德国尝试：43岁男性艾滋病患者被治愈属世界首例
发布者：hongkun 时间：2011-01-10 09:07:08 来源：《新世纪》-财新网
核心提示：自艾滋病病毒1981年被发现以来，终于有医生宣布病人被彻底治愈，但这只是一起特殊的个案 而在2010年12月的《血液》杂志上，胡特医生及其合作者做出了更加大胆的判断：布朗的艾滋病应该是被彻底治愈了。
自艾滋病病毒1981年被发现以来，终于有医生宣布病人被彻底治愈，但这只是一起特殊的个案
□ 本刊记者 戴廉 | 文
几位德国研究者的大胆尝试，燃起了治愈艾滋病的希望之光。
在2010年12月的美国《血液》杂志上，德国三所大学医学部的研究人员共同发表论文称，其研究结果有力地证明一位43岁男性艾滋病患者被治愈。
这应该是一个激动人心的结果——自艾滋病病毒1981年被发现以来，世界上还从未有任何一位病人被治愈。
不过，被“治愈”的并非普通艾滋病人。当前定居柏林的美籍男子蒂莫西·布朗（Timothy Brown），十几年前患上艾滋病，几年前又被确诊为白血病。2007年，他在德国柏林大学夏里特医学院接受了造血干细胞移植，用以治疗白血病。
不同的是，医生为他寻找了一位携带特殊基因的干细胞捐献者，而携带这种特殊基因的人能够天然抵抗艾滋病病毒的侵扰。
“这是一个十分不寻常的病例，它表明了在特定条件下，通过基因疗法可能会清除人体内的艾滋病病毒。”美国加州大学洛杉矶分校艾滋病研究所副所长、临床艾滋病研究与教育中心主任唐纳德·光泰（Ronald Mitsuyasu）对本刊记者表示，“但它本质上并不是基因疗法。迄今为止，还不能被复制。”
多位专注于艾滋病治疗的国内临床医生也对本刊记者表示，从目前情况来看，这一治疗方法“只是个案，要想在艾滋病人群中普及还很不现实”。
小概率事件
好似被闪电连续击中一样，布朗的艾滋病被治愈是个十足的“小概率事件”。而夏里特医学院的血液病医生杰罗·胡特（Gero Hü?tter）是这个事件中的关键人物。
胡特是布朗的主治医生。2006年，布朗因急性髓性白血病住进夏里特医学院附属医院，胡特为他设计的治疗方案中包括两个疗程的诱导化疗和一个疗程的巩固化疗。但是，在第一个诱导化疗期间，布朗出现了严重的肝中毒与肾衰竭反应，化疗方案难以继续。
于是，当时37岁的胡特医生记起了十年前一项关于艾滋病的发现。1996年，就在华裔科学家何大一提出抗病毒药物“鸡尾酒疗法”的同一年，有研究者发现，一些同性恋男子尽管与数百个性伴侣有过危险性行为，却没有感染艾滋病病毒，原因在于他们从父母双亲那里继承了一种特殊的突变基因，能够抵御艾滋病毒的进攻。
艾滋病病毒能够融入病人的DNA中，隐藏在所谓的“避难细胞”里，很难被清除出体内。但要想进入到细胞之中，病毒通常还须依赖人体内其他因子，比如3号染色体短臂上的CCR5基因。它们相当于艾滋病病毒进入细胞的大门，当其发生突变而缺失32个碱基时（被称为CCR5⊿32）时，病毒就会不得其门而入。
研究还发现，约1%的欧洲人继承了这种CCR5突变，北欧人中这个比例更高；非洲人、亚洲人和南美洲人则很少携带该突变基因。
解放军302医院王福生教授及其同事后来开展的调查显示，中国汉族人该基因的突变率仅为0.16%，而维吾尔族人高达3%以上。
尽管胡特对于艾滋病治疗是个外行，但他仍然提出一个奇思妙想：为什么不能同时治疗这两种病？最终，他向布朗推荐了干细胞移植疗法，并希望找到携带CCR5⊿32的骨髓捐献者。
布朗的足够幸运之处在于，全德国一共只找到80个合适的骨髓捐献者，而检测到第61个捐献者的样本时，胡特医生的同事发现了这种突变基因。2007年2月，干细胞移植顺利施行。
为了预防移植手术通常会出现的排异反应，胡特医生用药物和放疗手段杀死了布朗体内的骨髓细胞和很多免疫细胞。这个过程对于艾滋病病毒藏身的许多“避难细胞”来说是致命的。很多科学家认为，这些准备工作也正是布朗体内艾滋病毒得以消除的重要因素之一。
胡特医生及其同事心里并没有底。他们原本计划，一旦发现艾滋病病毒重新出现在布朗的血液里，就让他走上服用抗病毒药物的老路。
在干细胞移植前，布朗接受过四年的高活性抗逆转录病毒治疗，即服用药物。这是当下最常见的艾滋病治疗方式，可有效控制病情，但无法彻底治愈。
