2017 EASL慢乙肝领域新进展—抗病毒治疗肾脏、骨骼安#8131

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Viread (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults. This indication is based primarily on data from the treatment of nucleoside-treatment-naïve patients, and a smaller number of patients who had previously received lamivudine or adefovir. Patients were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease. The number of patients in clinical trials who had lamivudine- or adefovir-associated substitutions at baseline was too small to reach conclusions of efficacy. Viread has not been evaluated in patients with decompensated liver disease.

Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The following points should be considered when initiating therapy with Viread for the treatment of

HIV-1: Viread should not be used in combination with Truvada (emtricitabine/tenofovir disoproxil fumarate) or Atripla® (efavirenz/emtricitabine/tenofovir disoproxil fumarate).

The recommended dose for the treatment of chronic hepatitis B and HIV infection is 300 mg once daily taken orally without regard to food. The dosing interval of Viread should be adjusted in patients with renal impairment.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleos(t)ide analogs, including Viread, in combination with other antiretrovirals.

Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Viread. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including Viread. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

New onset or worsening of renal impairment including cases of acute renal failure and Fanconi syndrome has been reported with the use of Viread. It is recommended to assess creatinine clearance (CrCl) before initiating treatment with Viread and monitor CrCl and serum phosphorus in patients at risk, including those who have previously experienced renal events while receiving Hepsera. Administering Viread with concurrent or recent use of nephrotoxic drugs should be avoided.

Viread should not be used with other tenofovir-containing products (e.g. Atripla, Truvada). Viread should not be administered in combination with Hepsera.

HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with Viread. Viread should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection.

Decreases in bone mineral density (BMD) have been observed in HIV-infected patients. It is recommended that BMD monitoring be considered for patients with a history of pathologic fracture or who are at risk for osteopenia. The bone effects of Viread have not been studied in patients with chronic HBV infection.

Redistribution/accumulation of body fat has been observed in HIV-infected patients receiving antiretroviral combination therapy.

Immune reconstitution syndrome has been observed in HIV-infected patients receiving antiretroviral combination therapy, including Viread, which may necessitate further evaluation and treatment.

Early virologic failure has been reported in HIV-infected patients on triple nucleoside-only regimens. Patients on an antiretroviral therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

In controlled clinical trials in patients with chronic hepatitis B, the most common adverse reaction (all grades) was nausea, observed in 9 percent of patients taking Viread at week 48. Other adverse reactions observed at week 48 in greater than 5 percent of patients treated with Viread include abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash. In HIV-infected patients, the most common adverse reactions (incidence ≥10 percent, grades 2-4) are rash, diarrhea, headache, pain, depression, asthenia and nausea. No significant change in the tolerability profile was observed in patients continuing treatment with Viread for 144 weeks.

Important Information about Hepsera (adefovir dipivoxil)

Hepsera is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histological, virological, biochemical and serological responses in adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg-positive chronic hepatitis B virus infection with compensated liver function.

The recommended dose for the treatment of chronic hepatitis B is 10 mg once daily taken orally without regard to food. The dosing interval of Hepsera should be adjusted in patients with renal impairment.

Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B therapy, including Hepsera. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

In patients at risk of or having underlying renal dysfunction, chronic administration of Hepsera may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment. It is important to monitor renal function for all patients during treatment with Hepsera.

HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated HIV infection treated with anti-hepatitis B therapies, such as therapy with Hepsera, which may have activity against HIV.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleos(t)ide analogs alone or in combination with other antiretrovirals.

HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with Hepsera.

For patients with lamivudine-resistant HBV, adefovir dipivoxil should be used in combination with lamivudine. For all patients, consider modifying treatment in case serum HBV DNA remains above 1000 copies/mL with continued treatment.

Co-administration with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir and/or the co-administered drug. Monitor for Hepsera associated adverse events. The most common adverse reaction (less than 10 percent) in compensated disease patients is asthenia and in pre- and post-transplantation lamivudine-resistant liver disease patients is increased creatinine.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Australia.

