研究表明前所未有的3个星期的丙型肝炎治疗

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Study suggests unprecedented 3-week hepatitis C cure

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By Jon Cohen
30 October 2015 5:45 pm
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Yet another stunning victory in the drug battle against the liver-damaging hepatitis C virus (HCV) may be in the offing: A small study suggests it may be possible to cure some people of their infections in as few as 3 weeks.

Fresh on the heels of recent approvals of four new combinations of HCV drugs that clear infections of many different types of the virus in about 3 months, a team led by hepatologist George Lau of the Humanity & Healthy GI and Liver Centre in Hong Kong, China, has mixed and matched various compounds to see whether they could further shorten the route to a cure. Following 3 weeks of treatment, 18 HCV infected people given three different combinations of drugs met the standard definition of being cured—at 12 weeks after treatment began, they had no signs of HCV’s genetic material, RNA, in their blood on standard tests. The researchers plan to present this data publicly for the first time at a scientific conference known as The Liver Meeting in 2 weeks.

Until the new HCV drugs emerged, infected people required treatment for 8 months, and the therapies often failed and had severe side effects. Now, standard treatment protocol calls for taking HCV drugs for just 12 weeks. Cutting that treatment time even more dramatically is “really, really intriguing” says Shyam Kottilil, an HCV researcher at the Institute of Human Virology in Baltimore, Maryland. And if the results hold, it could slash the overall treatment cost of $100,000 required by the most popular drugs used for the 12-week treatment. Kottilil’s own study of a 4-week treatment—which tested different drug combinations on a different patient population—had only a 40% cure rate in the 50 participants. (That study is in press at Annals of Internal Medicine.)

Other researchers point out several caveats to the 3-week success, most notably that the 18 people treated had several characteristics of patients who respond well to HCV drugs. “It’s very interesting, but not unexpected,” says David Nelson, a hepatitis researcher at the University of Florida in Gainesville.

Raymond Schinazi, a biochemist from Emory University in Atlanta who collaborated with Lau, acknowledges that this is only a pilot study and needs confirmation in a larger clinical trial. “But when you get 100%, it’s always statistically significant,” says Schinazi, who helped develop one of the new blockbuster HCV drugs, sofosbuvir, that was part of the combinations tried in the new study.

The rapid clearance of HCV from the body seen in the study upends mechanistic models about how treatment cures people of HCV. “Our models did not predict this at all,” says another collaborator, Alan Perelson, a biophysicist at the Los Alamos National Laboratory in New Mexico, who has done key work on how treatment leads to clearance of both HCV and HIV. “There’s some piece of basic science about viral clearance that we’re still missing.”

Until May 2011, the only drugs approved to cure HCV worked by murky and nonspecific antiviral and immune mechanisms, had significant side effects, and failed 40% of the time. Since then, a dozen so-called direct-acting antivirals have come to market—all of which are expensive—and many similar, promising candidates are in development.

The Hong Kong study tested three different triple combinations of the most effective direct-acting antivirals, each of which homes in on different HCV enzymes or proteins important to its replication. Sofosbuvir—created by a small biotech Schinazi started that was bought out by Gilead Sciences of Foster City, California—targets HCV’s RNA polymerase and was the backbone of all three regimens. Widely considered the “first-in-class” in the HCV drug world, sofosbuvir has a relatively high potency, causes few side effects, and is rarely foiled by drug-resistance mutations. (Its initial retail sales price, $1000 per pill, triggered international controversy.) The researchers combined it with either ledipasvir or daclatasvir, which cripple a viral protein known as NS5a. To finish the cocktail, the researchers added one of two HCV protease inhibitors, simeprevir or asunaprevir.

Three different Big Pharma companies make the various drugs, and Schinazi asserts that to protect their markets, they have resisted collaborating with each other. “I want to show these companies that they should have done this study a long time ago themselves,” says Schinazi, who helped pay for the drugs used in the study. “When you put the best drugs together, you get fabulous results.”

To obtain those results, the researchers purposefully went for the lowest hanging fruit—and Hong Kong was an ideal test site. HCV has six different genotypes that, in turn, divide into subtypes. In China, the most prevalent is genotype 1b, which responds more readily to drug treatment than any other genotype: Earlier studies have shown that 8 weeks of sofosbuvir and ledipasvir can cure almost everyone. Large studies have also found that 84% of Chinese HCV patients have a variant of an immune gene (technically known as IL28b cc) that leads to a strong natural attack against the virus, giving them an advantage when treated with effective drugs. “So you’re actually looking at [a] population that not only has the best genotype but the host may be playing a role,” says Mark Sulkowski, director of the viral hepatitis center at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

The investigators stacked the deck in two other ways. As is commonly done in HCV drug clinical trials, they excluded HCV-infected people who have suffered cirrhosis of the liver and thus are harder to cure. What’s more, the study used an unusual study design called response-guided therapy.  In all, 26 people began the treatment and the researchers checked their HCV blood levels after 2 days, selecting 18 people who had the biggest drops in viral loads for the short duration therapy and treating the others for the standard 12 weeks. These 18 participants also had lower HCV viral loads pretreatment.

