53rd AASLD: Treatment of Hepatitis B Infection

liver411

  

53rd American Association for the Study of Liver(AASLD)
   Diseases Annual Meeting
   November 1-5, 2002, Boston MA

By Mack C. Mitchell, MD



Introduction
     
The last 5 years represent an exciting period in the understanding and treatment of chronic hepatitis B infection.  In this time, the efficacy of treatment of chronic hepatitis B infection has increased dramatically.  

Nucleoside analogues and interferon-Alfa are both effective in treatment of HBV.  The lower side effect profile of the nucleoside analogues has made them preferred agents for first-line therapy, although concerns about resistance developing during monotherapy has tempered enthusiasm somewhat.

At this year’s meeting of the 53rd AASLD, there were several reports on newer nucleoside analogues including Hepsera (adefovir dipivoxil), entecavir, Coviracil (emtricitabine; FTC) and telbivudine (formerly LdT), and a report on Pegasys (pegylated interferon-alfa 2a) as well as follow-up studies on the use of Epivir-HBV (lamivudine; 3TC).   




Phase III Trial of Hepsera (Adefovir Dipivoxil) in Treatment of Lamivudine-Resistant HBV (Abstract 831)

Epivir HBV (lamivudine) is currently the standard of care for pre- and post-transplant treatment of advanced chronic hepatitis B infection.  Treatment with lamivudine is effective in preventing hepatic decompensation in most patients pre-transplant.  The combination of lamivudine and treatment with HBIG is highly effective in preventing recurrence of hepatitis B after liver transplantation.  The main drawback to lamivudine monotherapy is development of resistance (YMDD) in a significant percentage of patients.  

Dr. Schiff and colleagues reported experience in an open-label, non-randomized trial of adefovir dipivoxil for treatment of patients who had developed resistance to lamivudine.  ALT normalization was achieved in 60% of both pre- and post-transplant patients.  

Undetectable levels of HBV DNA (< 400 copies/ml) were achieved in up to 50% of patients after 48 weeks and up to 70% after 96 weeks.  

The median reduction in DNA levels was 4.1 logs after 48 weeks.  Serum creatinine elevations were noted in a proportion of patients, most of whom also had multiple risk factors for renal damage such as concomitant use of nephrotoxic immunosuppressants.  Overall 2% discontinued treatment due to renal toxicity.  

These findings indicate that adefovir is effective in treatment of patients with lamivudine resistance, but remind us of the need to monitor carefully for nephrotoxicity during therapy.  


Effects of Adefovir on Liver Histology and Viral Suppression at 48 Weeks (Abstract 840 and 841)

Analysis of the first year of the phase III trial of adefovir in patients with HBeAg + CHB was presented by Dr. Goodman and colleagues.  Primary endpoints in the trial included a two-point reduction in the inflammatory component of the Knodell HAI score.  This was achieved in 53% (p = NS) of patients treated with adefovir 10 mg daily and 59% (p < .0001) of those treated with 30 mg daily compared to 25% of placebo treated patients.   

Improvement in the 6-point Ishak fibrosis score was also evaluated.  Improvement of > 1 stage was seen in 35% of those treated with 10 mg daily and 41% of those treated with 30 mg daily.  Significant improvements in the overall fibrosis scores (2.20 pre to 1.95 post-treatment) were seen in the 10 mg daily group.  In addition, fewer patients treated with adefovir (11%) showed evidence of worsening compared with those on placebo (22%).

After 48 weeks, the HBeAg seroconversion rate was 12% for the 10 mg daily group compared to 6% of those on placebo. Seroconversion increased to 20% after 72 weeks.  HBeAg loss was much higher—24% at 48 weeks and up to 40% at 72 weeks.  ALT normalization was observed in 48% of the 10 mg daily group compared to 16% of placebo recipients.  HBV DNA was < 400 copies/ml in 21% of patients on adefovir and an additional 21% of 71 patients who continued therapy beyond 48 weeks had undetectable levels of HBV DNA.

Of note, no resistance to adefovir was observed in any patients during the entire duration of the study, which is a distinct difference from the results reported previously for lamivudine monotherapy.  

The Roche Amplicor assay is much more sensitive than the Abbot hybridization assay used in the original lamivudine studies which makes direct comparison of the results of those trials with this one problematic.  In the lamivudine trials, the 52-week seroconversion rates were somewhat higher (15-16%) in the treated group with a similar rate of seroconversion (4-5%) in the placebo group.  

Direct comparison between lamivudine and adefovir was not included and it is hard to know whether the study populations were comparable.  Since seroconversion rates are highly dependent on pre-treatment ALT levels, the differences may not be clinically important.


Eradication of cccDNA from the Liver in Patients on Adefovir (Abstract 534)

Complete eradication of HBV has proven to be a difficult problem despite the availability of several anti-viral agents that are potent inhibitors of viral replication.  In part, HBV is difficult to eradicate because of the persistence of the covalently closed circular DNA (cccDNA) which serves as the template for viral replication.  Measurement of this pool of HBV requires liver biopsy since the cccDNA does not circulate in the plasma.  In general, very little is known about how this pool of virus is affected by antiviral therapy.  

During the phase III trial of adefovir dipivoxil, cccDNA was measured in liver biopsy specimens obtained at baseline and after 48 weeks of therapy with adefovir.  Interestingly, those patients who seroconverted had lower baseline levels of cccDNA (median 0.62 copies/cell) than those who did not seroconvert (1.66 copies/cell).  Treatment with adefovir lowered cccDNA to a similar extent in both groups (93% vs 83%).  Final levels of cccDNA as well as the baseline levels were lower in the seroconverters than in those who had persistent HBeAg.  At this time, it is unclear whether cccDNA levels must be lowered below a particular range to achieve a sustained response, but the results are intriguing.  


Entecavir for Treatment of Lamivudine-resistant Chronic HBV (Abstract 550)

Entecavir is another one of the next generation of nucleoside analogues with potent, anti-HBV activity now in clinical trials for treatment of chronic HBV infection.  This report is from an international, multicenter trial of entecavir in patients who failed therapy with lamivudine based on either the presence of YMDD mutation OR with persistently positive serum HBV DNA (> 10 mEq/ml on the Quantiplex bDNA test) AND persistent elevation of ALT after at least 24 weeks of treatment with lamivudine.  

