Recent Research on Treatment of Chronic Hepatitis B1

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Recent Research on Treatment of Chronic Hepatitis B



Introduction



Over the last decade, there has been slow but steady progress in the development of effective treatments for chronic hepatitis B infection.  The rate of progress has clearly accelerated in recent years.  There are now two drugs that have been approved by the FDA for treatment of chronic hepatitis B--interferon alfa-2b (Intron A) and lamivudine (Epivir-HBV).  Both are effective in enhancing seroconversion from HBeAg to HBeAb in patients with active, replicating HBV infection.  At this year’s meeting data were presented on the efficacy of several new nucleoside and nucleotide analogues and on pegylated interferon.  Although many investigators favor the potential use of combination therapy, there were relatively few studies reporting the safety and efficacy of combination therapy for HBV.



Effects of Extended Treatment with Epivir-HBV (Lamivudine)



Histology



At the AASLD 2000 meeting, Dr. Eugene Schiff and colleagues reported improved histological activity index (HAI) scores in HBeAg positive patients treated with lamivudine for up to 2 years.  Their findings showed improvements both in inflammation and also in extent of fibrosis.  In some patients, there was evidence of “regression of cirrhosis” since the improvement in fibrosis was significant enough to revert to an earlier, less severe stage of bridging fibrosis.  These exciting findings were observed in patients both with and without YMDD type drug resistance to lamivudine and suggested that continued treatment might improve liver disease even in the absence of seroconversion.  



Two papers presented at this year’s meeting challenge those observations for the subset of patients who develop YMDD drug resistance.  Dr. Marc Ghany and his colleagues from the NIH reported that only 4/14 HBeAg + patients had sustained improvements in ALT and hepatic histology 4 years after treatment with lamivudine.  None of these 4 had evidence of viral resistance.  One lost HBsAg and stopped therapy.  However, in the 10 who developed resistance to lamivudine, ALT, and fibrosis scores were similar to the pre-treatment biopsies.  (Abstract 606).   



Dr. Nancy Leung and colleagues reported similar experiences in Asian patients who developed YMDD mutations.  During 3 years of treatment with lamivudine, YMDD type drug resistance developed in 56% of Asian patients with HBeAg + chronic HBV.  Liver biopsies at baseline and after 3 years of treatment were evaluated in 62/358 patients originally enrolled in phase III trials.  A small percentage of this group was treated for the first year of the study with placebo before being randomized to lamivudine.  In those without drug resistance, there was significant and sustained improvement in ALT and hepatic inflammation, with no worsening of fibrosis.  In those who developed YMDD mutation, there was a return in ALT elevation and the degree of inflammation was similar to that seen in the baseline biopsy.  In the small group with YMDD resistance for 2-3 years, worsening fibrosis was noted.  (Abstract 707)



Commentary



Unfortunately, the nature of both of these studies was observational and not placebo controlled.  Although the first year of the Asian study had a placebo group for comparison with the treated group, all patients were given lamivudine in the subsequent years of the study, making it difficult to evaluate whether the rate of deterioration in the YMDD resistant group was different from that which might have occurred in untreated patients who therefore would have persistent wild-type viral infection.  For example, in the earlier studies, the incidence of cirrhosis in patients treated with placebo was up to 7%.  It is clear that those individuals who do not develop YMDD resistance during treatment with lamivudine, have a higher rate of HBeAg seroconversion, normalization of ALT and improved histology in both the short and long term.  Those who develop resistance may not enjoy long-term benefits of treatment, but whether their disease progresses more rapidly or is overall worse than those who are not treated remains to be determined.  Unfortunately, this question will be difficult to answer without long-term, placebo controlled studies of the natural history of chronic HBV infection and that is unlikely now that effective treatments are available.











[ 此消息由 liver411 在 2001-11-26.12:53:03 编辑过 ]



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