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Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2007; 13(18): 2554-2567
Published online May 14, 2007. doi: 10.3748/wjg.v13.i18.2554
Future prospectives for the management of chronic hepatitis B
WF Leemans, HLA Janssen, RA de Man
WF Leemans, HLA Janssen, RA de Man, Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
Author contributions: All authors contributed equally to the work.
Correspondence to: RA de Man, MD, PhD, Department of Gastroenterology and Hepatology, Room H 437, Erasmus MC, University Medical Center Rotterdam’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. r.deman@erasmusmc.nl
Telephone: +31-104-635942 Fax: +31-104-365916
Received: December 15, 2006
Revised: December 18, 2006
Accepted: March 8, 2007
Published online: May 14, 2007

Abstract

Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately one million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load (HBV-DNA) plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory (interferons) and antiviral suppressants (nucleoside and nucleotide analogues) all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross-resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion: chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.

Key Words: Hepatitis B virus, Cirrhosis, Treatment, Interferon, Nucleoside analogues, Nucleotide analogues, Lamivudine, Adefovir, Entecavir, Telbivudine, Tenofovir, Resistance, Genotype



INTRODUCTION

Treatment of chronic hepatitis B remains an important clinical objective. Estimates are that 2 billion people have been infected worldwide and chronic hepatitis B currently affects about 400 million people, particularly in developing countries[1]. Chronic hepatitis B is responsible 500000 to 1.2 million deaths annually from liver cirrhosis and hepatocellular carcinoma (HCC)[2]. It is one of the most common infectious diseases and among the world's leading causes of death. There are two strategies to decrease these numbers, prevention of new infections and treatment of those already chronically infected. Treatment options consist of immunomodulatory and viral suppressant drugs. In this review the current standard of care and the future developments in the field of chronic hepatitis B are discussed.

WHAT IS THE OPTIONAL TREATMENT
Naïve patients

The ideal treatment for hepatitis B is an effective cheap treatment, resulting in HBsAg loss and formation of anti-HBs, with finite treatment duration and little side effects. Currently none of the HBV treatments fulfill these conditions. With interferon based therapy HBsAg loss occurs in 3%-10% of the patients within one year of start of therapy and increases in sustained responders to 11%-32%[3-9]. HBsAg loss is rare (< 2% after one year of treatment) in patients treated with nucleos(t)ide analogues, which is about the rate observed in the natural history of the disease[10-16]. However, in a small cohort treated with tenofovir, HBsAg loss was observed in 14% of 35 patients[17]. More large size trials have to be conducted to investigate the rate of HBsAg loss for the newer nucleos(t)ide analogues or their combinations. Treatment with Interferon-α or PEG-interferon-α treatment is of finite duration and response is often durable off-treatment. However, this treatment has side effects and only a minority responds. Nucleosides/nucleotides are well tolerated and most patients respond to therapy but treatment is hampered by the selection of drug resistant mutants leading to loss of efficacy and frequent relapse after discontinuation. As none of the current registered therapies for chronic HBV is ideal, none of the drugs is regarded as the standard first-line therapy for HBV. Strategies have particularly aimed at selecting host and virus characteristics either before or during therapy to increase treatment efficacy and also withdraw ineffective treatments. The argument about the poor tolerability of interferon has been weakened by the introduction of PEG-interferon-α, which only has to be administered once a week. Furthermore it is believed PEG-interferon-α is more potent than the conventional interferons; however good comparative studies have not been performed[18]. Based on treatment outcomes, the preferable treatment shifts to interferon based therapy or nucleoside/nucleotide analogue therapy for different patient groups. In Table 1 the known predictors for response are given for both interferon-α based therapies or nucleos(t)ide analogues.

Table 1 Baseline factors influencing likelihood of response to antiviral therapy.
TreatmentIncreased likelihood of responseDecreased likelihood of response
(PEG) interferonBaseline ALT > 2 ULN[28,145,146]Baseline ALAT < 2 ULN[28,145,146]
Baseline HBV DNA < 109 c/mL[4,28]Baseline HBV DNA > 109 c/mL[4,28]
Genotype A or BGenotype C or D
Longer treatment duration[33-35,147]
Nucleoside/nucleotide analoguesBaseline serum aminotransferases > 2 ULN[148,149]Baseline serum aminotransferases < 2[148,149]
Baseline HBV DNA < 109 c/mL[148]Baseline HBV DNA > 109 c/mL[148]

Recent studies found a strong correlation between HBV DNA level and the development of liver cirrhosis and HCC. However, as none of the studies concerning natural history separately analysed the outcome in patients with prolonged normal aminotransferases the exact influence of the viral load is not known[19-21]. Interferon based therapies are generally ineffective in patients with low pre-treatment serum aminotransferase levels, and for these patients nucleoside/nucleotide treatment would be indicated. Low pre-treatment serum aminotransferases and high HBV DNA levels also decrease the likelihood of response for these agents; however, this confers to HBeAg loss/seroconversion. In theory nucleoside/nucleotide analogues are effective in lowering the viral load and thereby decreasing the risk for development of cirrhosis and HCC[22]. However, the benefit of this approach on survival is not supported by clinical trials.

For therapy of treatment naïve patients with elevated ALT levels, consensus guidelines have no preference for interferon or nucleoside/nucleotide therapy. Treatment outcomes for different therapies are provided in Table 2. Genotype proved to be an important predictor for the response to interferon-α or PEG-interferon-α therapy, especially in HBeAg positive patients. Genotype A and B show superior end of treatment responses as well as off treatment responses compared to genotypes C and D[3,4,18,23-25]. HBeAg loss occurred in 34%-36% of patients. In addition HBsAg seroconversion was observed in 13%-22% of patients with genotype A[18,26,27]. Therefore, a 48 wk course of PEG-interferon-α should be considered as first-line therapy for HBeAg positive patients with genotype A or B.

Table 2 Treatment outcomes after 1 year of treatment for different antiviral drugs for the management of chronic hepatitis B.
Author; Journal; YearHBeAgloss (%)HBeAg seroconversion(%)HBsAgloss (%)Decline viral load (log10 copies/mL)HBV DNAnegativity(%)ALT normalisation (%)Histological improvement (%)Resistance (%)
HBeAg pos
PEG-IFN-α 2aCooksley; J. Viral Hepatitis; 2003[18]353339935
PEG-IFN-α 2aLau: NEJM; 2005[4]34323122.41444149
PEG-IFN-α 2bJanssen; Lancet; 2005[3]362972.374325310
LamivudineChang; NEJM; 2006[13]201815.4362606213
LamivudineAlexander; BMC Gastroenter; 2005[150]42285610
LamivudineChan; Ann Intern Med; 2005[151]282802.7410178591140
LamivudineYao; Hepatobil Pancr Dis Int; 2004[152]108367212
LamivudineJonas; NEJM; 2002[153]2626165519
LamivudineMazur; Med Sci Monit; 2002[154]4944537856
LamivudineBarbaro; J Hepatol: 2001[155]19023271016
LamivudineDienstag; NEJM 1999[47]3217244741521032
LamivudineGane; J Hepatol; 2006[63]23215.540275568
AdefovirMarcelin; NEJM; 2003[16]24123.621448530
AdefovirLee; Hepatology; 2006[102]144.0295790
Adefovir15Zheng; Hepatology; 2006[124]13804.5282790
AdefovirBzowej; Hepatology; 2006[65]20185.7392812
EntecavirChang; NEJM; 2006[13]222126.967268720
TelbivudineGane; J Hepatol; 2006[63]26226.560277653
TelbivudineBzowej; Hepatology; 2006[65]31276.6582774
HBeAg neg
PEG-IFN-α 2aMarcellin; NEJM; 2004[5]42.31945959
LamivudineMarcellin; NEJM; 2004[5]04.273473581441
LamivudineLai; NEJM; 2006[15]04.572271616
LamivudineLai; NEJM; 199916072561014
AdefovirHadzyannis; NEJM; 2003[14]3.951472640
EntecavirLai; NEJM; 2006[15]05.090278700
Mixed
LamivudineOoga; J Gastroenterology; 2004[156]7857816
LamivudineSuzuki; Intervirology; 2003[108]4228088686
LamivudineYao; J Hepatology; 2006[64]184.343278
EntecavirYao; J Hepatology; 2006[64]155.976290

For HBeAg negative patients the distinctions are less clear. Genotype D responds less to PEG-interferon-α compared to genotypes A, B or C. Sustained ALT normalisation and a viral load < 20000 copies/mL was observed in 27%, 44%, 52% and 16%, for genotype A, B, C and D, respectively. Sustained response occurred significantly more frequently in genotypes B and C compared to genotype D. The difference in sustained response between genotype A and D was not significant, probably due to the small number of genotype A infected patients[28]. However, only patients with genotype A, treated with PEG-interferon-α for 48 wk, had a considerable chance (18%) to develop HBsAg seroconversion[27]. The long-term follow-up is not known for PEG-interferon-α. Two years of follow-up showed a decrease in response (HBV DNA < 2.0 × 104 copies/mL) from 43% after 24 wk of follow-up to 29%[29]. However, long-term follow-up studies with conventional interferon showed high relapse rates[2,5,30]. Nucleos(t)ide analogues are effective across all genotypes in both HBeAg positive and HBeAg negative patients and have proven to be a good treatment option for chronic active hepatitis B[31,32].

Retreatment of non-responders

Treatment of non-responders to previous treatment is little studied and most studies are of small size. Studies show that retreatment with conventional interferon can induce HBV DNA loss and HBeAg seroconversion; however the overall results are not conclusive (Table 3). Most of the results are difficult to interpret as the initial schedule of interferon therapy differs as well as the time to retreatment. The retreatment schedules often differ from the initial schedule, and treatment duration is often prolonged influencing treatment outcome positively[33-35]. The real benefit of interferon retreatment, especially with pegylated interferon is unclear. Nucleos(t)ide analogues appear to be effective in interferon failures, although efficacy may be different and data are limited[36]. A clinical trial using adefovir dipivoxil included 123 HBeAg positive and 48 HBeAg negative patients failing prior interferon therapy. HBeAg seroconversion rates were similar for interferon naïve and experienced patients[37]. The efficacy of the use of interferon for lamivudine failures is unclear (Tables 3 and 4). It appears interferon is effective in patients who received lamivudine, but did not develop resistance. Interferon-α therapy probably has a low efficacy in lamivudine resistant patients, but the numbers published are small[38,39].

