DDW2012:Opinion:HCV Patients May Be Able to Delay Therapy

StephenW

HCV Patients May Be Able to Delay TherapyBy Kristina  Fiore, Staff Writer, MedPage TodayPublished: May 22, 2012


SAN DIEGO  --  Hepatitis C patients without significant fibrosis may be able to delay triple therapy and wait for simpler, shorter, and potentially all-oral regimens that are currently under investigation, researchers said here.
The addition of new protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) to previous standard therapy of interferon and ribavirin have significantly boosted sustained viral response for many patients, especially for blacks and Latinos, according to Maribel Rodriguez-Torres, MD, of the Fundacion de Investigation in Rio Piedras, Puerto Rico.
But patients with less severe disease may be able to hold off until a handful of newer agents  --  offering less complex regimens that potentially cut the symptomatic interferon from the mix  --  come to market, possibly within the next two years, Rodriguez-Torres said during a symposium at Digestive Disease Week (DDW) here.
"This is a slowly progressing disease and most of the time we have the time and opportunity to determine what's the best [treatment strategy] for our patients," she said. "Patients without significant fibrosis should wait. Those with more advanced disease should consider therapy today."
Triple Therapy Presents Challenges
Clinicians have cited a number of challenges with triple therapy. Both new agents are only indicated for patients with genotype 1 disease  --  though this comprises the majority of patients  --  and they add a significant cost to treatment, Rodriguez-Torres said.
The regimen is also complex and long-lasting, with both new agents adding multiple daily pills to ribavirin's four to six pills per day and weekly interferon injections, extending for 24 to 48 weeks.
There's also an increased risk of drug-drug interactions, as both new agents inhibit the common CYP34A metabolic pathway, potentially increasing levels of other drugs metabolized that way. That list includes some statins and ACE inhibitors, which "aren't unusual drugs," Rodriguez-Torres said.
Side effects include anemia, a concern because ribavirin already lowers blood hemoglobin levels, she said. Also, telaprevir appears to cause rash in more than 50% of patients.
Instead, a "dream regimen" is a simple one with fewer pills, contains only oral agents, spans all genotypes, and is highly effective with an excellent safety and tolerability profile  --  though that possibility is not that far from reality, Rodriguez-Torres said.
Improvements Are on the Horizon
"We've never had such an explosion of drug development in the last 75 years compared to what we see now in chronic hepatitis C," she said. That robust pipeline includes not only a number of protease inhibitors and NS5A inhibitors  --  which are typically genotype-specific  --  but also nucleoside and cyclophilin inhibitors that are pan-genotypic.
Such robustness may help keep prices down as a result of increased competition, Rodriguez-Torres said. Also, the majority of drugs in development are dosed once or twice daily and some have a much shorter duration of therapy than the current standard of 24 to 48 weeks.
Early data also have shown that it's possible to drop interferon from the regimen. Last month at the European Association for the Study of the Liver meeting Barcelona, researchers reported that high proportions of patients has sustained virologic response rates with an all-oral regimen of ribavirin plus two investigational agents, ABT-450/r, a protease inhibitor, and ABT-072, a non-nucleoside NS5B polymerase inhibitor.
Also at that meeting, an early trial showed that a combination of daclatasvir, an NS5B inhibitor, plus GS-7977, a nucleotide NS5B inhibitor, led to rapid and sustained viral response in patients with genotypes 1-3, with or without ribavirin.
Treatment Issues Remain Complex
The pressing question facing clinicians, then, has been determining who to treat and when. Rodriguez-Torres said the simple answer is to treat those with severe fibrosis now, but hold off on treating those without significant fibrosis.
But Andrew Muir, MD, clinical director of hepatology at Duke University, told MedPage Today the decision should rest largely with the patient.
"I get concerned about us being too heavy handed deciding which patients should or should not get hepatitis C treatment," he said. "Our role should be to guide patients about potential options, and those discussions can take quite a bit of time."
He noted, however, that the side effects "will be much better for these patients with future therapies. But I have had patients elect to proceed with treatment even with early-stage disease. Some have felt it was the right time for them to proceed with treatment for a number of personal reasons. Some worried if they would have stable health insurance in the future."
On the other hand, Zobair Younossi, MD, of Inova Health System in Great Falls, Va., said some of his patients actually "warehouse themselves for regimens that do not include interferon."
Muir also noted that even some advanced fibrosis patients may be eligible for watchful waiting, since not all of them will progress quickly.
"If the patient has great risks to treatment, or if the patient does not think the chance of response is good enough to take on the side effects, then delaying therapy is the right thing for that individual [advanced fibrosis] patient as well," he told MedPage Today. "If they do not take treatment, they must get aggressive about liver wellness. That means no alcohol, get in shape and lose weight if needed, and get tight control of your blood sugars if you have diabetes."
Rodriguez-Torres reported relationships with Abbott Laboratories, Anadys, Bristol-Myers Squibb, Glaxo-SKB, Idera, Intarcia, Merck, Novartis, Pfizer, Pharmasset, Roche, Sanofi-Aventis, Valeant, Vertex Pharmaceuticals, ViroChem Pharma Inc, and Wyeth.
The other researchers reported no conflicts of interest.


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Kristina Fiore
Staff Writer
Kristina Fiore joined MedPage Today after earning a degree in science, health, and environmental reporting from NYU. She’s had bylines in newspapers and trade and consumer magazines including Newsday, ABC News, New Jersey Monthly, and Earth Magazine. At MedPage Today, she reports with a focus on diabetes, nutrition, and addiction medicine.

