丙型肝炎病毒

Updated March, 2008

Steven K. Herrine, MD, Raymond T. Chung, M.D.
 

译者:周佳鑫 博士

   北京协和医院 内科

   Email: zhoujiaxin@pku.org.cn

审阅者:周宝桐 主治医师

概述：

Virology Guided Medline Search

病毒学

               The discovery of hepatitis C virus (HCV) as the major cause of non-A, non-B hepatitis in 1989 was accomplished through incisive use of the modern tools of molecular biology (21). Despite this technological breakthrough progress on understanding the virology and pathophysiology of HCV has been hampered by the lack of suitable laboratory models. The HCV replicon system has been the standard tool used to investigate HCV replication and inhibition (14,74), while HCV functional pseudoparticles and other modeling systems have been employed to further investigate the virus (9, 57). Based on these, and other, methods, HCV has been classified as a Flavivirus, Hepacivirus genus. Similar viruses include yellow fever virus, dengue virus and bovine viral diarrhea virus. Molecularly, HCV contains a 9.6 kb plus-strand RNA genome composed of a 5' noncoding region, a long open reading frame encoding a polyprotein precursor of about 3000 amino acids, and a 3' NCR. The structural proteins include the core protein, thought to represent the viral nucleocapsid and the envelope glycoproteins E1 and E2. The envelope proteins form a non-covalent complex, the function of which is not fully understood.

        1989年，丙型肝炎病毒（HCV）作为非甲/乙类肝炎的主要病原被发现(21)。尽管有此技术上的突破，但由于缺乏合适的试验模型，对HCV的病毒学和病理生理学的进一步了解仍受到限制。HCV复制子系统为目前研究HCV复制和病毒抑制的标准模型(14,74)，而HCV功能性假颗粒和其他模型系统也被用于进一步研究该病毒(9, 57)。基于上述以及其他方法，HCV在分类上属于黄病毒，丙型肝炎病毒属。类似的病毒还包括黄热病病毒，登革热病毒和牛病毒性腹泻病毒。从分子学角度上看，HCV包括一个9.6kb的正链RNA基因组，其中含有一个5’非编码区域，一个编译大约有3000个氨基酸的多蛋白前体的长开放读码框，以及一个3’的非编码区域。结构蛋白包括：核心蛋白，主要指病毒的核衣壳和包膜糖蛋白E1和E2。包膜蛋白形成了一个非共价键的复合物，但对其功能尚未能完全了解。

               Based on genetic sequencing, HCV is divided into six genotypes, named 1 through 6 which are further subdivided in to over 50 subtypes which are named alphabetically. The viral sequence can vary by up to 35% between genotypes highlighting its genetic diversity. Within a subtype the sequence may vary by about 2%, resulting in a heterogenous virus population in each chronically infected person known as quasispecies. There is some evidence to suggest that the presence or emergence of quasispecies may result in poorer response to therapy in certain infected individuals (36, 133).

        通过基因测序，HCV可分为六种基因型，命名为基因型1-6，并可进一步分类为超过50种亚型，以字母顺序命名。不同基因型中病毒序列的差异可高达35%，这凸显了其基因学上的差异。而在同亚型中的病毒序列差异约有2%，这导致在任何一个慢性感染的患者体内均可能存在不同变异株构成异质性的病毒群，称之为准种。一些证据表明，在特定被感染者中，准种的存在可能会导致对治疗的反应不佳(36, 133)。

Berger S.  Emergence of Infectious Diseases into the 21st Century, 2008.

Epidemiology Guided Medline Search

流行病学

               Hepatitis C virus infection is a leading cause of global hepatic morbidity and mortality. Although the prevalence of chronic HCV infection varies geographically, it has recently been estimated that global prevalence is about 2%, or some 123 million persons (97). The existence of and quality of seroprevalence data varies widely across the globe. Most experts concur that the infection is most prevalent in Africa and Asia, with lower seroprevalence rates in the industrialized countries such as those of the Americas, Europe and Australia. Some of the highest reported seroprevalence rates are from Egypt (22%), Pakistan (4%), and China (3.2%). The lowest reported rates are from Germany (0.6%), Australia (1.1%), France (1.1%), India (0.9%) and Canada (0.8%). Somewhat higher rates are reported in the US (1.8%), Japan (15-2.3%) and Italy (2.2%) (11).  Peak incidence of HCV infections appears to have taken place during the decade of the 1980s, with significantly lower incidence in subsequent years. This decreased incidence is thought to be a result of lower transmission rates among those persons injecting drugs, rather than screening of the blood supply. Because of the prolonged latency of HCV infectious complications, prevalence and impact of chronic infection is estimated to in increase over the next two decades before going into slow decline (27).

        尽管在不同地区慢性HCV感染的患病率不一，最近的研究表明在全球范围内的患病率约为2%，约1亿两千三百万人(97)。在世界各地，关于血清感染率的现实情况和特征的数据不尽相同。绝大多数专家认为在非洲和亚洲的感染率最高，而在发达国家例如美国、欧洲和澳大利亚中的感染率较低。最高的血清感染率的报告来自于埃及（22%），巴基斯坦（4%）和中国（3.2%）。而感染率最低的报告来自于德国（0.6%），澳大利亚（1.1%），法国(1.1%)，印度（0.9%）和加拿大（0.8%）。 在美国（1.8%），日本（1.5-2.3%）和意大利（2.2%）中的发病率也较高(11)。HCV感染的发生的高峰率在20世纪80年代，随后有明显下降。发病率的明显下降的主因是由于在静脉注射毒品的人群中的传播率下降，而不是因对血制品供应的筛查。由于HCV感染并发症的潜伏期很长，预计在接下来的二十年中，慢性感染的患病率和影响在缓慢下降之前会有所增加(27)。

               The leading modes of transmission of HCV infection, like prevalence rates, vary globally, but the majority can be attributed to intravenous drug use, blood transfusion and unsafe therapeutic injection practices. Other parenteral exposure risks such as medical procedures, tattooing, body piercing, scarification practices, and sexual transmission are less important modes of transmission. In the US, Europe and Australia, intravenous drug use has been the leading mode of HCV transmission since the discovery of the virus. Rates of such transmission are clearly diminishing due not to improvement in blood supply, but in large part to safer injection practices. In the developing world, unsafe therapeutic injection has emerged as a major source of new HCV infections, accounting for an estimated 2 million new HCV infections in 2000 (45).  It has become clear that the household reusable syringes in common use throughout the world are a common reservoir for ongoing HCV infection. An important example of this type of risk as part of a public health initiative is Egypt’s schistosomiasis eradication campaign using reusable glass syringes, which has resulted in the world’s highest seroprevalance of HCV (39).  Other important data regarding this transmission mode is available from Pakistan (75) and Taiwan (72).

        类似于患病率分布情况，在世界各地，导致HCV感染的主要传播模式不尽相同，但大部分仍归因于静脉注射毒品、输血和不安全的治疗性注射操作。其他经胃肠道外暴露的风险例如医疗操作，纹身，刺身，划痕和经性接触传播均为相对少见的传播方式。在美国、欧洲和澳大利亚，静脉注射毒品在HCV病毒被发现之后曾经是首要的HCV传染方式。这种传播风险正在明显降低，这主要是因为更安全的注射操作，而非供血方面的进步。在发展中国家中，不安全的治疗性注射已成为导致新发HCV感染的主要原因，在2000年有约两百万新发的HCV感染归因于此(45)。目前已明确在全世界范围内，家庭中使用多次性的注射器的广泛使用是HCV感染的常见来源。关于公共卫生行动所致的风险，有一个重要的例子，在埃及消灭血吸虫运动中，由于使用多次性的注射器，从而导致了世界上HCV最高的感染率出现(39)。其他和这种传染方式相关的重要数据来自于巴基斯坦(75)和台湾(72)。

               Despite the rarity of blood transfusion-related HCV transmission in the industrialized nations, such transfusion is like to significantly contribute to HCV incidence in the developing world. Transfusion-related infection has virtually disappeared from the US, Europe and Australia, largely to the adoption of all-volunteer system, but further aided by blood product screening for ALT, anti-HCV antibody, and HCV RNA (112).  Many countries around the world continue to use paid blood donors (31, 102).  Furthermore, the WHO estimated than only some 42% of blood products are screened for infectious agents (130).  Sexual transmission is thought to exist as a risk factor for HCV acquisition, but is considered to be inefficient and relatively unimportant from a public health standpoint (122, 126).  The CDC recommends no change in sexual practices for monogamous couples in which one is chronically infected with HCV. Vertical transmission rates have been estimated at between 2.7% and 8.4% and appear to be increased in mother co-infected with HCV and HIV (38, 131).