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risks that physicians may not prescribe Viread over other existing HBV medications. In addition, as Viread is used over longer periods of time by many patients with underlying health problems, taking numerous other medicines, safety, resistance, drug interaction or other issues may arise, which could reduce the market acceptance of Viread. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the second quarter of 2009, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Viread is available at www.Viread.com
U.S. full prescribing information for Hepsera is available at www.Hepsera.com
U.S. full prescribing information for Truvada is available at www.Truvada.com
Viread, Hepsera, and Truvada are registered trademarks of Gilead Sciences, Inc.
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

For more information on Gilead, please call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit www.gilead.com.



Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Investors
Susan Hubbard, 650-522-5715
or
Media
Michael Claeys, 650-522-2459

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介绍替诺福韦针对hiv的应用，跟咱们没关系，
针对乙肝中大三（或大小三混合）的数据就是红色字体部分：
1，金牌的。给药3年能有8%的金牌概率，在乙肝临床治疗上是具有突破性进展标致的。
2，银牌的。大三，26%的人可以获得e抗原转阴；34%的人可以发生e抗原血清转换。
3，铜牌的。71%的人可以获得dna低于检测线

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放牛哥哥

http://www.hbvhbv.com/forum/thread-895790-1-2.html

沁园春 乙肝

乙肝大国,十人之中，一人中招
望中国内外，闻之慌慌
转酶肝功，忽低忽高,
心急如焚，四处名访，欲与骗术试比高
又传来，听战友摘金，分外妖娆
生活如此煎熬
引无数英雄竞折腰
惜工作被刷,十分气恼
女友抛弃，苍天求饶
几度恩替，百分干扰,只求病毒直线掉
俱往矣,数风流人物，心态可好

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www.adicon.com.cn
武汉江汉经济开发区江旺路8号 汉口创业中心爱帝楼5楼
TEL: 027-8336 5120
FAX: 027-8336 5123
实验室主管：陈进军 1582 7370 416
[email protected]

今天打电话区咨询了一下价格：
dna定量 罗氏设备，试剂不知，120元；
dna高规格定量 500元。问是不是雅培，答曰，不知道；问是不是cobas法测 的，答曰，不知道。只知道精度要高。
三系是罗氏设备和试剂，一个单项30元；
s抗原精确定量，i2000设备，雅培试剂， 100元。血样送到上海艾迪康检测。
HBV c区变异11个位点位点检测780元；
HBV p区基因排序（核苷耐药位点）检测780元；

报告发送方式：电邮，快递。可以电话询问结果。

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作者：佚名 文章来源：本站收集整理 点击数：135 更新时间：2007-11-6 15:13:30  

乙型肝炎病毒（HBV）是一种DNA病毒，它通过逆转录在肝细胞中进行复制。HBV感染肝细胞后，附着在肝细胞上，然后穿透肝细胞，进入细胞核，形成共价闭合环状DNA（covalently closed circular DNA，cccDNA），宿主RNA聚合酶Ⅱ以ccc DNA为模板，转录出长短不一的mRNA，进入细胞质。mRNA是HBV基因组复制时反转录的模板，逆转录为负链HBV DNA，然后再以负链DNA为模板复制出正链DNA与病毒外壳进行装配，然后释放到细胞外。HBV一般不会直接引起肝脏的病变，而通过机体的免疫机制，对HBV表达产物引起应答，导致肝脏损害。由于HBV持续地复制，刺激机体产生持续的免疫反应，从而造成更多的肝细胞破坏，引起肝脏疾病的产生。
　　核苷(酸)类似物是目前临床上治疗乙型肝炎的重要抗病毒药物，此类药物如拉米夫定、阿德福韦 ,恩替卡韦和替比夫定通过直接抑制病毒复制，进而改善肝脏组织学病变，延缓乙型肝炎病情进展。但目前还没有一类药物能够抑制肝细胞核内HBVcccDNA。因此，目前还没有办法治愈乙型肝炎。只有通过长期有效的抗病毒治疗抑制体内的病毒水平，防止肝脏并发症的发生。但长期治疗发生病毒耐药是此类药物面临的共同问题。耐药的发生增加了治疗失败的风险，可导致病毒学反弹及病情恶化，并且使后续治疗药物疗效下降，处理十分棘手。

