我对AASLD 2020HBV治疗的看法*

StephenW

My Take on HBV Treatment Advances From AASLD 2020 Virtual*

         

Kwo_Paul_100x100_Circle


        


Paul Y. Kwo, MD
Professor of Medicine
Director of Hepatology
Stanford University School of Medicine
Palo Alto, California
        
        

Whereas the efficacy of direct-acting antiviral therapy has ushered in the possibility that we can eliminate hepatitis C without a vaccination, a cure for hepatitis B has been more elusive and we remain early in the journey toward a cure. Despite the availability of effective HBV therapies that can suppress viral replication, these therapies must be continued indefinitely for most patients. The AASLD 2020 meeting highlighted some of the strategies that are being pursued to improve functional cure rates, as well as provided insights into how we can further refine the use of our current treatments.

Nucleos(t)ide Analogue Therapy
Several very interesting presentations at the conference addressed whether or not patients with hepatitis B, or at least select patients with hepatitis B, receiving nucleos(t)ide analogues can stop therapy. The first was a prospective study from the Hepatitis B Network that examined whether or not a 24-week course of peginterferon (pegIFN) in combination with tenofovir disoproxil fumarate (TDF) given for a total of 192 weeks could lead to improved hepatitis B surface antigen (HBsAg) loss at Week 240. In the study, investigators randomized 201 individuals to either TDF alone or TDF plus an initial 24-week course of pegIFN alfa-2a, followed by protocolized TDF withdrawal at Week 192 (for patients without cirrhosis who were hepatitis B e antigen [HBeAg] negative by Week 144, who were anti-HBe positive by Week 180, and who had HBV DNA levels < 1000 IU/mL by Week 192).

Overall, the rates of HBsAg loss were not significantly different for patients in the TDF vs TDF plus pegIFN groups at either Week 192 (1.0% vs 4.3%; P = .21) or Week 240 (4.5% vs 5.7%; P = .74). Alanine aminotransferase (ALT) flares requiring retreatment occurred in 24% and 31% of patients in the TDF vs TDF plus pegIFN groups, respectively, but occurred earlier in the pegIFN group. Taken together, this prospective study demonstrated that withdrawal of TDF can be done safely in select patients, but the addition of pegIFN for 24 weeks does not improve the rate of HBsAg loss.

The second study I would like to discuss on this topic is RETRACT-B, a retrospective cohort study of 1541 patients with chronic HBV infection who discontinued nucleos(t)ide analogue therapy at 12 centers across North America, Europe, and Asia. For inclusion, patients were required to have undetectable HBV DNA and to be HBeAg negative when stopping therapy and could not have received interferon within 12 months prior to stopping nucleos(t)ide analogue therapy.

The results demonstrated that HBsAg loss increased over time with 3%, 8%, 12%, and 14% of patients achieving HBsAg loss at 1, 2, 3, and 4 years, respectively. A multivariate analysis of factors associated with HBsAg loss showed that White race (vs Asian race) was significantly predictive of HBsAg loss (HR: 5.8; 95% CI: 3.6-9.5). Indeed, at 4 years, 41% of White patients vs only 11% of Asian patients had HBsAg loss. In addition, an age of 50 years or older was significantly predictive of retreatment (HR: 1.6; 95% CI: 1.3-1.9). A total of 56% of patients experienced virologic and biochemical relapse, defined as HBV DNA ≥ 2000 IU/mL and ALT ≥ 2 x the upper limit of normal, and one third of individuals had an ALT flare.

Finally, a single-center study from Calgary examined outcomes in a real-world study of stopping long-term nucleos(t)ide analogue therapy. In this retrospective study of 1337 individuals with hepatitis B and minimal fibrosis, 47 stopped therapy. Of these, 6 had to restart therapy due to viral load rebound (HBV DNA ≥ 2000 IU/mL) or ALT flares (ALT ≥ 2 x the upper limit of normal). Only 1 of the individuals achieved HBsAg loss, but this individual also experienced ALT flares highlighting that these patients must still be followed carefully.

