Hepatitis: Gane E

Anonymous00371, McCaughan GW, Omata M, Amarapurkar D, Bowden S, Chow WC, Chutaputti A, Dore G, Gane E, Guan R, Hamid SS, Hardikar W, Hui CK, Jafri W, Jia JD, Lai MY, Wei L, Leung N, Piratvisuth T, Sarin S, Sollano J, Tateishi R. · Centenary Research Institute, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, NSW 2006, Australia. · J Gastroenterol Hepatol. · Pubmed #17444847 No free full text.

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Gane E. · No affiliation provided · N Z Med J. · Pubmed #15778746 No free full text.

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Gane E. · No affiliation provided · N Z Med J. · Pubmed #11346152 No free full text.

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Gane E. · New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, New Zealand. · Med J Malaysia. · Pubmed #16108183 No free full text.

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Gane E. · New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, New Zealand. · Med J Malaysia. · Pubmed #16108179 No free full text.

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Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, Gane E, Kao JH, Omata M, Anonymous00046. · Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan. · Liver Int. · Pubmed #15910483 No free full text.

Abstract: BACKGROUND/AIMS: A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update. METHODS: New data were presented, discussed and debated in an expert pre-meeting to draft a revision. The revised contents were finalized after discussion in a general meeting of APASL. RESULTS: Conceptual background, including the efficacy and safety profile of currently available and emerging drugs, was reviewed. Nineteen recommendations were formed and unresolved issues and areas for further study were suggested. CONCLUSION: The current therapy of chronic hepatitis B is modestly effective but not satisfactory. The development of new drugs and new strategies is required to further improve the outcomes of treatment.

Mohamed R, Desmond P, Suh DJ, Amarapurkar D, Gane E, Guangbi Y, Hou JL, Jafri W, Lai CL, Lee CH, Lee SD, Lim SG, Guan R, Phiet PH, Piratvisuth T, Sollano J, Wu JC. · Department of Medicine, University Malaya, Kuala Lumpur, Malaysia. · J Gastroenterol Hepatol. · Pubmed #15304110 No free full text.

Abstract: The Asia-Pacific Expert Committee on Hepatitis B Management recently reviewed the impact of hepatitis B in the region and assessed the differences and similarities observed in the practical management of the disease in individual Asia-Pacific countries. Hepatitis B is a major health concern in the Asia-Pacific region, and of all chronically infected carriers worldwide, approximately 75% are found in Asia. The disease poses a considerable burden on healthcare systems, and is likely to remain a cause of substantial morbidity and mortality for several decades. Disease prevention activities, including screening and vaccination programs, have been implemented successfully in some Asia-Pacific countries and similar measures are being established in other parts of the region. The management of hepatitis B in the Asia-Pacific varies throughout the region, with each country confronting different issues related to treatment options, disease monitoring and duration of therapy. The influence of cost, availability of diagnostic equipment, and patient awareness and compliance are of additional concern. Although guidelines such as those developed by the Asian Pacific Association for the Study of the Liver have been created to address problems encountered in the management of hepatitis B, many physicians in the region still find it difficult to make satisfactory management decisions because of the treatment choices available. This article examines the different approaches to hepatitis B management in a number of Asia-Pacific countries, and highlights the difficulties that can arise when adhering to treatment guidelines and disease prevention solutions that have proved to be successful in the region.

Gane E. · New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, New Zealand. · Liver Transpl. · Pubmed #14586892 links to  free full text

Abstract: 1. Recurrence of hepatitis C infection is universal and immediate after liver transplantation. 2. Graft and patient survival is reduced in liver transplantation recipients with recurrent hepatitis C virus infection compared with hepatitis C virus-negative recipients. 3. The natural history of chronic hepatitis C is accelerated after liver transplantation compared with nontransplantation chronic hepatitis C; 20% to 40% of patients progress to allograft cirrhosis within 5 years, compared with less than 5% of nontransplantation patients. 4. The rate of fibrosis progression is not uniform and may change over time. 5. The rate of progression from cirrhosis to decompensation is accelerated after liver transplantation. The rate of decompensation is >40% at 1 year and >60% at 3 years, compared with <5% and <10%, respectively, in immunocompetent patients. 6. The rate of progression from decompensation to death is also accelerated after liver transplantation. The 3-year survival is <10% after the onset of hepatitis C virus-related allograft failure, compared with 60% after decompensation in immunocompetent patients.

