科普-乙型肝炎的药物治疗
Drug Therapy： Hepatitis B Virus Infection
乙肝病毒感染的药物治疗 （原文发表于2008年10月的NEJM）
Jules L. Dienstag, M.D.
Reports of successful antiviral therapy for chronic hepatitis B virus (HBV) infection appeared three decades ago,1 and during the past decade, progress has accelerated dramatically. Along with progress, however, has come complexity. So much more is known now than at the dawn of the antiviral era about the protean clinical expressions of HBV infection that determining whom, when, and how to treat has become progressively more challenging.
成功的乙肝抗病毒治疗已经出现了几十年，但是随着对HBV认识的增加，其感染后的临床表现使哪些感染者，什么时候以及怎样接受治疗变得越发困难
Virologic and Epidemiologic Factors and Natural History
病毒及流行病学因素以及疾病自然史
HBV, a DNA virus transmitted percutaneously, sexually, and perinatally, affects 1.25 million persons in the United States and 350 to 400 million persons worldwide. HBV infection accounts annually for 4000 to 5500 deaths in the
乙肝病毒经皮肤？，性生活，和围产期哺乳传播，全世界有3.5到4亿感染者，导致世界范围内每年有100万患者死于肝硬化，肝衰和肝细胞癌
Viral proteins of clinical importance include the envelope protein, hepatitis B surface antigen (HBsAg); a structural nucleocapsid core protein, hepatitis B core antigen (HBcAg); and a soluble nucleocapsid protein, hepatitis B e antigen (HBeAg). Serum HBsAg is a marker of HBV infection, and antibodies against HBsAg signify recovery. A serum marker of active viral replication, HBeAg, is accompanied by serum levels of HBV DNA that are 100,000 to 1 million IU per milliliter or higher. HBV relies on a retroviral replication strategy (reverse transcrīption from RNA to DNA),7 and eradication of HBV infection is rendered difficult because stable, long-enduring, covalently closed circular DNA (cccDNA) becomes established in hepatocyte nuclei and HBV DNA becomes integrated into the host genome (Figure 1).
具有临床意义的病毒蛋白包括包膜蛋白，乙肝表面抗原，结构性核衣壳核心蛋白，乙肝核心抗原，以及一可溶性核衣壳蛋白，乙肝e抗原。HBsAg表明乙肝病毒感染，HBeAg的出现意味着乙肝病毒DNA复制达到10万到100万，乙肝病毒的复制是逆转入，其中会产生稳定的共价闭合环状DNA整合到患者自身的的基因组。
Progression from acute to chronic HBV infection is influenced by the patient's age at acquisition of the virus; age is also related to a dichotomy in the clinical expression of HBV infection between high-prevalence (e.g., Asian) and low-prevalence (e.g., Western) countries (Figure 2). In the
急慢性肝炎的转变受患者感染病毒的年龄影响。在远东（中国），乙肝病毒的感染多发生在婴儿围产期，90%以上的婴儿的感染都会是慢性的终身的。但是在西方，乙肝病毒感染多发生在青少年时期导致急性肝炎，但是只有1%左右的人会感染。
Immunologic tolerance to HBV established during perinatal infection is profound and lifelong, but not complete; a low level of liver injury occurs and accounts for up to a 40% lifetime risk of death from liver disease among men.9 This risk is lower among women.9 A so-called immune-tolerant phase occurs in the early decades of life, with negligible HBV-associated liver injury despite high-level HBV replication. An immune-clearance phase occurs in the later decades of life with active liver disease. This categorization of phases reflects relatively higher immunologic tolerance early and relatively lower tolerance later in the natural history of chronic HBV infection acquired early in life.5,6,10 Such categorization, however, does not explain the presence of substantial liver injury and fibrosis during the apparent immune-tolerant period in some patients11,12 or the presence of necroinflammatory quiescence during the immune-clearance phase later in the course of chronic HBV infection.