181 patients were divided into 4 groups (.1, .5 and 1.0 mg entecavir daily or continued treatment with lamivudine 100 mg daily) for 48 weeks of treatment.  Results are summarized in the table below:

Drug                ALT Normal      HBV DNA log decrease         HBV DNA negative
Entecavir 1 mg       43%*                   2.78*                                    4%
Entecavir .5 mg      59%*                   4.46*                                  26%*
Entecavir 1.0 mg    68%*                   5.11*                                  26%*
Lamivudine 100 mg 4%                     1.41                                      4%


p < .05

These findings suggest that entecavir is effective in treatment of patients who have developed YMDD resistance to lamivudine.  Results of seroconversion are not yet analyzed, but will be presented within the next few months, perhaps at EASL.  Within the time of study, no patients developed evidence of resistance to entecavir.  

Side effects were similar in all groups and included headache, abdominal pain and fatigue.


Emtricitabine Follow-on Study for Treatment of Chronic HBV for 96 weeks (Abstract 838)

Emtricitabine; FTC (Coviracil) is a nucleoside analogue that is structurally similar to lamivudine.  Results of an open label follow-on study for an additional period (96 weeks) were reported at this year’s meeting.  The original phase III RCT was conducted for 48 weeks.  During the first year, 50% of patients lost HBeAg, 23% seroconverted to HBeAb and HBV DNA decreased by a median of 2.92 log and was undetectable (< 4700 copies/ml) in 55%.  Resistance to emtricitabine developed in 6% of those treated.  Because of the structural similarity of emtricitabine, it is unlikely to be effective in treatment of YMDD-lamivudine resistant HBV.  

Sustained virologic responses were observed in 41% of patients with 19% resistance after 96 weeks of therapy.  Favorable serological responses including a seroconversion rate of 29% and HBeAg loss of 51% were also reported.  Unfortunately, the study design allowed inclusion of a significant number (64 pts) who had not previously been treated with a nucleoside analogue.  Those patients who developed resistance experienced an increase in ALT, but had a favorable evolution.

The rate of seroconversion observed in the randomized controlled trial makes this nucleoside an interesting possible addition to the therapeutic options for treatment of chronic HBV.   However, longer experience will be needed to determine whether the rate of resistance increases further with prolonged therapy.


Telbivudine for Treatment of Chronic HBV (Abstract 554)

Telbivudine (LdT), a small nucleoside analogue, is a potent inhibitor of HBV polymerase in vitro.  The results of a phase II dose escalation study indicated that 400-600 mg/day rapidly reduced HBV DNA levels by 3-4 logs from baseline values.  104 HBeAg positive patients with elevated ALT were enrolled in a phase IIb trial to receive LdT 400 or 600 mg daily alone or with lamivudine 100 mg daily for 24 weeks.  

                                3T    LdT400   LdT600   LdT400 + Lam   LdT600 + Lam
Median log10 drop 4.67    6.08        6.11         6.21                      6.15

HBV neg by PCR     16%    41%        23%        29%                      35%


As shown in the table above, Telbivudine resulted in a dramatic decrease in the HBV DNA levels within a relatively short time.  ALT normalized in 70-80% of all groups over the same 24 week interval.  Previous data have suggested that rapid decrease in HBV DNA leads to a much lower rate of development of resistance and may also translate into a higher rate of seroconversion.  The follow-up from this study is not yet long enough to determine rates of HBeAg seroconversion or to know about the pattern of resistance that may or may not develop.  However, the rapid decrease in HBV DNA is an exciting observation.  


Treatment of HBeAg Negative, HBV DNA positive Chronic HBV with Lamivudine (Abstract 835)

In some patients with chronic HBV, active viral replication continues after HBeAg seroconversion.  Active viral replication in this group usually indicates the presence of the pre-core or core promoter mutation, which allows the intact virus to be made without expressing the E antigen.  Since these patients can have progressive liver disease, treatment may be warranted.

This study reported experience in treating HBeAg negative, HBeAb positive, HBV DNA positive chronic hepatitis B.  Lamivudine (100 mg) was given daily for an average of 24 months.  421/443 patients had an initial virologic response, which was 88% at 1 year and decreased to 66.2% at 2 years, 51.5% at 3 years and 42.5% at 4 years.  During therapy YMDD resistance developed in 31.4% of patients.  In 34/139 patients a flare in hepatitis (elevated ALT) occurred.  

The outcome of these flares in ALT depended on the baseline histology and clinical status of patients.  In those with only chronic hepatitis, there were no cases of hepatic decompensation, but in those with Childs A cirrhosis, 6/15 (40%) developed decompensation and 2/15 (13%) died.  Even worse outcomes were seen in those with more advanced disease, 4/5 patients with Childs B/C cirrhosis decompensated and 3/5 died.  Hepatocellular carcinoma developed in 4.6% of those without YMDD and in 10.7% of those with YMDD mutations (results were not statistically significant).  

These observations highlight the importance of the extent of liver disease at baseline in determining the ultimate outcome of HBV with or without treatment.  Other studies have shown clearly that lamivudine can improve clinical status (decrease Childs-Pugh scores) and reduce fibrosis.  However, this study sounds a cautionary note for physicians who are following patients with advanced stages of HBV.  Any evidence of elevation of ALT should be monitored carefully and alternative therapy such as adefovir should be considered if there are signs of hepatic decompensation.  

Lamivudine for the Treatment of Fulminant Hepatitis B Infection (Abstract 848)

Fulminant hepatitis B is a rare (1%) complication of acute hepatitis B infection.  The mortality rate for fulminant hepatitis B is approximately 50% without liver transplantation.  Lamivudine has been shown to be very effective in treatment of chronic hepatitis B infection, including those patients with advanced liver disease, but has generally not been used for treating acute hepatitis B, which is usually a self-limited illness.  