Gane E. · New Zealand Liver Transplant Unit, Auckland Hospital, Auckland, NZ. · Liver Transpl. · Pubmed #12362295 links to  free full text

Abstract: 1. Treatment of established recurrent hepatitis C with interferon-alpha monotherapy does not achieve sustained virologic response (SVR). 2. Treatment of established recurrent hepatitis C with combination interferon plus ribavirin achieves SVR rates of 17% to 27%, but dropout rates approach 30%. 3. Pretransplant prophylaxis against recurrent hepatitis C with combination interferon plus ribavirin is poorly tolerated in patients with decompensated hepatitis C cirrhosis. 4. Posttransplant prophylaxis with combination interferon plus ribavirin prevents both recurrent viremia and hepatitis in 15% to 20% of patients, but dropout rates approach 50%. 5. Hepatitis C virus genotype is the best predictor of response to antiviral prophylaxis and treatment of recurrent hepatitis C. 6. Interferon-alpha therapy is not associated with an increased risk of allograft rejection in liver transplant recipients. 7. Ribavirin therapy is associated with increased hemolysis in liver transplant recipients. 8. Preliminary data suggest pegylated interferon monotherapy will have similar efficacy but better tolerability than combination interferon plus ribavirin. 9. In a recent study, posttransplant immunoprophylaxis with polyclonal hepatitis C immunoglobulin had no effect on recurrent viremia or hepatitis.

Gane E, Pilmore H. · New Zealand Liver Transplant Unit, Auckland Hospital, New Zealand. · Transplantation. · Pubmed #12352899 No free full text.

Abstract: Hepatitis C virus (HCV) infection is present in 2-50% of renal transplant recipients and patients receiving hemodialysis. Renal transplantation confers an overall survival benefit in HCV positive (HCV+) hemodialysis patients, with similar 5-year patient and graft survival to those without HCV infection. However, longer-term studies have reported increased liver-related mortality in HCV-infected recipients. Unfortunately, attempts to eradicate HCV infection before transplant have been disappointing. Interferon is poorly tolerated in-patients with end-stage renal disease and ribavirin is contraindicated because reduced renal clearance results in severe hemolysis. Antiviral therapy following renal transplantation is also poorly tolerated, because of interferon-induced rejection and graft loss. Although the prevalence of hepatitis B virus (HBV) infection has declined in hemodialysis patients and renal transplant recipients since the introduction of routine vaccination and other infection control measures, it remains high within countries with endemic HBV infection (especially Asia-Pacific and Africa). Renal transplantation is associated with reduced survival in HBsAg+ hemodialysis patients. Unlike interferon, lamivudine is a safe and effective antiviral HBV treatment both before and after renal transplantation. Lamivudine therapy commenced at transplantation should prevent early posttransplant reactivation and subsequent progression to cirrhosis and late liver failure. This preemptive therapy should also eradicate early liver failure from fibrosing cholestatic hepatitis. Because cessation of treatment may lead to severe lamivudine-withdrawal hepatitis, most patients require long-term therapy. The development of lamivudine-resistance will be accelerated by immunosuppression and may result in severe hepatitis flares with decompensation. Regular monitoring with liver function tests and HBV DNA measurements should enable early detection and rescue with adefovir. Chronic HCV and HBV infections are important causes of morbidity and mortality in renal transplant recipients. The best predictor for liver mortality is advanced liver disease at the time of transplant, and liver biopsy should be considered in all potential HBsAg+ or HCV+ renal transplant candidates without clinical or radiologic evidence of cirrhosis. Established cirrhosis with active viral infection should be considered a relative contraindication to isolated renal transplantation.

