Publishing: 357]  [Article Influence: 39.7]  [Reference Citation Analysis (0)]
48.  Lim YS, Han S, Heo NY, Shim JH, Lee HC, Suh DJ. Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology. 2014;147:152-161.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 114]  [Cited by in F6Publishing: 114]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
49.  Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, Guo W, Zhang H, Wang H, Cheng S. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol. 2013;31:3647-3655.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 193]  [Cited by in F6Publishing: 215]  [Article Influence: 19.5]  [Reference Citation Analysis (0)]
50.  Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M, Hayashi K, Honda T. Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma. J Gastroenterol Hepatol. 2007;22:1929-1935.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Jin YJ, Shim JH, Lee HC, Yoo DJ, Kim KM, Lim YS, Suh DJ. Suppressive effects of entecavir on hepatitis B virus and hepatocellular carcinoma. J Gastroenterol Hepatol. 2011;26:1380-1388.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 12]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
52.  Chan AC, Chok KS, Yuen WK, Chan SC, Poon RT, Lo CM, Fan ST. Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Arch Surg. 2011;146:675-681.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 94]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
53.  Nakanishi S, Michitaka K, Miyake T, Hidaka S, Yoshino I, Konishi I, Iuchi H, Horiike N, Onji M. Decompensated hepatitis B virus-related cirrhosis successfully treated with lamivudine allowing surgery for hepatocellular carcinoma. Intern Med. 2003;42:416-420.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 9]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
54.  Honda K, Seike M, Maehara S, Tahara K, Anai H, Moriuchi A, Muro T. Lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis. World J Gastroenterol. 2012;18:2586-2590.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 2]  [Cited by in F6Publishing: 4]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]