围产期婴儿的感染所产生的免疫耐受是很明显的，也是终身的，但是并不彻底。它仍然会导致肝脏的轻度损伤，高达40%的男性感染者最终会因为乙肝病毒感染所导致的肝脏疾病而死亡，但是这个比率在女性低。这些感染者的早年会经历免疫耐受期，此段时间，感染者体内的病毒复制很高但是HBV相关的干损伤几乎没有。但是最后，这些感染者会经历一个免疫清除期，此段时间里，患者会活动的肝脏疾病。此疾病自然史，并没能解释在免疫耐受期，感染者仍存在实质性干损伤和肝纤维化，也没能解释在免疫清除期，为什么会有炎症坏死的静止期。
The HBeAg status distinguishes two additional categories of chronic HBV infection. HBeAg-reactive chronic HBV infection is accompanied by high-level HBV replication, and spontaneous seroconversion from HBeAg-positive to antibody (anti-HBe)–positive infection coincides with a reduction in HBV replication and clinical improvement.13,14,15 HBeAg-negative chronic HBV infection, in which precore or core-promoter gene mutations preclude or reduce the synthesis of HBeAg, accounts for an increasing proportion of cases.16 Patients with HBeAg-negative chronic HBV infection tend to have progressive liver injury, fluctuating alanine aminotransferase (ALT) activity, and lower levels of HBV DNA than patients with HBeAg-reactive HBV infection; however, they cannot have treatment-induced HBeAg seroconversion, a durable response that may permit the discontinuation of antiviral therapy.
根据乙肝表面抗原，乙肝又分HBeAg阳性和HBeAg阴性。HBeAg阳性德慢性乙肝患者可以受益于HBeAg血清转化疗法和HBeAg抗体，但是HBeAg阴性患者不能益于HBeAg血清转化疗法，他们有进展的肝损害，变化的血清谷丙转氨酶，低溶度的HBV DNA（相对于HBeAg阳性患者）。
Eight HBV genotypes — and differences in clinical outcome according to genotype — are recognized.17,18,19 For example, patients with genotype A are more likely to undergo interferon-induced HBeAg seroconversion20; HBeAg seroconversion and slower disease progression are more frequent in patients with genotype B than in patients with genotype C.19 These differences, however, are not sufficiently established to guide management.
HBV共有8种基因型，临床治疗效果取决于患者HBV的基因型。例如，A型患者更多地会接受干扰素诱导的HBeAg血清转化疗法，B型中的HBeAg血清转化疗法和病情缓解较C型好。但是仍不足以指导临床应用。
The progression of liver disease in HBV infection is fostered by active virus replication, reflected by the presence in serum of an HBV DNA level above a threshold of approximately 1000 to 10,000 IU per milliliter. Persons with a serum HBV DNA level below 1000 IU per milliliter and a normal ALT level consistently are considered to be inactive carriers with a low risk of clinical progression,21 although, rarely, reactivation can occur spontaneously or with immunosuppression.22,23 Although perinatal infection can result in high-level HBV replication without substantial liver injury in the early decades of life, ultimately the risk of progression to cirrhosis and hepatocellular carcinoma is proportional to the level of HBV DNA maintained persistently over time.24,25
肝脏的损害和其DNA复制成正比，血清HBV DNA溶度高于1000 到1万单位反映肝损害进展。而低于1000单位表示为隐性携带者.尽管围产期感染者最初表现为免疫耐受，其DNA容度高但是肝脏多无实质性损害，但是最终的肝硬化和肝细胞癌的进展情况仍与DNA量呈比例
Goals of Antiviral Therapy
抗病毒治疗目标
Because clinical and histologic improvement accompanies reductions in HBV replication, interventions that reduce HBV replication are expected to limit progressive liver disease and improve the natural history of chronic HBV infection. Practically, however, serious outcomes of HBV infection evolve over decades, whereas clinical trials of antiviral therapy are limited to 1 to 2 years and, rarely, up to 5 years. Therefore, surrogate end points that are achievable during time-limited clinical trials are used. These end points are serologic (i.e., HBeAg loss or seroconversion, usually reflecting a transition to inactive HBV carriage, and, more rarely, HBsAg loss or seroconversion, representing serologic recovery), virologic (i.e., a log10 reduction in the HBV DNA level or suppression of HBV DNA to an undetectable level [<10 to 100 IU per milliliter]), biochemical (i.e., normalization of the serum ALT level), and histologic (i.e., improvement in the necroinflammatory grade and stage of fibrosis).5,6 A course of antiviral therapy may lead to responses that are sustained after treatment withdrawal; more commonly, therapy must be continued to maintain responses achieved during therapy.