Tillman and colleagues reported that lamivudine treatment significantly reduced the length of stay in the ICU (5.4 ± 5.9 days for lamivudine vs 21.2 ± 28.8 days for standard therapy) and the need for liver transplantation (16/21 with standard therapy vs 1/8 lamivudine treated).  Although the study was not randomized, the differences between the groups were both statistically significant and impressive.  These findings justify a randomized controlled trial of lamivudine or other antiviral agents given the shortage of donor organs for transplantation which is needed in many patients with fulminant hepatitis B infection.


Prevention of Reactivation of Hepatitis B in Patients Treated with Chemotherapy (Abstract 836)

The immune system plays an important role in suppressing replication of hepatitis B in patients, who remain HBsAg positive, with chronic hepatitis B.  Previous studies have reported relapse of clinical hepatitis in patients who have been treated with anti-neoplastic chemotherapy or other immunosuppressive regimens.  Viral replication is reactivated during the time of immunosuppression and when discontinued, the larger amount of virus present stimulates an exaggerated immune response that can lead to severe exacerbations in chronic hepatitis.  Since lamivudine is effective in suppressing viral replication, the investigators reasoned that pre-treatment with lamivudine before administration of chemotherapy might prevent serious relapses following chemotherapy.  

Patients were treated either with lamivudine before beginning chemotherapy or at the time of diagnosis of reactivation of hepatitis B infection.  One of the 11 patients pre-treated with lamivudine had evidence of clinical hepatitis, whereas 5/11 not pre-treated developed reactivation hepatitis that was severe in 3 patients with a fulminant course in 1/3.  On the basis of this observation, the authors concluded that lamivudine pre-treatment was preferable to waiting for evidence of reactivation in patients with chronic HBV undergoing chemotherapy.


Pegylated (40 kDa) Interferon-alfa 2a (Pegasys) for Chronic HBV Infection (Abstract 846)

Although much of the recent attention has been focused on nucleoside analogues for treatment of CHB, interferon remains an alternative therapy.  Patients and physicians have generally resisted use of interferons because of expense, side effects and the fact that it must be administered by injection.  Furthermore, standard interferon dosing regimens were not very effective in producing HBeAg seroconversion in patients with low ALT and high HBV DNA levels.  

The advent of pegylated interferons has simplified treatment to a once weekly injection regimen that appears to have somewhat fewer side effects than the high dose (5 MU) daily injections of α-interferon.  

Cooksley and his colleagues reported on the use of 40 kDa pegylated α-interferon 2a (Pegasys) for treatment of HBeAg positive CHB. Patients were given weekly injections of 90, 180 or 270 μg of Pegasys or 4.5 million units three of interferon α2a, three times weekly for a total of 24 weeks.  

At the end of an additional follow-up period of 24 weeks, 24% of patients treated with Pegasys had lost HBeAg, normalized ALT and suppressed HBV DNA to < 500,000 copies/ml (Roche Amplicor assay) compared with 12% of those treated with standard α-interferon 2a (p < .05).  

Subset analysis indicated that patients with ALT > 5 x ULN had the highest rates of HBeAg loss, suppression of HBV DNA and normalization of ALT (29%), with similar results for both Pegasys and interferon alfa-2a.  However, patients with ALT 2-5 x ULN and < 2 x ULN derived more benefit when treated with Pegasys compared with the standard interferon.  

The combined response of HBeAg loss, HBV DNA suppression and normalization of ALT occurred in 27% vs 11% for ALT < 2 x ULN and 22% vs 7% for ALT 2-5 x ULN for Pegasys-treated patients. A similar observation of improved efficacy was noted in those patients with high DNA levels.  

Several points are worth noting about these findings.  

Although statistical significance was not achieved in the subset analyses because of relatively small numbers, the results are intriguing.  There is a clear suggestion that those patients who are traditionally most resistant to treatment (high DNA levels and low ALT) are the ones who will benefit the most from pegylated interferon.  This is an important observation if it holds up since there are many patients who fall into this category and were previously not believed to be good candidates for lamivudine or standard interferon dosing because of lack of efficacy.  

Although seroconversion to HBeAb was not reported, the loss of HBeAg and ALT normalization was relatively high (comparable to nucleoside analogues).  Presumably, as reported with other studies of interferon treatment in CHB, seroconversion to HBeAb may be delayed for up to 1 year after completion of therapy.  

It was somewhat surprising that suppression of HBV DNA to < 500,000 copies was used as an endpoint, since most recent studies of adefovir and other nucleoside analogues have used detection limits of < 400 copies/ml as an endpoint.  


Conclusions

In 2002, we finally have several options for the treatment of chronic hepatitis B infection.  Two nucleoside analogues (lamivudine and adefovir dipivoxil) and interferon alfa-2b (PEG-Intron) are FDA-approved for therapy.  The nucleoside analogues can be taken orally and have fewer short-term side effects than interferon, but require a longer course of treatment to achieve HBeAg to HBeAb seroconversion.  

Patients on lamivudine (Epivir-HBV) monotherapy develop resistance with courses of treatment more than 6-12 months, with rates approaching 60% after 4-5 years of therapy.  However, seroconversion can occur after development of resistance.  

Resistance to adefovir has not yet been reported, but the rate of seroconversion is somewhat lower than for lamivudine. The potential for adefovir-associated nephrotoxicity requires cautious use in patients with pre-existing renal disease or who are at high risk for developing kidney problems.  Other patients tolerate the approved dose of 10 mg daily with relatively few side effects.  

The course of interferon is shorter (4-6 months) with seroconversion rates similar to 1 year on nucleoside analogues (15-20%), but short-term side effects of fatigue, arthralgias, headache, fever, etc make some patients reluctant to complete therapy.  

While side effects of the pegylated interferons are similar, the seroconversion rates may be higher, particularly for the high HBV DNA, low ALT subgroup.  The highest response rates for all drugs are seen in those patients with ALT > 2 x ULN and active inflammation on liver biopsy.  Because of the risk of progression of disease in this group, strong consideration should be given to treatment with one of the 3 available drugs or inclusion in a clinical trial of newer agents.


