Recent Research on Treatment of Chronic Hepatitis B 7-->可可转移

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Treatment of HBeAg Negative, HBV DNA Positive Chronic Hepatitis B With wild-type hepatitis B infection, HBeAg is associated with active replication of the virus. However, naturally occurring mutations of HBV that result in a loss of E antigen with continued replication have been described. Both the pre-core and the core promoter mutants continue to replicate and cause necroinflammatory disease in the absence of expression of HBeAg. In some individuals, these mutants develop as a later phase of the natural history of the infection. Unfortunately, progression of liver disease and cirrhosis can occur either before or after development of the mutants. Although HBV DNA levels give a good indication of the extent of replication, the absence of HBeAg makes establishing a serological endpoint for treatment difficult. Several studies at this year’s meeting reported results of lamivudine treatment of HBeAg negative, DNA + CHB. The percentage of patients with normal ALT and undetectable DNA are summarized in the table below (Abstract 604 presented results of emtricitabine, FTC and is included for comparison): Year 1 Year 2 Year 3 Abstract ALT DNA ALT DNA ALT DNA 598 90% 69% 79% 54% 69% 44% 605 82% 59% n/a n/a n/a n/a 613 87% 84% 92% 75% n/a n/a 1097 65% 66% 47% 43% 33% 64% 604 95% 00% n/a n/a n/a n/a FTC 200 mg Dr. Esteban and colleagues presented results of extended lamivudine therapy on liver histology as measured by hepatic activity index (HAI). 57% of patients developed YMDD mutations during the 3-year period of treatment. Of those with YMDD, 4/14 (29%) progressed to bridging fibrosis, whereas none of the patients without YMDD progressed. 8/18 patients with fibrosis at baseline showed improvement in fibrosis, 25% (2/8) of whom were YMDD positive. Necroinflammatory disease was worse in 7/26 that were YMDD positive and only in 1/22 without YMDD mutation. Although progression was noted only in a minority of patients with YMDD, these findings indicate a clear advantage to those without the mutation. (Abstract 1097) In a similar study, Dr. Andreone and colleagues reported histological improvement (2 pt change in HAI) in 11/14 patients treated with lamivudine for 2 years. Of those who improved, 8/11 were YMDD + and 3/11 were negative. Worsening occurred in 1 patient from each group. However, 2/16 patients with genotypic resistance decompensated after development of YMDD. (Abstract 598) In a study of Chinese patients, YMDD resistance rates were 16% at one year and 36% after 2 years of continuous lamivudine therapy. None of the patients decompensated after developing YMDD mutations. Furthermore, most patients maintained both virologic and biochemical responses after 2 years. (Abstract 613) Tassopoulos and colleagues found improvement in HAI necroinflammatory score in 73% and improvement in fibrosis score in 38% after 1 year of treatment with lamivudine. Commentary HBeAg negative/HBV DNA positive phase of chronic hepatitis B is associated with mutations that make treatment endpoints difficult to establish. At this time, most treatment studies have been conducted for a relatively short time. Although early results are quite promising, longer duration of therapy will be needed to assess the impact on the natural history of infection. In addition, larger numbers of patients with and without cirrhosis will be needed to determine whether pre-treatment histology (i.e. pre-existing cirrhosis) is a major determinant of outcomes such as decompensated liver disease, etc. However, the bulk of the evidence suggests that this condition is not always benign, particularly in the subset with significant elevation of both ALT and DNA. This subgroup is probably most in need of long-term treatment to prevent adverse outcomes of chronic liver disease. Need for Vaccination of Patients with Chronic HCV Against HBV Infection Several recent studies have observed increased morbidity and mortality from acute hepatitis A infection in patients with chronic hepatitis C. Although there was evidence of worse outcome of liver disease in patients with HBV/HCV coinfection, there was relatively little data regarding the outcome of acute hepatitis B infection in those with chronic HCV. Sagnelli, et al reported a case control study of acute HBV infection in 19 patients with chronic HCV and 19 age-matched control subjects with acute hepatitis B and 19 with chronic HCV without evidence of acute HBV. The major findings were 1) suppression of HCV replication with lower titers of HCV RNA during acute HBV infection and 2) severe (decompensated) liver disease in 5/19 patients with chronic HCV infection. Only 1/19 developed combined chronic HBV/HCV coinfection. Furthermore, there was sustained suppression of HCV replication in 5/9 patients who developed acute HBV for more than 5 months. The significant frequency of severe liver disease in this population adds support to unofficial recommendations for HBV vaccination of patients with chronic HCV infection. (Abstract 568) References Andreone P and others. Response to extended lamivudine treatment of HBeAg negative chronic hepatitis B. Abstract 598. Barbarini G and others. 