因为肝炎病毒复制数的降低伴随着肝炎患者临床症状和组织学结构的改善，所以减少肝炎病毒复制是治疗的目标。但是事实上，因为肝炎的严重结局通常需要数十年，而临床药理实验通常为1到两年，很少有到5年的。所以替代性的结局指标被采用。这些替代指标包括血清学（如HBeAg的消失或血清转化通常表明患者转变成静息的肝炎病毒携带者，当然也有极少部分代表患者血清意义上的康复）、病毒学、生化和组织学指标。一个疗程的抗病毒治疗可以在停止治疗后仍然发挥作用，但是更常见的是治疗应该持续以维持疗效。
Antiviral Drugs
抗病毒药物
Seven drugs are licensed in the United States for the treatment of HBV infection: interferon alfa,26,27,28,29 pegylated interferon alfa
在美国有七种药物允许上市用于治疗乙肝病毒感染，他们是：a干扰素，pegylated interferon alfa-2a，拉米夫定，adefovir, entecavir, telbivudine, tenofovir50。干扰素因其需要每天或者每周三次注射已经被长效pegylated 干扰素（每周只需注射一次）所取代。
As shown in Table 1 and Table 2, treatment for 1 year generally results in the reduction of serum HBV DNA levels by 3.5 to 6.9 log10, a level of serum HBV DNA that is undetectable by polymerase chain reaction in 13 to 95% of patients, normalization of the ALT level in 38 to 79% of patients, histologic improvement in 38 to 74% of patients, and HBeAg seroconversion in 12 to 27% of patients; drugs that suppress HBV DNA more profoundly more often achieve clinical end points (except perhaps HBeAg seroconversion). Among the oral agents, which differ in resistance profile, the nucleotide analogues adefovir and tenofovir are not cross-resistant with lamivudine, telbivudine, or entecavir. Adefovir resistance is negligible during the first year of therapy but approaches 30% by the end of 4 years. Adefovir is very effective in lamivudine-resistant HBV infection.37,38,39,40,53,54,55 Limiting its appeal among the available drugs, adefovir is the least potent, the slowest to suppress HBV DNA levels, the least likely to induce HBeAg seroconversion, and the most likely to result in "primary nonresponse" (i.e., failure to achieve a reduction in the HBV DNA level of 2 log
在抗病毒治疗一年以后，血清PCR病毒检测有13%到95%的病人乙肝病毒DNA是阴性的，38-79%的病人谷丙转移酶是正常的，38-74%的病人的组织结构得到改善，12-27%的患者HBeAg发生血清转换。强效抑制HBV DNA的药物更易达到临床疗效指标要求（HBeAg血清转换除外）。口服抗病毒药物主要是存在药物抵抗的区别，核苷类似物adefovir 和tenofovir与拉米夫定、elbivudine或者 entecavir不会产生交叉抗药性。Adefovir第一年治疗的抗药性几乎没有，但是在治疗的第四年末可以达到30%。而Adefovir在拉米夫定抵抗的乙肝患者的治疗中非常有效。但是以下因素限制了Adefovir的临床应用：它能最弱，抑制HBV DNA水平最慢，产生雪情转换的可能性最小，最容易导致原发无反应。
八成的HBeAg阳性口服抗病毒药物患者在血清转换后接受6到12个月或者更长的巩固 治疗可以获得一个长期的疗效
Consolidation treatment for 6 to 12 months or more after HBeAg seroconversion achieves a durable response in approximately 80% of HBeAg-positive patients who have received oral agents,57,58,59 whereas all but a small minority of HBeAg-negative patients usually have a relapse after therapy.31,60 Because responses are not always durable, careful post-treatment monitoring is required to identify relapse (especially rare, severe, and sometimes fatal post-treatment flares in patients with cirrhosis) and to reinstitute therapy. Thus, nearly all HBeAg-negative patients and approximately 80% of HBeAg-positive patients who do not undergo HBeAg seroconversion should continue nucleoside or nucleotide therapy after the first year; in the absence of resistance, such therapy generally maintains clinical effectiveness.39,40,45,61,62,63
Successful antiviral therapy retards hepatic fibrosis,33,37,38,64,65 even reverses cirrhosis,66,67 and improves survival.68,69,70 Unlike pegylated interferon, oral agents are effective in patients who previously did not have a response to interferon,33,35,37,42,44 can be used safely and effectively as salvage therapy in patients with hepatic decompensation (delaying or averting liver transplantation),71,72,73,74 and, in patients with advanced fibrosis and cirrhosis, may prevent hepatic decompensation.75 Thus, the introduction of oral nucleoside and nucleotide analogues has been lifesaving in HBV infection, paralleling a 30% reduction (from 586 patients in 2000 to 406 patients in 2006) in the number of patients listed for liver transplantation annually in the