Table 3 Response to interferon-α or PEG-interferon-α after having failed a prior course of interferon or response to interferon-α or PEG-interferon-α after having failed a prior course of lamivudine.
Author; Journal; YearTreatment regimenPretreatment HBeAg status (n)HBeAg lossHBeAg seroconversion (%)HBV DNA loss (%)ALT normalisation (%)
Janssen; J Hepatology; 1993[157]IFN 1.5 MU daily for 4 wk followed by 3 MU daily for 8 wk and then 5 MU daily for 4 wkPositive (18)1117
Carreno; Hepatology; 1999[158]IFN 9 MU thrice weekly for 24 wkPositive (27)412244522
Munoz; J Hepatology; 2002[159]IFN 6 MU 5 times weekly for 24 wkPositive (11)1818118
Munoz; J Hepatology; 2002[159]IFN 6 MU 5 times weekly for 24 wkNegative (18)22144
Ballauff; Eur J Pediatr;[160]IFN 5-9 MU/m2 thrice weekly for 16-24 wkPositive (15)33334
Teuber; Z Gastroenterol; 1995[161]Positive (27)3059
Flink; Hepatology; 2004[162]PEG-IFN-α 2b 100 μg/wk for 32 wk followed by 50 μg/wk for 20 wkPositive (18)280222
Lau; J Hepatology; 2005[163]PEG-IFN-α 2a for 48 wkPositive (30)43
Prev lamivudine
Flink; Hepatology; 2004[162]PEG-IFN-α 2b 100 μg/wk for 32 wk followed by 50 μg/wk for 20 wkPositive (8)500247
Lau; J Hepatology; 2005[163]PEG-IFN-α 2a 180 μg/wk for 48 wkPositive (31)32
Marcellin; J Hepatology; 2006[164]PEG-IFN-α 2a 90-180 μg/wk for median 48 wkPositive (71)376326473651
Marcellin; J Hepatology; 2006[164]PEG-IFN-α 2a 90-180 μg/wk for median 48 wkNegative (36)673652
Table 4 Treatment outcomes after 1 year of treatment for different antiviral drugs for the management of lamivudine resistant chronic hepatitis B for both HBeAg positive and HBeAg negative patients.
nAuthor; Journal; YrHbeAg loss (%)HBeAg serocon-version(%)HbsAg loss (%)Decline viralload (log10 copies/mL)HBV DNA negativity (%)ALT normalisation (%)Histological improvement(%)Resistance (%)
HBeAg pos
PEG-IFN-α 2b16Leemans; J Hepatology; 2006[38]131360.66419
Adefovir45Buti; Hepatology; 2004[165]13033751
Adefovir19Peters; Gastroenterology; 2004[118]16114.0265470
HBeAg neg
PEG-IFN-α 2b20Vassiliadis; WJG; 2006[39]5410
Adefovir75Buti; Hepatology; 2004[165]051763
Adefovir20Manilakopoulos; Hepatology; 2005[119]3.3725
Adefovir + lamivudine44Manilakopoulos; Hepatol; 2005[119]3.3870
Adefovir26Koskinas; J Hepatology; 2005[166]2.5924
Adefovir + lamivudine74Lampertico; Hepatology; 2005[167]786820
Adefovir + lamivudine23Koskinas; J Hepatology; 2006[166]2.8870
Adefovir + lamivudine49Vassiliadis; AP&T; 2005[168]06.557475
Mixed
Adefovir18van Bömmel; Hepatology; 2004[17]1902.8444
Adefovir + lamivudine20Peters; Gastroenterology; 2004[118]1763.6355530
Adefovir57Lee; Hepatology; 2006[102]202.41936018
Adefovir + lamivudine46Perrillo; Gastroenterology; 2004[61]15804.620130
Adefovir ± lamivudine11126Schiff; Hepatology; 2003[59]4.1814760
Adefovir + lamivudine34Moriconi; J Hepatology; 2006[169]681
Adefovir ± lamivudine65Hann; J Hepatology; 2006[132]7102.4215
Entecavir42Chang; Gastroenterology; 2005[170]1145.6264680
Entecavir141Sherman; Gastroenterology; 2006[129]10115.127261557
Entecavir42Karino; J Hepatology; 2006[171]153.860478600
Entecavir116Yao; J Hepatology; 2006[172]865.827285
Tenofovir ± lamivudine935van Bömmel; Hepatology; 2004[17]5.510040
Tenofovir ± lamivudine44Hann; J Hepatology; 2006[132]4105.0865
Tenofovir + lamivudine911Van der Eijk; J Viral Hepatitis; 2005[173]10005.091
Tenofovir910Dore; J Infect Dis; 2004[174]20104.925
Tenofovir912Núñez; Aids; 2002[175]1183.8581
Tenofovir920Nelson; Aids; 2003[176]254.0
Tenofovir912Benhamou; NEJM; 2003[177]0003.8
Cirrhotic patients

The life expectancy of patients with cirrhosis, if untreated, is greatly diminished with a 5-year survival of 84% for compensated and 14%-35% for decompensated cirrhosis[40-42]. Interferon has to be used with caution in cirrhotic patients and its use is limited to Child A cirrhosis. Interferon may be effective in compensated cirrhotics in which treatment outcomes do not differ from those without cirrhosis[6,33,35,43,44]. Adverse events, dose reductions and early discontinuation occur more frequently in cirrhotic patients[45,46]. Nucleos(t)ide analogues appear to be as effective in cirrhotics as in those without cirrhosis regardless of HBeAg status[47-49]. Lamivudine treatment in patients with advanced fibrosis or compensated cirrhosis reduced the progression of liver disease. Loss of efficacy due to resistance resulted in an increase of disease progression[50]. Entecavir treatment resulted in undetectable HBV DNA loss (LLD 300 copies/mL) in > 90%, ALT normalisation in over 60% and histological improvement in > 70% of patients with compensated cirrhosis[51].

Decompensated cirrhotic patients should be treated with nucleoside analogues as interferon-α is contra-indicated[52,53]. The timing of the initiation of therapy is essential. If the bilirubin level has risen above 3.5 mg/dL the 3 mo survival is poor and probably cannot be influenced by nucleos(t)ide analogue therapy. Several studies have confirmed the efficacy of lamivudine therapy in patients with HBV related decompensated cirrhosis. Therapy resulted in a significant improvement in virological, biochemical and markers of disease status[54-58].

Treatment of lamivudine refractory patients, who waited for liver transplantation, with adefovir for 48 wk resulted in a 4.1 log10 copy decline in viral load. Liver functions improved significantly and the Child Pugh-Turcotte score (CPT) improved or remained stable in 92% of the patients[59]. Adefovir therapy initiated in pre-transplant patients resulted in undetectable serum HBV DNA in 76% and normal ALT in 84% of the patients after 96 wk of treatment. Markers of synthetic liver function improved in most patients, the Child-Pugh scores improved, or remained the same and survival was over 80% after two years[60]. Another study in lamivudine refractory patients with decompensated cirrhosis showed a HBV DNA response (≤ 105 copies/mL or ≥ 2 log decrease from baseline) in 92%, over half of the patients had ALT normalisation and there was improvement of liver synthesis function and Child-Pugh scores after one year of treatment[61]. Although it is possible to inhibit viral replication and prevent clinical decompensation, the occurrence of HCC is not prevented. After 5 years of continuous lamivudine therapy or add-on therapy with adefovir in lamivudine resistant cases in HBeAg negative cirrhotic patients, 16% of patients had died, or had a liver transplantation. However, 24% was diagnosed with HCC[62]. The moment of initiation of nucleos(t)ide analogues to prevent the occurrence of HCC has yet to be determined. In cirrhotic patients there seems to be no benefit, but a study including patients with advanced liver fibrosis or cirrhosis showed a reduction in HCC in lamivudine treated patients compared to placebo. Patients with lower fibrosis and Child-Pugh scores were less prone to disease progression[50]. The data suggest nucleos(t)ide analogue therapy has to be initiated before the development of cirrhosis to prevent HCC and has to be continued indefinitely[50,62].

TREATMENT WITH NUCLEOSIDE/ NUCLEOTIDE ANALOGUES

Four oral nucleoside or nucleotide analogues, lamivudine, adefovir, entecavir and telbivudine, are currently marketed and approved as a first line of therapy for the treatment of chronic hepatitis B. All therapies result in reduction of viral load, ALT levels and improvement of liver histology (Table 2). It is difficult to point out one compound which should be the first nucleoside or nucleotide used for the treatment of chronic hepatitis B. At least two major points at least have to be taken into account: (1) efficacy of the treatment on the short and long term, including the development of resistance and (2) the costs. Comparing the efficacy of treatment is difficult; however, some comparative studies have been performed. Both entecavir and telbivudine proved superior efficacy over lamivudine after 1 year of treatment[13,15,63,64]. Direct comparison of telbivudine or adefovir for 52 wk showed superior efficacy on viral and biochemical parameters for telbivudine, but resistance was not assessed[65]. Adefovir has not directly been compared to lamivudine. Direct comparison of entecavir and adefovir for a duration of 24 wk showed a decline of HBV DNA of 6.97 log10 copies/mL for entecavir and 4.84 log10 copies/mL for adefovir. PCR undetectability (HBV < 300 copies/mL) was reached in 45% of entecavir treated patients vs 13% of those receiving adefovir[66]. Tenofovir looks a promising new drug, but is only used in small series in lamivudine or adefovir treatment failures. The long term outcomes are only known for lamivudine and adefovir. Another problem with interpretation and positioning of the outcomes of clinical studies is the lack of standardisation of outcome measures.