References

AASLD 2002 all rights resrved

龙漂飘

仅翻译结论部分

In 2002, we finally have several options for the treatment of chronic hepatitis B infection.
2002年，我们最终发现很多的可以选择的药物来治疗HBV感染。

Two nucleoside analogues (lamivudine and adefovir dipivoxil) and interferon alfa-2b (PEG-Intron) are FDA-approved for therapy.
两个核苷类似物（拉米和阿德福韦adefovir dipivoxil）和a-2b干扰素已经获得FDA批准可以用于治疗。

The nucleoside analogues can be taken orally and have fewer short-term side effects than interferon, but require a longer course of treatment to achieve HBeAg to HBeAb seroconversion.
核苷类似物可以口服，而且短期的副作用比干扰素更小，但要达到HBeAg 到HBeAb的血清转换，则需要更长的治疗过程。


Patients on lamivudine (Epivir-HBV) monotherapy develop resistance with courses of treatment more than 6-12 months, with rates approaching 60% after 4-5 years of therapy. However, seroconversion can occur after development of resistance.

如果病人仅使用拉米治疗，在超过6-12 月的时间后，会产生耐药性。而接受拉米4-5年治疗的病人，其产生耐药性的 比例接近60%，但血清转换即使在产生耐药性后也会发生。
Resistance to adefovir has not yet been reported, but the rate of seroconversion is somewhat lower than for lamivudine. The potential for adefovir-associated nephrotoxicity requires cautious use in patients with pre-existing renal disease or who are at high risk for developing kidney problems. Other patients tolerate the approved dose of 10 mg daily with relatively few side effects.
阿德福韦产生耐药性未见报道，但在某中程度上，阿药导致的血清转换的效果低于拉米。对于有肾病或可能会出现肾病危险的人，根据与服用阿药有关的毒性显示，着类病人必须小心阿药。其他病人在服用10MG每天的剂量的药物后，副作用很小。



The course of interferon is shorter (4-6 months) with seroconversion rates similar to 1 year on nucleoside analogues (15-20%), but short-term side effects of fatigue, arthralgias, headache, fever, etc make some patients reluctant to complete therapy.

干扰素能在4-6个月内使血清转换，而相应的核苷类似物（15%-20%）则需要1年
但其短期的副作用主要是：疲劳、关节痛、头疼、发烧等等，导致一些病人不愿意接受彻底的 治疗。

While side effects of the pegylated interferons are similar, the seroconversion rates may be higher, particularly for the high HBV DNA, low ALT subgroup. The highest response rates for all drugs are seen in those patients with ALT > 2 x ULN and active inflammation on liver biopsy. Because of the risk of progression of disease in this group, strong consideration should be given to treatment with one of the 3 available drugs or inclusion in a clinical trial of newer agents.
乙？二醇化（pegylated ）干扰素的副作用与干扰素相似，但血清转换比例要高些，尤其对于高HBVDNA，低ALT子群（subgroup）更始如此。而血清转换反应比例最高的是：在肝活检中发现活动炎症（是否指处于活动期的慢性肝炎）和ALT> 2 x ULN的病人。
由于在这些群体中存在病情升级的危险性，在使用这三种可得到的药物或包含临床试用的新试剂时，应给病人提供详细的需要考虑的事项。

[此贴子已经被龙漂飘于2002-12-10 15:47:27编辑过]

