惠尔丁®产品综述
惠尔丁®（通用名恩曲他滨胶囊，英文名emtricitabine capsules）是一种新型的核苷类逆转录酶抑制药，美国肝病指南（AASLD）[1]、欧洲肝病指南（EASL）[2]、亚太肝病指南（APASL）[3]等国际权威慢性乙肝（CHB）治疗指南都将该药物纳入乙肝治疗药物，其化学结构与目前临床上广泛使用的其他核苷类似物不同之处在于5-碳位置上的氟基，其血浆半衰期更长，且不受饮食限制，抗病毒活性更好。2003年7月获美国FDA批准在美国上市，目前在中国恩曲他滨胶囊是国家限艾滋病医保药品。恩曲他滨原研为美国吉利德公司，河北医科大学制药厂于近年完成科研，恩曲他滨开发研究项目被获得科学技术进步二等奖，并通过国家食品药品监督管理局批准上市，目前属于独家上市药品，其企业生产的恩曲他滨胶囊根据《中华人民共和国药品管理法》经国家食品药品监督管理局审核并通过获得《新药证书》。河北医科大学制药厂是中国恩曲他滨的产品标准的起草单位。
2005年惠尔丁获得CFDA颁发的药品生产批件，但因专利未到期限所以该产品一直等到2014年才正式进入临床使用阶段，国内权威的肝炎领域专家联合发布了中国《恩曲他滨临床应用专家共识》[4]，并于2014年6月在《中华实验和临床感染病杂志》正式发布。
惠尔丁®（通用名恩曲他滨胶囊，英文名emtricitabinecapsules）与现有的核苷类抗乙肝病毒产品有着多层面的区别，具体内容如下：
l 已纳入中国艾滋病医保药品；
l 恩曲他滨具有非常好的安全性，是美国FDA批准的唯一可用于0岁以上儿童的产品[4]；
l 该产品属于妊娠B级药品，可用于妊娠期预防性母婴传播阻断及活动性感染者的抗乙肝病毒治疗，除该产品外乙肝治疗药物仅有两种妊娠B级药物[2][4]；
l HIV/HBV合并感染者如需同时进行抗HIV与HBV治疗，该产品被各国指南推荐为一线用药，推荐在常规的HAART治疗中加入恩曲他滨[1][2][4]。并且该产品治疗艾滋病适应症时属于国家医保乙类药品范围；
l 经过多年治疗的慢性乙型肝炎患者耐药率逐年增加，该产品在各国肝病指南中均被列为耐药患者挽救治疗的一线用药[1][2][3][4]；
l 肝移植术后预防HBV再复发，大型国际临床试验证实联合恩曲他滨是截止目前唯一可缩短注射乙肝免疫球蛋白周期的治疗方案，提升患者便利性，并大大降低因注射乙肝免疫球蛋白所带来的不良反应，国内外相关指南均予以推荐[2][4]。
l 恩曲他滨可用于失代偿期肝硬化的治疗，较传统治疗方案安全性高，不良反应小[3][4]。
l 高基线病毒载量HBV患者，恩曲他滨联合替诺福韦抑制HBV作用明显优于替诺福韦单药制剂，为其他抗病毒药物抑制HBV 作用不佳的患者提供一种新的治疗选择[1][4]。
产品基本信息：
【药品名称】
通用名称：恩曲他滨胶囊
商品名称：惠尔丁
英文名称：Emtricitabine Capsules
汉语拼音：Enqutabin Jiaonang
【性状】本品内容物为白色或类白色颗粒或粉末。
【适应症】
1、与其他抗病毒药物合用于成人HIV-1感染的治疗。患者为未经过逆转录酶抑制剂治疗和经过逆转录酶抑制剂治疗病毒已被抑制者。
2、用于慢性乙型肝炎治疗。
【规格】0.2g*7粒， 零售价234元， 重庆挂网价：167.82元
【用法用量】成人口服一日一次，一次0.2g，可与食物同服。
参考文献【1】： AASLDPRACTICE GUIDELINES -Chronic Hepatitis B: Update 2009（2009年美国肝病学会乙型肝炎诊治指南
l 内容节选：HEPATOLOGY, Vol. 50, No.3, 2009 第17页
AdefovirResistance.………Thismay be related to a higher dose of tenofovir being used 300 mg versus adefovir10mg. However, serum HBV DNA remained detectable and adefovir-resistantmutations persist after switching to tenofovir monotherapy indicating thatthese two drugs are cross-resistant. By contrast, rescue therapy withcombination of lamivudine or emtricitabine and tenofovir resulted in suppression ofserum HBV DNA to undetectable levels. One case series reported that twopatients with adefovir-resistant HBV responded to entecavir with a decrease inserum HBV DNA to undetectable levels.