The development of resistance is the most important factor for loss of efficacy. Lamivudine has a high rate of resistance of 18%-27% after 1 year and this increases over time, being 44% at year 2, 60% at year 3, and after 4 years of treatment almost 70% has developed resistance[5,67-73]. Adefovir showed no resistance after 1 year, but rates increased to 1%-3%, 11%, 18% and 28% at year 2, 3, 4 and 5[14,16,74]. Entecavir showed no resistance up to 2 years of treatment; however, complete non-responders did not receive treatment in year 2[75]. Telbivudine had a resistance rate of 2%-4% after 1 year of treatment[63,65].

With long-term lamivudine treatment HBeAg seroconversion increases to 27%, 40%, 47% and 50% at year 2, 3, 4 and 5, respectively, despite the development of resistance[67,71,73,76]. Prolonged therapy with adefovir in HBeAg positive subjects resulted in viral load below 103 copies/mL in 28% at year 1, 45% and 56% at year 2 and 3. ALT levels became normal in 48%, 71% and 81% after 1, 2 and 3 years of treatment. Rates of HBeAg-loss increased to 42% and 52% and HBeAg seroconversion rates increased to 29% and 43% at year 2 and 3[77]. A study with continued treatment up to 2 years showed an increase in viral reduction from -4.5 to -5.0 log10 copies/mL, increased in PCR-negativity (lower limit of detection 300 copies/mL) from 28% to 42%, but the percentage of ALT normalisation remained unchanged (79% to 78%). The percentage HBeAg-loss increased from 13% to 19% and the percentage of patients with HBeAg seroconversion increased to 15%[78]. In HBeAg negative subjects prolonged adefovir therapy of 2 years, showed little additional decline in viral load, but consolidated the response to adefovir as 71%-75% of the patients had a viral load below 103 copies/mL and ALT normalisation in 73%-79%. Long term treatment up to 5 years resulted in a viral load below 103 copies/ml in 78%-79% at year 3, 65%-68% at year 4 and 67% after 5 years of continuous treatment. ALT levels were normal in 69%-78% at 3 years, 70%-75% at 4 years and 69% after 5 years[74]. Also entecavir showed a continuous viral decline in patients with detectable HBV DNA beyond wk 48 and HBeAg seroconversion rates increased[79,80]. Another aspect which is little studied is the sustainability of response after discontinuation of therapy. In HBeAg positive subjects who seroconverted during therapy, response is durable in over half of the subjects[13,81-84]. In HBeAg positive patients treated with lamivudine who discontinued after achieving a complete response (HBeAg loss, undetectable HBV DNA and normal ALT) had a sustained response of 78%, 72%, 70%, 67% and 64% after 1, 2, 3, 4 and 5 years of follow-up, respectively[85]. In HBeAg positive subjects with HBeAg seroconversion during adefovir therapy the response was sustained in 91%[84]. In entecavir treated HBeAg positive subjects for 48 wk the sustained response (HBeAg loss and HBV DNA < 7.0 × 105 copies/mL) was 82% after a 24 wk follow-up[86]. The durability can be increased by continuing treatment for several months after HBeAg seroconversion. Therefore, it is recommended to continue treatment for at least 3-4 mo[82,83]. As many clinical trials had a predetermined endpoint, sustainability could be a bit higher if treatment was continued for a longer period in those patients who underwent HBeAg seroconversion within 3 mo before discontinuation. In HBeAg negative subjects the durability of response is often poor. Patients treated for two years with lamivudine who had undetectable HBV DNA levels (LLD 200 copies/mL) discontinued treatment. After 12 mo of follow-up the virological relapse rate was 50%[87]. The viral load at discontinuation and duration of treatment do not accurately predict sustainability of response in HBeAg negative patients.

Other parameters such as intrahepatic total HBV DNA and intrahepatic cccDNA and HBcore expression and the level of hepatitis B virus core related antigen appear to be superior in prediction of sustained response compared to viral load at the end of therapy. The studies were, however, small and the results have not been confirmed by others[88,89].

MANAGEMENT OF TREATMENT FAILURES TO NUCLEOS(T)IDE ANALOGUES

A distinction can be made for patients failing therapy: due to resistance or other reasons. Many patients do not achieve complete suppression of HBV DNA during treatment. Several factors may contribute such as non-compliance, inefficient conversion from the prodrug to its active metabolite, inadequate phosphorylation within the hepatocytes or underdosing of the drug. Some patients failing to respond initially to treatment may already harbour a resistant mutant prior to the start of therapy[90,91]. Underdosing is particularly an issue with adefovir treatment as the 10 mg dose was chosen for safety reasons. The 30 mg dose was more effective, but also more nephrotoxic[16].

Little is known why some patients have suboptimal viral suppression. The known baseline predictors for response provide information on the likelihood of response, but outcome cannot be predicted (Table 1). A high baseline viral load is probably one of the reasons why more HBeAg-positive patients have a suboptimal response compared to HBeAg-negative patients[13-16]. Recently, genotypic dependent polymorphisms have been described associated with primary treatment failure and more might be detected[91,92]. As viral factors, as well as host factors play an import role in response, it is difficult to assess the optimal treatment for sub-optimal responders. Presuming study randomisation led to an equal distribution of both viral and host factors, it is to be expected that more potent drugs are able to suppress viral replication in subjects with suboptimal suppression. Entecavir and telbivudine proved their superior potency over lamivudine in a head to head comparison and for telbivudine this observation also has been made in comparison with adefovir[13,15,63-65]. In adefovir treatment failures the more potent drug tenofovir showed good viral suppression[93]. Patients responding to tenofovir and switched to adefovir showed viral relapse, while no mutants could be detected[94]. Another strategy could be adding a second drug to the failing compound. In vitro testing demonstrated that combining adefovir with an L-nucleoside (lamivudine, telbivudine, emtricitabine) exerted additive antiviral effects[95]. Clinically the combination of adefovir and emtricitabine resulted in stronger viral suppression[96]. In patients failing adefovir switching therapy to tenofovir and either emtricitabine or lamivudine resulted in decrease in viral load in most patients[97].

PREVENTION OF RESISTANCE

For nucleoside/nucleotide analogue treatment, a number of risk factors for resistance have been identified. For lamivudine this includes: prior course of lamivudine, duration of lamivudine therapy, high body weight and body mass index, male sex and high baseline HBV DNA, insufficient HBV DNA suppression at month three, and elevated ALT levels during treatment[98-100]. For adefovir the following risk factors for resistance have been reported: lamivudine resistance at start of treatment, high baseline viral load, < 1 mo continuation of lamivudine after the start of adefovir therapy in case of lamivudine resistance, insufficient HBV DNA suppression during treatment[101-103]. For entecavir, lamivudine resistance and suboptimal suppression of HBV DNA on treatment were found as risk factors[75]. A key factor in the development of resistance is the persistence of viral replication. Several studies found a relation between ongoing viral replication and the development of resistance. Patients with a serum HBV DNA > 103 copies/mL after 6 mo of lamivudine treatment had a 63% chance for developing resistance[100]. Another study in 24 patients, found that none of the subjects with excellent viral suppression (nadir HBV DNA < 50 copies/mL), two out of 5 patients with a nadir viral load between 50-300 copies/mL and all 11 patients with a nadir viral load > 300 copies/mL developed resistance[99]. For adefovir, a load of over 105 copies/mL after 48 wk of treatment is a risk factor for resistance[103]. In a study in which patients were treated with either telbivudine, or lamivudine, a viral load > 103 copies/mL after 24 wk of treatment was associated with an increased risk for resistance.

The role of genotypes is controversial as some have reported influence of the genotype on the development of resistance, while others do not find this association[101,100-111]. Genotype might influence the mutational pattern. When genotype A and D in lamivudine resistant patients were compared, the rate of M204V mutants and rates of mutations at position rtL180 was higher in genotype A. The rate of M204I mutations was higher in genotype D. The median time of shift from M204I to M204V was shorter in genotype A. Additional resistance associated mutations were only detected in patients infected with genotype D[112]. In genotype C patients HBV DNA was significantly higher compared to genotype B after the development of YMDD mutants[104]. Studies are often hampered by their small size. For compounds with a low rate of resistance it is hard to determine the role of the genotype as large numbers have to be treated often for a prolonged period.

The current strategy of continuous monotherapy is insufficient to completely suppress viral replication in a large number of patients. In vitro testing has to be done in order to find promising combinations of drugs. These combinations of drugs then have be to investigated in long-term large scale trials with clinical response and resistance as outcome measures[95].

It is important to detect resistance as early as possible during treatment with nucleoside or nucleotide analogues. In case of virological breakthrough, which is generally agreed to be a 1 log10 increase in viral load in either copies/ml or IU/L after an initial response in compliant patients[113-115]. Sensitive quantitative HBV DNA assays are therefore advised for monitoring as a viral rebound can be detected earlier. Virological breakthrough mostly precedes biochemical breakthrough and the time lapse may vary from weeks to months[116]. Genotypic testing provides information on the type of mutation which arises during treatment and if there might be decreased drug sensitivity. Knowledge of the specific mutation will be increasingly important in the future as different mutations may have a distinct influence on treatment efficacy of other compounds. Newly detected mutations should be investigated by phenotypic assays to determine their replication fitness and susceptibility to other compounds[117].

MANAGEMENT OF RESISTANCE
Lamivudine resistance

Adefovir has proven to be effective for lamivudine resistant mutants. Adefovir monotherapy is able to suppress viral load by 2.4-4.0 log10 copies/mL[102,118]. The data of adefovir and lamivudine combination therapy by adding adefovir to ongoing lamivudine is controversial. A randomised study found no difference in viral decline[118]. Another study did not find a difference in viral suppression after one year of treatment, but at month 18 adefovir and lamivudine showed a stronger viral decline (4.3 log10 copies/mL) vs adefovir monotherapy (3.4 log10 copies/mL)[119]. A study comparing combination therapy to monotherapy in lamivudine resistant patients showed significantly higher rates of PCR-negativity (81% vs 40%) in patients with a baseline viral load ≥ 5 log10 copies/mL[120].