独孤求败

3x！

liverbj

以下是引用liver411在2002-11-23 11:08:00的发言： 53rd American Association for the Study of Liver(AASLD) Diseases Annual Meeting November 1-5, 2002, Boston MA 第53届美国肝脏疾病研究协会年会 2002年11月1日－5日 波斯顿 By Mack C. Mitchell, MD Introduction 介绍 The last 5 years represent an exciting period in the understanding and treatment of chronic hepatitis B infection. In this time, the efficacy of treatment of chronic hepatitis B infection has increased dramatically. 过去5年来对慢性乙型肝炎的理解和治疗是一个令人振奋的时期。这段时间，对慢性乙肝治疗的效果取得了引人注目的增长。 Nucleoside analogues and interferon-Alfa are both effective in treatment of HBV. The lower side effect profile of the nucleoside analogues has made them preferred agents for first-line therapy, although concerns about resistance developing during monotherapy has tempered enthusiasm somewhat. 核苷酸类似物和阿拉法干扰素对HBV的治疗都有效果。 较低的副作用使核苷酸类似物作为治疗的首选。虽然对在单一疗法期间对抗药性增长的关注会多少阻碍这种热情。 At this year’s meeting of the 53rd AASLD, there were several reports on newer nucleoside analogues including Hepsera (adefovir dipivoxil), entecavir, Coviracil (emtricitabine; FTC) and telbivudine (formerly LdT), and a report on Pegasys (pegylated interferon-alfa 2a) as well as follow-up studies on the use of Epivir-HBV (lamivudine; 3TC). 今年的年会有一些关于新的核苷酸类似物的报道，包括Hepsera（adefovir--也许是阿第福伟（译者注） dipivoxil）,entecavir--也许是恩第卡伟（译者注），Coviracil(emtricitabine;FTC) 和 telbivudine(以前叫LdT），还有关于Pegasys（长效阿拉法2a干扰素）的一篇报道，另外还有关于使用Epivir-HBV（拉米夫丁；3TC）的后续研究。 Phase III Trial of Hepsera (Adefovir Dipivoxil) in Treatment of Lamivudine-Resistant HBV (Abstract 831) 对拉米夫丁有抗药性的HBV在使用Hepsera（Adefovir Dipivoxil--也许是阿地福伟）的三期试验。 Epivir HBV (lamivudine) is currently the standard of care for pre- and post-transplant treatment of advanced chronic hepatitis B infection. Treatment with lamivudine is effective in preventing hepatic decompensation in most patients pre-transplant. The combination of lamivudine and treatment with HBIG is highly effective in preventing recurrence of hepatitis B after liver transplantation. The main drawback to lamivudine monotherapy is development of resistance (YMDD) in a significant percentage of patients. Epivir HBV(拉米夫丁）是目前严重慢性乙肝移植前和移植后的标准的治疗手段。拉米夫丁治疗对于移植前的大多数患者来说对阻止肝代谢失常是有效果的。联合使用拉米夫丁和HBIG对于阻止移植后复发乙型肝炎有着更高的效果。对于拉米夫丁单一疗法的主要缺陷是有很高百分比的患者会发生抗药性增强（YMDD） Dr. Schiff and colleagues reported experience in an open-label, non-randomized trial of adefovir dipivoxil for treatment of patients who had developed resistance to lamivudine. ALT normalization was achieved in 60% of both pre- and post-transplant patients. Shiff医生和同事们报道了一起open-lebel，非随机性的实验，是关于那些对拉米夫定产生抗药性的患者使用阿德福伟（adefovir dipivoxil)的情况。ALT正长率达到了60％，无论对于移植前还是移植后的患者。 Undetectable levels of HBV DNA (< 400 copies/ml) were achieved in up to 50% of patients after 48 weeks and up to 70% after 96 weeks. 分别有50％和70％的患者在48周和96周的HBV DNA达到检测不到的程度 The median reduction in DNA levels was 4.1 logs after 48 weeks. Serum creatinine elevations were noted in a proportion of patients, most of whom also had multiple risk factors for renal damage such as concomitant use of nephrotoxic immunosuppressants. Overall 2% discontinued treatment due to renal toxicity. 48周之后DNA水平平均减少了4.1logs. 血清肌苷酸上升在一部分患者身上被注意到，他们中的大多数对于肾脏损害有成倍的风险例如对于损害肾脏的免疫抑制剂伴随物的使用。超过2％的暂停治疗是因为肾脏损害。 These findings indicate that adefovir is effective in treatment of patients with lamivudine resistance, but remind us of the need to monitor carefully for nephrotoxicity during therapy. 这些发现指出阿德福伟对于对拉米夫定产生抗药性的患者的治疗是有效果的，但是有提醒我们需要在治疗过程中仔细检测肾脏损害。 Effects of Adefovir on Liver Histology and Viral Suppression at 48 Weeks (Abstract 840 and 841) 阿德福伟对于肝组织学以及路过型病毒的抑制在48周之内的效果（抽样840和841）。 Analysis of the first year of the phase III trial of adefovir in patients with HBeAg + CHB was presented by Dr. Goodman and colleagues. Primary endpoints in the trial included a two-point reduction in the inflammatory component of the Knodell HAI score. This was achieved in 53% (p = NS) of patients treated with adefovir 10 mg daily and 59% (p < .0001) of those treated with 30 mg daily compared to 25% of placebo treated patients. 关于阿德福伟对于那些e抗原阳性的慢性乙肝患者第一年的三期试验的分析由Goodman医生和同事进行。 试验初步的结果包括a two-point reduction in the inflammatory component of the Knodell HAI score???(不知道怎么翻译）.有53％（P=NS）的使用了阿德福伟10mg每天的患者和59％（P<.0001）的使用了30mg每天的患者达到了这一点，相对于那些25％使用安慰剂的患者。 Improvement in the 6-point Ishak fibrosis score was also evaluated. Improvement of > 1 stage was seen in 35% of those treated with 10 mg daily and 41% of those treated with 30 mg daily. Significant improvements in the overall fibrosis scores (2.20 pre to 1.95 post-treatment) were seen in the 10 mg daily group. In addition, fewer patients treated with adefovir (11%) showed evidence of worsening compared with those on placebo (22%). 对于6－point Ishak纤维化程度的患者的（疗效）改进也被评估。 >1 阶段患者的改进中有35％的患者使用了10mg每天，41％的患者使用了30mg每天。 对于所有使用10mg每天的纤维化患者中都有显著的改善（治疗之前2.20，治疗之后1.95)。另外，有少数使用阿德福伟的患者（11％）显示出恶化的证据，对比那些使用安慰剂的患者。 After 48 weeks, the HBeAg seroconversion rate was 12% for the 10 mg daily group compared to 6% of those on placebo. Seroconversion increased to 20% after 72 weeks. HBeAg loss was much higher—24% at 48 weeks and up to 40% at 72 weeks. ALT normalization was observed in 48% of the 10 mg daily group compared to 16% of placebo recipients. HBV DNA was < 400 copies/ml in 21% of patients on adefovir and an additional 21% of 71 patients who continued therapy beyond 48 weeks had undetectable levels of HBV DNA. 48周之后，10mg每天的患者HBeAg的血清转换率是12％，相对于6％的使用安慰剂的患者。