但艾滋病毒再也没有出现。两年后，标准的艾滋病毒检测已经不能探测到布朗血液中的病毒，在艾滋病病毒常常隐藏的大脑和直肠组织中同样不见其踪影。
2008年，布朗的病例首次在一次学术会议上展示。当时，大多数研究者认为，一些病毒或许隐藏在病人体内却无法引发感染，无论如何，病人大概“从机能上被治愈”了。
在2009年2月的《新英格兰医学杂志》上，胡特医生以第一作者身份发表论文称，在停止抗病毒药物治疗并接受干细胞移植20个月之后，病人体内没有病毒反弹迹象。但他和同事当时只是谨慎地表示，这一结果显示了基因疗法在控制艾滋病病毒感染方面的关键作用。
而在2010年12月的《血液》杂志上，胡特医生及其合作者做出了更加大胆的判断：布朗的艾滋病应该是被彻底治愈了。
此时，距离布朗接受干细胞移植已近四年。
基因疗法路漫漫
然而，这个难以复制的“小概率事件”在带来艾滋病治疗曙光的同时，也备受争议。
加州大学洛杉矶分校的唐纳德·光泰教授指出，要想复制这一治疗方法，需要满足多项条件，并且花费昂贵，其长期风险也未可知。
实际上，已经有科学家担心，在足够长的时间之后，艾滋病病毒可能适应这种突变，导致病毒反弹。
还有人对CCR5突变本身的副作用表示担心。一项研究显示，拥有这种突变的人更容易死于西尼罗病毒。
更多的人则忧虑，由于利用强力药物和放射物来摧毁人体原有的免疫系统，干细胞移植或骨髓移植通常只用于晚期癌症患者，对其他人群可能并不适用，已经有人称这种疗法本身的死亡率可高达30%。
据《华尔街日报》报道，早在1989年，美国加州希望之城癌症中心约翰·罗斯（John Rossi）医生就遇到过和布朗十分类似的病例。一位41岁的病人同时患有艾滋病和淋巴瘤。他接受了化疗和药物治疗，并接受捐赠者的新细胞。由于当时科学界还未发现CCR5突变的意义，这位捐赠者是否具有突变基因不得而知。接受移植之后，艾滋病病毒从病人的血液和多个器官中消失了。但可惜的是，病人在接受移植47天后死亡。
2008年，在布朗病例公开不久，诺贝尔奖得主大卫·巴尔迪摩（David Baltimore）认为，这一病例意义重大，是一个非常好的信号，是“对基因疗法的实质性证明”。
巴尔迪摩和加州大学洛杉矶分校的陈（Irvin S. Y. Chen）教授还设计了一个应对艾滋病的基因疗法，其思路与布朗病例相似。两人专门为此成立了一个私人公司。
在加州希望之城癌症中心，罗斯及其同事则开始尝试通过基因改造使艾滋病病毒本身变得无害，并将三个基因注入到患者白细胞中：一个用以阻止CCR5的活动，另外两个用以削减艾滋病病毒的能力。他们已在数位病人身上完成试验。
问题是，理论上可行的基因疗法在现实中面临诸多技术挑战。比如，当前大多数基因疗法需在体外对基因进行改造，然后将其重新注入体内——这是一个非常复杂的程序。巴尔迪摩等人试图发明一种类似于疫苗的简易治疗方法。但他接受媒体采访时承认，目前进展不顺，虽然“已经为此工作很长时间了”。
2009年3月，光泰等人在《自然医学》杂志发表论文，介绍了一项关于抗艾滋病病毒基因疗法的临床试验。这也是全球第一起关于基因疗法的随机、双盲、对照二期临床试验。他们将74位艾滋病病毒感染者分为治疗组和对照组，分别注射一种抗艾滋病病毒核酶（一类具有催化功能的RNA分子）和安慰剂。约一年后，研究者在两组受试者中并未发现病毒载量的统计学差异；当然，在某些时间段，治疗组患者体内的艾滋病病毒含量低得多。
这篇论文发表后，研究便止步不前。“我们没有做三期试验，”光泰表示，“因为拥有该疗法的公司决定不再做三期试验，而且取消了进一步开发产品的计划。我们仍在对参与二期试验的病人的安全性进行跟踪，这也是FDA对人体基因疗法试验的要求。我们目前也在和其他研究者合作开发其他基因疗法的产品和方法，但只是处在调查研究的基础阶段。”
光泰直言不讳地指出，“对于绝大多数艾滋病患者而言，基因疗法在近期内可能还无法成为一个广泛应用的方法，其他的药物疗法效果也已经非常好了。尽管抗病毒疗法需要病人终身服药，但其副作用和毒性通常很小。而基因疗法尚未被证明能有效治疗艾滋病，其花费很高，治疗方法也很不方便。所以，在对新的基因、新的介质和新的方法进行更多试验之前，基因疗法还不能被更广泛运用。”
王福生及其同事也在进行干细胞移植治疗艾滋病的研究。