Although adefovir is effective for the treatment of lamivudine refractory patients there seems to be some degree of cross-resistance as in vitro testing shows a 2.8-16 fold increase in IC50 values for adefovir for lamivudine resistant strains[121-123]. Clinically mutations also associated with lamivudine resistance appear to influence treatment outcomes. Viral decline and ALT normalisation might be less in lamivudine resistant patients compared to treatment naïve patients, but other studies do no report such difference[102,124,125]. The rate of resistance is increased in patients with lamivudine resistance switched to adefovir monotherapy compared to the large phase III trials and to patients switched to adefovir and lamivudine combination therapy[14,16,101,102,120]. Considering the mounting evidence of more potent antiviral effect and a lower rate of resistance adding adefovir to the ongoing lamivudine therapy is to be preferred above switching to adefovir monotherapy. If chosen to switch to adefovir monotherapy lamivudine has to be continued for at least 2-3 mo as this overlap may prevent the emergence of adefovir resistance[101,126].

Lamivudine resistance shows some cross-resistance with entecavir in cell culture, but lamivudine resistant strains remain sensitive to entecavir[127,128]. Although very effective, treatment outcomes with 1 mg entecavir in lamivudine were less compared to 0.5 mg entecavir in treatment naïve patients as viral decline (6.9 log10 copies/mL vs 5.1 log10 copies/mL) and rates of PCR-negativity (67% vs 19%) were lower after 48 wk of treatment (Table 4)[13,129]. Entecavir has a high barrier to resistance as multiple mutations are necessary for the virus to be resistant. Lamivudine refractory patients already harbour some of these mutations and entecavir resistance occurs, therefore, more frequently in lamivudine resistant patients. After 1 year 1.4% of patients became resistant increasing up to 9% after two years and 15%-19% after 3 years of treatment[75,129,130].

Tenofovir disoproxil fumarate possesses potent activity against lamivudine resistant hepatitis B (Table 4)[17,93,131,132]. Lamivudine resistant mutants lead to a slight 1.8-5.7 fold increase in IC50 values. The known mutants however, remain sensitive to tenofovir and the mutation pattern of tenofovir has no overlap with the mutational pattern of lamivudine[121,123,133]. Most studies add tenofovir to lamivudine, though tenofovir mono therapy seems to be equally effective[134]. Tenofovir is thought to be a more potent viral suppressing agent for lamivudine resistant HBV compared to adefovir, but its efficacy is only investigated in relatively small groups of patients. Many of them including HIV-HBV co-infected patients[17,132]. Being a very promising drug, more studies have to be conducted to determine the exact role or the combination with other compounds for the treatment of lamivudine resistant hepatitis B.

Adefovir resistance

Adefovir resistant strains are susceptible to lamivudine and lamivudine can thus be used for rescue therapy[135]. Indeed clinically lamivudine is able to reduce the viral load in adefovir resistant patients[136,137]. The effect of adefovir associated mutations on long-term treatment is unknown. It is likely that lamivudine resistant strains severely limit the use of lamivudine. In vitro a strain conferring resistance to both adefovir and lamivudine is viable and has reduced sensitivity to all common drugs used for hepatitis B, although tenofovir and entecavir are likely to be able to suppress HBV DNA[135]. Adefovir resistant strains are susceptible to entecavir and tenofovir in vitro[135,138]. In very small series tenofovir and entecavir proved effective against adefovir resistant HBV[101,139].

Entecavir resistance

Entecavir resistance is highly cross-resistant with lamivudine as entecavir resistance requires lamivudine resistance[127]. This mutant strain is sensitive in vitro to adefovir and clinical treatment with adefovir resulted in decline of the viral load[127,140].

Future directions for the management of resistance

The development of resistance is the largest limiting factor for long-term treatment with nucleoside or nucleotide analogues and should therefore be studied in detail. Lamivudine as well as many other L-nucleosides have high rates of resistance caused by a single mutation. Due to the high resistance rate and being the only oral drug available for a long time it gave the opportunity to study the mechanisms and outcomes of resistance. The large number of patients treated with lamivudine with subsequent development of resistance made it possible to study the effect of salvage therapy. Entecavir and adefovir proved their efficacy in large populations. But despite all these opportunities we still do not know the exact incidence of adefovir resistance in lamivudine resistant patients. Although the balance tips to lamivudine and adefovir combination therapy over adefovir monotherapy, the definite answers have not been provided, especially the question whether monotherapy comes with higher rates of resistance. Tenofovir looks very promising, although studies are small and little is known on the effect of tenofovir monotherapy on lamivudine resistant strains. Very little data is available on the occurrence and management of adefovir and entecavir as well as newer drugs. Studying resistance for compounds with low rates is difficult as large numbers have to be treated. Large scale initiatives are necessary to study the effectiveness and resistance. Insight in the mutational patterns is very important as each pattern has its own influence on replication fitness and cross-resistance. In vitro studies and molecular modelling have to provide these answers to design optimal treatment regimens. This approach is needed as many drugs have been developed and it is not feasible to test all drugs or combinations for all mutational patterns.

CONCLUSION

The knowledge and therapeutic options have come a long way since the discovery of the hepatitis B virus. Today chronic hepatitis B virus infection is a treatable disease. However, much remains unknown and treatment options are far from perfect. The natural history is only partially understood and only recently the importance of viral load has been revealed[19-21]. Further studies have to identify the factors involved in progression of disease in order to be able to identify those patients in need of treatment. Treatment options are diverse and have limitations in tolerability and efficacy. More data are needed to be able to predict treatment outcome in patients. This is especially important for treatment with interferon, which is costly and is associated with considerable side effects and an overall success rate between 30%-40%. However, this treatment has proven to be able to inactivate the disease for long periods in responders, which might result in HBsAg-seroconversion. Research to identify those patients likely to respond before start of therapy or within a few weeks after start of treatment is urgently needed. Nucleoside or nucleotide analogue therapy is the alternative for interferon based treatments and the response rates on treatment are higher compared to interferon. However, relapse is frequent after discontinuation, while identifying those relapsing is not possible. This has resulted in long-term treatment, although it is known that response can be sustained off-treatment. By identifying the factors responsible for sustained response it might be possible to accurately predict sustainability. In theory this could result in nucleos(t)ide analogue therapy of limited duration. This is especially important in young adults who often have a desire for pregnancy, whilst the antiviral drugs have not been investigated on safety for the unborn child or long term in patients themselves.

Data on treatment efficacy in treatment experienced patients is limited. Therefore, large cohorts of patients have to be studied. Especially the rate of resistance and the mutational patterns are hard to assess. For some therapies resistance rates are low or mutational patterns are diverse. Genotypic and phenotypic testing and molecular modelling are helpful to determine the level of cross-resistance with other compounds. Promising rescue therapies should be studied clinically in order to determine their efficacy. The data on resistance (mutational patterns, replication fitness, molecular modelling and cross resistance) is scattered, and therefore, it is almost impossible to look up the implications of a specific mutational pattern. A large central database combining all the data on resistance could provide this information and would be of great value for everyone interpreting mutational patterns. This database could also provide clinicians advice on treatment for an individual resistant patient. More specific knowledge on resistance calls for the development of new techniques that are sensitive, able to detect new variants, able to determine if multiple variants are located on the same genome, easy to perform and interpret, cheap and suitable for mass screening.

As none of the current treatments for chronic hepatitis B is optimal, prevention of infection should be one of the cornerstones of management of chronic hepatitis B. Safe and well tolerated vaccines for hepatitis B have been developed and their effectiveness have been proved. There have been some concerns about the luxation of autoimmune phenomena[141]. Three WHO large scale evaluations revealed no increased risk for the development of autoimmune diseases[142-144].

In conclusion: The management of chronic hepatitis B has evolved fast and currently hepatitis B is a treatable disease. More research on the factors involved in response to treatment or treatment failure is needed to tailor treatment to the individual patient. Much attention should be paid to universal worldwide vaccination as this may significantly change the burden of disease.