        尽管在发达国家中罕见输血导致的HCV感染，但在发展中国家输血仍为导致HCV感染的重要因素。在美国、欧洲和澳大利亚，输血相关感染实际上已绝迹，这主要因为采用全部无偿献血系统，并得益于对血制品筛查ALT、抗-HCV抗体和HCV RNA(112)。目前很多国家仍在继续使用有偿献血员(31, 102)。此外，WHO 估计仅有42%的血制品进行了病原学方面的筛查(130)。性传播也被认为是HCV获得性感染的危险因素之一，但目前认为其传播效率低，从公共卫生角度上看重要性相对要低(122, 126)。 美国疾病控制中心目前推荐，单一性伴侣的夫妻中一方有慢性HCV感染时，无需对性生活方式做出改变。目前估计垂直传播率约为2.7%至8.4%，在HCV和HIV合并感染的母亲中感染率可能更高(38, 131)。

HCV-HIV Co-Infection: It is estimated that 25% to 30% of HIV-infected individuals are co-infected with HCV (1, 8). Injection drug use results in higher rates of co-infection, but rates attributable to sexual transmission are on the increase. The natural history and clinical course of HCV is also altered by HIV co-infection. Persons with HIV co-infection tend to have higher HCV viral loads and are less likely to clear the HCV spontaneously (25). Before the advent of highly active antiretroviral therapy (HAART), HCV did not appear to have any significant effect on progression of HIV disease or death in HIV infected patients. With the advent of HAART, there has been a sharp decline in overall mortality in patients with HIV infection, largely due to a decrease in opportunistic infection. At the same time, liver disease has become a leading cause of mortality in HIV infected patients (13, 104). While in 1991, only 11.5% of deaths in HIV infected persons were due to liver disease, 50% of the deaths in 1998-1999 were due to end stage liver disease. Among the liver disease related deaths in 1998-1999, 93.8% of the patients had antibodies to HCV (13). Person co-infected with HCV/HIV are more likely to develop cirrhosis, have lower virologic response rates to interferon-based therapy, and are more likely to experience HAART therapy-related hepatotoxicity (81, 12, 105).

HCV-HIV共感染: 据估计在25%至30%的HIV感染患者合并有HCV的感染(1, 8)。静脉注射毒品可导致合并感染的发病率更高，但由性接触所致的比率也在增加。由于合并HIV感染，HCV的自然病程和临床进展也发生了变化。合并HIV感染的人群中HCV的病毒负荷常更高，且HCV自发清除的可能性更低(25)。在高效联合抗病毒治疗(HAART) 出现之前，HCV并未对HIV的病情进展或HIV感染患者的死亡起到明显影响。在HAART出现之后，由于机会感染的大幅减低，HIV感染患者的整体死亡率明显下降。与此同时，肝病已经成为导致HIV感染患者死亡的主要因素(13, 104)。在1991年，仅仅11.5%的HIV患者死于肝病；而在1998-1999年，50%的死亡是由于终末期肝病。在1998-1999年肝病相关的死亡病例中，93.8%的患者抗-HCV抗体阳性(13)。HCV/HIV共感染的患者常更易进展为肝硬化，对以干扰素为基础的治疗方案的病毒学应答率要更低，且更容易出现HAART治疗相关的肝毒性(81, 12, 105)。

[Review Article: Rockstroh JK, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infect Dis. 2004 Jul;4(7):437-44.]

[综述文献: Rockstroh JK, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infect Dis. 2004 Jul;4(7):437-44.]

Natural History of HCV Infection: HCV infection resolves spontaneously in an estimated 15% to 40% of acutely exposed persons, while the remainder develops chronic infection with detectable virus in the serum. A number of series now demonstrate that recognition of acute HCV infection and early treatment results in a very high rate of viral eradication (107). Of those with chronic infection, 60% to 70% will have intermittently or persistently abnormal serum ALT levels. When retrospective and prospective data are combined, it is estimated that 15% to 20% of persons with HCV infection progress to cirrhosis, while approximately 5% will develop hepatocellular carcinoma (71,124). In one study of blood-transfusion recipients, the mean times between exposure to HCV and the development of chronic HCV infection, cirrhosis, and hepatocellular carcinoma were 13.7, 20.6, and 28.3 years, respectively (124). Several factors are known to increase the risk for fibrotic progression, including more advanced age, alcohol consumption, and histologic fibrosis (119,129).  Patients with persistently normal levels of serum ALT have a lower risk for fibrotic progression (80). The average time from infection to development of cirrhosis is between 20 to 30 years. The progression can be significantly accelerated by HIV co-infection and alcohol consumption. Patients with HIV co-infection progress to cirrhosis after about 7 years as compared with those with HCV infection alone in whom the average time for such progression is about 23 years (13,15,118).  Male sex, older age at diagnosis, co-infection with HBV and active IDU also increase the risk of progression of disease (15).

HCV感染的自然病程: 在急性暴露的人群中，估计有15%-40%的HCV感染可自行缓解，而其余患者则发展为慢性感染，血清中可检测到病毒。有系列的研究数据表明，及早发现和治疗急性HCV可以获得非常高的病毒清除率(107)。在那些慢性感染的患者中，有60%-70%会间断或持续血ALT水平异常。结合回顾性和前瞻性的数据，估计约有15%-20%的HCV感染患者会进展为肝硬化，约5%的患者会进展至肝细胞肝癌(71,124)。在一个关于接受受输血者的研究中，暴露于HCV到进展为慢性HCV感染、肝硬化和肝细胞肝癌间的平均时间分别为13.7、20.6和28.3年(124)。已知一些因素可增加肝脏纤维化进展的风险，包括年龄，酒精摄入和组织学纤维化(119,129)。ALT水平持续正常的患者纤维化进展的风险相对要低(80)。从感染进展为肝硬化的平均时间为20-30年。合并HIV感染和摄入酒精可明显增快病情进展。合并HIV感染的患者进展为肝硬化的平均时间约为7年，而单纯HCV感染的患者平均为23年(13,15,118)。男性，发病年龄偏大，合并HBV感染和活跃吸毒均可提高病情进展的风险(15)。

Clinical Manifestations Guided Medline Search

临床表现

Acute Viral Hepatitis: The overwhelming majority of hepatitis C infections that are seen clinically are chronic in nature. It should be noted however, that there is a growing recognition of acute HCV infection, especially in the context of needle stick injury and intravenous drug use. The realization that acute infection, when treated early, has a very high therapeutic response rate, has led to increase vigilance and surveillance from such infections. Acute hepatitis C presents in a similar fashion to the other hepatotropic viruses. Many infections will be subclinical, others may present with classic symptoms such as nausea, vomiting, right upper quadrant pain and malaise. A smaller percentage of cases will present with jaundice. There have been very few reported cases of HCV presenting with fulminant hepatic failure. The acute symptoms are self-limited, but the duration and severity of symptoms give no indication of the probability of chronicity. The significant spontaneous clearance rate of acute HCV infection has led to specific treatment delay recommendations when taking a clinical approach to such patients.

急性病毒性肝炎:临床见到的绝大多数丙型肝炎病毒感染临床上呈慢性病程。但需提出的是，对急性HCV感染的认识亦逐渐增加，特别在发生针刺伤或静脉吸毒时。由于目前认识到若能尽早治疗急性感染，会有很高的治疗有效率，因此促使大家提高对该类感染的警惕和监测。急性丙型肝炎病毒感染的表现和其他嗜肝病毒类似。很多感染呈亚临床性，其它则会有恶心、呕吐、上腹痛和无力等典型症状。少部分患者会出现黄疸。也有很少数表现为爆发性肝衰的报道。急性症状为自限性，但是其持续时间和严重程度与是否慢性化无关。由于急性HCV感染自发缓解率很高，因此在临床诊治该类患者时，可建议暂缓进行特异性的治疗。

Chronic Viral Hepatitis: Chronic HCV is the most common hepatotropic virus infection in the industrialized nations. The frequency with which the infection becomes chronic is in the range of 85% of exposed persons, explaining the high prevalence of chronic infection. Many cases of chronic HCV infection are asymptomatic or associated only with mild non-specific symptoms such as fatigue. Such non-specific symptoms can be disruptive or even disabling, with consistently lower quality of life scores in HCV patients compared to match controls. The most common presentation of chronic HCV is the incidental notation of mildly elevated serum aminotransferases. In such patients with a positive anti-HCV antibody, viremia can be detected in about 85%, denoting chronic infection. In those patients with detectable anti-HCV antibody but repeatedly undetectable virus, the difference between false-positive antibody and resolved infection can be delineated by the recombinant immunoblot assay (RIBA). Up to 30% of chronically infected patients with have persistently normal aminotransferases, so a high index of suspicion to potential infectious risk factors is necessary (98).  Natural history studies have shown that some 20% of chronically infected patients will develop hepatic cirrhosis over a period estimated from 20-30 years. Although clinical evidence of cirrhosis may be suggested in some patients by physical examination, laboratory assessment or radiographic studies, most patients, even those with significant liver fibrosis, will not demonstrate such findings. Therapeutic decisions regarding antiviral therapy must incorporate the estimated rate of progression (50).  Fibrotic progression is higher is male patients, those who drink larger amounts of alcohol, those with HIV co-infection, and in those who have evidence of fibrosis on a liver biopsy.