据“成都全搜索”网站报道，该院院长吕吉云透露其研究正处于临床试验阶段，试验申请已获得卫生部批号。但王福生婉言谢绝了本刊记者的采访要求。
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| 图示∶2010年12月即将出版的《中国特色医疗金鉴》登载的刘君主任及其机构 |
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Germany Try: 43-year-old male AIDS patients were cured of the world's first
Posted by: hongkun Time :2011-01-10 09:07:08 Source: "New Century" - Finance new network
Core Tip: Since the discovery of HIV since 1981, and finally a doctor said the patient was completely cured, but only with the special case in December 2010 the "blood" magazine, Dr. Hu Te and its partners to make a more aggressive judgments: Brown's AIDS should be completely cured.
Since the discovery of HIV since 1981, and finally a doctor said the patient was completely cured, but only with the special case
□ reporter Dai Lian | text
A bold attempt by several German researchers, lit a beacon of hope for a cure for AIDS.
In December 2010 the United States, "blood" magazine, Germany, three researchers at the University of Medicine, said co-published papers, the results strongly demonstrate a 43-year-old male AIDS patients were cured.
This should be an exciting result - since the discovery of HIV since 1981, the world has never had any patients were cured.
However, there was "cured" of AIDS is not the ordinary people. American men currently live in Berlin Timothy West Brom (Timothy Brown), a dozen years ago, suffering from AIDS, a few years ago and was diagnosed with leukemia. In 2007, he Xia Lite Medical University in Berlin, Germany received hematopoietic stem cell transplantation for the treatment of leukemia.
The difference is that he sought a doctor to carry a special gene stem cell donors, and those who carry this particular gene to the intrusion of natural resistance to HIV.