    一、HBV耐药对临床的影响

    抗病毒药物耐药的产生是由于治疗过程中的适应性突变所导致，反映出的是药物对病毒抑制作用的敏感性降低。耐药突变可分为两种：一种为主要耐药突变位点，可使病毒对药物抑制的敏感性下降；另一种为代偿性突变，这种突变能使耐药株的生存能力提高。

　　HBV对核苷(酸)类似物耐药后有如下临床后果：血清HBV DNA升高，血清ALT升高，HBeAg血清学转换减少，肝脏组织学损伤加重，肝病发展，原位肝移植后乙型肝炎复发率增加和耐药HBV的传播。此外，病毒耐药还可影响后续抗病毒治疗的疗效，使疗效不佳或对后续治疗耐药率增高。

    二、耐药的诊断

    美国NIH2006年讨论会纪要对HBV病毒耐药的诊断标准为：PCR定量法测定证明患者血清HBV DNA水平较治疗时最低水平升高≥1 log,可确定为病毒学反弹（Breakthrough）。除此之外，耐药出现的指征还包括血清ALT水平升高、临床恶化以及在病毒聚合酶的编码基因中能检测到耐药株基因型标志物的存在。

　　以拉米夫定治疗为例，说明HBV 耐药株产生的过程。患者治疗前ALT和HBV DNA都比较高，治疗后病毒载量开始下降，ALT也逐步下降，在此过程中，虽然此时HBV DNA和ALT都在较低水平，其实患者体内的病毒已经开始发生了变化（可以检测到对拉米夫定耐药的基因突变株）。随着复制的继续进行，耐药病毒株被选择出来，不断复制，变成占主导地位的病毒株，HBVDNA水平再度升高，最后ALT也出现反弹，ALT的变化落后于HBV DNA的升高，肝脏疾病继续进展。因此，拉米夫定治疗获得的临床益处随着耐药株的产生逐渐丧失。

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三、耐药突变产生的主要影响因素

    慢性乙肝患者病毒复制水平的高低（治疗前HBV DNA水平）、药物的选择压力、药物耐药的基因屏障、肝脏的复制空间（ALT水平）、耐药突变株的适应性、以及治疗过程中HBV DNA是否充分抑制等，都可影响治疗过程中耐药的发生。

　　HBV的复制效率很高，复制量非常大，每天可以产生1012-13个病毒颗粒，这个复制率比HCV高10倍，比HIV高100倍。HBV聚合酶是一种逆转录酶，缺乏校错功能，因此在每复制105个碱基对的时候就会产生一个突变。按照这样的突变产生率，可以计算出每个患者体内的病毒每天有1010-11个位点发生突变。HBV的长度为3.2kb，如此高的突变率，HBV全基因组每个位点每天都可能产生突变。突变依赖复制，只要有复制存在，就会有突变产生。突变产生后遗传信息具有多样性，导致各种各样准种的产生。如果给予一个抗病毒药物，给准株产生一种选择压力，根据适者生存的原理就会把突变株选择出来。因此，应该把抑制病毒复制最彻底的状态作为我们治疗的目标。(图略)

    抗病毒药物耐药的基因屏障即产生耐药突变所需要的基因突变的数目。另外，药物内在的化学结构对耐药的发生也有重要影响。拉米夫定的基因屏障非常低，只需要一个位点突变就能产生耐药。阿德福韦从化学结构上与它们的底物非常相似，对于病毒，难以对这类化学结构产生耐药。另外，由于阿德福韦10mg剂量对病毒没有强效的抑制，选择压力较小，因此尽管阿德福韦也只需要一个位点就能对它产生耐药，但与拉米夫定相比，阿德福韦的耐药率较低。恩替卡韦的耐药基因屏障高，需要3个或3个以上的位点同时突变才有可能产生耐药，再加上它内在的化学结构使病毒不容易对它产生耐药，因此恩替卡韦的耐药率很低。