慢性病毒性肝炎: 在发达国家，慢性HCV为最常见的嗜肝病毒感染。85%的暴露人群会转为慢性感染，这也说明了慢性感染的高发生率。很多慢性HCV感染无症状，或仅表现为疲劳等轻度的非特异性症状。这些非特异性的症状有时可产生明显影响甚至导致患者丧失劳动能力，使HCV患者和健康人群相比生活质量评分明显降低。慢性HCV感染最常表现为偶然发现血清转氨酶轻度升高。约85%抗-HCV抗体阳性的患者会有病毒血症，提示慢性感染。在抗-HCV抗体阳性却反复检测不到病毒的患者中，可通过重组免疫印迹法（RIBA）区别抗体假阳性和感染痊愈。多达30%慢性感染者的转氨酶持续正常，因此对有潜在危险因素的患者应高度警惕(98)。对自然病程的研究表明，约20%的慢性感染患者在20-30年后会进展至肝硬化。尽管对于部分患者，通过查体，实验室检查或影像学分析提示可能有肝硬化，但对大多数患者，即使已有明显的肝纤维化化，仍无明显表现。做出抗病毒治疗的决定时必须同时评估病情进展速度(50)。在男性患者，大量饮酒者，合并HIV感染者，或肝穿已证实有纤维化的患者中，纤维化进程会更快。

Laboratory Diagnosis Guided Medline Search

实验室诊断

               The most common clinical presentation of the individual infected with HCV is the incidentally noted elevation of serum chemistries. Abnormal serum alanine aminotransferase (ALT) levels, if confirmed on repeat testing, should prompt a search for HCV infection risk, as well as serologic testing for HCV antibody by enzyme immunoassay (EIA) (103). Because as many as 30% of patents with chronic HCV infection have persistently normal ALT levels, a high index of suspicion is necessary to identify those chronically infected (98). The sensitivity and specificity of currently utilized HCV enzyme immunoassays in high prevalence populations are in the range of 98% to 100% (23, 128). The HCV EIA assay, now in its third generation, is available in kit form from several manufacturers and provides highly reproducible results (23, 61).

        HCV感染患者最常见的临床表现为偶然发现的血清酶学升高。若经重复检测后仍证实血清丙氨酸氨基转移酶（ALT）水平异常，应积极寻找HCV的感染风险，并通过酶免疫分析法（EIA）测定血清中的HCV(103)。由于30%慢性HCV感染患者的ALT水平持续正常，因此应高度警惕以识别慢性感染患者(98)。目前应用的酶免疫分析法在高流行人群中的敏感性和特异性在98%至100%之间(23, 128)。HCV EIA法目前已发展至第三代，多家厂商均已生产出试剂盒，能够提供有高度可重复性的结果(23, 61)。

               In low-prevalence populations, such as asymptomatic blood donors, 40% of patients with anti-HCV by enzyme immunoassay represent false positives. Use of the recombinant immunoblot assay (RIBA) or HCV RNA can be helpful in this situation (5). In clinical practice, confirmatory testing is always undertaken, usually using HCV RNA testing, both to eliminate possibility of a false-positive antibody test and to provide prognostic information regarding the potential success of antiviral therapy. HCV RNA testing is based on a number of assays, including target amplification (RT-PCR), signal amplification (branched-chain DNA), or target-mediated amplification (TMA). Automated kits are available and are now used by many reference labs. In practice, qualitative detection assays detect 50 HCV RNA IU/mL or less, and have equal sensitivity for the detection of all HCV genotypes (20). Molecular assays are now capable of detecting HCV viremia at concentrations as low as 5 IU/ml (109). The diagnostic tests for HCV are summarized in Table 1.

        在低流行人群，例如无症状献血者中，有40%酶联免疫分析法提示有HCV的患者为假阳性。此时可应用重组免疫印迹法（RIBA）或测定HCV RNA来帮助检测(5)。在临床实践中，经常要进行确证试验—常为测定HCV RNA，以避免抗体检测假阳性的出现，同时可为抗病毒治疗的效果提供预后方面的信息。测定HCV RNA检测通常基于一系列的试验，包括原位扩增（RT-PCR），信号放大（支链DNA），或目标介导的扩增技术(TMA). 目前已有自动检测的试剂盒，并已被很多实验室使用。在检测时，定量方法可测出50 HCV RNA IU/ml乃至更低水平，并且对所有的HCV基因型均有相同的敏感性(20)。目前分子生物学技术已可测定血液中HCV RNA浓度低至5 IU/ml(109)。表1总结了HCV 的诊断性检测方法。

               Chronic HCV infection is characterized by positive HCV antibody and RNA. Patients with acute hepatitis C usually have a positive HCV RNA with a negative HCV antibody, although the HCV antibody may be present in acutely infected patients who have seroconverted. A positive HCV antibody in the setting of undetectable HCV RNA is indicative of cleared infection, false positivity, or of extremely low level viremia.

        慢性HCV 感染的特点为HCV抗体及RNA阳性。尽管在出现血清转换的急性HCV感染患者中HCV抗体可为阳性，但急性丙型肝炎患者通常为HCV RNA 阳性同时HCV抗体阴性。HCV抗体阳性但是HCV RNA 阴性多提示感染已清除，假阳性或病毒浓度非常低。

               The quantification of HCV RNA is an important component of the management of patients chronically infected with HCV. There is no correlation between viral load and disease severity. The quantitative HCV PCR provides information to assist decision-making regarding success and duration of therapy, but not natural history of disease. Therefore, there is no need to order serial quantitative PCR in untreated patients. Quantitative HCV RNA testing is increasingly used to make treatment decisions during the administration of interferon-based anti-viral therapy. Because the failure to reduce viral load by at least 2 log -fold by 12 weeks of therapy is highly predictive of ultimate treatment non-response (high negative predictive value), therapy should be stopped in patients who fail to achieve this milestone (37,93). Analysis of interferon treatment data also suggests that the lack of virologic eradication by 24 weeks of therapy is strongly predictive of the lack of ultimate SVR (82). Therapy should therefore be stopped in patients who fail to meet this milestone as well. The investigation of even earlier predictive algorithms is underway (62).  The achievement of an RVR may justify truncation of therapy in genotype 2 or 3-infected patients to 12-16 weeks (78, 127), although a recent large randomized trial in genotype 2 and 3-infected patients comparing 16 with 24 weeks of PEG-IFN and flat dose (800 mg/d) RBV therapy found a higher response rate in patients receiving 24 weeks (114).

        HCV RNA定量是治疗慢性HCV感染者的重要一环。病毒载量与疾病严重程度之间并无联系。HCV的定量PCR测定可为判断治疗成功与否及其疗程提供信息，但并不预示疾病的自然进程。因此，对于未接受治疗的患者，勿需连续的PCR定量测定HCV。在进行以干扰素为基础的抗病毒治疗时，定量测定HCV RNA的使用已日益增加以帮助确定治疗方案。因为在治疗12周后，若病毒载量下降小于2个指数，则高度提示最终对治疗无反应（高阴性预测值），所以在没有达到这一目标的患者应停止治疗(37,93)。对干扰素治疗相关资料的分析还提示在治疗24周后若未能清除病毒，则强烈预示缺乏最终的持续病毒学应答（SVR），因而对这部分患者也应中止治疗(82)。关于更早的预后判断方法的研究亦在进行中(62)。在感染2型或3型病毒的患者中若能达到快速病毒学应答，则支持在治疗12-16周时即终止治疗(78, 127)，不过最近有一项新的大规模随机临床试验比较了在感染2型或3型病毒的患者中分别接受16周和24周的PEG-IFN以及固定剂量（800mg/d）的利巴韦林的治疗，结果表明接受24周治疗的患者的应答率要更高(114)。

               There at least 6 major genotypes of HCV, with many subtypes (52, 91). This exceptional genetic heterogeneity may help to account for the resistance of HCV to therapy and vaccine development. Over 75% of patients in the US are infected with genotype 1, 15% with type 2 and 10% with genotype 3. There is no correlation between HCV genotype and severity of disease, but response rates to interferon-based regimens are significantly higher in those patients infected with genotypes 2 and 3 (28). Therefore, genotyping on a single occasion is recommended to provide information regarding expected response rates and duration of antiviral therapy. Commercial HCV genotyping kits rely on sequence analysis of the 5’ noncoding region (42,116,117 133).

        HCV至少有6种主要的基因型，并有多种亚型(52, 91)。这种特殊的基因异质性可能有助于解释HCV的耐药性和疫苗开发的难度。在美国，超过75%的患者感染的是1型HCV，感染2型HCV的占15%，而感染3型HCV的占10%。HCV基因型和疾病严重程度之间并无联系，但在感染2型和3型 病毒的患者中，对基于干扰素的治疗方案应答率明显要高(28)。 因此在一种情况下建议做基因分型，即为获得关于预期应答率和抗病毒治疗疗程的信息。目前已有主要依靠对5’非编码区的序列分析(42,116,117 133)所研发出的HCV基因检测试剂盒的商品。

               Most hepatologists prefer to include an examination of liver histology in the management of patients with chronic hepatitis C. Random core biopsy reveals information about the inflammatory grade and fibrotic stage of chronic HCV. In patients with mild inflammation and no significant fibrotic change, treatment is less urgent because risk for progressive liver disease is lower. The presence of severe inflammation or bridging fibrosis should serve as an impetus for therapy. Histologic evaluation of the liver also aids in guiding the therapy of patients who do not respond to antiviral treatment. In persons with milder disease, further therapy can be deferred until more effective treatment regimens are developed. For patients whose biopsy reveals more advanced disease, further treatment should be considered. Liver biopsy has several limitations. It is attended by a serious adverse event rate of about 0.3% (predominantly bleeding) (100). Pain is not infrequent following the procedure. The potential for sampling error has also come under scrutiny (10). The general recommendation for repeat samples over time in untreated patients stems partially from this concern. In recent years, the development of non-invasive (serologic and elastography) assessment of hepatic fibrosis has provided a potential alternative (41, 58, 106). Although these tests have not yet entered the mainstream, it is reasonable to predict that their use will increase over the next decade.