【译文】………恩曲他滨或拉米夫定联合替诺福韦是阿德福韦酯耐药管理中可将血清HBV DNA降低至检测下限的挽救治疗方案………。
l 内容节选二：HEPATOLOGY, Vol. 50, No.3, 2009 第19-20页
1) Tenofovir (Viread) ………Efficacy inVarious Categories of Patients. ………At week 48, patients in the adefovir group were switchedto tenofovir, and patients in both groups who had detectable serum HBV DNA byPCR at week 72 received, in addition, emtricitabine. In the patients who were originally on adefovir, a further decreasein the proportion with undectable HBV DNA occurred such that by week 96, asimilar proportion of patients in the two treatment groups had undetectableserum HBV DNA (78% vs 78%), HBeAg seroconversion (26% vs 24%) and HBsAg loss(4% vs 5%).………………At week 48, patients in the adefovir group were switchedto tenofovir, and patients in both groups who had detectable serum HBV DNA byPCR at week 72 also received emtricitabine. As observed in the HBeAg-positive cohort, switching totenofovir resulted in further virus suppression in the patients originallytreated with adefovir such that by week 96, a similar percent of patients inthe two treatment groups had undetectable serum HBV DNA (91% vs 89%). However,none of the patients lost HBsAg.
【译文】………替诺福韦的III期注册试验数据显示，无论是E抗原阳性或阴性慢乙肝患者，当治疗至72周，患者血清HBVDNA若仍高于检测下限者，及时加用恩曲他滨治疗至96周，无论是替诺福治疗组还是最初使用阿德福韦酯的对照组，其各项指标的应答率均相同。………
2) Tenofovir Resistance. ………………In the two phase IIIclinical trials, 7 patients were observed to have virologic breakthrough during96 weeks of treatment but tenofovir-resistant HBV mutations were not detectedin any of these patients. It should be emphasized that 17 patients who hadpersistent detection of serum HBV DNA at week 72 and were at the greatest riskof tenofovir resistance received additional treatment with emtricitabine . Therefore, data on resistance totenofovir monotherapy beyond 72 weeks cannot be determined from the two pivotaltrials. ………
【译文】………替诺福韦的III期注册试验数据显示，72周时若血清HBVDNA仍可检测，应及时加用恩曲他滨以降低耐药发生的风险。………
l 内容节选三：HEPATOLOGY,Vol. 50, No. 3, 2009 第21页
Other Therapies………Emtricitabine (Emtriva, FTC)is a potent inhibitor ofHIV and HBV replication. FTC hasbeen approved for HIV treatment as Emtriva (FTC only) and as Truvada (incombination with tenofovir as a single pill). Because of its structuralsimilarity with lamivudine (3TC), treatment with FTC selects for the same resistant mutants. In one study of248 patients (63% were HBeAg positive) FTC200 mg daily resulted in a significantly higher rate of histologic (62%vs 25%), virologic [undetectable HBV DNA by PCR assay] (54% vs 2%) andbiochemical (65% vs 25%) responses at week 48 compared to placebo but HBeAgseroconversion rates were identical—12% in the two groups. FTC-resistantmutations in the YMDD motif were detected in 13% of patients. ………
【译文】恩曲他滨是一种有效的艾滋病毒和乙肝病毒抑制剂。美国FDA已经批准该产品治疗HIV感染的两种剂型Emtriva（恩曲他滨单一制剂）和Truvada的(联合替诺福韦)。其结构与拉米夫定(3TC)相似,治疗时会选择相同的耐药株。在一项研究中,248名患者每日服用(63%是e抗原阳性患者)恩曲他滨 200毫克，与安慰剂组比较，存在显著的组织学应答差异(62% vs 25%),病毒学应答差异 (54% vs 2%)和生化学应答差异(65% vs 25%)。………