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. Abstract 586. Cooksley WGE and others. KDA peginterferon alfa-2A (Pegasys®: Efficacy and safety results from a phase II, randomized, actively controlled, multicenter study in the treatment of HBeAg positive chronic hepatitis B. Abstract 710. Esteban R and others. Clinical & histological outcome of extended lamivudine in patients with HBeAg negative chronic hepatitis B. Abstract 1097. Fung SK and others. Lamivudine treatment in Chinese patients with HBeAg negative chronic hepatitis B: indefinite vs finite duration of therapy. Abstract 613. Ghany MG and others. Changes in liver histology after four years of lamivudine therapy in chronic hepatitis B. Abstract 606. Gish R and others. HBeAg Profile in patients with chronic HBeAg+ hepatitis B (CHB) treated with emtricitabine (FTC) for 1 year. Abstract 578. Heathcote EJ and others. Serum HBV DNA suppression and seroconversion following long-term adefovir dipivoxil therapy in chronic hepatitis B patients. Abstract 575. Hou J and others. Hepatitis B virus genotypes and response to interferon alpha treatment in chronic hepatitis B. Abstract 1100. Jonas MM and others. A follow-on study in children with chronic hepatitis B (CHB) who completed a placebo controlled lamivudine study – A 6-month interim analysis. Abstract 707. Lai C and others. Safe and potent suppression of hepatitis B virus (HBV) with l-deoxythymidine (LDT): Results of a dose-escalation trial. Abstract 597. Lai M and others. Efficacy of interferon alfa plus ribavirin versus interferon alone in the treatment of hepatitis B E antigen-positive patients with chronic hepatitis B. Abstract 591. Leung N and others. A randomized, double-blind, comparison of 3 doses of emtricitabine (FTC) in patients with chronic hepatitis B (CHB) given 48 weeks of treatment (FTCB-102). Abstract 709. Leung NW and others. Durable HBeAg response in Chinese patients treated with lamivudine. Abstract 705. Marcellin P and others. Anti-HBV activity and tolerability of clevudine, a novel nucleoside analogue: initial results of a phase I/II 28-day study. Abstract 593 Marcellin P and others. GS-98-437 A double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) for the treatment of patients with HBeAg+ chronic hepatitis B infection: 48 week results. Abstract 674. Morrissey DV and others. Combination of HepBZyme™, and Anti-HBV nuclease resistant ribozyme, with lamivudine or interferon improves inhibition of HBV replication in cell culture. Abstract 1101. Negro F and others. The hepatitis C virus replication in vivo results in the transcription of a huge excess of subgenomic, possibly defective RNAS. Abstract 697. Perrillo R and others. The addition of adefovir dipivoxil to lamivudine in decompensated chronic hepatitis B patients with YMDD variant HBV and reduced response to lamivudine-preliminary 24-week results. Abstract 708. Sagnelli E and others. Acute hepatitis B in HCV chronic carriers: virological interaction on clinical course. Abstract 568. Schiff ER and others. Safety and Efficacy of adefovir dipivoxil for the treatment of lamivudine resistant HBV in patients post liver transplantation. Abstract 1098. Sung Pil H and others. Additional lamivudine therapy after HBeAg seroconversion would prolong the durability of response in HBV endemic area. Abstract 600. Tassopoulos N and others. Entecavir is effective in treating patients with chronic hepatitis B who have failed lamivudine therapy. Abstract 673. Westland CE and others. Week 48 resistance surveillance in chronic hepatitis B patients enrolled in a phase III clinical study of adefovir dipivoxil. Abstract 1099. Willems B and others. Three-year durability of HBeAg and HBsAg seroconversion after lamivudine for chronic hepatitis B (CHB). Abstract 574. Yang H and others. Resistant monitoring in chronic hepatitis B patients exposed to adefovir dipivoxil for 72 to 136 weeks. Abstract 577. 摘自美国52届肝病会议,11/09-11/13, 2001 德州, Dallas