"This is a very unusual case, which shows that under certain conditions, through gene therapy may clear the body of HIV." University of California at Los Angeles AIDS Institute, deputy director, clinical director of the Center for AIDS Research and Education Donald Light Thai (Ronald Mitsuyasu) of the correspondents said, "but it is essentially not a gene therapy. So far, not be copied."
Many focus on the domestic AIDS treatment clinic doctors said on correspondents from the current situation, this treatment "is just the case, in order to spread the AIDS population is still very unrealistic."
Small probability event
As if struck by lightning, like a row, Brown has been cured of AIDS is full of "small probability event." The Xiali Te Hematology Medical Doctor Jerome Kohut (Gero Hü? Tter) was a key figure in this event.
Huth is Brown's doctor. In 2006, Brown was admitted due to acute myeloid leukemia Xia Lite Medical College Hospital, Hu specially designed treatment program he designed to include two courses of induction chemotherapy and a course of consolidation chemotherapy. However, during the first induction chemotherapy, Brown experienced serious liver toxicity and kidney failure response, chemotherapy is difficult to continue.
Thus, when the 37-year-old Dr. Hu Te remember a decade ago a study on the discovery of AIDS. In 1996, Chinese scientist David Ho in proposed antiviral "cocktail therapy" the same year, researchers found that some gay men, although there have been hundreds of sexual partners, risky sexual behavior, but not infected with HIV, because They inherited from both parents a special mutant gene, can withstand the attack of HIV.
HIV can integrate into the patient's DNA, hidden in the so-called "asylum cell", the hard to be removed from the body. But to enter into the cell, the virus usually have to rely on the human body other factors, such as the short arm of chromosome 3 of the CCR5 gene. They are the equivalent of HIV into the cell door, when the mutation and deletion of 32 bases (the are called CCR5 ⊿ 32), the virus will enter the halls.
The study also found that about 1% of Europeans inherited the CCR5 mutation, a higher proportion of Nordic people this; Africans, Asians and South Americans are very rarely carry the mutant gene.
Professor Wang Fusheng PLA 302 Hospital, and colleagues conducted a survey later showed that the Chinese Han population mutation rate was 0.16%, while the Uighur people of up to 3%.
Although Huth AIDS treatment for a layman, but he still made a whim: Why can not treat these two diseases? Ultimately, he recommended to the Brown stem cell transplantation therapy, and hope to find carry CCR5 ⊿ 32 of the bone marrow donor.
Brown is lucky enough to place the whole of Germany found a total of only 80 suitable bone marrow donor, and testing to 61 donor samples, Dr. Hu Te colleagues found that this mutant gene. February 2007, the successful implementation of stem cell transplantation.
In order to prevent transplant rejection usually occurs, Dr. Hu Te by means of drugs and radiation kill bone marrow cells in vivo Brown and many immune cells. The process for the AIDS virus to hide many of the "asylum cell" is fatal. Many scientists believe that these preparations is also able to eliminate HIV in vivo Brown, one important factor.
Dr. Hu Te and his colleagues did not mind the end. They originally planned, once the re-emergence of HIV found in Brown's blood, let him take antiviral drugs onto the old road.
In stem cell transplantation before Brown received four years of high active antiretroviral therapy, that medication. This is the moment the most common AIDS treatments, which can effectively control the disease, but not completely cured.
However, HIV no longer appear. Two years later, the standard HIV testing has not detected the virus in the blood Brown, often hidden in the HIV brain and rectal tissues of the same out of sight.
In 2008, Brown's case the first time in an academic conference presentation. At that time, most researchers believe that some virus may hide in a patient can not cause infection, however, the patient probably "been cured from the function" of the.
In February 2009 the "New England Journal of Medicine", and Dr. Hu Te published as first author, said that the cessation of antiviral therapy and stem cell transplantation 20 months later, the patient showed no signs of viral rebound. But he and his colleagues was only cautioned that the results showed that the gene therapy of HIV infection in the control of the crucial role.
In December 2010 the "blood" magazine, Dr. Hu Te and its partners to make a more bold judgments: Brown's AIDS should be completely cured.
