VIENNA (EGMN) – With no new blockbuster drug on the horizon for chronic hepatitis B, researchers are focusing on ways to boost the effectiveness of pegylated interferon, the current standard treatment for hepatitis B.

Two such novel strategies were introduced at the annual International Liver Congress sponsored by the European Association for the Study of the Liver. One involves stopping pegylated interferon 12 weeks into the side effect–heavy therapy in patients who are extremely unlikely to benefit from continuing for the standard 48 weeks. The other method entails doubling treatment duration to 96 weeks.

Both of these strategies were developed specifically to boost the therapeutic yield in patients with hepatitis B e antigen–negative chronic hepatitis B, an infection that is more difficult to clear than hepatitis B e antigen–positive disease.

Dr. Vincent Rijckborst of Erasmus University, Rotterdam, presented an international multicenter randomized double-blind study involving 107 antigen-negative patients who completed 48 weeks of once-weekly therapy with 180 mcg of pegylated interferon alpha-2a (Pegasys) plus either placebo or 1,000-1,200 mg/day of ribavirin.

Twenty-two percent of both groups had a sustained response at follow-up 24 weeks after completing treatment. The goal of this retrospective analysis of serial hepatitis B surface antigen (HBsAg) and HBV DNA levels was to find the earliest possible point in treatment to identify who is most and least likely to sustain a response to pegylated interferon. Sustained responders exhibited a greater degree of HBsAg decline.

The best prediction of sustained response came from a combination of an HBsAg decline at week 12, along with a 2-log or greater drop in HBV DNA level at that time. Twenty-seven percent of the study population met those requirements, and they had a 39% sustained response rate.

At the other extreme, 20% of patients had neither a 2-log decrease in HBV DNA nor a decline in HBsAg level at 12 weeks, and that group had a sustained response rate of 0%, establishing what Dr. Rijckborst called “a solid stopping rule.”

“These patients should be advised to discontinue therapy,” he said. “On the other hand, patients with both declines had a 39% chance of sustained response, so those patients really should be encouraged to complete the treatment phase.”

Patients with a week-12 decline in one of the two measures had an intermediate sustained response rate of 24%-25%.

“We think the HBsAg decline reflects the decline in cDNA levels and the immunologic effects of [pegylated interferon], while the decline in HBV DNA levels appears to reflect the drug’s direct antiviral effect,” Dr. Rijckborst said.

In a second study, Dr. Pietro Lampertico of the University of Milan reported on 103 patients with hepatitis B e antigen–negative disease who were randomized in an open-label, multicenter study to 48 weeks or 96 weeks of pegylated interferon alpha-2a therapy.

The 96-week course resulted in a significantly higher sustained response rate 1 year after completing treatment, with 29% of patients demonstrating a sustained drop in HBV DNA to below 2,000 IU/mL, as compared with 12% of those treated for 48 weeks.

Moreover, 6% of patients in the prolonged treatment arm experienced HBsAg clearance. None did on the standard regimen, noted Dr. Lampertico.

The prolonged pegylated interferon therapy didn’t bring any increase in safety issues. That’s because most treatment-related adverse events happened in the first 6 months of the study. Roughly 80% of patients had one or more adverse events, one-quarter of subjects required a dose reduction, and 15% withdrew from participation because of side effects.

In reply to an audience member’s question whether he thinks it’s reasonable to routinely use 96 weeks of pegylated interferon in hepatitis B e antigen–negative patients, given that only 6% cleared HBsAg, Dr. Lampertico said he does not.

“My point is that we really have to change our approach to pegylated interferon in these patients,” he said. “We have to try to identify those patients who do not benefit from this monotherapy.” He added that he likes the 12-week stopping rule Dr. Rijckborst and his coworkers developed.

“The next step will be to try to develop a second stopping rule at 24 weeks so only a select subgroup of patients goes on for 2 years,” said Dr. Lampertico, a gastroenterologist. “And we really need to study combination therapies.”

Along those lines, Dr. Patrick Marcellin presented a randomized trial in which 159 hepatitis B e antigen–positive patients were randomized to pegylated interferon, the nucleoside analogue telbivudine (Tyzeka in this United States; Sebivo, internationally), or both in an effort to boost e antigen seroconversion rates.

At week 24, HBV DNA became undetectable in 35% of the telbivudine group, 7% of patients getting only pegylated interferon, and 71% of the group getting the combination. The combined-therapy group also experienced significantly greater declines in HBsAg and in e antigen. However, the trial had to be halted because eight patients on the combined therapy developed severe peripheral neuropathy.

“Despite increased efficacy, concomitant use of pegylated interferon and telbivudine should be avoided at present,” concluded Dr. Marcellin of Beaujon Hospital in Clichy, France.

The trial was supported by Novartis, where Dr. Marcellin serves as a consultant.

Dr. Rijckborst’s study was sponsored by Rotterdam’s Foundation for Liver and Gastrointestinal Research. He reported having no relevant financial interests.