Gane E. · NZ Liver Transplant Unit, Auckland Hospital, New Zealand. · J Gastroenterol Hepatol. · Pubmed #10921406 No free full text.

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Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. · Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, University of Paris 7 and INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hepatites Virales, Clichy, France. · N Engl J Med. · Pubmed #19052126 links to  free full text

Abstract: BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV, Di Bisceglie AM, Zeuzem S, Moon YM, Goodman Z, Chao G, Constance BF, Brown NA, Anonymous00003. · University Department of Medicine, Queen Mary Hospital, Hong Kong, China. · N Engl J Med. · Pubmed #18094378 links to  free full text

Abstract: BACKGROUND: Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B. METHODS: In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses. RESULTS: At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov].).

Prati D, Shiffman ML, Diago M, Gane E, Rajender Reddy K, Pockros P, Farci P, O'Brien CB, Lardelli P, Blotner S, Zeuzem S. · Ospedale A. Manzoni, Lecco and IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy. · J Hepatol. · Pubmed #16487620 No free full text.

Abstract: BACKGROUND/AIMS: In chronic hepatitis C, disease progression and clinical manifestations are heterogenous. To clarify the role and interactions of viral and host factors in inducing liver cell injury, we examined the associations of several virological and metabolic variables with serum alanine aminotransferase levels. METHODS: Patients with chronic hepatitis C enrolled in three phase III clinical trials of peginterferon alfa-2a (40KD) plus ribavirin (two studies analysing 'elevated' and one persistently 'normal' alanine aminotransferase) were included. RESULTS: Multivariate analyses of 2,881 patients before treatment and of 1,403 patients with a sustained virological response indicated that gender, viral factors (genotype, HCV RNA titer) and indicators of metabolic syndrome (body mass index, blood pressure, blood glucose, cholesterol and triglyceride concentration) were associated with alanine aminotransferase levels. In addition, hepatitis C virus infection influenced serum lipids concentration according to a genotype-specific effect. CONCLUSIONS: Heterogeneity in alanine aminotransferase levels in patients with chronic hepatitis C partially depends on the degree of derangement of fat and carbohydrate metabolism. As this is the result of an interaction of chronic hepatitis C infection with the patient's individual characteristics, treatment decisions should not be based on alanine aminotransferase level alone but rather on global evaluation of the patient.

Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Gane E, Fried MW, Chow WC, Paik SW, Chang WY, Berg T, Flisiak R, McCloud P, Pluck N, Anonymous00057. · Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China. · N Engl J Med. · Pubmed #15987917 links to  free full text

Abstract: BACKGROUND: Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. METHODS: A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. CONCLUSIONS: In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

Zeuzem S, Diago M, Gane E, Reddy KR, Pockros P, Prati D, Shiffman M, Farci P, Gitlin N, O'Brien CB, Lamour F, Lardelli P, Anonymous00311. · Saarland University Hospital, Homburg/Saar, Germany. · Gastroenterology. · Pubmed #15578510 No free full text.