Overall, discontinuation of long-term nucleos(t)ide analogue therapy in select patients is a very interesting approach that needs to be explored further. The data presented at the conference suggest that the strategy is safe but that these individuals must be followed very carefully. Personally, I do not believe this approach is ready for primetime yet, and I will anxiously await further data before integrating it into my practice.

Tenofovir Alafenamide for Prevention of Vertical HBV Transmission in Mothers With High Viremia
Current guidance to prevent vertical transmission in women with high HBV viral loads (HBV DNA > 200,000 IU/mL) is to administer TDF during the third trimester. Two studies at the 2020 conference examined whether tenofovir alafenamide (TAF), which is known to have a better bone and renal safety profile vs TDF, is also safe and effective in this population.

The first study was a retrospective study presented by Pan and colleagues of 71 HBeAg-positive mothers with HBV DNA > 200,000 IU/mL who received TAF during the second/third trimester. The second study presented by Zang and colleagues was a multicenter, prospective, observational study of TAF or TDF administered from gestational Weeks 24-35 to delivery in 232 mothers with HBV DNA > 200,000 IU/mL.

Both trials showed similar results, which were that TAF was highly effective and well tolerated; no women discontinued therapy due to adverse events; and no adverse outcomes, such as congenital defects or malformations, were observed in the infants. These data suggest, therefore, that although our primary treatment for this population remains TDF, data supporting the efficacy and safety of TAF, both in HBV and HIV, are rapidly accumulating such that TAF may soon be added to the sanctioned regimens to prevent mother-to-child transmission in patients with high HBV viral loads.

Reduction of HBV DNA Integration Into the Human Genome With Nucleos(t)ide Analogue Therapy
One of the very interesting aspects of HBV is that it can integrate into the human genome, and this seems to be a major driver of hepatitis B–related hepatocellular carcinoma. To add to our knowledge on this topic, 2 interesting presentations at the conference examined the impact of nucleos(t)ide analogue therapy on HBV DNA integration into the human genome. Historically, we have thought of nucleos(t)ide analogue therapy as being strictly suppressive therapy, but data on viral integrations presented with these therapies may suggest otherwise.

The first study by Hsu and colleagues examined integration events from 66 patients receiving TDF and 61 patients receiving placebo from a randomized, placebo-controlled trial of TDF in patients with chronic HBV infection. Investigators were able to show a significantly lower number of viral integrations in the TDF group vs the placebo group at 3 years (P = .037). Furthermore, they found that patients receiving TDF experienced a greater decrease in the number of dysregulated protein coding genes vs placebo (P = .007), perhaps suggesting that the risk of cancer may be decreased.

The second study was a longer-term study that examined the effect of nucleos(t)ide analogue therapy on HBV DNA integration in 28 patients with chronic HBV infection for up to 10 years. Patients received a variety of nucleos(t)ide analogues and had paired liver biopsies before treatment and 1 year after treatment, and 5 patients had a third liver biopsy 10 years later. Using inverse PCR, investigators were able to show that, although HBV DNA integration was detectable in all baseline and 1-year posttreatment biopsies, 1 year of nucleos(t)ide analogue therapy significantly reduced the extent of hepatitis B integration (P = .003). Furthermore, for the 5 individuals with 10-year posttreatment biopsies, integration was even further reduced with 3 individuals having no evidence of hepatitis B integration.

Taken together, these data may suggest potential advantages of treating patients with hepatitis B even earlier in the course of their disease than is currently recommended, considering that integration events could be reduced.

Novel Agents
Finally, there were several presentations at the conference detailing the safety and efficacy of novel agents with novel mechanisms of action for the treatment of hepatitis B. A general theme of these presentations is that it is becoming possible to reduce HBsAg levels more rapidly than we have typically observed with our currently approved therapies with ≥ 1 dose of treatment with novel agents such as small interfering RNAs (siRNAs) or antisense oligonucleotides, which provides promise that we are on the pathway to improving rates of functional cure. Ultimately, we will need to combine treatment regimens with multiple mechanisms of action, and these will likely comprise both antiviral and immunomodulatory therapies.

Your Thoughts
What data were you most excited about from AASLD 2020? Please answer the polling question and share your thoughts in the discussion section.