The side effects of pegylated interferon include flulike symptoms, marrow suppression, depression and anxiety, and autoimmune disorders, especially autoimmune thyroiditis; close medical supervision and laboratory monitoring are required. Most oral agents have an acceptable side-effect profile even after extended use,39,40,45,77 but because adefovir and tenofovir may cause nephrotoxic effects, periodic monitoring of renal function during nucleotide therapy is advisable.39,40 In preclinical rodent-toxicology studies, doses of entecavir that were 30 to 40 times higher than those that were used in humans were associated with lung, brain, and liver tumors, which have not been observed in higher species (e.g., rabbits and dogs).42,44,45 Telbivudine, too, appears to cause few major toxic side effects, although grade 3 and 4 elevations in levels of creatine kinase were more common in patients treated with telbivudine than in patients treated with lamivudine after 2 years of therapy,48 and peripheral neuropathy has been attributed to telbivudine.
Treatment with pegylated interferon for 1 year is more likely to result in HBeAg seroconversion than is treatment with an oral agent for 1 year30; however, oral agents are usually administered for more than 1 year and achieve similar rates of HBeAg seroconversion (approximately 30%) by the end of 2 years, approaching approximately 50% at 5 years.45,49,61,63 Similarly, earlier studies suggested that rates of HBsAg seroconversion at 1 year are higher for interferon-based therapy than for oral agents.26,30,31 However, rates of HBsAg loss are similar between pegylated interferon and some of the newer, more potent oral agents (Table 1 and Table 2).45,51 In addition, after successful HBeAg seroconversion and cessation of therapy in Western (not Asian) patients, patients who have received lamivudine appear to have rates of HBsAg seroconversion (20% at 3 years in one small study) that are similar to those achieved after interferon therapy.58,68,78,79 Reductions in cccDNA are similar in patients with spontaneous, interferon-induced, or oral-agent–induced HBeAg seroconversion.80
Two other oral agents that appear to be efficacious against HBV but are not yet approved by the Food and Drug Administration are emtricitabine and clevudine. Emtricitabine, which is similar in structure, efficacy, and resistance profile to lamivudine,81 appears to confer no advantage over lamivudine. Clevudine is distinguished from other oral agents by its sustained suppression of HBV DNA for several months after cessation of therapy.82,83,84 However, preliminary clinical trials suggest that clevudine is less potent than other oral agents in suppressing HBV DNA and inducing HBeAg seroconversion.83,84
Resistance to Antiviral Drugs
Resistance does not appear to emerge during pegylated interferon therapy. L-nucleosides (e.g., lamivudine and telbivudine) are associated with the emergence of mutations in the YMDD motif (tyrosine, methionine, aspartate, aspartate) of HBV DNA polymerase domain C and with upstream compensatory mutations in polymerase domains A and B that, collectively, reduce treatment efficacy. The nucleotide analogues (adefovir and tenofovir) are associated with mutations in polymerase domains B and D. Although resistance to lamivudine is sufficiently high to limit its clinical impact, resistance to the cyclopentyl guanine analogue entecavir and tenofovir remains low (Table 1 and Table 2). Ultimately, drug resistance reduces drug effectiveness66,75 and may precipitate hepatic decompensation in patients with advanced cirrhosis and after liver transplantation. In addition, because of cross-resistance between several of the oral agents, the emergence of resistance to one drug (e.g., lamivudine) eliminates the option for subsequent treatment with others (e.g., telbivudine and entecavir [see below]). Because of 1-to-2–year treatment-emergent resistance,49 telbivudine has not been