Abstract: BACKGROUND & AIMS: Patients with chronic hepatitis C and persistently normal alanine aminotransferase (ALT) levels have been routinely excluded from large randomized treatment trials; consequently, the efficacy and safety of antiviral therapy in this population are unknown. METHODS: Patients with at least 3 normal ALT values over an 18-month period were randomized (3:3:1) to treatment with peginterferon alfa-2a 180 mug/wk plus ribavirin 800 mg/day for 24 weeks (212 patients), the same combination for 48 weeks (210 patients), or no treatment (69 patients) in a multinational study. All patients were monitored for 72 weeks. The primary measure of efficacy was sustained virologic response (SVR), defined as undetectable serum hepatitis C virus (HCV) RNA by qualitative polymerase chain reaction at the end of 24 weeks of untreated follow-up. RESULTS: No patient cleared HCV RNA in the untreated control group. SVR rates of 30% and 52% were obtained in the 24- and 48-week treatment groups, respectively. In patients infected with HCV genotype 1, SVR rates of 13% and 40% were obtained with 24 and 48 weeks of treatment, respectively (P < .0001). In patients infected with genotypes 2 or 3, SVR rates were 72% and 78% with 24 and 48 weeks of treatment, respectively (P = .452). Treatment-related flares in ALT activity were not observed. CONCLUSIONS: The efficacy and safety of peginterferon alfa-2a and ribavirin combination therapy in patients with chronic hepatitis C and persistently normal ALT levels are similar to that in patients with elevated ALT levels. The indication for treatment of hepatitis C can be evaluated independently from baseline ALT activity.

Rasenack J, Zeuzem S, Feinman SV, Heathcote EJ, Manns M, Yoshida EM, Swain MG, Gane E, Diago M, Revicki DA, Lin A, Wintfeld N, Green J. · Klinikum der Albert-Ludwigs-Universität, Freiburg, Germany. · Pharmacoeconomics. · Pubmed #12627987 No free full text.

Abstract: BACKGROUND: Use of unmodified interferon alpha-2a in chronic hepatitis C is associated with impaired health-related quality of life during therapy. Treatment with peginterferon alpha-2a (40kD) provides an improved sustained response over unmodified interferon alpha-2a. OBJECTIVES: To compare health-related quality of life during treatment for patients receiving peginterferon alpha-2a (40kD) [Pegasys] versus unmodified interferon alpha-2a [Roferon]. DESIGN: A randomised, international, multicentre, open-label, parallel group study. SETTING: 36 centres worldwide. PATIENTS: Interferon-naïve patients (n = 531) with chronic hepatitis C. INTERVENTIONS: Peginterferon alpha-2a (40kD) 180 mirog once a week (n = 267) for 48 weeks or unmodified interferon alpha-2a 6 million IU three times a week for 12 weeks followed by 36 weeks of 3 million IU three times a week (n = 264). MEASUREMENTS: Fatigue Severity Scale and 36-item Short-Form Health Survey (SF-36). RESULTS: At weeks 2 and 12, differences favouring peginterferon alpha-2a (40kD) were seen on seven of eight domains and both summary scores of the SF-36 (p < 0.05 to p < 0.01). At weeks 2, 12 and 24, patients receiving peginterferon alpha-2a (40kD) had less disabling fatigue (p < 0.01) than those receiving unmodified interferon alpha-2a. CONCLUSION: Treatment with peginterferon alpha-2a (40kD) is associated with less disabling fatigue and less impairment in patient functioning and well-being during treatment than unmodified interferon alpha-2a. In addition to safety and efficacy, the impact on health-related quality of life may be an important consideration for physicians when selecting an optimal treatment regimen.

Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, O'Grady J, Reichen J, Diago M, Lin A, Hoffman J, Brunda MJ. · Klinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany. · N Engl J Med. · Pubmed #11106715 links to  free full text

Abstract: BACKGROUND: Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS: In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS: In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

Zeuzem S, Gane E, Liaw YF, Lim SG, DiBisceglie A, Buti M, Chutaputti A, Rasenack J, Hou J, O'Brien C, Nguyen TT, Jia J, Poynard T, Belanger B, Bao W, Naoumov NV. · Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt a. Main, Germany. · J Hepatol. · Pubmed #19345439 No free full text.