The University of Florida’s David Nelson says the study “is a great proof of concept,” but he questions how applicable the 3-week treatment scheme will be in the global response. Although genotype 1 accounts for an estimated 46% of all infections worldwide, the majority of Americans have the harder-to-treat 1a subtype. Some 22% of the world has genotype 3, which similarly is more difficult to cure than 1b. Ideally, says Nelson, one standard treatment protocol should work against all genotypes without the need to test initial responses and regardless of cirrhosis status.

Although Sulkowski agrees that ultrashort treatment won’t be a one-size-fits-all, he counters that it may be pragmatic in some settings. “This study really opens a philosophical discussion about how to treat hepatitis C,” Sulkowski says. “Maybe there’s a role for a complicated strategy that shortens therapy.” In the United States, for example, it may make economic sense in some health care systems to pay extra costs to test genotype 1b patients—who make up 25% of the infected population—2 days into therapy and select the responders for the 3-week treatment course. Consider that nearly 180,000 people who receive care from the Veterans Health Administration have tested positive for HCV: Estimates suggest it would cost $12 billion to treat everyone for 12 weeks even at steeply discounted rates for drugs. Shaving off 9 weeks for thousands of people could equal huge savings in drug costs.

Sulkowski says even if the ultrashort therapy scheme does not have a 100% cure rate, it may not pose great risks to patients. As he and others will reveal at The Liver Meeting, a growing body of evidence shows that patients who fail on one therapy often respond if treated again with different drugs. “If I can tell a patient I’m going to treat you for 4 weeks and if you don’t respond I can rescue you with another approach, that’s a reasonable strategy for a country like the U.S.”

Schinazi says combinations of more potent drugs and higher doses of existing ones could reduce the time to cure even further. “I think eventually we could go to 2 weeks,” he says.

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研究表明前所未有的3个星期的丙型肝炎治疗

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2015年5:45 PM 10月30日
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然而，在对肝脏损伤性丙型肝炎病毒（HCV）的药物战的另一个惊人的胜利可能是在酝酿之中：一个小的研究表明，有可能治愈的感染一些人在短短3周。

新鲜最近的HCV药物清除约3个月许多不同类型的病毒感染四个新组合，在香港，中国为首的人类肝病专家乔治·刘和健康的胃肠道和肝脏中心一队批准的高跟鞋已经混合和匹配各种化合物，看看他们是否能进一步缩短路线治愈。以下3个星期的治疗，18 HCV感染者给出了三种不同的药物组合，满足治愈，在治疗12周开始后，在标准的定义，他们有丙型肝炎病毒的遗传物质，RNA，没有任何迹象，其血液中的标准测试。研究人员计划在2周内称为肝会议科学会议上公开提出这一数据首次。

直到新的丙型肝炎病毒药物出现，感染者需要治疗8个月，治疗往往失败，并有严重的副作用。目前，标准治疗方案需要采取HCV药物只有12周。切削治疗时间更为显着是“真的，真的很有趣”的希亚姆Kottilil，与HCV研究员人类病毒学研究所在马里兰州巴尔的摩说。而如果结果成立，它可以削减$ 100,000的总治疗费用由用于治疗12周最流行的药物需要。 Kottilil自身研究为期4周的治疗，其中在不同的患者群，仅具有40％的治愈率在50名参加测试的不同的药物组合。 （这项研究是按在内科医学年鉴。）

其他研究人员指出一些警告到3周的成功，最显着的是，18人治疗过的是谁HCV药物反应不佳的患者几个特点。 “这很有趣，但并不意外，”大卫·尼尔森，肝炎研究人员在佛罗里达的盖恩斯维尔大学。

雷蒙德Schinazi，来自亚特兰大的埃默里大学的生化学家谁合作与刘承认，这只是在一个较大的临床试验，试验研究和需求确认。 “但是，当你得到100％的，它总是有统计学显著，”Schinazi，谁帮助开发新的重磅油炸弹HCV药物之一说，索非布韦，这是组合的一部分，试图在新的​​研究中。

丙型肝炎病毒的从出现在研究体内迅速清除颠覆了有关如何处理治愈丙型肝炎病毒的人机理模型。 “我们的模型没有预测这在所有的，”另一位合作者，艾伦Perelson，生物物理学家在洛斯阿拉莫斯国家实验室在新墨西哥州，谁做就怎么治疗会导致两者HCV和HIV的间隙重点工作。 “有一些片长约病毒清除，我们正在还缺基础科学的。”