        绝大多数肝病学家倾向于在治疗慢性HCV感染患者时要明确肝脏病理。通过随机中心活检可获得关于慢性HCV感染的炎症程度和纤维化分期的信息。对于炎症程度轻微且无明显纤维化改变的患者，由于其肝病进展的风险要低，因此并不急于治疗。而出现重度炎症或桥接坏死则提示应尽早开始治疗。对肝脏的组织学评价还有助于于指导那些对抗病毒反应不佳的患者的治疗案。对于肝脏病变较轻者，可暂缓行进一步治疗直至研究出更加有效的治疗方案。而对肝脏病理提示疾病更加进展的患者，应考虑行进一步治疗。肝脏活检亦存在不少局限性。其中出现严重并发症的几率约0.3%（多数为出血）(100)。 手术后疼痛亦不少见。关于取样误差的可能性也在仔细研究当中(10)。对未治疗患者推荐重复取活检也部分是基于如此考虑。近年来，无创性评价肝脏纤维化方法（如血清学和弹性图）的发展又提供了一条可能的选择(41, 58, 106)。尽管这些检查方法尚未成为主流，但有理由的预测，在以后的十年间，它们的应用会有所增加。

Pathogenesis Guided Medline Search

发病机制

               Although important advances have been made in the understanding of the natural history, the diagnosis and the treatment of chronic HCV infection, details on the pathogenesis of the infection remain incomplete. HCV is an RNA virus that has been classified as a flavivirus. It is estimated that 10 trillion viral particles are produced per day. Multiple quasispecies of the virus exist within any given host simultaneously (90). In humans and primates in which virus has cleared spontaneously, virus-specific responses by cytotoxic T lymphocytes and helper T cells have been described (68, 120). The very high chronicity rates of the infection, which differs so radically from the other known hepatotropic viruses, suggests an ineffective immune response in most individuals. Studies have been hampered by the number of variables in the host and the virus. The current understanding of chronic HCV infection points to the host immune response as the primary etiology of hepatocellular injury. Both humoral and cellular immunity is involved in this complex reaction, yet neither is capable of clearing infection in the large majority of affected individuals. Direct viral cytopathicity has been described, but is thought to be of less importance than host immune-mediated injury (89).

        尽管我们对慢性HCV感染的自然病程、诊断和治疗方面的了解已经取得重大进展，但对于HCV感染的详细发病机制仍不完全了解。HCV是一种RNA病毒，分类为黄病毒属。据估计每天约可产生10万亿个病毒颗粒。在一个宿主中，病毒会同时存在很多准种(90)。在那些病毒自发清除的人体或灵长类动物中，发现了发现了殺傷性T细胞和T辅助细胞的病毒特异性反应已有介紹(68, 120)。HCV和其他已知的嗜肝病毒完全不同，感染慢性化比率非常高，这提示绝大多数个体的免疫反应无效。相关研究受阻于宿主和病毒变量众多。目前对慢性HCV感染的认识认为宿主免疫反应是导致肝细胞损害的主要因素。细胞免疫和体液免疫均参与这个复杂的反应，但是任何一种均不能清除绝大多数患者体内的感染。也有人提出了病毒的直接致细胞病变作用，但认为其重要程度低于宿主免疫介导的损伤(89)。

               The life cycle of HCV is incompletely understood, but the following model has been proposed: HCV binding to an cell surface receptor, internalization into the host cell, cytoplasmic release and uncoating of the viral RNA genome, IRES-mediated translation and polyprotein processing by cellular and viral proteases, RNA replication, packaging and assembly, and virion maturation and release from the host cell (83).  Although a number of receptor candidates for HCV infection are being investigated, the details of this process are not understood (8).  A number of non-structural proteins have been identified and characterized, providing potential strategies for therapeutic intervention. For example, the NS3 serine protease (66) and the NS5B RNA dependent RNA polymerase (70) have emerged as potential targets for antiviral therapies.

        目前对HCV的生命周期还未完全了解，然而已提出的模型如下：HCV与细胞表面受体结合，通过内化作用进入宿主细胞，病毒RNA基因组在细胞质内释放和脱壳，内部核糖体（IRES）介导的翻译和由细胞和病毒蛋白酶作用的多聚蛋白合成，RNA复制，包装和组合，以及病毒颗粒的成熟和从宿主细胞中释放(83)。尽管目前已对一系列与HCV感染相关的受体进行了研究，但关于该过程的细节方面还尚未了解。目前一些的非结构蛋白已经被识别和鉴定，从而为治疗干预提供了潜在的策略。例如，NS3丝氨酸蛋白酶(66)和NS5B RNA依赖的RNA聚合酶(70)均已成为抗病毒治疗的可能靶位。

Review Article:  Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infectious Diseases 2007;7:460-472.

SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo

体内外的易感性

               Until recently, the advancement of our understanding of the mechanisms underlying HCV replication and persistence and the development of new antiviral therapeutics had been hampered by the lack of cell culture model systems capable of robust viral replication (33). Furthermore, a truly tractable small animal model does not yet exist for HCV, as HCV infects only humans and chimpanzees.

        直到最近，由于目前缺乏能够使病毒活跃复制的细胞培养模型，人们对于HCV复制和持续存在的机制以及发展新的抗病毒治疗方法的深入了解仍受到阻碍(33)。此外，由于HCV仅仅感染人类和黑猩猩，目前尚未有一个关于HCV的易于操作的小动物模型。

               The recent development of both subgenomic and genomic replicon cell culture models capable of high-level autonomous HCV RNA replication has greatly facilitated the evaluation of antiviral activities of new drug candidates as well as the study of viral RNA replication and persistence (6,7). Although they have proven very useful, the main drawback of HCV replicons is that they do not produce infectious viral particles. The recent development of a successful infectious cell culture system has enhanced the ability to validate prospective compounds. Indeed, a number of anti-HCV compounds currently in development have moved directly from replicon or tissue culture models to man. These model systems have also permitted evaluation of selection for drug resistance, with a reasonable correlation with isolates identified in vivo. We can anticipate accelerated development of assays to assess both genotypic and phenotypic resistance as the pace of small molecule antiviral drug development accelerates.

        最近开发出亚基因水平和基因水平上的复制子细胞培养模型，能够自行进行高水平的HCV RNA复制，从而能在很大程度上帮助评价候选新药的抗病毒活性以及研究病毒复制和持续感染情况(6,7)。尽管该系统目前已证实是非常有用的，但HCV复制子细胞的主要不足为它们不能产生具有传染性的病毒颗粒。最近发展出一种成功具有传染性的细胞培养系统，它能增强确认那些有前景的药物的有效性的能力。实际上，目前很多正在研究中的抗HCV药物均已直接从复制子或组织培养模型转移到人体中。这些模型系统还可被选用于评价耐药性，它们与在体内分离的种群之间存在合理的联系。由于目前小分子抗病毒药物在进行性发展，我们可以期待，随着小分子抗病毒药物发展步伐加速，评价基因型和表型耐药的方法也会加速发展。

ANTIVIRAL THERAPY Smart search

抗病毒治疗

Drug of Choice Guided Medline Search

药物选择

               The choice of whether or not to offer antiviral treatment to an individual infected with HCV is complex and must be individualized (Table 2).  Anti-viral therapy for HCV infection reached maturity with the development of interferon/ribavirin combination therapy (17). The treatment of choice and the current standard of care for treatment of HCV infected persons is the combination of pegylated interferon and ribavirin (Table 3).

        对于感染HCV的每个患者，选择是否给予抗病毒治疗需综合考虑，且要个体化(表2)。在推出干扰素/利巴韦林联合治疗后，HCV感染的抗病毒治疗走向成熟(17)。目前对HCV感染患者所选择的标准治疗方案为联合使用聚乙二醇干扰素和利巴韦林(表3)。

               When given for 48 weeks, this combination results in sustained virologic response (SVR) in about 54% of treated patients (29, 40, 46, 55, 73, 76, 82, 101). Treatment response is strongly dependent on HCV genotype. Patients with genotype 2 or 3 can expect SVR rates in the 76-84% range, while those with genotype 1 achieve SVR in about 42-52%. Patients infected with genotype 2 or 3 achieve similar sustained virologic response rates whether treated with pegylated interferon or the standard interferon (both in combination with ribavirin), and whether they are treated for 24 or 48 weeks (44, 46, 73, 76).  In those infected with genotypes 2 or 3 and exhibiting early response, even shorter courses of therapy may be effective (78). There is some evidence that genotypes 2 and 3 should be approached differently, especially patients with genotype 3 infection with high viral load, who may require higher doses of therapy for longer duration (132). The generally agreed upon current recommendations are a treatment duration of 48 weeks for those infected with genotypes 1 and 4, and 24 weeks for those infected with genotypes 2 and 3.

