以下是引用bkcui在2005-12-5 23:00:57的发言：
德国汉诺威医学院肝病学家Michael P. Manns教授对于乙肝治疗的展望
Editor's Note:Chronic hepatitis B remains one of the most common causes of chronic liver disease worldwide, and is associated with a high rate of morbidity and mortality. Although an effective vaccine against hepatitis B has been available for 2 decades, infection with the hepatitis B virus (HBV) still stands as a leading global health problem, with more than 1 million individuals dying each year from its major sequelae: cirrhosis and hepatocellular carcinoma. The overall goal of treatment is to prevent these long-term clinical sequelae by durable suppression of HBV DNA. Conventional interferon-based therapy has been used to treat hepatitis B since the mid 1980s with limited results, and the potential utility of pegylated formulations are now being actively investigated. However, the emergence of a number of nucleotide/nucleoside analogues, showing favorable toxicity profiles, may offer the promise of enhanced antiviral efficacy in patients with chronic hepatitis B. Medscape spoke with Michael P. Manns, MD, Professor, Chairman, and Director, Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany, to explore the current challenges facing the treating physician in managing the patient with hepatitis B, as well as the place of nucleotide/nucleoside analogues and other therapies in the therapeutic armamentarium against HBV infection, with a view toward future challenges.
Medscape: Seroconversion from hepatitis B e antigen (HBeAg) to anti-HBe (ie, antibody to HBeAg) represents the transition from chronic hepatitis B to the inactive hepatitis B surface antigen carrier state, marked by normal alanine aminotransferase levels and low/undetectable HBV DNA. This transition confers a favorable long-term outcome for most patients. However, some patients continue to have or redevelop high serum HBV-DNA and active disease, despite HBeAg seroconversion. Can you briefly discuss the key clinical differences between HBeAg-positive and HBeAg-negative chronic hepatitis B and the differential impact on morbidity and mortality?Dr. Manns: HBeAg is a hepatitis B virus-encoded protein secreted by the infected liver cell into blood. Usually, HBeAg in serum is associated with a high viral titer and active, progressive liver disease. Serum HBeAg loss and development of anti-HBe antibody (seroconversion) is associated with amelioration of disease and a reduction in viral load. This also involves normalization of serum aminotransferases as well as improvement in histology. However, some patients may be HBeAg-negative and anti-HBe-positive yet have high levels of virus and active disease. The latter is due to the presence of a variant form of the virus. The most common of these HBeAg mutations results in the introduction of a premature stop codon in the open-reading frame of the precore region of the virus; this leads to lack of HBeAg secretion into blood. These patients with precore mutant anti-HBe-positive hepatitis B have lower HBV DNA levels than HBeAg-positive patients. However, they suffer from progressive liver disease. Therefore, HBeAg status by itself is not sufficient to evaluate these patients. Apart form transaminases we now measure quantitative HBV DNA levels by real-time PCR technology. It remains a matter of debate whether HBV DNA levels alone can determine indication for treatment.Medscape: There has been marked progress in the treatment of hepatitis B in recent years. The primary goal of treatment is to decrease HBV replication in order to reduce necroinflammation and thus prevent progression of liver fibrosis. Given the current therapeutic arsenal, 2 overall strategies in management may be applied: sustained response following a limited duration of treatment, and a maintained response obtained during therapy. In this setting, can you explain the rationale underlying the use of nucleotide/nucleoside analogues in the management of hepatitis B?Dr. Manns: At present, in contrast to the situation with hepatitis C, we cannot "cure" hepatitis B. The aim of treatment is to enable the immune system to, in turn, control viral infection, and thus progression of liver disease. It would be ideal to achieve a sustained response with a finite course of treatment. This can be achieved in a proportion of patients with a fixed course of interferon-based therapy and treatment with oral nucleos(t)ide analogues 6 months post HBeAg seroconversion. It is difficult to achieve a sustained response in anti-HBe-positive precore mutant disease. In these patients, continuous suppression of viral replication without development of resistance is the most effective approach to prevent progression of liver disease, including cirrhosis, hepatic decompensation, and hepatocellular carcinoma. This has been shown elegantly in a study by Liaw and colleagues.