StephenW

丙型肝炎患者可能能够延迟治疗
克里斯蒂娜菲奥雷，员工作家，MedPage今天

出版日期：2012年5月22日，

圣迭戈 - 丙型肝炎患者无显着纤维化可能能够延缓三联疗法和等待更简单，更短，可能所有的口头方案，目前正在调查中，研究人员在这里说。

新的蛋白酶抑制剂telaprevir治疗（Incivek）和boceprevir（Victrelis）除了以前的标准干扰素和利巴韦林治疗已大大推动了许多患者，尤其是黑人和拉美裔，持续病毒反应，根据Maribel罗德里格斯·托雷斯，MD，基金会的调查，在里约Piedras，波多黎各。

罗德里格斯·托雷斯说，但不太严重的疾病患者可能会推迟，直到少数新制剂 - 提供较复杂的方案可能削减从混合对症干扰素 - 市场可能在未来两年内，研讨会期间，在消化疾病周（DDW）这里。

“这是一个缓慢的越来越严重，大部分时间，我们有足够的时间和机会来决定什么是最好的[治疗策略]为我们的病人，”她说。 “无显着纤维化的患者，应等待更先进的疾病者，应考虑治疗的今天。”

三联疗法提出了挑战

医师举出许多挑战与三联疗法。罗德里格斯·托雷斯说，两个新的代理商只表示为1型疾病患者 - 尽管这包括广大患者 - 他们添加了显着的治疗成本。

该方案是复杂和长期的，增加两个新的代理商利巴韦林的4至6丸，每天和每周的干扰素注射，每日多次丸延长为24至48周。

还有的药物相互作用的风险增加，既是新制剂抑制CYP34A常见的代谢途径，可能会增加其他药物的代谢，这样的水平。罗德里格斯·托雷斯说：“这份名单包括一些他汀类药物和血管紧张素转换酶抑制剂，其中”不寻常的药物。

副作用包括贫血，令人担忧，因为利巴韦林已经降低血液中的血红蛋白水平，“她说。此外，telaprevir治疗导致超过50％的患者出现皮疹。

相反，一个“梦想方案”是一个简单的一少药，只包含口服药物，涵盖所有基因型，并具有良好的安全性和耐受性是非常有效 - 尽管这种可能性是不从实际出发，罗德里格斯·托雷斯说。

改进是在地平线上的

“我们从来没有过这样的爆油炸药物开发在过去75年相比，我们现在看到在慢性丙型肝炎，”她说。这个强大的管道包括蛋白酶抑制剂和NS5A抑制剂不仅一个数字 - 这是典型的特定基因型 - 而且是泛基因型的核苷和亲环素抑制剂。

这种鲁棒性可能有助于保持价格竞争加剧的结果，罗德里格斯·托雷斯说。此外，药物开发中的多数是剂量一次或两次，每天和一些有治疗比现行标准的24至48周的时间要短得多。

早期的数据也表明，它可能下降从疗程的干扰素。上个月在巴塞罗那肝会议研究欧洲协会，研究人员报告说，高比例的患者的持续病毒学应答率与利巴韦林加两个研究药物时，ABT-450 / R，一种蛋白酶抑制剂，口服方案， ABT-072，非核苷NS5B聚合酶抑制剂。

此外，在该次会议上，早期试验表明，NS5B基因的抑制剂daclatasvir，再加上GS-7977，核苷酸NS5B基因抑制剂，结合或无利巴韦林，导致1-3基因型的患者的病毒反应的快速和持续的。

待遇问题仍然复杂

那么，面对医生的紧迫问题，已决定谁治疗时。罗德里格斯·托雷斯说，简单的答案是严重纤维化的治疗，但治疗没有显着纤维化关闭。

但肝病的临床主任，医学博士，美国杜克大学，安德鲁缪尔告诉MedPage今天的决定应由主要与病人。

他说：“我得到关注我们太重递给决定哪些病人应该或不应该得到C型肝炎治疗，”他说。 “我们的角色应该是引导患者潜在的选项，这些讨论可以采取相当长的时间。”

不过，他指出，副作用“将是未来治疗这些病人更好，但我有患者选择甚至与早期疾病进行治疗。有些人认为这是对他们进行正确的时间治疗一些个人原因。有些人担心，如果他们将不得不在未来的稳定健康保险。“

另一方面，祖贝尔Younossi，INOVA的卫生系统在大瀑布，位于弗吉尼亚州的医师，说他的一些患者其实是“仓库方案不包括干扰素本身。”

穆尔还指出，即使一些先进的肝纤维化患者可能是观察等待的资格，因为并不是所有的人都会进步很快。

“如果病人有很大的风险治疗，如果病人不认为反应的机会是不够好，副作用，再拖延治疗是正确的事情，以及为个别[晚期肝纤维化病人，”他告诉MedPage今天。他说：“如果他们不采取治疗，他们必须获得对肝脏健康积极的，这意味着无酒精，在形状和减肥，如果需要的话，如果你有糖尿病，严格控制血糖。”

罗德里格斯·托雷斯与Anadys雅培，百时美施贵宝，葛兰素史克，新光，Idera公司，Intarcia，默克，诺华，辉瑞，Pharmasset，罗氏，赛诺菲 - 安万特公司，非专利，Vertex制药制药公司ViroChem，和惠氏的关系。

其他研究人员报告没有利益冲突。

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克里斯蒂娜菲奥雷

员工作家

克里斯蒂娜菲奥雷加入MedPage今天后获得一定程度的科学，健康，和来自纽约大学的环境报告。她曾在报纸和杂志，包括“新闻日报”，ABC新闻，新泽西月刊，大地地理杂志的贸易和消费的署名。在MedPage今天，她报告了糖尿病，营养和药物成瘾的焦点。