直到2011年5月，是唯一批准的药物治疗丙型肝炎病毒通过阴暗和非特异性抗病毒和免疫机制的工作，有显著副作用，失败的时候40％。从那时起，十几个所谓的直接作用抗病毒药物已进入市场，所有这些都是昂贵的，和许多类似的，有希望的候选人正在开发中。

香港研究测试的最有效的直接作用抗病毒药物的三种不同的三重组合，其中每个家庭在不同的HCV酶或蛋白质很重要的复制。由一个小型生物技术索非布韦创建Schinazi开始被买断了福斯特市，加州的目标HCV的RNA聚合酶吉利德科学，是三个方案中的骨干力量。广泛认为是HCV药物世界“第一次在类”，索非布韦具有较高的效价，导致一些副作用，很少是由耐药突变挫败。 （其最初的零售销售价格，$ 1,000元每丸，引发国际争议。）研究人员用两种ledipasvir或daclatasvir，这削弱称为NS5A的病毒蛋白质的结合吧。要完成的鸡尾酒，研究人员增加了一个两HCV蛋白酶抑制剂，simeprevir或asunaprevir。

三种不同的大型制药企业做了各种药物，并Schinazi称，以保护他们的市场，他们已经拒绝与对方合作。 “我想告诉这些企业，他们应该做这个研究很久以前的自己，”Schinazi，谁帮助支付在研究中使用的药物说。 “当你把最好的药物一起，你会得到美妙的结果。”

为了得到这些结果，研究者有目的地去了唾手可得的成果，与香港是一个理想的试验场地。丙型肝炎病毒有六个不同基因型，反过来，分为亚型。在中国，最普遍的是基因型1b，这是为了响应更容易对药物治疗比其他基因型：早期的研究已经表明，8周索非布韦和ledipasvir可以治愈几乎每个人。大的研究还发现，中国HCV患者的84％具有的免疫基因（技术上称为IL28B毫升）的变体，导致针对病毒强烈的天然进攻，当与有效的药物治疗给他们的优点。 “所以，你实际上是在寻找[A]人口，不仅有最好的基因型但主机可以扮演一个角色，”马克说Sulkowski，病毒性肝炎中心的约翰霍普金斯大学医学院的巴尔的摩主任，马里兰。

研究者堆放在甲板上的其他两种方式。如通常在HCV药物的临床试验完成后，他们排除谁遭受肝硬化，因此更难治愈HCV感染的人。更重要的是，研究中使用的一个不寻常的研究设计称为应答指导治疗。总之，26人开始治疗和研究人员检查他们的HCV的血液水平后第2天，选择18人谁拥有最大滴病毒载量的持续时间短的治疗和治疗其他的标准12周。这18名学员也有较低的HCV病毒载量的预处理。

佛罗里达的戴维·纳尔逊大学说，这项研究“为理念的一大证据”，但他质疑3周的治疗方案将如何适用在全球响应。尽管基因1型占全球所有感染的估计有46％，大部分美国人都更难 - 治疗1A亚型。世界上的一些22％具有基因型3，这同样是更难以治愈比1b上。理想情况下，尼尔森说，一个标准的治疗方案应反对各种基因型，而不需要进行测试的初始反应，无论肝硬化状态。

虽然Sulkowski同意超短治疗不会是一个尺寸适合所有人，他反驳说，它可能是务实的一些设置。 “这项研究真正开启有关如何治疗丙型肝炎一个哲学讨论，”Sulkowski说。 “也许有一个复杂的策略，缩短治疗。一个角色”在美国，例如，它可能使经济意义在一些卫生保健系统支付额外的费用来测试基因型1b的患者，谁弥补的感染25％人口-2天进疗法，并选择反应为3周的疗程。考虑到近18人谁从退伍军人健康管理局收到护理测试了正面丙型肝炎病毒：据估计，这将花费$ 12个十亿对待每一个人，共12周，即使在急剧折扣率的药物。剃须9折星期，成千上万的人可以在药品费用等于享受更多折扣。

Sulkowski说，即使超短波治疗方案不具有100％的治愈率，它可能不会对病人极大的风险。当他和其他人就会发现，在肝脏会议，越来越多的证据体表明，谁不上的一个治疗的患者，如果用不同的药物治疗又常常做出回应。 “如果我可以告诉病人，我会好好对待你4周，如果你不回应，我可以救你用另一种方法，这对像美国这样一个国家合理的策略”

Schinazi说的更有效的药物和大剂量现有的组合可以减少甚至进一步固化的时间。 “我想最终我们可以去到2周，”他说。

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