l 内容节选四：HEPATOLOGY,Vol. 50, No. 3, 2009 第26-27页
Coinfectionwith HBV and HIV………For patients in whom HAART initiation is planned, it isbest to use a regimen that includes a drug/drugs with activity against HBV.Most experts recommend using two drugs. Combinations can include tenofovir pluslamivudine or tenofovir plus emtricitabine (Truvada_). ………35.Patients in whom treatment for both HBV and HIV is planned should receivetherapies that are effective against both viruses: lamivudine plus tenofovir oremtricitabine plus tenofovirare preferred. (II-3) ………
………对于HIV/HBV合并感染者，替诺福韦加上拉米夫定或者替诺福韦联合恩曲他滨(Truvada_)是优先推荐的治疗方案。………
l 内容节选五：HEPATOLOGY, Vol. 50, No.3, 2009 第24-25页
………………………
21. Treatment of patients withadefovir-resistant HBV
a. In patients with no prior exposure to otherNA, lamivudine, telbivudine or entecavir may be added. Alternatively, adefovirmay be stopped and tenofovir plus lamivudine or emtricitabine may be used. (III)
b. In patients with prior lamivudine resistancein whom lamivudine had been stopped when treatment was switched to adefovir,adefovir may be stopped and tenofovir plus lamivudine, emtricitabine (II-2) or entecavir (III) may be used but thedurability of response to this combination is unknown. ………
【译文】耐药患者管理………………对于拉米夫定、阿德福韦酯、恩替卡韦耐药患者，可选择恩曲他滨和替诺福韦的联合治疗作为挽救治疗方案。………
参考文献【2】：EASL Clinical Practice Guidelines: Management of chronichepatitis B virus infection（欧洲肝病学会乙型肝炎诊治指南）
l 内容节选一：Journal ofHepatology 2012 vol. 57 I 167–185，第171-172页
Results ofcurrent therapies………Drugsavailable for the treatment of CHB include IFN, PEG-IFN and six NAs. NAs forHBV therapy can be classified into nucleosides (lamivudine, telbivudine, emtricitabine, entecavir) andnucleotides (adefovir and tenofovir). ………
【译文】现有治疗方法………目前可用于乙肝治疗的药物包括干扰素、长效干扰素和六种核苷类似物。用于乙肝治疗的核苷类产品包括拉米夫定、替比夫定、恩曲他滨、恩替卡韦，核苷酸类产品包括阿德福韦酯、替诺福韦。………。
l 内容节选二：Journal ofHepatology 2012 vol. 57 I 167–185，第174-175页
1) Treatment failure………Incase of resistance to lamivudine, most experts based on the current evidencesuggest that switching to tenofovir is as effective as adding tenofovir tolamivudine [140].In case of adefovir resistance, a switch to entecavir or tenofovir or tenofovirplus emtricitabine (in asingle tablet) is an option [141,142].The efficacy of tenofovir monotherapy has been reported to be suboptimal inpatients with high serum HBV DNA levels due to virological breakthroughsassociated with adefovir resistance………
【译文】耐药患者管理………对于阿德福韦酯耐药的患者，可换用恩替卡韦加替诺福韦或者替诺福韦加恩曲他滨继续治疗。………
2) ………Tenofovirresistance: tenofovir resistance has not been detected to date andtherefore there is no experience, but it seems reasonable to add entecavir,telbivudine, lamivudine or emtricitabineif tenofovir resistance is confirmed (C2). A switch to entecavir may be sufficient ifthe patient has not been treated with lamivudine in the past, ……….