Footnotes

S- Editor Zhu LH L- Editor Karam SM E- Editor Chen GJ

References
1.  Kane M. Global programme for control of hepatitis B infection. Vaccine. 1995;13 Suppl 1:S47-S49.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 205]  [Cited by in F6Publishing: 68]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
2.  de Franchis R, Hadengue A, Lau G, Lavanchy D, Lok A, McIntyre N, Mele A, Paumgartner G, Pietrangelo A, Rodés J. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol. 2003;39 Suppl 1:S3-25.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Niesters HG, Zondervan P, Hansen B, Schalm SW. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-129.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 836]  [Cited by in F6Publishing: 242]  [Article Influence: 52.3]  [Reference Citation Analysis (0)]
4.  Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-2695.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1093]  [Cited by in F6Publishing: 323]  [Article Influence: 68.3]  [Reference Citation Analysis (0)]
5.  Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, Lu ZM, Piratvisuth T, Germanidis G, Yurdaydin C. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 810]  [Cited by in F6Publishing: 222]  [Article Influence: 47.6]  [Reference Citation Analysis (0)]
6.  Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, Häussinger D. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 580]  [Cited by in F6Publishing: 130]  [Article Influence: 23.2]  [Reference Citation Analysis (0)]
7.  Bortolotti F, Jara P, Barbera C, Gregorio GV, Vegnente A, Zancan L, Hierro L, Crivellaro C, Vergani GM, Iorio R. Long term effect of alpha interferon in children with chronic hepatitis B. Gut. 2000;46:715-718.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 70]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
8.  Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol. 2001;34:306-313.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 209]  [Cited by in F6Publishing: 46]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
9.  Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, Bonino F. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol. 2002;36:263-270.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 231]  [Cited by in F6Publishing: 62]  [Article Influence: 12.2]  [Reference Citation Analysis (0)]
10.  Liaw YF, Sheen IS, Chen TJ, Chu CM, Pao CC. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology. 1991;13:627-631.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 179]  [Cited by in F6Publishing: 124]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
11.  McMahon BJ, Alberts SR, Wainwright RB, Bulkow L, Lanier AP. Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med. 1990;150:1051-1054.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 107]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
12.  Huo TI, Wu JC, Lee PC, Chau GY, Lui WY, Tsay SH, Ting LT, Chang FY, Lee SD. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology. 1998;28:231-236.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 177]  [Cited by in F6Publishing: 159]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
13.  Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1014]  [Cited by in F6Publishing: 326]  [Article Influence: 67.6]  [Reference Citation Analysis (0)]
14.  Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, Lim SG, Goodman Z, Wulfsohn MS. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800-807.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 732]  [Cited by in F6Publishing: 164]  [Article Influence: 40.7]  [Reference Citation Analysis (0)]
15.  Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011-1020.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 841]  [Cited by in F6Publishing: 252]  [Article Influence: 56.1]  [Reference Citation Analysis (0)]
16.  Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 998]  [Cited by in F6Publishing: 242]  [Article Influence: 55.4]  [Reference Citation Analysis (0)]
17.  van Bömmel F, Wünsche T, Mauss S, Reinke P, Bergk A, Schürmann D, Wiedenmann B, Berg T. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004;40:1421-1425.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 270]  [Cited by in F6Publishing: 244]  [Article Influence: 15.9]  [Reference Citation Analysis (0)]
18.  Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, Chutaputti A, Chang WY, Zahm FE, Pluck N. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003;10:298-305.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 334]  [Cited by in F6Publishing: 302]  [Article Influence: 18.6]  [Reference Citation Analysis (0)]
19.  Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol. 2006;101:1797-1803.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 173]  [Cited by in F6Publishing: 159]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
20.  Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1074]  [Cited by in F6Publishing: 980]  [Article Influence: 71.6]  [Reference Citation Analysis (0)]
21.  Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, Shih WL, Kao JH, Chen DS, Chen CJ. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265-272.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 385]  [Cited by in F6Publishing: 366]  [Article Influence: 24.1]  [Reference Citation Analysis (0)]
22.  Yalçin K, Değertekin H, Kokoğlu OF, Ayaz C. A three-month course of lamivudine therapy in HBeAg-positive hepatitis B patients with normal aminotransferase levels. Turk J Gastroenterol. 2004;15:14-20.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes and the response to interferon therapy. J Hepatol. 2000;33:998-1002.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 329]  [Cited by in F6Publishing: 95]  [Article Influence: 16.5]  [Reference Citation Analysis (0)]
24.  Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology. 2002;36:1425-1430.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T, Häussinger D. Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut. 2005;54:1009-1013.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 159]  [Cited by in F6Publishing: 152]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
26.  Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol. 2006;101:297-303.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 171]  [Cited by in F6Publishing: 158]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
27.  Hadziyannis S, Lau G, Marcellin P, Piratvisuth T, Cooksley G, Bonino F, Chutaputti A, Diago M, Jin R, Pluck N. Sustained HBsAg seroconversion in patients with chronic hepatitis B treated with Peginterferon α-2a (40 kDa) (Pegasys®). J Hepatology. 2005;42 Suppl 2:178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
28.  Bonino F, Lau G, Marcellin P, Hadziyannis S, Kitis G, Jin R, Yao GB, Piratvisuth T, Germanidis G, Yurdaydin C. The first detailed analysis of pedictors of response in HBeAg-negative chronic hepatitis B: data from a multicenter, randomized, partially double-blin study of peginterferon-alfa-2a (40-KD) (Pegasys ®) alone or in combination with lamivudine vs lamivudine alone. Hepatology. 2004;40 Suppl 1:659A.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Marcellin P, Bonino F, Lau GK, Farci P, Yurdaydin C, Piratvisuth T, Luo K, Gurel S, Hadziyannis S, Wang Y. Suppression of HBV DNA in patients with HBeAg-negative CHB treated with PEG-Interferon alfa-2a (40 kD) /- lamivudine: 2-year follow-up results. Hepatology. 2006;44 Suppl 1:550A.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a workshop. Gastroenterology. 2001;120:1828-1853.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 522]  [Cited by in F6Publishing: 456]  [Article Influence: 26.1]  [Reference Citation Analysis (0)]
31.  Westland C, Delaney W, Yang H, Chen SS, Marcellin P, Hadziyannis S, Gish R, Fry J, Brosgart C, Gibbs C. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology. 2003;125:107-116.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 167]  [Cited by in F6Publishing: 38]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
32.  Yurdaydin C, Senturk H, Boron-Kaczmarska A, Raptopoulou-Gigi M, Batur Y, Goodman Z, Vaughan J, Brett-Smith H, Hindes R. Entecavir (ETV) demonstrates consistent responses throughout baseline disease and demographic subgroups for the treatment of lamivudine-refractory HBeAg(+) patients with chronic hepatitis B. J Hepatology. 2006;44 Suppl 2:S190-S191.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Lampertico P, Del Ninno E, Viganò M, Romeo R, Donato MF, Sablon E, Morabito A, Colombo M. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology. 2003;37:756-763.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 138]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
34.  Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology. 2001;121:101-109.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 154]  [Cited by in F6Publishing: 138]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
35.  Wong DK, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med. 1993;119:312-323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 726]  [Cited by in F6Publishing: 633]  [Article Influence: 25.9]  [Reference Citation Analysis (0)]
36.  Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, de Man RA, Goodman Z, Condreay LD, Crowther LM. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol. 2003;38:818-826.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 17]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
37.  Hui CK, Zhang HY, Lau GK. Management of chronic hepatitis B in treatment-experienced patients. Gastroenterol Clin North Am. 2004;33:601-616, x.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
38.  Leemans WF, Flink HJ, Janssen HL, Niesters HG, Schalm SW, de Man RA. The effect of pegylated interferon-alpha on the treatment of lamivudine resistant chronic HBeAg positive hepatitis B virus infection. J Hepatol. 2006;44:507-511.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 13]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
39.  Vassiliadis T, Patsiaoura K, Tziomalos K, Gkiourtzis T, Giouleme O, Grammatikos N, Rizopoulou D, Nikolaidis N, Katsinelos P, Orfanou-Koumerkeridou E. Pegylated IFN-alpha 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B. World J Gastroenterol. 2006;12:2417-2422.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  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: ]
41.  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: ]
42.  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: 201]  [Cited by in F6Publishing: 42]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
43.  Lai CJ, Terrault NA. Antiviral therapy in patients with chronic hepatitis B and cirrhosis. Gastroenterol Clin North Am. 2004;33:629-654, x-xi.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 9]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
44.  Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Lindsay K, Payne J, Dienstag JL, O'Brien C, Tamburro C, Jacobson IM. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med. 1990;323:295-301.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 652]  [Cited by in F6Publishing: 94]  [Article Influence: 21.0]  [Reference Citation Analysis (0)]
45.  Lampertico P, Del Ninno E, Manzin A, Donato MF, Rumi MG, Lunghi G, Morabito A, Clementi M, Colombo M. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology. 1997;26:1621-1625.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 129]  [Cited by in F6Publishing: 114]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
46.  van Zonneveld M, Flink HJ, Verhey E, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Hansen BE, Schalm SW, Janssen HL. The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther. 2005;21:1163-1171.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 44]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
47.  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: 976]  [Cited by in F6Publishing: 218]  [Article Influence: 44.4]  [Reference Citation Analysis (0)]
48.  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: 1275]  [Cited by in F6Publishing: 292]  [Article Influence: 55.4]  [Reference Citation Analysis (0)]