Abstract: BACKGROUND/AIMS: In the GLOBE trial, telbivudine treatment was identified as a significant, independent predictor of better outcomes at 2 years. We analyzed all telbivudine recipients in this trial to determine the predictors of optimal outcomes. METHODS: The intent-to-treat population comprised 458 HBeAg-positive and 222 HBeAg-negative telbivudine-treated patients. Multivariate logistic regression analyses were employed to evaluate baseline and/or early on-treatment variables. RESULTS: Baseline HBV DNA<9 log(10)copies/mL, or ALT levels > or = 2x above normal were strong pretreatment predictors for HBeAg-positive, but not for HBeAg-negative patients. However, non-detectable serum HBV DNA at treatment week 24 (TW24) was the strongest predictor for better outcomes for both groups. A combination of pretreatment characteristics plus TW24 response identified subgroups with the best outcomes: (1) HBeAg-positive patients with baseline HBV DNA<9 log(10)copies/mL, ALT > or = 2x above normal and non-detectable HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 89%, HBeAg seroconversion in 52%, telbivudine resistance in 1.8%; and (2) HBeAg-negative patients with baseline HBV DNA<7 log(10)copies/mL and non-detectable serum HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 91%, telbivudine resistance in 2.3%. CONCLUSION: During telbivudine treatment, non-detectable serum HBV DNA at treatment week 24 is the strongest predictor for optimal outcomes at 2 years.

Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, Heathcote EJ, Manns M, Bzowej N, Niu J, Han SH, Hwang SG, Cakaloglu Y, Tong MJ, Papatheodoridis G, Chen Y, Brown NA, Albanis E, Galil K, Naoumov NV, Anonymous00034. · Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan. · Gastroenterology. · Pubmed #19027013 No free full text.

Abstract: BACKGROUND & AIMS: The GLOBE trial has compared the efficacy and safety of telbivudine versus lamivudine treatment over 2 years in patients with chronic hepatitis B. METHODS: Hepatitis B e antigen (HBeAg)-positive (n = 921) and HBeAg-negative (n = 446) patients received telbivudine or lamivudine once daily for 104 weeks. The primary outcome, assessed in the intent-to-treat population, was therapeutic response (hepatitis B virus DNA <5 log(10) copies/mL and either HBeAg loss or normalization of alanine aminotransferase [ALT] level). RESULTS: The therapeutic response to telbivudine was superior to that of lamivudine in HBeAg-positive (63% vs 48%; P < .001) and HBeAg-negative (78% vs 66%; P = .007) patients. HBeAg-positive patients given telbivudine also had better outcomes compared with lamivudine in terms of nondetectable viremia (< 300 copies/mL) at 55.6% versus 38.5% (P < .001), HBeAg loss at 35.2% versus 29.2% (P = .056), and viral resistance at 25.1% versus 39.5% (P < .001). Hepatitis B e antigen seroconversion was 29.6% versus 24.7% (P = .095) in all patients and 36% versus 27% (P = .022) in patients with baseline ALT level > or = 2 times normal. Telbivudine-treated HBeAg-negative patients showed higher rates of nondetectable viremia compared with lamivudine at 82.0% versus 56.7% (P < .001) and less resistance at 10.8% versus 25.9% (P < .001). Adverse events occurred with similar frequency, whereas grade 3/4 increases in creatine kinase levels were more common in patients given telbivudine (12.9% vs 4.1%, P < .001). Multivariate logistic regression analyses identified telbivudine treatment, among other variables, as an independent predictor of better week 104 outcomes. CONCLUSIONS: Telbivudine is superior to lamivudine in treating patients with chronic hepatitis B over a 2-year period.

Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. · Victorian Liver Transplant Unit, Austin Health, Victoria, Australia. · Hepatology. · Pubmed #18925641 No free full text.