        当给药48周时，这种联合用药会在54%接受治疗的患者中达到持续病毒学应答 (SVR) (29, 40, 46, 55, 73, 76, 82, 101)。治疗反应很大程度上取决于HCV的基因型。感染2或3型病毒的患者中有76-84%会达到SVR，而感染1型的患者中有42-52%达到SVR。感染2或3型病毒的患者，无论在接受聚乙二醇干扰素或标准干扰素（均联合使用利巴韦林）时，且无论治疗24或48周，持续病毒学应答率是类似的(44, 46, 73, 76)。在那些感染2型或3型，并且有早期反应的患者中，更短的疗程亦有效(78)。有证据表明，对于2型和3型病毒仍应分别处理，特别是感染3型病毒且病毒载量高的患者，需接受较长疗程的大剂量治疗(132)。目前普遍推荐的方案为，在感染1型和4型病毒的患者中疗程为48周，而在感染2型和3型病毒的患者中疗程为24周。

               Two peginterferon formulations are approved: peginterferon alfa-2a is dosed at 180 mcg weekly and peginterferon alfa-2b given at 1.5 mcg/kg weekly (Table 3).

        目前已获批准的聚乙二醇干扰素剂型分两种：聚乙二醇干扰素 alfa-2a，180 mg/周，以及聚乙二醇干扰素 alfa-2b，1.5 m/kg/周(表3)。

               The dose of ribavirin should be based on patient weight in those infected with genotype 1 (1000 mg or 1200 mg per day, for body weight less than or greater than 75 kg, respectively), but current recommendations state that patients with genotype 2 or 3 infection may be treated with a lower dose (800 mg per day) (44).

        在感染1型病毒的患者中，利巴韦林的剂量应视患者体重调整（对于体重在75Kg以下和以上的患者，分别为1000mg和1200mg/天），但对于感染2或3型病毒的患者，目前的指南推荐使用较低剂量的利巴韦林（800mg/ 天）(44)。

Assessing Response to Treatment

治疗反应评价

               The primary end point in assessing treatment response is the sustained virologic response (SVR), defined as the absence of HCV RNA 24 weeks after any course of treatment. End of treatment response (ETR) is defined as the absence of HCV RNA at the end of a course of treatment. The reappearance of HCV RNA prior to the 24 week followup is defined as a relapse. With achievement of an SVR, late relapses are extremely rare. Biochemical response is defined as normalization of liver enzymes, and a histological response is defined as a measurable improvement in liver histology on a post-treatment liver biopsy specimen.

        评价治疗反应的主要终点是持续病毒应答（SVR），定义为在任何疗程的治疗结束24周后，HCV RNA仍不能检测出。治疗结束应答（ETR）定义为在经过一个疗程的治疗结束时，HCV RNA检测不到。在ETR之后的24周之内若HCV RNA再次出现，则定义为复发。如达到SVR，则罕有迟发性复发。生化学反应定义为肝酶水平正常，组织学反应则定义为在治疗后行肝活检可发现有明显的肝脏病理学方面的改善。

               The goal of treatment of HCV is eradication of HCV RNA, which is associated with reduction in hepatic necroinflammation, which in turn can lead to a regression in fibrosis and a delay in progression of cirrhosis to clinical complications, including variceal bleeding and hepatocellular carcinoma (Table 4).

        HCV治疗的目标为清除HCV RNA，这同时可伴有肝脏坏死性炎症的减轻，并可进一步减少肝脏纤维化以及随后肝硬化进展至出现临床并发症，如静脉曲张出血和肝细胞肝癌 (表4)。

               Treatment recommendations for HCV depend upon the genotype (Figure 1). All patients, regardless of genotype, should have persistent HCV viremia to be considered for treatment.

        HCV的治疗指南应根据不同的基因型而定 (图1)。所有患者，无论感染何种基因型的病毒，只有在出现持续的HCV病毒血症时方需考虑治疗。

               Genotype 1-infected patients should have their extent of liver injury assessed by a liver biopsy or indirectly by persistently elevated serum alanine and aspartate aminotransferases, in view of their relatively limited chance of achieving SVR. It is generally recommended to defer treatment for infected persons with no histologic abnormalities, since the rate of progression is likely to be very slow in these persons. Continued monitoring with serum biochemical markers and periodic liver biopsy (every 3 – 5 years) is recommended to monitor progression and to limit the effects of histologic sampling error (95).

        对于感染1型病毒的患者，由于在这类患者中达到SVR的机会相对较小，应直接通过肝活检或间接通过持续升高的血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平对肝脏损伤程度进行评价。对那些无组织学异常的患者，通常推荐暂缓治疗，因为在这类患者中病变进展的速度通常非常缓慢。对这类患者通常推荐持续监测血清生化指标，定期行肝活检（每3-5年），以监测病变进展，同时减少组织学取样误差的影响(95)。

               For those genotype 1 patients with more advanced liver injury who do require treatment, the HCV RNA level should be quantitated at baseline and at 12 weeks of therapy. If there is a 2-log decline or clearance of HCV RNA compared to baseline (early virologic response (EVR)), treatment should be continued. If HCV RNA is undetectable by a qualitative assay (lower level of detection < 50 IU/mL) at 24 weeks, then therapy should continue for the full 48 weeks, as there is a high likelihood of achieving SVR. Therapy should be stopped for those patients who fail to meet the criteria for continuing therapy at 12 and 24 weeks, as the chances for achieving SVR are extremely low in these patients. HCV RNA should be measured at end of treatment, then 24 weeks after treatment to determine if SVR is achieved  (20, 95). (Figure 1A)

        在那些感染1型病毒且肝脏损害明显，需要接受治疗的患者中， 应在治疗开始前及治疗12周后测定HCV RNA的水平。如果在治疗12周后与治疗前的HCV RNA水平有两个指数水平的下降或得到清除（早期病毒学应答(EVR)），则应继续治疗。若在治疗24周后通过定性检测未能测得HCV 水平（<50IU/ml），则治疗应继续直至满48周，因为此时达到SVR的可能性很高。若在治疗12周及24周时未能达到上述效果，则应终止治疗，因为在这类患者中达到SVR的可能性很低。在治疗结束时应测定HCV RNA的水平，然后在治疗后的24周再次测定应确定是否达到SVR (20, 95)。 (图1A)

               For genotype 2 and 3 patients, who have a very high likelihood of SVR, treatment can be recommended regardless of the severity of liver disease and an empiric course administered without a liver biopsy. Again, kinetic determinations of EVR, ETR and SVR apply (20, 95) (Figure 1B).

        对感染2和3型病毒的患者，因为这类患者达到SVR的可能性很高，因此无论肝脏病变程度如何，均推荐进行治疗，且无需肝脏活检即可行经验性的治疗。同样应监测动力学参数EVR，ETR和SVR (20, 95) (图1B)。

               Investigations of whether shorter courses of therapy for genotype 2 and 3 disease have been undertaken, but the result of these studies has been mixed. While 2 randomized controlled trials have indicated that 12 or 16 weeks of therapy produce SVR rates equivalent to those observed for 24 weeks in genotype 2 or 3 HCV (77, 78), a recent large trial indicated that the full 24-week course is associated with higher overall rates of sustained virological response compared to 16 weeks (114).

        对于感染2型和3型病毒的患者，是否可将疗程缩短，相应的研究正在进行当中，但是这些研究的结果却并不一致。有2个随机对照研究显示对感染2和3型病毒的患者，治疗12或16周可与治疗24周达到相同的SVR(77, 78)，但最近一个大的临床试验表明和治疗16周相比，完整治疗24周的SVR要更高(114)。  

               The treatment of genotype 4, 5, and 6 HCV has not been as extensively studied as that for genotypes 1, 2, and 3. It is therefore recommended that genotypes 4, 5, and 6 be treated for a total of 48 weeks with the interferon and ribavirin dosages appropriate for genotype 1. It is reasonable to apply similar stopping rules for these genotypes (20,  95).

        相比于1、2、3型而言，目前关于4、5、6型HCV感染的治疗还尚未有广泛的研究。因此目前对于4、5、6型HCV感染的患者，推荐按照以治疗1型HCV感染的干扰素和利巴韦林的剂量，完整的治疗48周。对这些基因型的终止治疗方案也类似。

               Treatment is less successful in persons with already established cirrhosis, but if stable these persons do benefit from treatment (47). However, treatment is currently not recommended for persons with decompensated liver disease. While many providers treat persons with chronic HCV and normal serum aminotransferases, the benefit of such treatment is not fully established. While many such patients have abnormal liver histology, the rate of progression of liver fibrosis is thought to be slower when compared with those with elevated serum aminotransferases (80, 69,104).  An added important potential benefit of treatment is a reduction in the rate of hepatocellular carcinoma. For example, a 2001 meta-analysis showed that hepatocellular carcinoma was less frequent in patients treated with interferon than untreated patients (8.2% vs. 21.5%) (92).