    从病毒学角度来说，复制空间是指肝脏被感染新的cccDNA分子的潜在能力，这种能力可使病毒复制增加。在被感染的肝脏中，必须要有未被HBV感染的肝细胞存在,当其被HBV感染后，才能有新cccDNA的合成。产生未被感染的肝细胞通常有3种情况：正常生长的肝脏、坏死炎症后肝细胞增殖/再生（一般是肝细胞发生炎症坏死后再生）和cccDNA通过非细胞溶解的方式从细胞清除。正常肝脏肝细胞的再生较缓慢，半衰期一般为100d左右，但如果有炎症坏死肝脏，肝细胞的再生非常快，半衰期不超过10d，也就是说ALT水平升高时，肝细胞的再生快，复制空间的大小可以通过ALT水平的高低反映出来。病毒感染需要有新的未感染病毒的肝细胞，因此治疗前ALT水平越高，预示着有更多的未被感染的肝细胞产生，这样就产生了一个很大的复制空间。如果有耐药病毒产生，就会感染新产生的未被感染的肝脏细胞。这就是为什么ALT水平（肝脏复制空间）能预测是否容易产生耐药的原因。（图略）

   病毒株的复制适应能力是指自然选择情况下产生后代的能力，病毒产生耐药要以复制能力和适应能力的下降为代价，但是代偿性突变的产生可使突变病毒的生存能力提高。比如拉米夫定耐药的HBV，如果是rtM204V/I一个位点产生突变，复制能力应该下降，但如果继续使用拉米夫定，在药物选择压力持续存在的情况下，会产生许多代偿性突变株，使耐药突变株的复制能力增加，从而导致耐药HBV的传播、治疗停止46周后仍然可以看到拉米夫定耐药株的存在。

    四、HBV耐药的特点

    拉米夫定和替比夫定的耐药位点相同，95%以上对拉米夫定和替比夫定的耐药突变都发生在rtM204V/I位点，一小部分病人的耐药突变发生在rtA181T/V位点，rtA181T/V位点与阿德福韦有交叉耐药，这就是为什么阿德福韦对拉米夫定耐药患者比对核苷初治患者治疗效果差的原因。阿德福韦最主要的耐药位点在rtN236T位点。对恩替卡韦耐药需要先有2个拉米夫定耐药突变位点：rtL180M和rtM204V/I，再加一个rtS184G或rtS202I或rtM250V位点突变才能产生耐药， 也就是说一定要在拉米夫定耐药的基础上才能产生恩替卡韦的耐药。

HBV耐药的主要7个位点通过3条通路产生耐药：rtM204V/I位点突变通路主要产生拉米夫定和替比夫定耐药；rtN236T位点突变通路主要引起阿德福韦耐药；rtA181T/V位点突变通路可以是拉米夫定、替比夫定的，也可以是阿德福韦的。恩替卡韦耐药突变主要是沿着rtM204V/I位点突变这条通路进行。临床上，初治患者开始接受核甘酸类似物治疗时，病毒为野生株，使用药物治疗后，病毒会沿着这几条通路发生变异，从而产生多种类型的耐药突变。

    目前HBV对抗病毒药物耐药的模式很复杂，主要耐药突变位点有2个：rtA181T/V、rtM204V/I和rtN236T位点。如果治疗继续，在药物选择压力持续存在的情况下，会产生许多代偿性突变，所以，有时候需要作HBV聚合酶编码基因的测序，来确定耐药突变的模式是怎样的，按哪个通路进行突变。（图略）