StephenW

我对AASLD 2020虚拟版对HBV治疗的看法*

  

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医学博士Paul Y.Kwo
医学教授
肝病学主任
斯坦福大学医学院
加利福尼亚帕洛阿尔托



鉴于直接作用抗病毒疗法的功效已带来了我们无需接种疫苗即可消除丙型肝炎的可能性，而乙型肝炎的治疗则更加难以捉摸，并且我们仍处于治疗的早期阶段。尽管有可以抑制病毒复制的有效HBV治疗方法，但对于大多数患者，这些治疗方法必须无限期继续。 AASLD 2020会议重点介绍了为提高功能治愈率而正在采取的一些策略，并对如何进一步改进当前治疗方法的使用提供了见解。

核苷类似物治疗
在会议上，几个非常有趣的演讲谈到了接受核苷酸类似物的乙型肝炎患者或至少部分乙型肝炎患者是否可以停止治疗。第一项是来自乙型肝炎网络的前瞻性研究，研究了将聚乙二醇干扰素（pegIFN）与替诺福韦二富马酸富马酸酯（TDF）合用24周的疗程，共给药192周是否可以改善乙型肝炎表面抗原（HBsAg）损失在第240周时发生。在研究中，研究人员将201个人随机分为TDF或TDF加最初的24周疗程的pegIFN alfa-2a，然后在第192周按协议撤回TDF（对于无肝硬化的第144周时乙型肝炎e抗原[HBeAg]阴性，第180周时抗HBe阳性，第192周时HBV DNA水平<1000 IU / mL。

总体而言，在第192周（1.0％对4.3％； P = 0.21）或第240周（4.5％对5.7％； P =。 74）。需要再治疗的丙氨酸氨基转移酶（ALT）发作分别发生在TDF与TDF加pegIFN组的患者中，分别占24％和31％，但在pegIFN组中则较早发生。两者合计，这项前瞻性研究表明，在部分患者中可以安全地撤回TDF，但是在24周内添加pegIFN并不能提高HBsAg的流失率。

我想讨论的第二项研究是RETRACT-B，这是一项回顾性队列研究，研究对象是1541例慢性HBV感染患者，这些患者在北美，欧洲和亚洲的12个中心终止了核苷酸类似物治疗。为纳入研究，患者必须在停止治疗时具有不可检测的HBV DNA且HBeAg阴性，并且在停止核苷酸类似物治疗前12个月内不能接受干扰素。

结果表明，随着时间的流逝，HBsAg的流失率增加，分别有1％，2％，3％和4年的HBsAg流失率分别为3％，8％，12％和14％。对与HBsAg丢失相关的因素进行多变量分析表明，白人（VS亚洲种族）显着预测了HBsAg的丢失（HR：5.8； 95％CI：3.6-9.5）。确实，在4年时，41％的白人患者与仅11％的亚洲患者有HBsAg丢失。此外，年龄在50岁或50岁以上可显着预测再次治疗（HR：1.6； 95％CI：1.3-1.9）。共有56％的患者经历了病毒学和生化学复发，定义为HBV DNA≥2000 IU / mL和ALT≥2倍于正常上限，并且三分之一的患者患有ALT发作。

最后，来自卡尔加里（Calgary）的单中心研究在一项现实世界中研究了停止长期核苷酸（t）类似物治疗的结果。在这项对1337例乙型肝炎和轻微纤维化患者的回顾性研究中，有47例停止了治疗。其中有6例由于病毒载量反弹（HBV DNA≥2000 IU / mL）或ALT爆发（ALT≥2 x正常上限）而不得不重新开始治疗。只有1个人达到HBsAg丢失，但是该个人也经历了ALT发作，这凸显了这些患者仍必须仔细随访。

总体而言，在某些患者中终止长期核苷酸（t）类似物治疗是非常有趣的方法，需要进一步探讨。会议上提供的数据表明该策略是安全的，但必须非常谨慎地遵循这些人员。就我个人而言，我认为这种方法尚不适合在黄金时段使用，因此，在将其整合到我的实践中之前，我会急切地等待进一步的数据。

