2020年行会专家分析

StephenW

EXPERT ANALYSIS FROM GUILD 2020

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

"We are going to have a laundry list of new drugs" that are in the pipeline now. Phase 2 results "look encouraging. You will hear much more about this in the years ahead," said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn't clear the HBV surface antigen, which is linked to liver cancer. "Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go," Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. "You have a hammer, you want to hit a nail," Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that "unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients."

This finding is one reason "we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning" to active disease. "I'm thinking we should really [lower] the age cutoff" to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus "patients feel really good when they know the virus is controlled, and so do physicians," Dr. Terrault said.
Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. "This led to a lot of concern that maybe we should be moving all our patients to tenofovir," she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, "the difference disappeared" (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be "treated many years ago and tended to have more severe [baseline] disease," Dr. Terrault said.

So "while we see this difference, there's not enough data yet for us to make a recommendation for our patients to switch from" entecavir to tenofovir. "Until a randomized controlled trial is done, this may remain an issue," she said.
A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

"The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates" – perhaps about 40% – "would be well worth the effort," editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It's an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn't be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

This story originally appeared on MDedge.com.

StephenW

2020年行会专家分析

夏威夷毛伊岛–洛杉矶南加州大学GI和肝脏学系主任Norah Terrault医学博士说，在未来几年中，就像现在正在丙型肝炎一样，乙型肝炎很可能治愈。 。

正在准备中的“我们将有一份新药的洗衣清单”。 2018年美国肝病研究协会（AASLD）乙型肝炎指南的主要作者Terrault博士说，第二阶段的结果“看起来令人鼓舞。在未来的几年中，您将听到更多的信息。”

但是目前，该领域主要限于核苷类似物替诺福韦和恩替卡韦。治疗通常是不确定的，因为尽管清除了乙型肝炎病毒（HBV）电子抗原，但通常无法清除与肝癌有关的HBV表面抗原。 Terrault博士在IBD胃肠病学会议的胃肠病学更新中说：“即使对于电子抗原阴性的患者，我们仍然认为无限期治疗的确是要走的路。”

该策略的最大问题之一是当乙肝病毒似乎对运营商来说不是太大问题时该怎么办。这样的患者被称为免疫耐受的。
新认识的癌症风险

免疫耐受的患者往往年轻，病毒载量极高，但无明显不良反应，ALT水平正常，组织学正常，无肝硬化迹象。尽管AASLD建议直到40岁才对这些患者进行治疗，但等待会让人们感到紧张。特拉特尔特博士说：“你有一把锤子，你想敲钉子。”

最近的评论（Gut。2018年5月； 67 [5]：945-52）表明，打钉子可能是一条路。韩国研究人员发现，平均年龄38岁的413名未经治疗的免疫耐受患者在10年内患肝癌的风险是近1,500名患有活动性疾病的患者的两倍。

研究人员得出结论：“通过对某些[免疫耐受]患者进行早期抗病毒干预，可以预防不必要的死亡。”

这一发现是“我们（AASLD）正在重新考虑不治疗免疫耐受的口头禅。有一群人正在向活动性疾病过渡”的原因之一。正如其他一些团体[欧洲肝病研究协会和亚太太平洋肝病研究协会]所做的那样，“我认为我们真的应该[降低]年龄界限”到30岁，此外，“患者感到当他们知道病毒可以控制时，这真的很好，医生也一样。”泰罗尔说。
恩替卡韦与替诺福韦

同时，最近的研究提出了替诺福韦在预防肝癌方面是否比恩替卡韦更好的问题。

JAMA肿瘤学（JAMA Oncol。2019 Jan 1; 5 [1]：30-6）对韩国约25,000名患者进行的研究发现，使用替诺福韦代替恩替卡韦治疗时，患肝癌的风险降低了32％。她说：“这引起了我们的担忧，也许我们应该将所有患者转移至替诺福韦。”

今年早些时候发表的另一项荟萃分析（Hepatol Int。2020 Jan; 14 [1]：105-14）证实了将这些发现与其他研究相结合时癌症风险的差异。荟萃分析的作者报告说，在对可能的混杂因素（包括疾病阶段和随访时间）进行调整后，“差异消失了”（危险比为0.87； 95％置信区间为0.73-1.04）。

Terrault博士说，接受恩替卡韦治疗的研究患者往往“在多年前就已接受治疗，并且往往患有更严重的[基线]疾病”。

因此，“尽管我们看到了这种差异，但尚无足够数据可为我们提供建议，建议患者从恩替卡韦转用替诺福韦。她说：“在完成随机对照试验之前，这可能仍然是一个问题。”
放假吗？

Terrault博士还回顾了一项研究，该研究表明，至少3年后，对于电子抗原阴性的患者，可以停止核苷类似物的治疗。

“越来越多的证据表明，与目前的长期NA策略相比，有限的NA [核苷类似物]治疗方法导致更高的HBsAg [乙型肝炎表面抗原]丢失率，并且可以被认为是诱导功能性治愈的合理策略。对于某些愿意接受密切随访监测的无肝硬化的HBeAg阴性患者，……目前观察到的功能治愈率“ –可能约为40％–”将是值得的，”编辑对此发表评论。结论（Hepatology.2018 Aug; 68 [2]：397-400）。

Terrault博士说，这是一个有趣的想法，但是这种病毒会在停药后8到12周爆发，这就是为什么在肝硬化患者中不应该考虑使用这种病毒的原因。

Terrault博士是AbbVie，Merck，Gilead和其他公司的顾问，并披露了这些公司和其他公司的资助。

这个故事最初出现在MDedge.com上。