        对于已明确有肝硬化的患者，治疗的成功率常较低，若这类患者的病情尚平稳，则仍可从治疗中获益(47)。但是，在失代偿性肝病的患者中，目前并不推荐治疗。尽管很多医生对血清氨基转移酶正常的慢性HCV感染患者进行治疗，但这些治疗是否有益还未明确。尽管许多这样的患者肝脏组织学不正常，但和那些血清氨基转移酶升高的患者相比，这些患者进展至肝硬化的速度要慢(80, 69,104)。此外，治疗还有一个重要的潜在益处就是降低肝细胞肝癌的发生率。例如，一个2001年的荟萃分析表明，对于接受干扰素治疗的患者，与未接受治疗的患者相比，肝细胞肝癌的发生率要更低（8.2% vs 21.5%）(92)。

Management of Side Effects

副反应的处理

               Commonly reported adverse events of interferon alfa-2 (both standard and pegylated formulations) include influenza-like symptoms, anorexia, psychiatric symptoms (especially depression), and neutropenia. Ribavirin causes dose-dependent hemolytic anemia and is teratogenic (76). Ribavirin is absolutely contraindicated in pregnancy and in patients and their partners who may conceive while on therapy and up to six months after stopping therapy (Table 5). The use of acetaminophen or nonsteroidal anti-inflammatory drugs after the initial interferon injections can abrogate influenza-like symptoms (88). Management of hematologic side effects of interferon therapy, primarily neutropenia and thrombocytopenia, may require dose reduction or discontinuation. Granulocyte-colony stimulating factor has been used to stimulate neutrophil counts, but this intervention has not been shown to improve outcome of therapy. Ribavirin-induced hemolysis is also treated by dose reduction. Erythropoietin is effective is raising hemoglobin levels on treatment and maintaining higher ribavirin dose, and improving quality of life, but effect on SVR has not yet been demonstrated (3). Neuropsychiatric side effects of antiviral therapy are common and can lead to poor compliance with treatment or treatment discontinuations. Antidepressants, especially SSRIs, have been shown to be effective in ameliorating some of these effects (64, 110) but do require time to work.

        目前对干扰素α-2（标准型和聚乙二醇剂型）常报道的副作用主要包括：流感样症状，厌食，精神症状（特别是抑郁）和中性粒细胞减少。利巴韦林可导致剂量相关的溶血性贫血，并且有致畸作用(76)。对于怀孕的患者或患者及其伴侣在治疗期间直到治疗结束后6个月内想怀孕的，利巴韦林是绝对禁忌， (表5)。在开始注射干扰素后使用对乙酰氨基酚或非甾类消炎药可缓解流感样症状(88)。关于干扰素治疗的血液系统方面副作用，主要为中性粒细胞减少以及血小板减少，处理方法为减少用药剂量或者停药。粒细胞集落刺激因子可用于刺激中性粒细胞数量增加，但是这并未能改善治疗的预后。利巴韦林导致溶血时也应减少其剂量。促红素可明显提高血红蛋白水平，并可保证利巴韦林以较高剂量使用，从而改善生活质量，但是对于SVR的影响目前仍不清楚(3)。精神方面的副作用为抗病毒治疗过程中所常见的，并可导致对治疗的依从性下降或治疗终止。抗抑郁药物，特别是5-羟色胺再摄取抑制剂，对减缓该类副反应有一定效果(64, 110)，但需一定时间方能起效。

Treatment in Special Populations

对特殊人群的治疗

Patients with HCV-HIV Co-infection: HCV-HIV co-infected persons pose a special treatment challenge. In these patients, SVR rates are lower than those seen in HCV mono-infected patients. In controlled trials, patients with HIV co-infection achieved SVR rates between 27% and 40% (22,63,67,87,125). Four major clinical trials in the HIV co-infected persons published in 2004 established peginterferon and ribavirin as the best therapy for these patients (19, 22, 65, 123, 125).

HCV-HIV共感染的患者:HCV-HIV共感染者为治疗带来了一个特别的挑战，这类患者的SVR要比单独感染HCV的患者要低。在对照试验中，合并感染HIV的HCV患者的SVR在27-40%之间(22,63,67,87,125)。2004年发表的四个大的临床试验确立了聚乙二醇干扰素和利巴韦林为HIV-HCV合并感染者的最佳治疗选择(19, 22, 65, 123, 125)。

               In the AIDS Clinical Trials Group study ACTG5071, subjects were treated with 180 micrograms of peginterferon alfa-2a weekly for 48 weeks or 6 million IU of standard interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. The overall SVR was higher in the pegylated interferon group (27% vs. 12%), though this is substantially lower than what has been reported for HCV mono-infected persons. Pegylated interferon plus ribavirin treatment led to a SVR of 14% in subjects with HCV genotype 1 infection compared with 73% SVR in those with genotype non-1. A significant improved in liver histology was seen in those who responded to treatment as well as 35% of non-responders (22).

        在艾滋病临床试验协作组研究ACTG5071中，受试者每周接受180微克的聚乙二醇干扰素alfa-2a共48周；或者六百万单位的标准干扰素alfa-2a 3次/周共12周，然后三百万单位的标准干扰素alfa-2a 3次/周共36周。两组患者均按照一个剂量递增的方案接受利巴韦林治疗。聚乙二醇干扰素组的整体SVR要更高（27% vs 12%），尽管这比已报道的在单独HCV感染的患者要低。聚乙二醇干扰素联合利巴韦林治疗在1型HCV感染中的SVR为14%，而在非-1型HCV感染中的SVR为73%。在治疗有效的患者以及35%的对治疗无反应的患者中，可发现肝脏组织学有明显的改善(22)。

               In an international study of HCV-HIV co-infected persons (APRICOT), subjects were assigned to receive peginterferon alfa-2a (180 mg per week) plus ribavirin (800 mg per day), pegylated interferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin. The SVR was substantially higher in the pegylated interferon alfa-2a plus ribavirin group (40%) when compared with interferon alfa-2a plus ribavirin (12%), or pegylated interferon alfa-2a plus placebo (20%). The SVR was 29% in those with genotype 1 infection in the pegylated interferon plus ribavirin group, and 62% in those with genotype 2 or 3 infection (125).

        在一个关于HCV-HIV共感染人群的国际性研究（APROCOT）中，受试者分别接受 聚乙二醇干扰素alfa-2a（180mg/w）联合利巴韦林（800mg/d），聚乙二醇干扰素alfa-2a 联合安慰剂，或干扰素alfa-2a（3百万IU×3次/周）联合利巴韦林。与干扰素alfa-2a联合利巴韦林组的SVR（12%），以及聚乙二醇干扰素alfa-2a 联合安慰剂的SVR（20%）相比，聚乙二醇干扰素alfa-2a联合利巴韦林组的SVR明显要高（40%）。在聚乙二醇干扰素联合利巴韦林组中，1型HCV感染的SVR为29%，而2或3型感染的SVR为62%(125)。

               A French group (RIBAVIC) also studied the effects of 48 weeks of interferon-alfa-2b plus ribavirin (800 mg per day) in HCV-HIV co-infected patients, with an overall SVR of 27%, with genotype 1 and 4 patients achieving a 17% SVR rate and other genotypes achieving a 44% SVR (19). A Spanish group also examined the effects of 48 weeks of peginterferon-alfa-2b plus ribavirin on HCV-HIV co-infected patients, with genotype 1 and 4 patients achieving a 38% SVR rate and other genotypes achieving a 53% SVR rate (65). The lower SVR rates in the RIBAVIC and ACTG studies may be attributable to the fact that the severity of baseline liver disease was high in each of these studies (123). Moreover, the ACTG study also had a high proportion of African-American patients with genotype 1 infection, a group with known decreased SVR rates (see below).

        一个法国的研究小组(RIBAVIC)也研究了在HCV-HIV共感染的患者中，使用48周的干扰素alfa-2b联合利巴韦林（800mg/d）的SVR大致为27%，在1和4型患者中的SVR为17%，而其他基因型中的SVR为44%。一个西班牙的研究小组也研究了在HCV-HIV共感染的患者中使用48周的干扰素alfa-2b联合利巴韦林的效果，在1型和4型患者中的SVR为38%，而在其它基因型中为53%(65)。在RIBAVIC和ACTG研究中的SVR要偏低，这可能归因于在这两个研究中受试者基础肝脏病变的严重程度要高(123)。此外，ACTG研究中还有很大一部分的感染1型HCV的非洲裔美国患者,已知该类患者的SVR要低（具体见下文）。

               These trials have generally included only patients with relatively intact immune function as measured by the CD4 counts (usually > 400 cells/mm3). CD4 counts in HCV-HIV co-infected patients consistently drop by an average of 100 cells/mm3 on peginterferon-based therapy, although CD4% actually increases. More importantly, no significant AIDS-defining illnesses have been reported on treatment. Patients with HIV are also more likely to have concurrent medical, psychiatric and substance abuse problems making them less than ideal candidates for HCV treatment. While patients in care in the Veterans Healthcare System are also more likely to have similar issues than the HIV infected patients (16, 54, 84), there is no data to suggest that treatment response in veterans is poorer than the non-veterans.