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五、拉米夫定治疗耐药的危害

   体外研究表明，HBV发生突变后对药物的敏感性下降。如HBV rtL180M和rtM204V/I位点突变后，对拉米夫定的耐药率高1000倍以上，对恩替卡韦的敏感性下降30倍，对阿德福韦的敏感性下降10倍，Ｌ核苷类似物对拉米夫定变异株都高度耐药。rtA181T/V位点突变后，对阿德福韦的敏感性下降１~５倍，rtN236T位点突变后下降7~10倍，敏感性下降足以使病毒对阿德福韦产生耐药。可幸的是恩替卡韦对阿德福韦耐药株仍然敏感。

拉米夫定单药治疗的患者主要沿着rtM204V/I位点突变这条通路发生耐药，可以与替比夫定和克利夫定产生交叉耐药；小部分患者会发生rtA181T/V位点的突变，这个位点突变后，可与阿德福韦和替诺福韦发生交叉耐药。如果rtM204V/I位点突变后，继续使用拉米夫定，就会产生许多代偿性突变，使后续使用恩替卡韦、阿德福韦和替诺福韦治疗疗效下降。因此，拉米夫定治疗的患者，产生耐药突变产生后，对后续治疗的效果都会下降。这就是为什么要在病毒还没有发生反弹时就需加用或改用药物的原因。

　　目前拉米夫定的耐药率很高，每年以23%的速度增加，恩替卡韦在核苷类似物初治患者中耐药率最低。对于核苷初治患者的治疗，初始药物的选择很重要，有研究表明，使用过拉米夫定治疗的患者再用阿德福韦，耐药率达到18%。一旦药物产生耐药，很大程度上会影响后续治疗。因此，一定要抓住初始治疗的机会，选择强效且耐药率低的药物。

　　六、耐药的防治

    最近召开的亚太肝脏病学会年会提出，在选用一线抗HBV药物时,不推荐长期使用耐药发生率高的药物。因为耐药不仅会缩短患者病情有效控制的时间，使药物治疗的临床利益消失，还可能导致病情恶化，而且容易导致多药耐药，对后续治疗产生重大影响。另外，患者一旦出现耐药，只有换用新药，这个时候用药剂量相应增大，花费也会更大。因此，对于慢性乙型肝炎患者，开始治疗时的选药成为治疗成功与否的关键。从治疗一开始就要优先选用抗病毒能力强、耐药率低的药物变得尤为重要。

　　在HBV治疗中，治疗耐药最好的方式是在开始的时候就预防耐药的发生，预防耐药的发生主要有三个方面：(1) 使用强效的抗病毒药物,快速持续抑制病毒载量至不可测水平。病毒耐药的发生与病毒抑制程度密切相关，减少耐药发生率首先是减少血液中病毒的数量或者尽可能降低病毒载量。病毒复制越低，发生变异的可能性越小，耐药率的发生也就越低。因此应使用强效的抗病毒药物,快速持续抑制病毒载量至不可测水平。(2) 选择具有高耐药基因屏障的抗病毒药物，也就是需要多个位点同时突变才能产生耐药的药物。1个位点发生变异的几率大概为5万分之一，而3个位点同时发生变异的几率则在一千万分之一左右。在初治患者中，恩替卡韦能强效快速抑制病毒复制、并需要3个以上位点同时突变才能产生耐药，这就是为什么恩替卡韦4年内耐药发生率低于1%的原因。（3）提高患者的依从性、早期应答不理想及时换药及避免单药序贯治疗等，有助于预防耐药的发生。

　　另外，乙型肝炎治疗的发展也需要其他领域的密切配合：(1) 提高分子诊断的技术。HBV病毒检测水平的单位应统一为国际单位IU/mL。如果拉米夫定产生耐药后，需要对耐药位点进行检测，只有明确耐药突变位点，知道患者耐药突变的模式，才能找到最好的挽救方案。(2) 需病毒学家提供更多表型方面的支持。(3) 对医生和护士进行教育和培训。只有这样，我们才不有效防治乙型肝炎，最大限度减少耐药的发生。

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