49.  Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, Dhillon A, Moorat A, Barber J, Gray DF. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut. 2000;46:562-568.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 374]  [Cited by in F6Publishing: 325]  [Article Influence: 17.8]  [Reference Citation Analysis (0)]
50.  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: 1605]  [Cited by in F6Publishing: 518]  [Article Influence: 94.4]  [Reference Citation Analysis (0)]
51.  Schiff E, Lee WM, Chao Y-C, Sette H, Schalm SW, Brett-Smith H, Zink R. Efficacy and safety of entecavir (ETV) and lamivudine (LVD) in compensated, cirrhotic patients with chronic hepatitis B. Hepatology. 2005;42 Suppl 1:583A-584A.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology. 1993;104:1116-1121.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Perrillo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, Schiff E, Bodicky C, Miller B, Denham C. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology. 1995;109:908-916.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 137]  [Cited by in F6Publishing: 109]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
54.  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: 297]  [Cited by in F6Publishing: 263]  [Article Influence: 14.1]  [Reference Citation Analysis (0)]
55.  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: 137]  [Cited by in F6Publishing: 21]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
56.  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: 203]  [Cited by in F6Publishing: 169]  [Article Influence: 10.2]  [Reference Citation Analysis (0)]
57.  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: 107]  [Cited by in F6Publishing: 22]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
58.  Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, Martin P, Dienstag J, Adams P, Dickson R. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001;33:424-432.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 335]  [Cited by in F6Publishing: 284]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
59.  Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann HL, Samuel D, Zeuzem S, Lilly L. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419-1427.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Schiff E, Lai CL, Neuhaus P, Tillman H, Samuel D, Villeneuve J, Hadziyannis S, Xiong S, Arterburn S, Brosgart C. Adefovir dipivoxil (ADV provides significant clinical benefits, reduces MELD score and prevents liver transplantation in chronic hepatitis B patients wait-listed for liver transplantation (OLT) with lamivudine-resistance (LAM-R). J Hepatol. 2005;42 Suppl 2:S5.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
61.  Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, Moorat A, Gardner S, Woessner M, Bourne E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology. 2004;126:81-90.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 304]  [Cited by in F6Publishing: 269]  [Article Influence: 17.9]  [Reference Citation Analysis (0)]
62.  Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Five years of sequential LAM to LAM ADV therapy suppresses HBV replication in most HBeAG-negative cirrhotics, preventing decompensation but not hepatocellular carcinoma. Hepatology. 2005;42 Suppl 1:582A-583A.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Gane E, Lai CL, Liaw YF, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV. Phase III comparison of telbivudine vs lamivudine in HBeAg-positive patients with chronic hepatitis B; efficacy, safety and predictors of response at 1 year. J Hepatol. 2006;44 Suppl 2:S183-S184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 1]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
64.  Yao G, Chen CJ, Lu W, Ren H, Tan D, Wang Y, Xu D, Jiang M, Liu J, Xu D. Entecavir is superior to lamivudine for the treatment of chronic hepatitis B (CHB): results of a phase 3 Chinese study (ETV-023) in nucleoside-naïve patients. J Hepatol. 2006;44 Suppl 2:S193.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Bzowej N, Chan HLY, Lai C-L, Cho M, Moon YM, Chao Y-C, Heathcote EJ, Meyers R, Minuk G, G . Marcellin P, Jeffers L, Sievert W, Kaiser R, Harb G, Chao GC, Brown NA. A randomized trial of telbivudine (LDT) vs. adefovir for HBeAg-positive chronic hepatitis B: final 52 week results. Hepatology. 2006;44 Suppl 1:563A.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Leung N, Peng C-Y, Sollano J, Lesmana L, Yuen M-F, Jeffers L, Han H-W, Sherman M, Zhu J, Mencarini K. Entecavir results in higher HBV DNA reduction vs adefovir in chronically infected HBeAg(+) antiviral-naïve adults: 24 wk results (E.A.R.L.Y. study). Hepatology. 2006;44 Suppl 1:554A.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmundson S. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology. 2001;33:1527-1532.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 456]  [Cited by in F6Publishing: 417]  [Article Influence: 22.8]  [Reference Citation Analysis (0)]
68.  Hadziyannis SJ, Papatheodoridis GV, Dimou E, Laras A, Papaioannou C. Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2000;32:847-851.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 252]  [Cited by in F6Publishing: 235]  [Article Influence: 12.0]  [Reference Citation Analysis (0)]
69.  Buti M, Cotrina M, Jardi R, de Castro EC, Rodriguez-Frias F, Sánchez-Avila F, Esteban R, Guardia J. Two years of lamivudine therapy in anti-HBe-positive patients with chronic hepatitis B. J Viral Hepat. 2001;8:270-275.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 33]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
70.  Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, Hawley S, Barber J, Condreay L, Gray DF. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology. 1999;29:889-896.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, Ng KY, Nicholls GJ, Dent JC, Leung NW. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol. 2004;19:1276-1282.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 183]  [Cited by in F6Publishing: 168]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
72.  Liaw YF, Chien RN, Yeh CT. No benefit to continue lamivudine therapy after emergence of YMDD mutations. Antivir Ther. 2004;9:257-262.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Guan R, Lai CL, Liaw YF, Lim SG, Lee CM. Efficacy and safety of 5 years lamivudine treatment of Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol. 2001;16 Suppl 1:A60-A61.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  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. N Engl J Med. 2005;352:2673-2681.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 388]  [Cited by in F6Publishing: 99]  [Article Influence: 24.3]  [Reference Citation Analysis (0)]
75.  Colonno R, Rose R, Levine S, Baldick J, Pokornowski K, Plym M, Yu C, Mazzucco C, Fang J, Hsu M. Entecavir two year resistance update: no resistance observed in nucleotide naïve patients and low frequency resistance emergence in lamivudine refractory patients. Hepatology. 2005;42 Suppl 1:573A.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Chien RN, Dent J, Roman L, Edmundson S. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119:172-180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 501]  [Cited by in F6Publishing: 448]  [Article Influence: 23.9]  [Reference Citation Analysis (0)]
77.  Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Xiong S, Brosgart CL, Currie G. Increasing serologic, virologic and biochemical response over time to adefovir dipivoxil (ADV) 10 mg in HBeAg chronic hepatitis B (CHB) patients. J Hepatology. 2005;42 Suppl 2:31-32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
78.  Mao YM, Zheng MD, Yao GB, Xu DZ, Hou JL, Chen YG, Dixon JS, Barker KF. Efficacy and safety of two years therapy with adefovir dipixoxil (ADV) in Chinese subjects with HBeAg positive chronic hepatitis B (CHB). J Hepatology. 2006;44 Suppl 2:S185.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
79.  Gish RG, Chang TT, de Man RA, Gadano A, Sollano J, Han KW, Lok A, Arbor A, Zhu J, Cross A. Entecavir results in sustantial virologic and biochemical improvement and HBeAg seroconversion through 96 weeks of treatment in HBeAg(+) chronic hepatitis B patients (study ETV-022). Hepatology. 2005;42 Suppl 1:267A.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Colonno RJ, Rose RE, Baldick CJ, Levine SM, Klesczewski K, Tenney DJ. High barrier to resistance results in no emergence of entecavir resistance in nucleoside-naïve subjects during the first two years of therapy. J Hepatology. 2006;44 Suppl 2:S182.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 1]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
81.  Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, Woessner M, Gardner S, Schiff E. Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology. 2003;37:748-755.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 165]  [Cited by in F6Publishing: 159]  [Article Influence: 9.2]  [Reference Citation Analysis (0)]
82.  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;32:803-806.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 242]  [Cited by in F6Publishing: 231]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
83.  Ryu SH, Chung YH, Choi MH, Kim JA, Shin JW, Jang MK, Park NH, Lee HC, Lee YS, Suh DJ. Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study. J Hepatol. 2003;39:614-619.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 15]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
84.  Chang TT, Schiffman ML, Tong M, Liaw YF, Komolmit P, Sorbel J, Arterburn S, Mondou E, Chuck S, Marcellini P. Durability of HBeAg seroconversion following adefovir dipivoxil treatment for chronic hepatitis B. J Hepatology. 2006;44 Suppl 2:S187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
85.  Lee HW, Han K-W, Myoung SM, Chung YH, Park JY, Lee JH, Kim JK, Ahn SH, Paik YH, Lee KS. Virologic response can be durable in HBeAg positive patients with chronic hepatitis B after lamivudine monotherapy during long-term follow-up. Hepatology. 2006;44 Suppl 1:516A-517A.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Gish RG, De MAn RA, Pedersen C, Bialkowska J, Chang TT, Apelian D, Zhu J, Cross A, Wilber R. Sustained response off-treatment to entecavir and lamivudine after 48 weeks of treatement in nucleoside-naïve, HBeAg( ) patients: 24-week follow-up results of phase 3 study ETV-022. J Hepatology. 2005;42 Suppl 2:177.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
87.  Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat. 2004;11:432-438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 97]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
88.  Sung JJ, Wong ML, Bowden S, Liew CT, Hui AY, Wong VW, Leung NW, Locarnini S, Chan HL. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy. Gastroenterology. 2005;128:1890-1897.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 154]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
89.  Fukada M, Yatsuhashi H, Hamada R, Nakao R, Hai N, Miyazato M, Ozawa E, Kamihira T, Nagaoka S, Taura N. Hepatitis B virus core-related antigen as an indicator of safe discontinuation of lamivudine therapy. Hepatology. 2006;44 Suppl 1:562A.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Huang ZM, Huang QW, Qin YQ, He YZ, Qin HJ, Zhou YN, Xu X, Huang MJ. YMDD mutations in patients with chronic hepatitis B untreated with antiviral medicines. World J Gastroenterol. 2005;11:867-870.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Schildgen O, Sirma H, Funk A, Olotu C, Wend UC, Hartmann H, Helm M, Rockstroh JK, Willems WR, Will H. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med. 2006;354:1807-1812.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 52]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
92.  Schildgen O, Hartmann H, Gerlich WH. Replacement of tenofovir with adefovir may result in reactivation of hepatitis B virus replication. Scand J Gastroenterol. 2006;41:245-246.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 9]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
93.  van Bömmel F, Zöllner B, Sarrazin C, Spengler U, Hüppe D, Möller B, Feucht HH, Wiedenmann B, Berg T. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology. 2006;44:318-325.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 208]  [Cited by in F6Publishing: 185]  [Article Influence: 13.9]  [Reference Citation Analysis (0)]