Abstract: Prior to effective prophylaxis, liver transplantation for hepatitis B virus (HBV)-related disease was frequently complicated by recurrence, which could be severe and rapidly progressive. Combination hepatitis B immunoglobulin (HBIG) and lamivudine prophylaxis reduces this rate of recurrence to <5% at 5 years; however, HBIG administration is costly and inconvenient. We conducted a multicenter randomized study of adefovir dipivoxil substitution for low-dose intramuscular (IM) HBIG in patients without HBV recurrence at least 12 months posttransplantation for HBV-related disease. Thirty-four patients were randomized, 16 to adefovir (1 patient withdrew consent at 3 months and is not considered in the results) and 18 to continue HBIG. All continued lamivudine. Groups were well matched by age, sex, and time since transplantation (median, 4.5 years), and background virological risk for HBV recurrence (30% of patients in the adefovir group, 24% in the HBIG group having detectable HBV DNA at transplantation). All patients were alive at study completion without recurrence. One patient in the adefovir group became hepatitis B surface antigen-positive at 5 months but was persistently HBV DNA undetectable via polymerase chain reaction (sensitivity 14 IU/mL) over the following 20 months. Median creatinine was not significantly changed over the course of the study in either group. One patient in the adefovir group with a background of diabetic and hypertensive nephropathy (baseline creatinine 150 micromol/L) developed increased creatinine leading to dose reduction and ultimately cessation of adefovir at 15 months. Yearly cost of combination adefovir/lamivudine prophylaxis was $8,290 versus $13,718 IM HBIG/lamivudine. CONCLUSION: Compared with combination HBIG plus lamivudine prophylaxis, combination adefovir plus lamivudine provides equivalent protection against recurrent HBV infection but with better tolerability and less cost.

Vandepapelière P, Lau GK, Leroux-Roels G, Horsmans Y, Gane E, Tawandee T, Merican MI, Win KM, Trepo C, Cooksley G, Wettendorff M, Ferrari C, Anonymous00441. · GlaxoSmithKline Biologicals, 1330 Rixensart, Belgium. · Vaccine. · Pubmed #18031872 No free full text.

Abstract: Induction of curative immune responses by therapeutic vaccination in chronic viral infections such as chronic hepatitis B (CHB) is expected to be facilitated by reduction of viral load by antiviral treatment. In this open label, controlled, randomized study, 195 patients with HBeAg positive CHB were randomized to receive 12 doses of HBsAg with AS02B adjuvant candidate vaccine plus lamivudine daily for 52 weeks or lamivudine daily alone. The combined administration of vaccine and lamivudine was safe and well tolerated, but did not improve the HBe seroconversion rate (18.8%) when compared to treatment with lamivudine alone (16.1%) (p=0.6824). Despite induction of a vigorous HBsAg-specific lymphoproliferative response, cytokine production and anti-HBs antibodies, therapeutic vaccination with an adjuvanted HBsAg vaccine administered concomitantly with lamivudine did not demonstrate superior clinical efficacy in HBeAg positive CHB patients as compared to lamivudine therapy alone.

Lacey LF, Gane E. · LaceySolutions Ltd, Skerries, Republic of Ireland. · J Viral Hepat. · Pubmed #17927611 links to  free full text

Abstract: The purpose of this study was the economic evaluation of short-duration treatments of chronic hepatitis B (CHB) and longer duration antiviral treatment for up to 5 years. Two 10-health state Markov models were developed for hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients respectively. The perspective of this economic evaluation was the Singapore healthcare system and CHB patient. The models followed cohorts of HBeAg-positive and HBeAg-negative CHB patients, respectively, over a period of 40 years, by which time the majority of the cohorts would have died if left untreated. Costs and benefits were discounted at 5% per annum. Annual rates of disease progression and the magnitude of treatment effects were obtained from the literature, with a focus on data obtained in Asian patients and meeting the criteria for therapy as described in internationally recognized management guidelines. Short-course therapy with alpha-interferon, or 1-year treatment with pegylated interferon alpha-2a, lamivudine or adefovir had limited impact on disease progression. In contrast, treatment of CHB with antiviral therapy for 5 years substantially decreased the rate of disease progression. Treatment with lamivudine for 1-year is highly cost-effective compared with no treatment of CHB but has limited effect on reducing the rate of disease progression. Compared with 1-year treatment with lamivudine, sequential antiviral therapies for up to 5 years (i.e. lamivudine plus adefovir on emergence of lamivudine resistance or adefovir plus lamivudine on emergence of adefovir resistance) are highly cost-effective by international standards. These conclusions are robust to uncertainties in model inputs and are consistent with the findings of other recently published studies.