Dr. Lampertico’s study was sponsored by Roche, and he is a consultant to that company.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

维也纳(EGMN)——短期内没有慢性乙肝的新型重磅药品上市，故研究者们目前重点寻找提高当前乙肝标准治疗药——聚乙二醇干扰素疗效的方法。

 

在由欧洲肝脏研究学会(European Association for the Study of the Liver)主办的年度国际肝病会议(International Liver Congress)上提出了两项这样的新策略。其中之一为，对于出现严重治疗副作用、从持续48周标准治疗中获益甚小的患者，在12周聚乙二醇干扰素治疗后停药；另一种方法为，疗程延长2倍至96周。

 

这两种策略的目的均为提高对乙肝e抗原阴性的慢性乙肝患者的疗效。这种感染类型的清除难度较e抗原阳性的乙肝更大。

 

鹿特丹Erasmus 大学的Vincent Rijckborst博士公布了一项国际、多中心、随机、双盲研究，受试者为107例抗原阴性的患者，这些患者完成了48周聚乙二醇干扰素α(180 μg，1次/周，Pegasys)+安慰剂或利巴韦林(1,000~1,200 mg/d)治疗。

 

两治疗组均有22%的受试者在完成治疗后第24周随访时存在持续应答。对系列乙肝表面抗原(HBsAg)和HBV DNA水平进行回顾性分析，旨在找出以确定对聚乙醇干扰素持续应答可能性最大与最小患者的最早治疗时点。持续应答者表现为HBsAg有较大的降幅。

 

持续有效的最佳预测指标为12周时HbsAg下降且此时HBV DNA水平下降≥2 log。27%的研究群体达到这些要求，他们的持续应答率为39%。

 

与之相反，20%的患者HBV DNA未下降2 log，且12周时HbsAg水平亦无下降，该组持续应答率为0，这形成了Rijckborst博士所称的“确凿的停药规定。”

 

“应建议这些患者停止治疗，”他说。“另一方面，上述两项指标均下降者存在持续应答的几率为39%，因此确实应该鼓励这部分患者完成治疗期。”

 

在12周两项指标之一下降的患者中等持续应答率为24%~25%。

 

“我们认为，HbsAg下降可反映cDNA水平的下降及聚乙二醇干扰素的免疫学效应，而HBV DNA水平降低似乎反映了药物的直接抗病毒效应，”Rijckborst博士说。

 

在另一项研究中，米兰大学Pietro Lampertico博士报告了对103例e抗原阴性的乙肝患者的研究结果，在这项开放性多中心研究中，受试者被随机分配接受48周或96周聚乙二醇干扰素α-2a治疗。

 

在完成治疗后的1年，96周疗程产生的持续应答率显著增高，有29%的患者显示HBV DNA水平持续下降，低于2,000 IU/ml，而相比之下，疗程为48周者有12%出现这种情况。

 

另外，疗程延长组的患者中有6%出现了HbsAg清除，而标准治疗方案组无此情况发生，Lampertico博士指出。

 

长期聚乙二醇干扰素治疗并没有增加安全问题，原因为大多数治疗相关的不良事件发生于研究的最初6个月内。大致有80%的患者发生了1例或多例不良事件，25%的受试者需要减量，15%因副作用而退出研究。

 

有听众提问，事实上仅6%的受试者清除了HbsAg，Lampertico博士是否认为对e抗原阴性的乙肝患者常规进行96周聚乙二醇干扰素治疗为合理方案？Lampertico博士对此做出否定回答。

 

“我认为，我们确实必须改变这些患者的聚乙二醇干扰素用药方案，”他说。“我们必须尽量识别哪些患者接受这种单药治疗无收益。”他补充说，他欣赏Rijckborst博士及其同事提出的12周停药法则。

 

“下一步将是努力再制定一项24周停药法则，这样仅少量亚组患者可持续2年用药，”胃肠病学家Lampertico博士说。“我们实际上需要研究联合治疗方案。”

 

另外，Patrick Marcellin博士还公布了一项对159例e抗原阳性的乙肝患者进行的随机试验，试验中受试者被随机安排接受聚乙二醇干扰素或核苷类似物替比夫定(美国商品名为替泽卡；国际商品名为素比伏)治疗，或两者联合治疗，以努力提高e抗原血清转阴率。

 

在第24周时，替比夫定治疗组有35%无法检出HBV DNA，聚乙二醇干扰素治疗组有7%，两药联合治疗组有71%。联合治疗组HbsAg和e抗原均发生显著下降。然而，该试验因联合治疗组的8例患者发生了重度周围神经病变而停止。

 

“尽管疗效获得增加，但现阶段应避免聚乙二醇干扰素与替比夫定联用，”法国Clichy Beaujon 医院 的Marcellin博士总结道。

 

该试验由诺华资助，Marcellin博士担任该公司的顾问。

 

Rijckborst博士的研究由鹿特丹肝脏及胃肠研究基金会赞助。他本人无相关的经济利益报告。

 

Lampertico博士的研究由罗氏资助，他本人担任该公司的顾问。

 

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