widely used for the treatment of chronic HBV infection. The nucleotides are effective in nucleoside resistance and vice versa.54,55,85 Entecavir, at a dose of 1 mg, is approved for lamivudine-resistant HBV; however, entecavir resistance emerges in 7% of patients at the end of year 1, in 16% of patients at the end of year 2, in 35% of patients at the end of year 3, and in 43% of patients at the end of year 4.86,87 Specialized assays are available to detect these mutations. However, the emergence of resistance can usually be detected by an increase in HBV DNA of greater than 1 log10 after an initial virologic response (in the absence of nonadherence,88 which accounts for breakthrough in 30% of patients treated in clinical trials5), especially when accompanied by an elevation in the ALT level. More detailed overviews of antiviral resistance in HBV infection appear elsewhere.6,89,90,91,92
Predictors of Response
Factors that are most predictive of a response include a high ALT level, a low HBV DNA level, and mild-to-moderate histologic activity and stage.93,94 The genotype is associated with higher frequencies of spontaneous (B>C)19,95 and pegylated interferon alfa-2b–related (A>B>C>D) HBeAg and HBsAg seroconversion,20,96 but it does not correlate with the degree of HBV DNA suppression associated with the oral agent.97 In clinical trials of oral agents, numbers of events were too small to determine the influence of the genotype on HBeAg seroconversion. The rapidity and profundity of HBV DNA suppression during oral-agent therapy is predictive of the virologic, serologic, biochemical, and histologic benefit at the end of 1 year of therapy.5,48,52,98,99 Three oral agents have low genetic barriers to resistance — lamivudine, telbivudine, and, to a lesser degree, adefovir. In lamivudine and telbivudine, the level of residual HBV DNA at the end of the first half-year of therapy is inversely proportional to the frequency of drug resistance by the end of the year of therapy. In adefovir, the level of residual DNA at the end of a full year is inversely proportional to the frequency of drug resistance by the end of the second year. Other factors favoring resistance to lamivudine, telbivudine, and adefovir include high baseline HBV DNA and treatment of long duration.6,89,90,91,92
Combination Therapy
Combinations of available antiviral drugs for HBV infection in patients who have not received treatment do not increase efficacy. Although combinations of pegylated interferon and lamivudine yielded a reduction in HBV DNA of an extra 1 to 2 log10 during therapy, the combination did not result in a durable post-therapy benefit.30,31 Similarly, telbivudine and lamivudine combined did not achieve additional antiviral activity over that of telbivudine alone.47 Combination therapy with agents of differing resistance profiles should limit the emergence of resistance; however, resistance is so negligible during the early years of treatment with entecavir or tenofovir that demonstrating the superiority of preemptive combination therapy over initial monotherapy will be challenging. Indeed, adding a second, complementary drug after the emergence of resistance has been a very successful strategy.54,55,100 Because of the lack of data to provide support for the efficacy of combination therapy over monotherapy in patients who have not received treatment, current treatment guidelines5 do not recommend combination therapy except for patients in whom drug resistance can precipitate or aggravate hepatic failure, as in decompensated cirrhosis or after liver transplantation. Among patients with drug-resistant HBV who have received treatment, available data provide support for adding, rather than switching to, a second drug with a different resistance profile.5,6,100
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