Entecavir Monotherapy Suffices in Many Cases of Chronic Hepatitis B

StephenW

Entecavir Monotherapy Suffices in Many Cases of Chronic Hepatitis B

By: SUSAN LONDON, Family Practice News Digital Network

12/23/11


SAN FRANCISCO – When treating patients with chronic hepatitis B, two antiviral agents are not necessarily better than one, according to the results of an international randomized trial called BE-LOW.

About 80% of patients achieved viral suppression regardless of whether they received entecavir alone or entecavir combined with tenofovir, with no significant difference between groups, Dr. Anna S. Lok reported at the annual meeting of the American Association for the Study of Liver Diseases.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10**8 IU/mL."

However, combined therapy was more efficacious than monotherapy among the subset of patients who were hepatitis B e antigen (HBeAg) positive and had a high viral load at baseline.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10**8 IU/mL," she commented. "It is possible that there may be some clinical settings in patients with high viral load in which rapid viral decline is important, where combination therapy may have a role."

An attendee asked whether the better response with the combination in those HBeAg-positive patients might have been due to the tenofovir alone. "Obviously, the limitation of this study was that there was no tenofovir monotherapy group, so we don’t know," Dr. Lok replied. "Maybe this would be just because of tenofovir and we don’t need the combination."

The trial tested combination therapy for several reasons. "Entecavir and tenofovir are both potent antiviral agents with nonoverlapping resistance profiles, and they are also generally very well tolerated. Combination therapy may provide additive or synergistic antiviral activity and reduce the risk of resistance development," she explained. "But this potential benefit has not yet been confirmed, and the safety of the combination also needs to be established."

Patients were eligible for the phase IIIb trial if they were aged 16 years or older, had been hepatitis B surface antigen (HBsAg) positive for at least 24 weeks, and had not previously received a nucleoside or nucleotide analogue.

"Because one of the purposes was to determine if combination therapy might have a preferential advantage in patients with high baseline hepatitis B virus (HBV) DNA, the study was designed to cap the number of HBeAg-negative patients at 30% to enrich for patients with high baseline viral load," noted Dr. Lok, who is director of clinical hepatology at the University of Michigan, Ann Arbor.

In all, 384 patients were randomized in balanced fashion to open-label treatment with entecavir (Baraclude) alone or entecavir at the same dose combined with tenofovir (Viread).

The patients had a mean age of 39 years. Roughly half of the patients were white and the other half were Asian. Seventy percent were HBeAg positive.

About 7% of patients in the monotherapy group and 12% of patients in the combination therapy group discontinued treatment before 96 weeks. "In the majority of the patients who came off treatment, it was because of loss to follow-up. There were some patients who discontinued because of adverse events, but those adverse events were not related to renal side effects or anything significant – they were more sort-of constitutional symptoms," Dr. Lok said.
In a modified intention-to-treat analysis, in which patients lost to follow-up were considered not to have achieved suppression, the 96-week rate of viral suppression (HBV DNA less than 50 IU/mL), was 76.4% with entecavir alone and 83.2% with entecavir plus tenofovir, not a statistically significant difference. The results were essentially the same in a per-protocol analysis.

However, in the HBeAg-positive subset of patients, the rate was higher with the combination therapy (80.4% vs. 69.8%, P = .046), and further analysis showed that this difference was solely due to a higher rate among those who had a high viral load at baseline, with an HBV DNA of at least 108 IU/mL (78.8% vs. 62.0%).

For other end points in the trial population overall, there were numerical trends actually favoring monotherapy when it came to rates of alanine aminotransferase normalization, HBeAg loss, and HBeAg seroconversion.

The rate of virologic breakthrough was 1.0% with the monotherapy and 3.6% with the combination therapy. There were no cases of genotypic resistance specific for the study drugs in either group.

"Safety was also very comparable between the two groups," Dr. Lok reported, with similar rates of serious adverse events.

Three patients in the monotherapy group developed hepatocellular carcinoma, compared with none in the combination therapy group. In all three cases, HBV DNA was undetectable at the time of the cancer diagnosis.

Dr. Lok reported that she is an adviser or reviewer for Bristol-Myers Squibb, Gilead, Merck, Roche, Abbott, Bayer, and GlaxoSmithKline, and that she receives research or grant support from Bristol-Myers Squibb, Gilead, Merck, Roche, and GlaxoSmithKline.