Bartlett AS, McCall JL, Koea JB, Holden A, Yeong ML, Gurusinghe N, Gane E. · Department of Hepatobiliary and Transplant Surgery, New Zealand Liver Transplant Unit, Level 15, Support Building, Auckland City Hospital, Park Road, Grafton, Auckland, New Zealand. · World J Surg. · Pubmed #17610112 No free full text.

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Treatment options include liver resection, tumor ablation, and liver transplantation. METHODS: We report the results of all patients undergoing partial hepatectomy for HCC with curative intent from a center where all major treatment modalities were available. RESULTS: A series of 53 patients were identified, of whom 72% had underlying liver disease, mostly chronic hepatitis B infection. Altogether, 57% of patients underwent major resections, of whom 43% had histologically proven cirrhosis. Postoperative morbidity and mortality occurred in 41.5% and 7.5%, respectively. After a median follow-up of 34 months, the survival probabilities at 1, 3, and 5 years were 74.1%, 54.1%, and 42.6%, respectively. A total of 47% developed recurrent disease over the study period with a median disease-free survival of 13.8 months. The probabilities of recurrence at 1, 3, and 5 years were 35.2%, 49.4%, and 55.9%, respectively. Among those who developed recurrence, 76% died, with a median time to death from the time the recurrence was diagnosed of 7.8 months. There was a good association between the CLIP score and survival following liver resection. Multivariate analysis showed that only tumor recurrence and the presence of cirrhosis was a significant determinant of the risk of tumor-related death. CONCLUSION: These findings confirm that with careful patient selection liver resection for HCC can achieve good long-term patient survival and acceptable risks.

Abbott W, Gane E, Winship I, Munn S, Tukuitonga C. · New Zealand Liver Transplant Unit, Auckland City Hospital, Private Bag 92-024, Auckland, New Zealand. · Immunogenetics. · Pubmed #17211638 No free full text.

Abstract: Intron 1 of the interferon-gamma (IFNG) gene contains two polymorphisms. The 12 CA-repeat allele of the +875 IFNGCA microsatellite and the T allele of the +A874T single nucleotide polymorphism (SNP) have been associated with increased in vitro IFNG production and a variety of clinical phenotypes. The purpose of this study was to determine whether these polymorphisms influence total serum IgE levels [tsIgE] and the outcome of a hepatitis B virus (HBV) infection. IFNGCA and +A874T were typed in 186 asthmatics of Niuean ancestry and in Polynesian women with a chronic HBV infection (n = 60) and with natural immunity to the HBV (n = 66). The IFNGCA genotype was associated with [tsIgE] in asthmatic children (n = 51, p = 0.004) but not adults (n = 135, p = 0.87). The data were consistent with a co-dominant influence of the 12 CA-repeat allele on high [tsIgE]. The IFNGCA genotype was also associated with the risk for chronic HBV infection (chi (2) = 11.6, p = 0.003) because of a dominant effect of the 12 CA-repeat allele on developing natural immunity in homozygotes (OR = 5.8, p = 0.003) and heterozygotes (OR = 2.7, p = 0.01). Similar associations were found for the T allele of the +A874T SNP. The possibility that these associations were due to linked alleles in the adjacent 783 bp of the promoter and 3'-untranslated region of the IFNG gene was excluded by direct sequencing. In summary, high-IFNG-producing alleles in intron 1 of the IFNG locus are associated with high [tsIgE] in asthmatic children from Niue and with natural immunity to the HBV in Polynesian women. These findings are consistent with a previous report of an association between +875 IFNGCA and [tsIgE] and provide preliminary evidence of a new association with the outcome of an HBV infection.