72周之后血清转换率上升为20％. HBeAg的降低则要高得多－24％（48周）和高达40％（72周）。 ALT正常率是48％（10mg每天），相对于16％的安慰剂组。 21％阿德福伟组HBV DNA<400拷贝／ml，另外在71位48周之后继续治疗的患者中有21％的HBV DNA达到检测不到的水平。 Of note, no resistance to adefovir was observed in any patients during the entire duration of the study, which is a distinct difference from the results reported previously for lamivudine monotherapy. 值得注意的是，在整个研究期间，没有发现对阿德福伟的抗药性，这对于以前报道的拉米夫定单一疗法具有明显的不同。 The Roche Amplicor assay is much more sensitive than the Abbot hybridization assay used in the original lamivudine studies which makes direct comparison of the results of those trials with this one problematic. In the lamivudine trials, the 52-week seroconversion rates were somewhat higher (15-16%) in the treated group with a similar rate of seroconversion (4-5%) in the placebo group. Roche Amplicor试验比用于拉米夫定研究的Abbot hybridization试验更加敏感，后者的实验结果同有问题的这次直接的比较。在拉米夫定的实验中，52周的血清转换率有一点高（15－16％），但是使用安慰剂的那一组是相同的。 Direct comparison between lamivudine and adefovir was not included and it is hard to know whether the study populations were comparable. Since seroconversion rates are highly dependent on pre-treatment ALT levels, the differences may not be clinically important. 拉米夫定和阿德福伟的直接比较没有被包括，而且被研究的人群是否具有可比性很难说。因为血清转换率对于治疗前ALT的水平具有很高的依赖性，所以差异对于临床来说也许不重要。 Eradication of cccDNA from the Liver in Patients on Adefovir (Abstract 534) 使用阿德福伟患者肝脏中cccDNA的清除（抽样534） Complete eradication of HBV has proven to be a difficult problem despite the availability of several anti-viral agents that are potent inhibitors of viral replication. In part, HBV is difficult to eradicate because of the persistence of the covalently closed circular DNA (cccDNA) which serves as the template for viral replication. Measurement of this pool of HBV requires liver biopsy since the cccDNA does not circulate in the plasma. In general, very little is known about how this pool of virus is affected by antiviral therapy. 彻底清除HBV被证实是非常困难的，尽管几种对于滤过型病毒复制具有很强抑制性的药物已经可以得到。部分的，HBV之所以难以根除是因为共价闭环DNA（cccDNA）的顽固，cccDNA就是滤过型病毒复制的模板。对这个HBV池的测量要求肝脏活组织切片检查，因为cccDNA不在血液中循环。总的来说，关于这个病毒池是如何被抗滤过型病毒制剂影响的所知甚少。 During the phase III trial of adefovir dipivoxil, cccDNA was measured in liver biopsy specimens obtained at baseline and after 48 weeks of therapy with adefovir. Interestingly, those patients who seroconverted had lower baseline levels of cccDNA (median 0.62 copies/cell) than those who did not seroconvert (1.66 copies/cell). Treatment with adefovir lowered cccDNA to a similar extent in both groups (93% vs 83%). Final levels of cccDNA as well as the baseline levels were lower in the seroconverters than in those who had persistent HBeAg. At this time, it is unclear whether cccDNA levels must be lowered below a particular range to achieve a sustained response, but the results are intriguing. 在阿德福伟三期试验中，cccDNA的测量是在48周阿德福伟治疗之后的肝组织切片活检样本中进行的。 有趣的是，发生血清转换的患者有较低的cccDNA基线（均值0.62拷贝／细胞），相对于没有发生血清转换的患者（1.66拷贝／cell)。阿德福伟的治疗在两组之间都降低了cccDNA到差不多的程度（93％对83％）。发生血清转换的患者的cccDNA的最终水平和基线水平都要低于那些HBeAg顽固的患者。这次试验中，是否水平必须低于一个特殊的水平才能达到持续的应答并不是很清楚，但是结果是很吸引人的。 Entecavir for Treatment of Lamivudine-resistant Chronic HBV (Abstract 550) 对于慢性乙肝拉米夫定抗药性患者的恩替卡伟的治疗。 Entecavir is another one of the next generation of nucleoside analogues with potent, anti-HBV activity now in clinical trials for treatment of chronic HBV infection. This report is from an international, multicenter trial of entecavir in patients who failed therapy with lamivudine based on either the presence of YMDD mutation OR with persistently positive serum HBV DNA (> 10 mEq/ml on the Quantiplex bDNA test) AND persistent elevation of ALT after at least 24 weeks of treatment with lamivudine. 恩替卡伟是另一个下一代的强大的,在临床试验中治疗慢性乙肝的核苷酸类似物。这个报告是一个跨国的，多通道的恩替卡伟试验，针对的患者是基于那些用于拉米夫丁治疗至少24周的，YMDD变异并且顽固HBV DNA(>10 mEq/ml on the Quantiplex bDNQA test)血清阳性，ALT一直很高的那一部分。 181 patients were divided into 4 groups (.1, .5 and 1.0 mg entecavir daily or continued treatment with lamivudine 100 mg daily) for 48 weeks of treatment. Results are summarized in the table below: Drug ALT Normal HBV DNA log decrease HBV DNA negative Entecavir 1 mg 43%* 2.78* 4% Entecavir .5 mg 59%* 4.46* 26%* Entecavir 1.0 mg 68%* 5.11* 26%* Lamivudine 100 mg 4% 1.41 4% p < .05 These findings suggest that entecavir is effective in treatment of patients who have developed YMDD resistance to lamivudine. Results of seroconversion are not yet analyzed, but will be presented within the next few months, perhaps at EASL. Within the time of study, no patients developed evidence of resistance to entecavir. Side effects were similar in all groups and included headache, abdominal pain and fatigue. 181个患者被分为4组，（.1, .5 和 1.0mg恩替卡伟每天或者用拉米夫丁100mg每天持续治疗的），经过48周治疗。结果被总结为下表： 药 ALT标准 HBV DNA log 减量 HBV DNA 阴 恩替卡伟1mg(疑为.1mg) 43％* 2.78＊ 4％ 恩替卡伟.5mg 59%* 4.46* 26%* 恩替卡伟1.0mg 68%* 5.11* 26%* 恩替卡伟100mg 4% 1.41 4% P<.05 这些发现建议对那些已经发展成为YMDD对于拉米夫丁产生抗药性的患者的治疗是有效地。血清转换的结果还没有被分析，但是下几个月结果就将出来，也许在EASL。 在研究的过程中，没有患者被发现对恩替卡伟具有抗药性。副作用在所有组中都差不多，包括头痛，腹痛和乏力。