At this point, stem cell transplants from Brown for almost four years.
Long Way gene therapy
However, the hard copy of the "small probability" in the dawn to bring AIDS treatment, but also controversial.
UCLA Professor Donald Light and Thailand, in order to replicate the treatment, need to meet a number of conditions, and expensive, and its long-term risks are unknown.
In fact, scientists have been worried that a long enough time, the AIDS virus could adapt to this mutation, leading to viral rebound.
Mutation of CCR5 also expressed concern about their side effects. A study with this mutation are more likely to die of West Nile virus.
More people are worried, because the use of drugs and radiation Qiangli to destroy existing human immune system, stem cell transplantation or bone marrow transplantation is often used only for patients with advanced cancer, may not apply to other groups, have called this treatment their own mortality can be as high as 30%.
According to "The Wall Street Journal" reported that as early as 1989, California City of Hope Cancer Center, John Ross (John Rossi) and the doctors encountered a very similar case of Brown. While a 41-year-old patient suffering from AIDS and lymphoma. He received chemotherapy and drug treatment, and receive the new donor cells. At that time the scientific community has not found the meaning of CCR5 mutation, the donor is not known whether the mutant gene. After the transplant, AIDS virus from the patient's blood and multiple organs disappeared. Unfortunately, the patient underwent transplantation 47 days after the death.
In 2008, the Brown case open soon, Nobel laureate David Baltimore (David Baltimore) that is significant in this case is a very good signal, is "substantial proof of gene therapy."
Baltimore and the University of California, Los Angeles, Chen (Irvin SY Chen) also designed a professor of gene therapy to deal with AIDS, the Brown case with similar ideas. They specifically for this set up a private company.
In the City of Hope Cancer Center in California, Ross and his colleagues then began to try to make AIDS virus by genetic modification itself becomes harmless, and three genes in white blood cells injected into the patient: one to stop the activities of CCR5, the other two with the ability to reduce HIV. They have several patients who completed the trial.
The problem is, in theory, gene therapy feasible in the real world face many technical challenges. For example, most current gene therapy to be carried out in vitro gene transformation, and then re-injected into the body - this is a very complicated process. Baltimore, who tried to invent a simple treatment like vaccines. Media interview, he admitted that the progress is not smooth, although the "have worked on this for a long time."
March 2009, light Thai and others in "Nature Medicine" magazine published a paper describes a study on anti-HIV gene therapy clinical trials. This is also the world's first gene therapy on from a randomized, double-blind, controlled phase II clinical trials. They were 74 HIV infections were divided into treatment group and control group were injected with an anti-HIV ribozyme (catalytic function of a class of RNA molecules) and placebo. About a year later, the researchers did not find in the two groups of subjects a significant difference in viral load; course, in some time, the treatment of HIV patients in vivo concentration is much lower.
The paper was published, the study will be stalled. "We did not do phase III trials," Light Tai said, "because they have the therapy company decided not to do phase III trials, and the cancellation of plans for further development of products. We are still in Phase II trials on the safety of patients track, which is human gene therapy trials FDA requirements. We are also working with other researchers to develop gene therapy products and other methods, but only at the basic stage of research. "
Light Thai bluntly, "For the vast majority of AIDS patients, gene therapy in the near future may not become a widely used method, the other effects of drug therapy has also been very good. Despite the life-long antiviral therapy needs of patients medication, but its side effects and toxicity are usually very small. The gene therapy has not been proven effective in the treatment of AIDS, the cost is high, treatment is also very convenient. Therefore, the new genes, new media and new methods more before the test, gene therapy still can not be used more widely. "
Fu-Sheng Wang and his colleagues also conduct stem cell transplantation for treatment of AIDS research.
According to the "Chengdu full search" website reported that the dean Lvji Yun said the research is in clinical trials, test batch applications have been the Ministry of Health. Wang Fusheng politely refused but the reporter's interview request.
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