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发表于 2002-6-18 02:57
| 刚刚在旧金山召开的 "2002年消化周大会" 对于乙肝治疗的回顾,展望写了几个重点, 看看大家谁有时间可翻译参考. 谢谢)
A Review of Selected Highlights on Treatment of Chronic Hepatitis B from Digestive Disease Week 2002
By Mack Mitchell, Jr, MD
Chronic hepatitis B infection remains a major problem worldwide. The magnitude of the problem and the increased understanding of the molecular biology of the hepatitis B virus are leading to a number of promising new treatments for this problem.
In many instances, the same drugs which have been developed for HIV infection are proving valuable in the treatment of chronic hepatitis B. Since being licensed for use in hepatitis B, lamivudine (Epivir-HBV) has become the most widely used first line agent for treatment of chronic HBV infection in the U.S. Interferon-alpha is also still used for treatment of the pre-cirrhotic stages of chronic hepatitis B. Meanwhile there are several promising new antiviral drugs in various stages of development.
Natural History of Hepatitis B Infection
Should Epivir-HBV (Lamivudine) Therapy Be Continued after Emergence of YMDD Resistance?
Combination Therapy for HBV
Combination Therapy for HBV/HIV Coinfection
New Treatments for Chronic Hepatitis B Infection
Natural History of Hepatitis B Infection
Several studies at this year’s DDW meeting reported information about the risk of complications related to chronic HBV infection and the long term prognosis. In Italy, a cohort of volunteer blood donors who tested positive for HBsAg at the time of donation were studied to determine the natural history of hepatitis B infection. The donors were not proven to have chronic hepatitis at the time of donation. At the time of follow-up, 30 years later, 67% remained positive for HBsAg, but 22% had antibodies to HBs. 42% were HBV DNA positive by PCR, including 11% who were HBsAg negative at follow-up. Liver-related morbidity and mortality (1%) was very low in this population. Although some members of this cohort may not have had chronic hepatitis B at the time of original identification, the prognosis of hepatitis B infection in this population was not as ominous as has been reported in other populations that may have been infected at an earlier age (Abstract 85).
Several reports have recently investigated the influence of HBV genotype on the natural history of HBV infection, the risk of complications and the response to antiviral therapy. The authors of this report add further data to support the association between HBV genotype C and development of HCC. In their multivariate analysis of 100 patients with chronic HBV infection followed prospectively, genotype C had the highest proportional hazards ratio (6.06) of predicting development of HCC. Age was also implicated as a risk factor which is not surprising since most of those individuals studied presumably acquired hepatitis B infection in the neonatal period. While these findings are intriguing and consistent with other reports, the molecular basis for these differences is not yet clear. Further studies will be needed before the true importance of genotype in determining outcome of HBV is fully understood (Abstract T1354).
Should Epivir-HBV (Lamivudine) Therapy Be Continued after Emergence of YMDD Resistance?
Perhaps the most controversial topic in treatment of chronic hepatitis B is whether therapy with lamivudine should be continued after the emergence of YMDD mutation.
Prior studies have shown a progressive increase in the percentage of HBeAg seroconversion during continued treatment even after the emergence of YMDD mutation. However, there have also been reports of worsening liver disease, particularly in those with advanced liver disease after YMDD mutation.
After emergence of YMDD mutation, lamivudine was continued in 66 patients and discontinued in 62. However, the decision to discontinue lamivudine was not randomized, but was determined by patient and physician preference. Outcomes in these two groups were compared. ALT flares and evidence of hepatic decompensation were similar in both groups as was the frequency of HBeAg seroconversion.
Based on these findings, the investigators concluded that there was no advantage to continuing therapy with lamivudine beyond the emergence of YMDD mutation. Although this study was relatively large, it should be noted that the decision to stop therapy was not randomized which makes comparison more difficult (Abstract 88).
One of the primary concerns about using lamivudine to treat HBV infection in patients with advanced liver disease is that emergence of YMDD mutants will adversely impact on the course of HBV post-transplantation.
The authors report their experience with 6 patients who were treated with lamivudine prior to transplantation. 3/6 had YMDD mutants before transplantation. All patients received a combination of lamivudine and anti-HBS after transplantation. Outcomes in this small group were similar in those with and without YMDD mutations. There were no clinically significant relapses of HBV in any of the patients in this study (Abstract T1425).
Combination Therapy for HBV
The investigators reported results of a trial of lamivudine monotherapy versus sequential combination therapy with lamivudine alone for 2 months followed by lamivudine plus 5 MU PEG-Intron (interferon alfa-2b) daily for 4 months, followed by lamivudine alone for the remainder of 1 year.
Normalization of ALT was similar (60%) in both groups. HBeAg seroconversion occurred in 17.6% of those on lamivudine monotherapy and 40% of those on combination therapy. 3 months after therapy was discontinued, an additional 2 patients in the combination therapy group seroconverted (total of 53%) which became statistically different from lamivudine monotherapy. One patient in the combination therapy group also lost HBsAg. Somewhat surprisingly, YMDD resistance was greater in the combination therapy group and occurred at an earlier time than in those on lamivudine monotherapy.
Although there was no significant difference in the rate of HBeAg seroconversion between lamivudine monotherapy and sequential combination therapy with interferon in the U.S. registration trials of lamivudine, many investigators still feel that the combination of lamivudine and interferon is promising. Clearly the number of patients treated in this study is small in comparison to the large number in the multicenter US trials. However, further evaluation of this combination seems warranted since results of several studies are conflicting (Abstract T1361).
Combination Therapy for HBV/HIV Coinfection
The investigators reported a small, uncontrolled trial of the combination of Famvir 500 mg BID and lamivudine 150 mg BID in 21 patients. 10/21 experienced a > 3 log reduction in HBV DNA. 7 had undetectable HBV DNA. Median CD4 counts were 350 in both responders and non-responders. Responders tended to be younger than non-responders, but no other differences between the two groups were observed. As noted by the authors, more effective combination therapy is needed for HIV/HBV co-infected patients (Abstract M1462).
New Treatments for Chronic Hepatitis B Infection
Although there are currently several nucleoside and nucleotide analogues with efficacy against HBV either in use or in development, lamivudine has become the standard against which other drugs are compared for several reasons. It is a very safe and easily tolerated medication with relatively few side effects.
New drugs are still needed for HBV since resistance to lamivudine develops in a substantial minority of patients treated for more than one year. LY582563 (MCC 478) is a new drug that was studied in 64 HBV DNA positive patients, 75% of whom were also HBeAg positive. In vitro, it h |
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