liverbj

以下是引用liver411在2002-11-23 11:08:00的发言：      Emtricitabine Follow-on Study for Treatment of Chronic HBV for 96 weeks (Abstract 838) Emtricitabine 用于慢性HBV96周治疗的后续研究 Emtricitabine; FTC (Coviracil) is a nucleoside analogue that is structurally similar to lamivudine. Results of an open label follow-on study for an additional period (96 weeks) were reported at this year’s meeting. The original phase III RCT was conducted for 48 weeks. During the first year, 50% of patients lost HBeAg, 23% seroconverted to HBeAb and HBV DNA decreased by a median of 2.92 log and was undetectable (< 4700 copies/ml) in 55%. Resistance to emtricitabine developed in 6% of those treated. Because of the structural similarity of emtricitabine, it is unlikely to be effective in treatment of YMDD-lamivudine resistant HBV. Emtricitabine;FTC（Coviracil）是结构上同拉米夫丁相似的一种核苷酸类似物。 对于他的附加的期间（96周）的open label后续研究在这次年会上也有报告。初始的三期RCT使用了48周。 在第一年里，50％的患者HBeAg减少，23%的患者发生血清转换产生e抗体并且HBV DNA平均减少2.95log,有55％的检测不到（<4700拷贝／ml）。 有6％的这次治疗中的患者产生对emtricitabine的抗药性。因为emtricitabine的结构相似性，对待YMDD-拉米夫丁产生抗药性的患者的治疗不可能有效。 Sustained virologic responses were observed in 41% of patients with 19% resistance after 96 weeks of therapy. Favorable serological responses including a seroconversion rate of 29% and HBeAg loss of 51% were also reported. Unfortunately, the study design allowed inclusion of a significant number (64 pts) who had not previously been treated with a nucleoside analogue. Those patients who developed resistance experienced an increase in ALT, but had a favorable evolution. 持续性的病毒应答在41％的患者中产生，其中有19％的患者在96周的治疗之后产生抗药性。有利的学情转换应答包括29％的血清转换率和51％的HBeAg减少。不幸的是，这次研究允许很多数量（64 pts)的以前没有经过核苷酸类似物治疗的患者参加。这些患者发生了抗药性，并且ALT升高，但是有比较好的进展。 The rate of seroconversion observed in the randomized controlled trial makes this nucleoside an interesting possible addition to the therapeutic options for treatment of chronic HBV. However, longer experience will be needed to determine whether the rate of resistance increases further with prolonged therapy. 在这次随机控制试验的血清转换率使这种核苷成为对付慢性乙肝另一种选择。但是，需要更长时间的试验来确定是否长期的治疗会产生更多的抗药性 Telbivudine for Treatment of Chronic HBV (Abstract 554) Telbivudine用于治疗慢性乙肝（抽样554） Telbivudine (LdT), a small nucleoside analogue, is a potent inhibitor of HBV polymerase in vitro. The results of a phase II dose escalation study indicated that 400-600 mg/day rapidly reduced HBV DNA levels by 3-4 logs from baseline values. 104 HBeAg positive patients with elevated ALT were enrolled in a phase IIb trial to receive LdT 400 or 600 mg daily alone or with lamivudine 100 mg daily for 24 weeks. 3T LdT400 LdT600 LdT400 + Lam LdT600 + Lam Median log10 drop 4.67 6.08 6.11 6.21 6.15 HBV neg by PCR 16% 41% 23% 29% 35% Telbivudine（LdT），一种小的核苷酸类似物，是一种强大的HBV聚合酶抑制剂。二期增大药物计量的研究的结果指出400－600mg／天能以3－4个log（基于基线值）迅速的降低HBV DNA的水平。参加二b期试验中的104个HBeAg阳性的患者ALT偏高，他们接受了LdT400或600mg每天或者联合100mg拉米夫丁每天的治疗，持续24周。 3T LdT400 LdT600 LdT400 + 拉米 LdT600 ＋ 拉米 Median log10 drop 4.67 6.08 6.11 6.21 6.15 HBV neg by PCR 16% 41% 23% 29% 35% As shown in the table above, Telbivudine resulted in a dramatic decrease in the HBV DNA levels within a relatively short time. ALT normalized in 70-80% of all groups over the same 24 week interval. Previous data have suggested that rapid decrease in HBV DNA leads to a much lower rate of development of resistance and may also translate into a higher rate of seroconversion. The follow-up from this study is not yet long enough to determine rates of HBeAg seroconversion or to know about the pattern of resistance that may or may not develop. However, the rapid decrease in HBV DNA is an exciting observation. 如上表所示，Telbivudine导致HBV DNA在相对短的时间内急剧下降。在同样的24周期间内所有组中70－80％的患者ALT正常了。以前的数据显示HBV DNA的快速降低会导致抗药性的发生率降低并且也许会产生更高比率的血清转换率。关于这次研究的后续研究时间还不够长到足以确定HBeAg血清转换率或者是到底会不会产生抗药性。但是，HBV DNA的快速降低是一个令人振奋的发现。 Treatment of HBeAg Negative, HBV DNA positive Chronic HBV with Lamivudine (Abstract 835) 对于HBeAg阴性，HBV DNA阳性的慢性乙肝的拉米夫丁的治疗（抽样835） In some patients with chronic HBV, active viral replication continues after HBeAg seroconversion. Active viral replication in this group usually indicates the presence of the pre-core or core promoter mutation, which allows the intact virus to be made without expressing the E antigen. Since these patients can have progressive liver disease, treatment may be warranted. 在有一些慢性乙肝患者中，发生HBeAg血清转换后病毒仍然在发生活跃的复制。在这一组中活跃的病毒复制通常表示发生了pre-core(也许是前C区）或者 core promoter变异,这使病毒会逃过E抗体对它们的作用。因为这些患者会经历持续发生肝脏疾病，所以治疗是必需的。 This study reported experience in treating HBeAg negative, HBeAb positive, HBV DNA positive chronic hepatitis B. Lamivudine (100 mg) was given daily for an average of 24 months. 421/443 patients had an initial virologic response, which was 88% at 1 year and decreased to 66.2% at 2 years, 51.5% at 3 years and 42.5% at 4 years. During therapy YMDD resistance developed in 31.4% of patients. In 34/139 patients a flare in hepatitis (elevated ALT) occurred. 这次研究报道了对HBeAg阴性，HBeAb阳性，HBV DNA阳性的慢性乙肝患者的治疗的经验。拉米夫丁（100mg）每天持续给药平均24个月。421／443个患者有了初步的病毒应答，在第一年有88％，第二年减少到66.2%，第三年51.5%，第四年42.5%.在治疗期间YMDD抗药性在31.4％的患者中产生。