[1]Medscape: Within this setting, the nucleoside analogue entecavir represents the most recently approved agent for the treatment of chronic hepatitis B in adults (as well as in adults with HIV coinfection). During this year's AASLD meeting, Gish and colleagues[2] presented the results of a study looking at the treatment of HBeAg-positive patients with entecavir through 96 weeks of therapy. What can you tell us about this study and what are the implications for clinical practice?Dr. Manns: This is a large phase 3 multicenter and multinational study comparing the most recently approved nucleoside analogue, entecavir, with lamivudine, the first approved oral antiviral hepatitis B agent in this class. Gish and colleagues[2] presented the 2-year results for HBeAg-positive patients treated with either 0.5 mg entecavir or 100 mg lamivudine. They found that entecavir was more effective in suppressing viral replication without development of resistance during the 96-week treatment period. Overall, the authors reported that through 96 weeks of treatment, entecavir was associated with reductions in serum HBV DNA and alanine aminotransferase levels, as well as with continued HBeAg seroconversion.Medscape: Let's discuss the important issue of viral resistance in some depth. The increased use of the nucleos(t)ide analogues, most notably when administered as monotherapy, has led to the emergence of mutations that confer viral resistance. Entecavir has demonstrated potent inhibition against HBV, and there has been no evidence of emerging resistance to entecavir among nucleoside-naive patients after 1 year of treatment. Indeed, high-level entecavir resistance requires preexisting lamivudine resistance substitutions and additional changes in HBV reverse transcriptase residues. During this year's meeting proceedings, Colonno and colleagues[3] presented 2-year data regarding entecavir resistance in nucleoside-treatment naive and lamivudine-refractory patients. What were the key findings of this study and what, in your view, are the clinical implications? What are the potential implications regarding future treatment options for lamivudine-treated patients?Dr. Manns: Colonno and colleagues[3] conducted this study to determine the long-term resistance rates of patients treated with entecavir. Overall, it appears that extended treatment for hepatitis B with entecavir is effective, even among those patients who are resistant to lamivudine. As far as we know, on the basis of data from the 2-year experience with this nucleoside analogue, entecavir resistance does not develop in treatment-naive patients up to 96 weeks. This favorable resistance profile may be due to the strong antiviral efficacy of this agent. However, a proportion of patients pretreated with lamivudine developed resistance. Therefore, entecavir may represent a first-line option in treatment and should not be used to "rescue" patients pretreated with lamivudine and developing resistance in this setting.Medscape: The future of chronic hepatitis B management likely involves the use of combination therapy regimens. Given the ongoing developments in the nucleotide/nucleoside analogue class of therapeutics, how do you view the path forward in this field?Dr. Manns: We now turn our focus to the outstanding challenges in the treatment of hepatitis B. There are currently several agents approved for the treatment of HBV infection, with additional drugs in the pipeline. The majority of the scientific community believes that combination therapy would offer an effective strategy in management, improving the efficacy of treatment and preventing the development of resistance. However, all of the combination regimens tried so far have failed to demonstrate efficacy. Potential reasons for this may be that the studies have included a limited number of patients or were designed relative to one of the drugs under investigation. In my view, future such studies should look at the combination of pegylated interferon alfa and a nucleoside analogue for a finite treatment period (eg, after 48 weeks pegylated interferon should be stopped and the oral nucleoside continued). The study by Marcellin and colleagues[4] has clearly shown that after 48 weeks, viral suppression with pegylated interferon plus lamivudine is greater than with either pegylated interferon or lamivudine alone. However, for this effect to be durable, this regimen must not be stopped, antiviral therapy has to continue (maybe with an oral antiviral or a combination thereof), with neither drug discontinued after 48 weeks.Medscape: Were there any other data presented during this year's AASLD meeting that would help put this information into better clinical context?Dr. Manns: In another study presented during this year's AASLD meeting, Hadziyannis and colleagues[5] demonstrated the long-term efficacy of the nucleotide analogue adefovir. They found that treatment with adefovir 10 mg/day for 5 years was associated with significant and increasing improvement in hepatic fibrosis. The agent was overall well tolerated, and the cumulative adefovir resistance rate after 5 years was 29%. These findings again support the potential of combination treatment in the future, because the mutations seen with adefovir treatment differ from those associated with lamivudine and other nucleos(t)ide analogues. In another study warranting mention, Lai and colleagues[6] looked at the efficacy of telbivudine, a novel oral antiviral drug with activity against hepatitis B, vs lamivudine, based on data from a large phase 3 study (the GLOBE trial). Our center also contributed to this study. Overall, results showed that telbivudine was associated with significantly greater antiviral efficacy compared with lamivudine, with a lower rate of associated resistance. Interferon-based therapy, which is associated with adverse effects, doesn't appear to demonstrate viral resistance. Therefore, this beneficial effect of interferon with respect to resistance development may be used in combination strategies with oral nucleos(t)ide analogues. There are also promising data regarding the use of therapeutic vaccines to induce HBV-specific T-cell responses.[7] Hopefully, an optimal use of combination therapy involving interferons, oral nucleos(t)ide analogues, and therapeutic vaccines will lead to the overall goal in the treatment of chronic hepatitis B -- namely, HBsAg seroconversion, which is the closest outcome to "cure."
发表于 2005-12-6 10:02