StephenW

恩替卡韦单药治疗慢性乙型肝炎的许多情况下足以

苏珊伦敦，家庭实践新闻数字网络

11年12月23日


旧金山 - 两种抗病毒药物治疗慢性乙型肝炎患者时，不一定比一个好，根据国际随机试验称为BE-LOW的结果。

约80％的患者无论是否得到单独或恩替卡韦恩替卡韦联合替诺福韦与组之间无显着差异，达到抑制病毒，安娜S.乐博士在美国肝病研究协会年会上报告。

“组合没有提供了一个比较恩替卡韦单药治疗的整体利益，但是，它可以提供在HBeAg阳性患者与基线病毒载量超过10**8国际单位/毫升的增量受益。”

然而，联合治疗比单药治疗乙肝e抗原（HBeAg）阳性的患者的一个子集之间更有效和高基线病毒载量。

“组合没有提供整体利益相比，恩替卡韦单药治疗，但是，它可以提供在HBeAg阳性患者与基线病毒载量超过10**8国际单位/毫升的增量受益，她评论道。” “这是可能的患者病毒载量高病毒的迅速下降是其中重要的是，联合治疗可能有一定作用，有可能是一些临床的设置。”

一位与会者问是否可能是由于替诺福韦单独与那些HBeAg阳性患者的结合更好的响应。 “显然，这项研究的限制，有没有替诺福韦单药治疗组，所以我们不知道，”乐博士回答。 “也许这将是仅仅因为替诺福韦和我们并不需要相结合。”

试验测试有以下几个原因的综合疗法。 “恩替卡韦和替诺福韦是有效的抗病毒药物，都与不重叠的耐药谱，他们也普遍很好的耐受性。联合疗法可能会提供相加或协同抗病毒活性，并减少耐药性的发展风险，”她解释说。 “但是，这个潜在的好处尚未得到证实，而且也需要建立相结合的安全。”

患者的阶段IIIB试验资格，如果他们16岁或以上，已乙肝表面抗原（HBsAg）至少24周的正面，和以前没有收到核苷或核苷酸类似物。

“因为的目的之一是，以确定是否联合治疗可能有一个优惠的优势在基线乙肝病毒（HBV）DNA患者，这项研究的目的是要限制在30％HBeAg阴性患者数量丰富为患者基线病毒载量高，乐博士指出：“谁是在密歇根大学安娜堡分校主任临床肝胆病。

在所有384名病人，平衡的方式，随机开放标签相同剂量结合替诺福韦（Viread）与恩替卡韦（博路定）单独或恩替卡韦治疗。

患者进行了平均年龄39岁。大约一半的患者是白人，另一半是亚洲人。 70％的受访HBeAg阳性。

约7％，在单药治疗组患者的中西医结合治疗组96周前终止治疗的患者和12％。 “大多数在离开治疗的患者，这是因为后续的损失，有一些患者因为不良事件而停止，但这些不良事件均与肾的副作用或任何显著 - 他们排序宪法症状，乐博士说。“
NA修改意向性治疗分析，使病人失去了后续不被认为是取得了抑制，病毒抑制率96周（HBV - DNA小于50国际单位/毫升），76.4％，单用恩替卡韦恩替卡韦和替诺福韦，而不是统计上的显著差异和83.2％。在每个协议的分析基本上是相同的结果。

然而，在HBeAg阳性患者的子集，率较高的综合疗法（80.4％比69.8％，P = 0.046），并进一步分析表明，这种差异完全是由于之间那些率较高在基线病毒载量高，至少108国际单位/毫升（78.8％与62.0％）HBV DNA。

对于整体试验人群中的其他终点，有数值的趋势，实际上有利于单药治疗，当它来到谷丙转氨酶正常化率，HBeAg转阴，HBeAg血清转换。

病毒学突破率为1.0％，与单药和联合治疗3.6％。有没有在任一组研究药物基因型耐药具体案件。

“安全也很两组之间的可比性，”乐博士报告，严重不良事件发生率相似。

在单药治疗组的患者发展为肝癌，与中西医结合治疗组没有。在所有这三种情况下，乙肝病毒DNA检测不到的癌症诊断的时间。

乐博士报道，她是，Gilead公司百时美施贵宝，默克，罗氏，雅培，拜耳和葛兰素史克公司的顾问或审阅，研究或赠款支持，她收到来自百时美施贵宝公司，Gilead公司，默克，罗氏和葛兰素史克。

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