有34／139个患者突发肝炎（ALT升高）。 The outcome of these flares in ALT depended on the baseline histology and clinical status of patients. In those with only chronic hepatitis, there were no cases of hepatic decompensation, but in those with Childs A cirrhosis, 6/15 (40%) developed decompensation and 2/15 (13%) died. Even worse outcomes were seen in those with more advanced disease, 4/5 patients with Childs B/C cirrhosis decompensated and 3/5 died. Hepatocellular carcinoma developed in 4.6% of those without YMDD and in 10.7% of those with YMDD mutations (results were not statistically significant). 这些ALT突发的结果依赖于基线组织学和患者的临床状态。在那些只有慢性肝炎的患者中，没有发生肝脏代谢失调的例子，但是在那些怀孕硬化？（with childs A cirrhosis）6／15（49％）发生代谢失调，并且有2／15（13％）死亡。在那些有更严重病情的患者中有更坏的结果，4／5的怀孕患者 B/C硬化代谢失常，3／5的患者死亡。发生肝癌的患者在有YMDD变异和没有变异的比例分别是4.6%和10.7%. These observations highlight the importance of the extent of liver disease at baseline in determining the ultimate outcome of HBV with or without treatment. Other studies have shown clearly that lamivudine can improve clinical status (decrease Childs-Pugh scores) and reduce fibrosis. However, this study sounds a cautionary note for physicians who are following patients with advanced stages of HBV. Any evidence of elevation of ALT should be monitored carefully and alternative therapy such as adefovir should be considered if there are signs of hepatic decompensation. 这些观察结果强调了肝暂疾病程度对于最终结果影响的重要性，无论是经过治疗还是没有经过治疗。其他的研究清楚的显示了拉米夫丁能够改进临床状态(decrease Childs-Pugh scores)并且能降低纤维化。然而，这次研究警戒那些医生要注意那些HBV到很严重阶段的患者。ALT升高的任何症状都应该被仔细监控，如果有迹象表明肝脏代谢失常应有替代疗法如阿德福伟。 Lamivudine for the Treatment of Fulminant Hepatitis B Infection (Abstract 848) 拉米夫丁对暴发性乙肝的治疗（抽样848） Fulminant hepatitis B is a rare (1%) complication of acute hepatitis B infection. The mortality rate for fulminant hepatitis B is approximately 50% without liver transplantation. Lamivudine has been shown to be very effective in treatment of chronic hepatitis B infection, including those patients with advanced liver disease, but has generally not been used for treating acute hepatitis B, which is usually a self-limited illness. 暴发性乙型肝炎在急性乙肝感染中发病率很低(1%). 不肝脏移植的话死亡率大约是50％。拉米夫丁显示出对于慢性乙肝很有效，包括那些严重肝脏疾病的患者。但是通常不会被用来治疗急性乙肝，急性乙肝通常是自限式疾病. Tillman and colleagues reported that lamivudine treatment significantly reduced the length of stay in the ICU (5.4 ± 5.9 days for lamivudine vs 21.2 ± 28.8 days for standard therapy) and the need for liver transplantation (16/21 with standard therapy vs 1/8 lamivudine treated). Although the study was not randomized, the differences between the groups were both statistically significant and impressive. These findings justify a randomized controlled trial of lamivudine or other antiviral agents given the shortage of donor organs for transplantation which is needed in many patients with fulminant hepatitis B infection. Tillman和同事们报道了拉米夫丁治疗能够显著减少在ICU中停留的时间（5.4 ± 5.9天，拉米夫丁对21.2 ± 28.8 天，标准疗法）和肝移植的需要（16／21标准疗法对1／8拉米夫丁疗法）。虽然研究不是随机的，不同组之间的不同结果在统计学上都很重要并且令人印象深刻。这些发现证实了拉米夫丁或者其他抗病毒药物的随机控制试验，它们使的短缺的捐献组织用于那些很多暴发性乙型肝炎患者的移植上。 Prevention of Reactivation of Hepatitis B in Patients Treated with Chemotherapy (Abstract 836) 化疗对于预防乙肝患者复发的作用(抽样836） The immune system plays an important role in suppressing replication of hepatitis B in patients, who remain HBsAg positive, with chronic hepatitis B. Previous studies have reported relapse of clinical hepatitis in patients who have been treated with anti-neoplastic chemotherapy or other immunosuppressive regimens. Viral replication is reactivated during the time of immunosuppression and when discontinued, the larger amount of virus present stimulates an exaggerated immune response that can lead to severe exacerbations in chronic hepatitis. Since lamivudine is effective in suppressing viral replication, the investigators reasoned that pre-treatment with lamivudine before administration of chemotherapy might prevent serious relapses following Chemotherapy. 免疫系统在抑制那些HBsAg阳性，慢性乙肝的患者的乙型肝炎病毒复制中起到了非常重要的作用。以前的研究报道了那些使用了抗肿瘤化学疗法或者是其他免疫抑制剂疗法的患者临床复发的情况。病毒复制在免疫抑制期间和结束之后重新开始活跃。大量的病毒刺激了免疫系统的过分反应，这将会导致慢性肝炎的严重恶化。因为拉米夫丁在抑制病毒复制中是有效果的，研究者详细论述了在化疗之前进行拉米夫丁治疗将会阻止在后续化疗中病情的严重复发。 Patients were treated either with lamivudine before beginning chemotherapy or at the time of diagnosis of reactivation of hepatitis B infection. One of the 11 patients pre-treated with lamivudine had evidence of clinical hepatitis, whereas 5/11 not pre-treated developed reactivation hepatitis that was severe in 3 patients with a fulminant course in 1/3. On the basis of this observation, the authors concluded that lamivudine pre-treatment was preferable to waiting for evidence of reactivation in patients with chronic HBV undergoing chemotherapy. 患者们在化疗开始的时候用了拉米夫丁或者是在诊断出乙肝病毒活跃的时候。11个预先用了拉米夫丁的患者中的一个有临床肝炎迹象，然而5／11个没有用的发展成病毒会复活动,有三个患者有爆发的过程比例是1／3。在这次观察的基础上，作者得出在进行化学疗法的慢性乙肝患者中，预先拉米夫丁治疗相对于等到出现病毒重新活跃的症状时是更好的选择这一结论 Pegylated (40 kDa) Interferon-alfa 2a (Pegasys) for Chronic HBV Infection (Abstract 846) 长效（40kDa）阿拉法干扰素 2a（Pegasys）对于慢性乙肝的治疗（抽样846） 以下至结论部分之前请参看长效干扰素治疗乙肝 Conclusions 结论部分请参看前面龙PP翻译的那一段

liverbj

有很多专业名词不是很懂，翻译的不好。还请行家指点。