94.  van Bömmel F, Berg T. Reactivation of viral replication after replacement of tenofovir by adefovir. Hepatology. 2005;42:239-240.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 15]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
95.  Delaney WE, Yang H, Miller MD, Gibbs CS, Xiong S. Combinations of adefovir with nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro. Antimicrob Agents Chemother. 2004;48:3702-3710.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 20]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
96.  Lau G, Cooksley H, Ribeiro RM, Bowden S, Mommeja-Marin H, Lewin S, Rousseau F, Perelson AS, Locarnini S, Naoumov NV. Randomized, double-blind study comparing adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy versus ADV alone in HBeAg(+) chronic hepatitis B: efficacy and mechanisms of treatment response. Hepatology. 2004;40 Suppl 1:272A.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Lucas JL, Carriero DC, Juriel A, Jaffe D, Dietrich DT. Effect of switching to tenofovir with either emtricitabine or lamivudine in patients with chronic hepatitis B failing to respond to an adefovir-containing regimen. Hepatology. 2004;40 Suppl 1:665A.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, Brown N, Woessner M, Boehme R, Condreay L. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687-696.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 454]  [Cited by in F6Publishing: 427]  [Article Influence: 25.2]  [Reference Citation Analysis (0)]
99.  Ide T, Kumashiro R, Koga Y, Tanaka E, Hino T, Hisamochi A, Murashima S, Ogata K, Tanaka K, Kuwahara R. A real-time quantitative polymerase chain reaction method for hepatitis B virus in patients with chronic hepatitis B treated with lamivudine. Am J Gastroenterol. 2003;98:2048-2051.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 14]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
100.  Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34:785-791.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 263]  [Cited by in F6Publishing: 263]  [Article Influence: 13.2]  [Reference Citation Analysis (0)]
101.  Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, Hussain M, Lok AS. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006;44:283-290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 247]  [Cited by in F6Publishing: 210]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
102.  Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, Chung YH, Lee YS, Yoo W, Kim SO. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385-1391.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 239]  [Cited by in F6Publishing: 214]  [Article Influence: 15.9]  [Reference Citation Analysis (0)]
103.  Locarnini S, Qi X, Arterburn S, Snow A, Brosgart C, Currie G, Wulfsohn M, Miller MD, Xiong S. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB). J Hepatology. 2005;42 Suppl 2:17.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Sun J, Wang Z, Ma S, Zeng G, Zhou Z, Luo K, Hou J. Clinical and virological characteristics of lamivudine resistance in chronic hepatitis B patients: a single center experience. J Med Virol. 2005;75:391-398.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 21]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
105.  Moskovitz DN, Osiowy C, Giles E, Tomlinson G, Heathcote EJ. Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance. J Viral Hepat. 2005;12:398-404.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 35]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
106.  Yuen MF, Tanaka Y, Lai CL. Hepatitis B genotypes in chronic hepatitis B and lamivudine therapy. Intervirology. 2003;46:373-376.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
107.  Yuen MF, Wong DK, Sablon E, Yuan HJ, Sum SM, Hui CK, Chan AO, Wang BC, Lai CL. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther. 2003;8:531-534.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Hosaka T, Someya T, Kobayashi M, Saitoh S, Ikeda K. Efficacy of lamivudine therapy and factors associated with emergence of resistance in chronic hepatitis B virus infection in Japan. Intervirology. 2003;46:182-189.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 58]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
109.  Orito E, Fujiwara K, Tanaka Y, Yuen MF, Lai CL, Kato T, Sugauchi F, Kusakabe A, Sata M, Okanoue T. A case-control study of response to lamivudine therapy for 2 years in Japanese and Chinese patients chronically infected with hepatitis B virus of genotypes Bj, Ba and C. Hepatol Res. 2006;35:127-134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 15]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
110.  Akuta N, Suzuki F, Kobayashi M, Tsubota A, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Arase Y. The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment. J Hepatol. 2003;38:315-321.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 25]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
111.  Zöllner B, Petersen J, Schröter M, Laufs R, Schoder V, Feucht HH. 20-fold increase in risk of lamivudine resistance in hepatitis B virus subtype adw. Lancet. 2001;357:934-935.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 17]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
112.  Zöllner B, Petersen J, Puchhammer-Stöckl E, Kletzmayr J, Sterneck M, Fischer L, Schröter M, Laufs R, Feucht HH. Viral features of lamivudine resistant hepatitis B genotypes A and D. Hepatology. 2004;39:42-50.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 82]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
113.  Locarnini S, Hatzakis A, Heathcote J, Keeffe EB, Liang TJ, Mutimer D, Pawlotsky JM, Zoulim F. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther. 2004;9:679-693.  [PubMed]  [DOI]  [Cited in This Article: ]
114.  Lok AS, McMahon BJ. AASLD Practice Guidelines. Chronic hepatitis B: update of therapeutic guidelines. Rom J Gastroenterol. 2004;13:150-154.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 354]  [Cited by in F6Publishing: 323]  [Article Influence: 20.8]  [Reference Citation Analysis (0)]
116.  Papatheodoridis GV, Dimou E, Laras A, Papadimitropoulos V, Hadziyannis SJ. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease. Hepatology. 2002;36:219-226.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 136]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
117.  Durantel D, Brunelle MN, Gros E, Carrouée-Durantel S, Pichoud C, Villet S, Trepo C, Zoulim F. Resistance of human hepatitis B virus to reverse transcriptase inhibitors: from genotypic to phenotypic testing. J Clin Virol. 2005;34 Suppl 1:S34-S43.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 10]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
118.  Peters MG, Hann Hw Hw, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray Df Df. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004;126:91-101.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 406]  [Cited by in F6Publishing: 356]  [Article Influence: 23.9]  [Reference Citation Analysis (0)]
119.  Manolakopoulos S, Bethanis S, Koutsounas S, Goulis J, Saverriadis A, Xristias E, Christidou A, Pavlidis C, Toubanakis C, Vlachogiannakos J. Adefovir alone or combination with lamivudine in patients with lamivudine-resistance chronic HBeAg-negative heptitis B. A non randomized multicenter controlled trial. Hepatology. 2005;42 Suppl 2:592A-593A.  [PubMed]  [DOI]  [Cited in This Article: ]
120.  Barbon V, Marzano A, Carenzi S, Lagget M, Aleesandria C, Olivero A, Gaia S, Ciancio A, Smedile A, Rizetto M. Treatment with adefovir alone or in combination with lamivudine in chronic hepatitis B lamivudine resistant patients: results after two years. J Hepatology. 2006;44 Suppl 2:S178-S179.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
121.  Lada O, Benhamou Y, Cahour A, Katlama C, Poynard T, Thibault V. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antivir Ther. 2004;9:353-363.  [PubMed]  [DOI]  [Cited in This Article: ]
122.  Ono SK, Kato N, Shiratori Y, Kato J, Goto T, Schinazi RF, Carrilho FJ, Omata M. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance. J Clin Invest. 2001;107:449-455.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 206]  [Cited by in F6Publishing: 74]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
123.  Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WE. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antivir Ther. 2005;10:625-633.  [PubMed]  [DOI]  [Cited in This Article: ]
124.  Zeng M, Mao Y, Yao G, Wang H, Hou J, Wang Y, Ji BN, Chang CN, Barker KF. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology. 2006;44:108-116.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 49]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
125.  Lee Y, Chung Y, Ryu SH, Kim JA, Choi MH, Jung SW, Kim SH, Shin JW, Kim KM, Lim YS. Hepatitis B virus with rtL80V/I mutation associates with poor response to adefovir dipivoxil therapy. Hepatology. 2005;42 Suppl 1:575A.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Liu CJ, Kao JH, Chen PJ, Chen TC, Lin FY, Lai MY, Chen DS. Overlap lamivudine treatment in patients with chronic hepatitis B receiving adefovir for lamivudine-resistant viral mutants. J Viral Hepat. 2006;13:387-395.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 7]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
127.  Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, Plym M, Pokornowski K, Yu CF, Angus P. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother. 2004;48:3498-3507.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 407]  [Cited by in F6Publishing: 120]  [Article Influence: 23.9]  [Reference Citation Analysis (0)]
128.  Levine S, Hernandez D, Yamanaka G, Zhang S, Rose R, Weinheimer S, Colonno RJ. Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. Antimicrob Agents Chemother. 2002;46:2525-2532.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 34]  [Article Influence: 8.2]  [Reference Citation Analysis (0)]
129.  Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, Boron-Kaczmarska A, Martin P, Goodman Z, Colonno R. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039-2049.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 306]  [Cited by in F6Publishing: 273]  [Article Influence: 20.4]  [Reference Citation Analysis (0)]
130.  Colonno RJ, Rose RE, Pokornowski K, Baldick CJ, Klesczewski K, Tenney D. Assessment at three years shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients. Hepatology. 2006;44 Suppl 1:229A-230A.  [PubMed]  [DOI]  [Cited in This Article: ]
131.  de Vries-Sluijs TE, van der Eijk AA, Hansen BE, Osterhaus AD, de Man RA, van der Ende ME. Wild type and YMDD variant of hepatitis B virus: no difference in viral kinetics on lamivudine/tenofovir therapy in HIV-HBV co-infected patients. J Clin Virol. 2006;36:60-63.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 12]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
132.  Hann HW, Chae HB, Dunn SR. Tenofovir (TNV) has stronger antiviral effect than adefovir dipivoxil (ADV) against lamivudine (LAM) resistant hepatitis B virus (HBV). J Hepatology. 2006;44 Suppl 2:S184-S185.  [PubMed]  [DOI]  [Cited in This Article: ]
133.  Sheldon J, Camino N, Rodés B, Bartholomeusz A, Kuiper M, Tacke F, Núñez M, Mauss S, Lutz T, Klausen G. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir. Antivir Ther. 2005;10:727-734.  [PubMed]  [DOI]  [Cited in This Article: ]
134.  Mauss S, Nelson M, Lutz T, Sheldon J, Bruno R, Bömmel vF, Rockstroh JK, Wolf E, Stoehr A, Soriano V. First line combination therapy of chronic hepatitis B with tenofovir plus lamivudine versus sequential therapy with tenofovir therapy after lamivudine failure. Hepatology. 2005;42 Suppl 1:574A-575A.  [PubMed]  [DOI]  [Cited in This Article: ]
135.  Brunelle MN, Jacquard AC, Pichoud C, Durantel D, Carrouée-Durantel S, Villeneuve JP, Trépo C, Zoulim F. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2005;41:1391-1398.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 201]  [Cited by in F6Publishing: 185]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
136.  Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, Brosgart C, Colledge D, Edwards R, Ayres A. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003;125:292-297.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 423]  [Cited by in F6Publishing: 115]  [Article Influence: 23.5]  [Reference Citation Analysis (0)]