替诺福韦拉芬酰胺预防高病毒血症母亲的垂直HBV传播
目前，在高HBV病毒载量（HBV DNA> 200,000 IU / mL）的女性中，防止垂直传播的指南是在妊娠中期给予TDF。在2020年会议上进行的两项研究检查了替诺福韦alafenamide（TAF）在该人群中是否也安全有效。
潘恩及其同事对71名HBeAg阳性母亲进行了回顾性研究，这些母亲的HBV DNA> 200,000 IU / mL，在中/晚期接受了TAF。 Zang及其同事提出的第二项研究是多胎，前瞻性，观察性研究，从妊娠24至35周至232例HBV DNA> 200,000 IU / mL的母亲分娩给予TAF或TDF。

两项试验均显示相似的结果，即TAF高效且耐受性良好。没有妇女因不良事件而中断治疗；在婴儿中未观察到不良后果，例如先天性缺陷或畸形。因此，这些数据表明，尽管我们对这一人群的主要治疗方法仍然是TDF，但在HBV和HIV中支持TAF疗效和安全性的数据正在迅速积累，以至于TAF可能很快会加入到经批准的治疗方案中，以预防母体感染。 HBV病毒载量高的患者的儿童传播。

用核苷类似物疗法减少HBV DNA整合入人类基因组
乙肝病毒的一个非常有趣的方面是它可以整合到人类基因组中，这似乎是乙肝相关肝细胞癌的主要驱动力。为了增加我们对该主题的了解，会议上有2个有趣的演讲，探讨了核苷酸（t）核苷酸类似物疗法对HBV DNA整合入人类基因组的影响。从历史上看，我们一直认为核苷类似物疗法是严格的抑制性疗法，但这些疗法所带来的病毒整合的数据可能暗示了其他情况。

Hsu及其同事进行的第一项研究检查了66例接受TDF的患者和61例接受安慰剂的患者的整合事件，该患者来自TDF的随机，安慰剂对照试验，用于慢性HBV感染患者。与安慰剂组相比，在3年时，研究人员能够显示TDF组的病毒整合数量显着降低（P = .037）。此外，他们发现接受TDF的患者与安慰剂相比，失调的蛋白编码基因的数量减少的幅度更大（P = .007），这可能表明患癌症的风险可能有所降低。

第二项研究是一项长期研究，研究了核苷酸（t）ide类似物疗法对长达10年的28例慢性HBV感染患者的HBV DNA整合的影响。患者接受了多种核苷酸类似物，在治疗前和治疗后1年进行了肝活检配对，而5位患者在10年后进行了第三次肝活检。使用反向PCR，研究人员能够显示，尽管在所有基线和治疗后1年活检中均可检测到HBV DNA整合，但1年核苷酸（t）类似物治疗显着降低了乙型肝炎整合程度（P = 0.003） ）。此外，对于有10年治疗后活检的5个人，甚至有3个人没有乙型肝炎整合的证据，其整合甚至进一步减少。

综上所述，考虑到整合事件可以减少，这些数据可能表明，即使在病程较早的情况下，治疗乙肝患者的潜在优势甚至比目前建议的要早。

新型特工
最后，会议上有几场演讲，详细介绍了具有新颖作用机理的新型药物治疗乙型肝炎的安全性和有效性。这些演讲的总体主题是，与我们现有的相比，降低HBsAg水平的速度越来越快通常会在我们目前批准的疗法中得到观察，这些疗法采用新型药物（例如小干扰RNA（siRNA）或反义寡核苷酸）进行≥1剂的治疗，这提供了我们有望提高功能性治愈率的途径。最终，我们需要将治疗方案与多种作用机制结合起来，这些可能包括抗病毒和免疫调节疗法。

你的想法
您对AASLD 2020感到最兴奋的是什么数据？请回答投票问题，并在讨论部分中分享您的想法。

hchu

综上所述，考虑到整合事件可以减少，这些数据可能表明，即使在病程较早的情况下，治疗乙肝患者的潜在优势甚至比目前建议的要早。

liuzai

就是抗病毒越早越好呗？

乙肝人1949

早抗早受益