        这些临床试验主要纳入的是通过检测CD4数目（通常>400/mm3）而确定免疫功能相对完善的患者。在以聚乙二醇干扰素为基础的治疗中，HCV-HIV共感染患者的CD4细胞数目平均要减少100/ mm3，尽管CD4细胞百分比实际上是提高了。更重要的是，在治疗期间未报告有艾滋病指征性疾病出现。HIV患者也常常更有可能存在医疗，精神和滥用药物问题，从而使他们并非理想的HCV治疗的受试者。美国退伍军人健保系统中的患者与HIV感染患者存在相似的问题(16, 54, 84)，但目前没有数据表明在退伍军人中的治疗反应要比非退伍军人差。

               For non-responders to a prior course of standard interferon and ribavirin, re-treatment with peginterferon plus ribavirin is associated with low rates of SVR (86). There are currently no recommended treatments for peginterferon and ribavirin non-responders. Several clinical trials employing higher dose peginterferon, alternative interferon formulations, or maintenance peginterferon are being conducted in this population.

        在对标准干扰素和利巴韦林治疗无反应的患者中，重新开始聚乙二醇干扰素联合利巴韦林治疗的SVR要低(86)。对于聚乙二醇干扰素联合利巴韦林治疗反应不佳的患者，目前并无推荐的治疗方案。在这类人群中，目前正在进行一些临床试验，其中有使用更高剂量的聚乙二醇干扰素，不同的干扰素剂型，或使用维持剂量的聚乙二醇干扰素。

African American Patients: African American patients have a higher prevalence of HCV infection than white patients, with a predominance of genotype 1 infection (2). The rate of hepatocellular carcinoma is higher compared to non-Hispanic whites and is growing at a faster rate (26). Even after adjusting for other factors, African American patients with genotype 1 infection have a poorer response to treatment than white Americans. Conclusions on actual rates and the reasons for diminished response have been limited by under representation in drug registration trials. Retrospective analysis suggests that interferon response rates vary by ethnicity (49) and in a prospective trial, the SVR in African American patients using combined peginterferon and ribavirin was 28% compared with 52% in white patients (60). The reasons for this disparity in response are not known. In a recent multicenter treatment trial, African American patients with chronic genotype 1 HCV had a lower SVR to peginterferon and ribavirin than Caucasian Americans (28% vs.  52%). These differences were not explained by disease characteristics, baseline viral levels, or amount of medication taken (24).

非洲裔美国患者: 与白人相比，非洲裔美国患者的HCV患病率要更高，主要为1型HCV感染(2)。与非拉丁美洲裔白人相比，肝细胞肝癌的发生率要更高，且仍在快速增长中(26)。即使在对其它因素进行校正之后，感染1型HCV的非洲裔美国患者对治疗的反应也要比白人差。由于药物注册试验数量较少，关于实际情况以及对治疗反应差的结论仍有局限性。回顾性分析表明不同的种族对干扰素治疗的反应是不一致的(49)，在一个前瞻性实验中，使用聚乙二醇干扰素联合利巴韦林治疗时，非洲裔美国患者的SVR为28%，而白人患者为52%(60)。这种不一致的原因还尚未清楚。在最近的一个多中心的治疗试验中，慢性1型HCV感染的非洲裔美国患者对聚乙二醇干扰素和利巴韦林的SVR要比白人患者低(28% vs. 52%)。这种差异并不能用疾病特点，基线病毒水平或治疗药物的剂量来解释(24)。  

Patients with Renal Disease: Patients with advanced renal disease also pose a special challenge because ribavirin is contraindicated in these patients. In patients with renal failure, the elimination of ribavirin is significantly impaired leading to a prolonged plasma half life and accentuated hemolytic anemia. Available data in these patients supports the (14, 18) use of pegylated interferon alfa-2a monotherapy at 135 mcg weekly (4, 99, 115).  Ribavirin should not be administered unless serum levels of ribavirin can be readily performed and monitored and dose of ribavirin modified according to the levels and hematocrit. These patients should generally be referred for clinical trials.

肾脏疾病患者: 对于患有进展性肾病的患者也存在特别的挑战，因为利巴韦林禁用于该类患者。在肾衰患者中，利巴韦林的清除明显受损，导致其血浆半衰期延长，从而加重溶血性贫血。目前有资料支持(14, 18)在该类患者中使用聚乙二醇干扰素α-2a 135mg/周的单药治疗(4, 99, 115)。除非能容易地的对血清利巴韦林浓度进行检查和监测，并且利巴韦林的剂量能够根据其血药浓度和红细胞压积水平进行相应调整，否则不能使用利巴韦林。这些患者应该纳入临床试验研究。

Patients with Decompensated Cirrhosis: Patients with decompensated liver disease, manifested by variceal bleeding, encephalopathy, prolonged prothrombin time, or other manifestations of portal hypertension of hepatic synthetic dysfunction are high risk candidates for treatment because of a significant chance of further decompensation and life threatening adverse events. Despite these risks, clinicians and investigators have evaluated such treatment given the growing problem of recurrent HCV following liver transplantation. Peginterferon/ribavirin therapy appears to have efficacy in cirrhotic patients, rivaling that in those without fibrosis, but cytopenias and physical side effects are limiting factors (79). Tolerability can be increased by use of a low accelerating dose regimen, even in patients with significant hepatic synthetic dysfunction (35). Because of the inherent risk of decompensation, this regimen should only be undertaken at transplant centers, and preferably after a patient has already been listed.

失代偿期肝硬化的患者：失代偿期肝硬化的患者，表现为静脉曲张出血，脑病，凝血时间延长，或有其他门静脉高压或肝脏合成功能异常相关的表现。这类患者为治疗的高危患者，因为有可能导致失代偿的进一步加重或出现危及生命的副反应。在这些风险之外，临床医生以及研究人员还认为对这样的病人治疗，导致在肝移植术后HCV复发的问题增多。聚乙二醇干扰素/利巴韦林联合治疗肝硬化患者是有效的，和未发生肝硬化的患者相当，但血细胞减少和身体方面的副作用为其限制因素(79)。即使在肝脏合成功能明显受损的患者当中(35)，通过缓慢加量的给药方案，也可增加对治疗的耐受程度。但由于失代偿的风险，这种治疗方案只能用于移植中心，且最好在患者已准备移植时使用。

Pediatric Patients: Treatment of children with chronic hepatitis is attractive in theory, because these patients face such long time periods of chronic inflammation and are likely to tolerate therapies well. Currently, unmodified interferon in combination with ribavirin is approved by the US Food and Drug Administration for treatment of children over age 3 with chronic hepatitis C (30). Pediatric SVR rates compare quite favorably with those seen in adults (43). No data in yet available regarding the use of peginterferon products in the pediatric population.

儿童患者:对于患有慢性肝炎的儿童的治疗在理论上是有吸引力的，因为这些患者会面临很长的慢性感染过程，并且可能对治疗有很好的耐受。目前，美国食品和药物管理局已通过了联合使用那些尚未改良的干扰素联合利巴韦林来治疗3岁以上患有慢性丙型肝炎的儿童患者(30)。儿童的SVR率要明显好于成人(43)。目前尚缺乏在儿童中使用聚乙二醇干扰素的资料。

Acute Hepatitis C

急性丙型肝炎

               The overwhelming majority of cases of HCV infection are discovered in the chronic phase, usually years to decades after transmission. In those infrequent cases when acute infection is identified, often in the setting of needlestick injury or injection drug use, response rates to antiviral therapy are very high. Because of the paucity of such cases compared to chronic infection, randomized prospective trials are small and underpowered. A meta-analysis of interferon monotherapy trials, published in 2002, reported an SVR rate of 32%. A more recent prospective single-center trial using high dose interferon monotherapy achieved a remarkable 98% SVR (59). Smaller series employing peginterferon were associated with similarly high rates of sustained virologic response (111). Most authorities recommend a 12 week waiting period after the acute infection to allow for spontaneous clearance of virus, which appears to take place in as may as half the cases (108).

        绝大部分HCV感染均在慢性期被发现，通常在被传染后的数年至数十年。对于那些并不常见的确诊为急性感染的病例（通常为针刺伤或注射毒品时）， 其抗病毒治疗的应答率非常高。由于和慢性感染相比，这类病例仅占很少量，相应的前瞻性随机对照试验规模很小并缺乏其说服力。一个02年发表的，关于干扰素单药治疗的荟萃分析报告的SVR为32%。在一个最新的单中心试验中，通过使用大剂量的干扰素单药治疗可使SVR达到惊人的98%(59)。一些更小的使用聚乙二醇干扰素的临床试验所得到的SVR率也类似(111)。绝大多数专家建议在急性感染后可先观察12周已等待病毒自发清除，这会出现在多达半数患者(108)。

Alternative Therapy

替代疗法

               Currently, peginterferon and ribavirin is the standard of care for anti-HCV therapy. There is no data to support the use of complementary or alternative medications.

        截至目前，聚乙二醇干扰素和利巴韦林为治疗HCV的标准疗法。目前没有任何相关的支持使用补充或替代药物治疗的证据出现。

ADJUNCTIVE THERAPY Guided Medline Search

辅助治疗

               Perhaps the most important aspect of treatment and prevention of progression to end stage liver disease is cessation of alcohol consumption. Even moderate amounts of alcohol can accelerate liver damage and decrease time of progression to cirrhosis (53). There is a growing body of evidence that fatty infiltration of the liver works in a synergistic way with chronic HCV infection to cause hepatic fibrosis (51, 85). Fatty change, which appears to be a consequence of insulin resistance, may also affect sustained virologic response rates in patients undergoing interferon-based treatment (94). Therefore, interventions aimed to reduce or eliminate drug and alcohol use, and to promote lean body habitus, control of lipids and glycemic control, should all be primary foci of treatment.