137.  Fung SK, Andreone P, Han SH, Rajender Reddy K, Regev A, Keeffe EB, Hussain M, Cursaro C, Richtmyer P, Marrero JA. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol. 2005;43:937-943.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 143]  [Cited by in F6Publishing: 130]  [Article Influence: 8.9]  [Reference Citation Analysis (0)]
138.  Delaney WE, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, Miller MD. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 2006;50:2471-2477.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 172]  [Cited by in F6Publishing: 70]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
139.  Villeneuve J, Willems B, Zoulim F. Efficacy of tenofovir in patients with chronic hepatitis B and resistance or sub-optimal response to adefovir. Hepatology. 2005;42 Suppl 1:588A.  [PubMed]  [DOI]  [Cited in This Article: ]
140.  Villet V, Pichoud C, Ollivet A, Villeneuve J, Trepo C, Zoulim F. Sequential antiviral therapy leads to the emergence of multiple drug resistant hepatitis B virus. Hepatology. 2005;42 Suppl 1:581A.  [PubMed]  [DOI]  [Cited in This Article: ]
141.  Marshall E. A shadow falls on hepatitis B vaccination effort. Science. 1998;281:630-631.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 38]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
142.  Ascherio A, Zhang SM, Hernán MA, Olek MJ, Coplan PM, Brodovicz K, Walker AM. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med. 2001;344:327-332.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 273]  [Cited by in F6Publishing: 42]  [Article Influence: 13.7]  [Reference Citation Analysis (0)]
143.  Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group. N Engl J Med. 2001;344:319-326.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 305]  [Cited by in F6Publishing: 55]  [Article Influence: 15.3]  [Reference Citation Analysis (0)]
144.  Jefferson T, Demicheli V. No evidence that vaccines cause insulin dependent diabetes mellitus. J Epidemiol Community Health. 1998;52:674-675.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 17]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
145.  Lok AS, Wu PC, Lai CL, Lau JY, Leung EK, Wong LS, Ma OC, Lauder IJ, Ng CP, Chung HT. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology. 1992;102:2091-2097.  [PubMed]  [DOI]  [Cited in This Article: ]
146.  Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology. 1989;10:761-763.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 225]  [Cited by in F6Publishing: 207]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
147.  Hui CK, Lai LS, Lam P, Zhang HY, Fung TT, Lai ST, Wong WM, Lo CM, Fan ST, Leung N. 48 weeks pegylated interferon alpha-2a is superior to 24 weeks of pegylated interferon alpha-2b in achieving hepatitis B e antigen seroconversion in chronic hepatitis B infection. Aliment Pharmacol Ther. 2006;23:1171-1178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
148.  Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, Heathcote EJ, Brown NA, Atkins M, Woessner M. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36:186-194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 217]  [Cited by in F6Publishing: 196]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
149.  Chien RN, Liaw YF, Atkins M. Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Asian Hepatitis Lamivudine Trial Group. Hepatology. 1999;30:770-774.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 175]  [Cited by in F6Publishing: 162]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
150.  Alexander G, Baba CS, Chetri K, Negi TS, Choudhuri G. High rates of early HBeAg seroconversion and relapse in Indian patients of chronic hepatitis B treated with Lamivudine: results of an open labeled trial. BMC Gastroenterol. 2005;5:29.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 4]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
151.  Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, Chan FK, Hung LC, Lee YT, Tam JS. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. 2005;142:240-250.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 199]  [Cited by in F6Publishing: 173]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
152.  Yao GB, Cui ZY, Wang BE, Yao JL, Zeng MD. A 3-year clinical trial of lamivudine in treatment of patients with chronic hepatitis B. Hepatobiliary Pancreat Dis Int. 2004;3:188-193.  [PubMed]  [DOI]  [Cited in This Article: ]
153.  Jonas MM, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, Greensmith MJ, Gardner SD, Bell MS, Sokal EM. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346:1706-1713.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 222]  [Cited by in F6Publishing: 41]  [Article Influence: 11.7]  [Reference Citation Analysis (0)]
154.  Mazur W, Król F, Cianciara J, Nazzal K, Gładysz A, Juszczyk J, Bolewska B, Adamek J, Czajka B, Swietek K. A multi-center open study to determine the effect of lamivudine on HBV DNA clearance and to assess the safety of the regimen in patients with chronic hepatitis B infection. Med Sci Monit. 2002;8:CR257-CR262.  [PubMed]  [DOI]  [Cited in This Article: ]
155.  Barbaro G, Zechini F, Pellicelli AM, Francavilla R, Scotto G, Bacca D, Bruno M, Babudieri S, Annese M, Matarazzo F. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial. J Hepatol. 2001;35:406-411.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 16]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
156.  Ooga H, Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M. Efficacy of lamivudine treatment in Japanese patients with hepatitis B virus-related cirrhosis. J Gastroenterol. 2004;39:1078-1084.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 7]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
157.  Janssen HL, Schalm SW, Berk L, de Man RA, Heijtink RA. Repeated courses of alpha-interferon for treatment of chronic hepatitis type B. J Hepatol. 1993;17 Suppl 3:S47-S51.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 4]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
158.  Carreño V, Marcellin P, Hadziyannis S, Salmerón J, Diago M, Kitis GE, Vafiadis I, Schalm SW, Zahm F, Manzarbeitia F. Retreatment of chronic hepatitis B e antigen-positive patients with recombinant interferon alfa-2a. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1999;30:277-282.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 41]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
159.  Muñoz R, Castellano G, Fernández I, Alvarez MV, Manzano ML, Marcos MS, Cuenca B, Solís-Herruzo JA. A pilot study of beta-interferon for treatment of patients with chronic hepatitis B who failed to respond to alpha-interferon. J Hepatol. 2002;37:655-659.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 6]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
160.  Ballauff A, Schneider T, Gerner P, Habermehl P, Behrens R, Wirth S. Safety and efficacy of interferon retreatment in children with chronic hepatitis B. Eur J Pediatr. 1998;157:382-385.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 10]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
161.  Teuber G, Dienes HP, Meyer zum Büschenfelde KH, Gerken G. Re-treatment with interferon-alpha in chronic hepatitis B and C virus infection. Z Gastroenterol. 1995;33:94-98.  [PubMed]  [DOI]  [Cited in This Article: ]
162.  Flink HJ, Hansen BE, Zonneveld M, Schalm SW, Janssen HL. Succesful treatment with pegylated interferon in HBV non-responders to standard interferon and lamivudine. Hepatology. 2004;40 Suppl 1:663A-664A.  [PubMed]  [DOI]  [Cited in This Article: ]
163.  Lau GK, Piratvisuth T, Luo K-X, Marcellin P, Thongsawat S, Gane E, Fried MW, Cooksley G, Button P, Liaw YF. PEG-interferon α-2a (40 kDa) (Pegasys®) versus PEG-interferon α-2a plus lamivudine in HBeAg-positive chronic HBV: effect of of previous treatment and drug exposure on sustained response. J Hepatology. 2005;42 Suppl 2:15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
164.  Marcellin P, Boyer N, Piratvisuth T, Tanwandee T, Pooi Huat R, Gadano A, Mercado R, Pridadi F, Zhang HY, Wu Y. Efficacy and safety of peginterferon alpha-2a (40kD) (Pegasys) in patients with chronic hepatitis B who had received prior treatment with nucleos(t)ide analugues - the pegalam cohort. J Hepatology. 2006;44 Supp 2:S187.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 1]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
165.  Buti M, Esteban R, Escartin P, Calleja JL, Enriquez J, Pons F, Crespo J, Bengoechea MG, Prieto M, Casanova T. Continued efficacy and safety of adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistant HBV: 1 year results. Hepatology. 2004;40 Suppl 1:671A.  [PubMed]  [DOI]  [Cited in This Article: ]
166.  Koskinas J, Manesis EK, Kountouras D, Papaioannou CH, Pantazis K, Agelopoulou O, Archimandritis A. Adefovir dipivoxil alone or in combination with lamivudine in HBeAg negative patients with lamivudine resistant chronic hepatitis B: a prospective, randomized study. J Hepatology. 2005;42 Suppl 2:S181.  [PubMed]  [DOI]  [Cited in This Article: ]
167.  Lampertico P, Viganò M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology. 2005;42:1414-1419.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 202]  [Cited by in F6Publishing: 184]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
168.  Vassiliadis T, Nikolaidis N, Giouleme O, Tziomalos K, Grammatikos N, Patsiaoura K, Zezos P, Gkisakis D, Theodoropoulos K, Katsinelos P. Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. Aliment Pharmacol Ther. 2005;21:531-537.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 13]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
169.  Moriconi F, Flinchman D, Ciccorossi P, Coco B, Sacco R, Oliveri F, Colombatto P, Bonino F, Brunetto MR. HBV Quasispecies selected during lamivudine treatment may contribute to adefovir dipivoxil resistance. J Hepatology. 2006;44 Suppl 2:S188.  [PubMed]  [DOI]  [Cited in This Article: ]
170.  Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, Pastore G, Bacon BR, Poynard T, Joshi S. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005;129:1198-1209.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 189]  [Cited by in F6Publishing: 178]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
171.  Karino Y, Toyota J, Kumada H, Katano Y, Izumi N, Shiratori Y, Sata M, Seriu T, Omata M. Efficacy and safety of entecavir in Japanese adult patients with incomplete response to current lamivudine treatment: a phase II clinical trial. J Hepatol. 2006;44 Suppl 2:S185-S186.  [PubMed]  [DOI]  [Cited in This Article: ]
172.  Yao G, Zhou X, Xu D, Wang BC, Ren H, Jiang M, Liu J, Xu D, MacDonald L. Entecavir results in early viral load reduction in chronic hepatitis B patients who have failed lamivudine therapy: a randomized placebo-controlled trial. J Hepatol. 2006;44 Suppl 2:S193.  [PubMed]  [DOI]  [Cited in This Article: ]
173.  van der Eijk AA, Hansen BE, Niesters HG, Janssen HL, van de Ende M, Schalm SW, de Man RA. Viral dynamics during tenofovir therapy in patients infected with lamivudine-resistant hepatitis B virus mutants. J Viral Hepat. 2005;12:364-372.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 22]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
174.  Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, Lu B, Cheng AK. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004;189:1185-1192.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 175]  [Cited by in F6Publishing: 156]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
175.  Núñez M, Pérez-Olmeda M, Díaz B, Ríos P, González-Lahoz J, Soriano V. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. AIDS. 2002;16:2352-2354.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 73]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
176.  Nelson M, Portsmouth S, Stebbing J, Atkins M, Barr A, Matthews G, Pillay D, Fisher M, Bower M, Gazzard B. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003;17:F7-10.  [PubMed]  [DOI]  [Cited in This Article: ]
177.  Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med. 2003;348:177-178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 111]  [Cited by in F6Publishing: 17]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]