【译文】………对于替诺福韦耐药的患者，可加用恩替卡韦、替比夫定、拉米夫定或者恩曲他滨继续治疗。………
l 内容节选三：Journal of Hepatology 2012 vol. 57 I 167–185，第177页
Prevention of recurrent hepatitis B after livertransplantation………Shorter courses and lower dosesof HBIg and other forms of prophylaxis, including tenofovir with emtricitabine or entecavirmonotherapy, are being studied. Recently, entecavir prophylaxis without HBIGwas shown to be safe and effective in preventing HBV recurrence. Preliminarysafety and efficacy data with tenofovir andemtricitabine with or without HBIG have also been reported . In thesetting of liver transplantation, nephrotoxicity should be always consideredand renal function should be carefully monitored because of the concomitant useof calcineurin inhibitors. ……
【译文】肝移植术后复发的预防………替诺福韦联合恩曲他滨，加或不加用乙肝免疫球蛋白的临床试验数据已经发布，显示出较好的的安全性和有效性。…………
l 内容节选四：Journal of Hepatology 2012 vol. 57 I 167–185，第177页
Treatment in special patient groups………HIVco-infected patients HIV-positive patients with CHBwere at increased risk of cirrhosis before HAART and a higher risk of HCC issuggested . Treatment of HIV may lead to flares of hepatitis B due to immunereconstitution, but the risk of developing cirrhosis is negligible in HBV/HIVco-infected patients on long-term tenofovir combined with emtricitabine or lamivudine therapy. The indications fortherapy are the same as in HIV-negative patients, based on HBV DNA levels,serum ALT levels and histological lesions. In agreement with recent HIVguidelines, it is recommended that most co-infected patients should besimultaneously treated for both HIV and HBV denovo. Tenofovir combined with emtricitabine or lamivudine plusa third agent active against HIV are indicated. The strong rationale for earlydual anti-HIV and anti-HBV therapy have simplified the recommendations forwidening the use of tenofovir and emtricitabine or lamivudine in HBV–HIVco-infected patients, irrespective of immunological, virological orhistological considerations...………
特殊患者的治疗………对于HIV/HBV合并感染者，长期使用替诺福韦加恩曲他滨或拉米夫定的治疗方案可阻止肝纤维化的进展。………近期发布的艾滋病指南当中，对于合并感染者均推荐应当同时治疗HIV/HBV两种病毒。替诺福韦联合恩曲他滨或者拉米夫定，再加用抗艾滋病毒药物的治疗方案已被强效证据证实有效。因此对于HIV/HBV合并感染者，强烈推荐早期双抗艾滋病和乙肝病毒治疗方案：替诺福韦加恩曲他滨或拉米夫定，且与自身的免疫学、病毒学或组织学因素无关。...………
l 内容节选五：HEPATOLOGY, Vol. 50, No.3, 2009 第178页
Pregnancy………(PEG-)IFN is contraindicated during pregnancy (A1).Lamivudine, adefovir and entecavir are listed by the FDA as pregnancy categoryC drugs, and telbivudine tenofovir and emtricitabineas category B drugs . These classifications are based on the risk ofteratogenicity in preclinical evaluation. The safety of entecavir in pregnancyis not known. There is a considerable body of safety data from theAntiretroviral Pregnancy Registry in pregnant HIV-positive women who havereceived tenofovir and/or lamivudine oremtricitabine . Among them, tenofovir should be preferred, because ithas better resistance profile and more extensive safety data in pregnant, HBVpositive women………
【译文】妊娠期乙肝患者………拉米夫定、阿德福韦酯、恩替卡韦被美国FDA认定为妊娠C类药物，替比夫定、替诺福韦和恩曲他滨为妊娠B级药物，该分类是基于动物实验的致畸性数据。恩替卡韦在妊娠安全性方面没有得到证实。来源于抗逆转录病毒药物妊娠妇女安全数据注册表中的庞大数据量证实了替诺福韦和/加拉米夫定或恩曲他滨的安全性。………