        目前治疗并阻止向终末期肝病进展最重要的环节可能就是戒酒。即便中等量的饮酒也能加速肝脏损伤，并缩短进展至肝硬化的时间(53)。越来越多的证据表明肝脏的脂肪浸润和慢性HCV感染可在导致肝脏纤维化的过程中起到协同作用(51, 85)。 脂肪变性是因为细胞胰岛素受体抗性提高而产生，这可能会影响接受以干扰素为基础的治疗的患者中的持续病毒应答率(94)。因此，包括减少或戒除毒品和酒精的使用，保持瘦体型，控制血脂肪和血糖等干预措施，都是为治疗所要关注的。

               In addition to these lifestyle modifications, it is important to exclude coexistent hepatic disease processes, such as metabolic liver disease (hemachromatosis, Wilson’s disease, alpha-1-antitrypsin deficiency) or autoimmune hepatitis, particularly where clinical suspicion exists. HCV-infected patients should also be vaccinated against hepatitis A and hepatitis B if they have no evidence of prior immunity.

        在这些生活方式的改善之外，去除并发的肝脏病变也很重要，例如代谢性肝病（血色病，Wilson’s病，α-1抗胰蛋白酶缺乏症）或自身免疫性肝炎，尤其是在临床疑诊时。HCV患者若尚未对HAV和HBV产生免疫，则应接种相应的疫苗。

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

治疗观察终点

               The primary end point in assessing treatment response is the SVR, defined as the absence of HCV RNA by a sensitive, qualitative assay 24 weeks after completion of a course of treatment. End of treatment response (ETR) is defined as the absence of HCV RNA by a qualitative assay at the end of a course of treatment. The reappearance of HCV RNA during the 24 week followup period after ETR is defined as a relapse. The frequency of late relapses after 24 weeks of followup is extremely rare.

        评价治疗反应的主要终点是SVR，定义为在经过一个疗程治疗后的24周，使用敏感的定性试验检测不到HCV RNA。治疗结束应答率（ETR）定义为在疗程结束时，HCV RNA定性试验阴性。在ETR之后随访，若果24周之内HCV RNA再次出现则定义为复发。24周以后的迟发性复发是非常罕见的。

               For genotype 1-infected patients who require treatment, the HCV RNA level should be quantitated at baseline and at 12 weeks of therapy. If there is a 2-log decline or more in HCV RNA level at 12 weeks (EVR), treatment should be continued. If HCV RNA is undetectable at 24 weeks, then therapy should continue for the full 48 weeks, as there is a high likelihood of achieving SVR, particularly with achievement of HCV RNA clearance at 4 weeks (RVR). Therapy should be stopped for those patients who fail to meet the criteria for continuing therapy at 12 and 24 weeks, as the likelihood of accomplishing SVR is extremely low. HCV RNA should be measured 24 weeks after treatment to assess for SVR. (20, 95) (Figure 1A).

        对接受治疗的感染1型HCV的患者而言，应在开始治疗前及治疗12周时定量测定HCV RNA的水平。如果在12周后HCV RNA的水平下降2个指数或者更多（EVR），则应继续治疗。若在24周时已检测不出HCV RNA，应继续治疗直至满48周，因为这样达到SVR的可能性很高，特别是在治疗4周后HCV RNA即已清除时（RVR）。若患者在治疗12周和24周后未能达到上述标准，那么达到SVR的可能性则很低，此时应中断治疗。应在治疗后的24周测定HCV RNA以评价SVR。(20, 95) (图1A)

               Other endpoints for monitoring therapy include biochemical or histologic response. Biochemical response is defined as normalization of serum ALT levels, but is not well correlated with end of treatment or sustained response. Histologic response is defined as an improvement in necroinflammatory activity, fibrosis or both in a post-treatment liver biopsy compared with pre-treatment. Even patients who do not achieve a sustained virologic response may experience a significant improvement in histology, or least a delay in progression of liver disease over a period of time (113). This premise underlies the design of so-called maintenance trials of IFN to slow liver fibrosis progression.

        其他监测治疗的终点包括生化学或组织学的应答。生化学反应定义为血清ALT水平正常化，但这与结束治疗或持久应答并无很好的相关性。组织学应答定义为在治疗前后分别行肝活检所示坏死性炎症活动程度，纤维化或两者的改善。即使未能达到持续病毒学应答，患者仍可能在组织学上有明显改善，或至少可以在一段时间内延缓肝病的进展(113)。这一点也成为设计IFN维持治疗试验以延缓肝脏纤维化进展的基础。

VACCINES Guided Medline Search

疫苗

               There are no vaccines currently available for HCV, and prospects for imminent development of a broadly protective vaccine are limited. Nonetheless, the existence of partially protective neutralizing antibodies, and the observed ability to spontaneously clear acute HCV infection offer plausibility to such an approach. In this regard, vaccine development is ongoing, and the efficacy of at least one protein-based vaccine is undergoing prospective evaluation in clinical trials (32, 56).  The utility of vaccine-based approaches for management of chronically infected persons is also being studied. Due to the heterogeneity of HCV virus, newer approaches include the development of “multi-genotype” vaccines, which targets a number of specific genotypes and viral subtype, and “library” vaccines which target pooled HCV genetic information from pooled patient cohorts (34).

        至今尚未有HCV的疫苗，且于近期开发出一种广谱保护牲疫苗的前景仍是有限的。虽然如此，目前存在有部分保护作用的中和性抗体，并观察到对急性HCV感染有自行清除能力，这均为该研究提供了可能性。因此，疫苗的开发仍在进行中，并且至少有一种以蛋白质为基础的疫苗的有效性正在临床试验中进行前瞻性的评估(32, 56)。对以疫苗为基础的慢性感染患者治疗方案的效用亦在研究中。由于HCV病毒的异质性，新的研究方向包括开发“多基因型”的疫苗，从而可以作用于一系列的特定基因型和病毒亚型，以及“库”疫苗以作用于源于整个患者群体的HCV基因信息库(34)。

PREVENTION Guided Medline Search Smart search

预防

General

概述

               Education about the risk factor for acquisition of HCV is critical to break the infection cycle. Unsafe needles, whether used by practitioners in resource poor countries, by IDU or used for body piercing or tattooing, unscreened blood products and unsafe sexual practices should be avoided.

        为阻断HCV的感染途径，针对传染HCV的高危因素的教育是非常有必要的。不安全的针具，不论是在资源匮乏的国家中经专业人士还是以及通过静脉注射毒品或用于刺身或纹身使用，未经筛检的血制品以及不安全的性行为均应避免。

Infection Control

感染的控制

               Universal precautions should be practiced by all health care workers. Proper sterilization and disinfection techniques should be employed in hospitals, especially hemodialysis, endoscopic and surgical units. The risk of transmission of HCV from an infected surgeon to a patient is very low but not zero. It is difficult to make any recommendations at this time whether HCV infected surgeons should continue to perform surgical procedures with added precautions. It makes sense to limit them from performing any emergency procedures where the chances of a breach of sterile surgical technique may be higher than routine procedures (96).  Sexual transmission of HCV is undoubtedly possible, but not efficient. The CDC currently recommends no change in sexual practice in monogamous couples in which one partner is HCV positive. HCV-infected individuals with multiple sexual partners should be advised to employ barrier methods to decrease transmission risk (122).  Users of intravenous drugs should not share needles and should employ injection equipment sterilization techniques. Although data is mixed, tattooing and body piercing may connote HCV risk; the use of sterile instruments is essential in these settings (48)

        所有的医疗工作者均应开展普遍性预防措施。医院里应有适当的灭菌和消毒技术，特别在血透室，內镜中心和手术室。HCV从被感染的外科医生传染至患者的可能性是非常低的，但并非为零。在这种情况下，很难给出对感染HCV的医生是否应采取额外的保护措施才可以继续做手术的建议。根据常识，应限制这些医生進行緊急的手术,因为在这种情况下违反外科无菌操作规程的可能性较常规手术要高(96)。HCV通过性传播无疑是可能的，但传播的效率不高。CDC目前推荐对于夫妻双方有一方患HCV时，在性交时并不需特殊保护。而对有多位性伴侣的丙肝患者，则建议采取保护措施以减低传播风险(122)。药物成瘾患者应避免共用针头，并使用注射器具灭菌措施。尽管数据各异，纹身和刺身也存在感染HCV的风险；在这些场所时使用无菌器械也是必需的(48)。

TABLES AND FIGURE

Table 1. A summary of diagnostic laboratory tests for HCV

Table 2. Indications for treatment of HCV infection

Table 3. Approved drugs and commonly used dosages for treatment of chronic HCV infection.

Table 4. Goals of therapy for HCV infection

Table 5. Contraindications to treatment with Interferon alfa/Ribavirin.

Figure 1 (A&B): Genotype 1,4,5, or 6

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