HBV基因型和变异、疾病演化和抗病毒治疗反应的关系（2005.8.16）

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Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy



Journal of Viral Hepatitis
Volume 12 Issue 5 Page 456 - September 2005

A. Kramvis and M. C. Kew
MRC/University Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa

Summary. Phylogenetic analysis has led to the classification of hepatitis B virus into eight genotypes, designated A to H. The genotypes have differences in biological properties and show heterogeneity in their global distribution. These attributes of the genotypes may account not only for differences in the prevalence of hepatitis B virus mutants in various geographic regions, but also be responsible for differences in the clinical outcome and response to antiviral treatment in different population groups.

Introduction
Hepatitis B virus (HBV), a DNA virus, is a member of the family Hepadnaviridae [1] that replicate by reverse transcription of the encapsidated pregenomic RNA by the viral encoded polymerase [2]. The viral polymerase lacks proofreading activity and sequence heterogeneity is therefore a feature of HBV.

Phylogenetic analysis has led to the classification of HBV into eight genotypes, defined by an inter-group divergence of >8% in the complete genome sequence [3,4] and of >4% in the S gene [5]. Since the first description of four genotypes (A-D) of HBV in 1988 [4], four more have been identified, designated E and F [6], G [7] and H [6-8]. Moreover, subgenotypes with distinctive sequence characteristics and a divergence in the complete genome of >4% have been found within genotypes A [9-11], B [12-14], C [15] and F [16,17].

The eight genotypes show a distinctive geographical distribution. Genotype A is prevalent in north-western Europe, North America and Africa [18-20]. Genotypes B and C are characteristic of Asia [4,19,20], whereas genotype D has a worldwide distribution but predominates in the Mediterranean area [19,20]. Genotype E is found in Africans [6,19,21], genotype F in the aboriginal populations of South America [18,22] and genotype H is confined to the Amerindian populations of Central America [8,23]. To date, the isolation of genotype G has been limited to HBV carriers in France and Georgia, USA [7], UK [20], Italy [20] and Germany [24].

The first instance of genotype-related differences in the biological properties of HBV was the observation that the precore 1896 stop-codon mutant was commonly found in regions where genotype D prevailed and was absent in regions were genotype A occurred [25]. The reason for the association of the 1896 mutant with genotype D was that this mutation enhanced the stability of the encapsidation signal (e) allowing replication, whereas in genotype A it would lead to its destabilization and therefore prevent replication [26]. Subsequently, it has become increasingly evident that the heterogeneity in the global distribution of HBV genotypes may account not only for differences in the prevalence of HBV mutations in the different populations but also be responsible for differences in the clinical outcomes of HBV infections and the response to antiviral treatment.

Genotypes and disease progression

Because disease progression can be affected by a number of factors, such as the age of acquisition and route of the infection [41], the immune competence of the host, and the influence of environmental factors such as alcohol intake, iron overload and exposure to aflatoxin, care should be exercised when interpreting the role of genotypes in disease progression.

The majority of studies on the effect of genotypes on disease progression have been undertaken in South-east Asia where HBV is hyperendemic and genotypes B and C prevail. A greater frequency and severity of liver dysfunction was initially reported in patients infected with serotype ayr (mainly genotype C) compared with adw (mainly genotype B) [78-80]. Seroconversion from HBeAg- to anti-HBe positivity occurs much earlier in genotype B than genotype C carriers [42,45,46,61,78,81-85]. Higher HBV-DNA levels have been detected in patients infected with genotype C compared with those infected with genotype B in some studies [44,81,86], but not in others [45,46]. The difference might be attributed to the HBeAg status of the patients. Genotype C was found to have lower HBV DNA levels than genotype A, B and D in the HBeAg-positive phase [20]. In south-western Japan carriers of genotype D were younger and exhibited earlier anti-HBe seroconversion than carriers with genotype C [87].

Patients infected with genotype B are more likely to have a sustained biochemical remission after spontaneous HBeAg seroconversion than patients infected with genotype C [85], who are more likely to develop chronic and advanced liver disease [44,86]. Genotype C is more prevalent in patients with fibrosis or cirrhosis [43,46,82] and is associated with more severe histological liver damage than genotype B [88] or genotype D [87]. Patients infected with genotype C have higher scores of histological activity and fibrosis [41,42] and higher alanine aminotransferase (ALT) levels relative to those infected with genotype B [44,83], genotype A or D [89].

The majority of studies in Far Eastern countries have shown a greater risk of HCC development with genotype C than with genotype B [43,68,90,91]. However, patients infected with genotype B exhibit earlier HBe seroconversion and progress to liver fibrosis and HCC at a slower rate than those infected with genotype C, and it has been suggested that the life-long risk of progression to advanced fibrosis and development of HCC may not differ among genotype B- and C-related chronic liver disease [46,61]. Because most studies have been cross-sectional, it will be helpful if prospective, longitudinal studies are undertaken to determine whether the genotypes influence the incidence of disease in the long term.

In contrast to genotype B found in Taiwan [82] and China [83], which is associated with the development of HCC at a young age, in Japan, the mean age of HCC patients infected with genotype B is significantly older than those infected with genotype C [46,81,92]. Although it has been suggested that this discrepancy between Chinese and Japanese HCC patients, could be a result of host factors and the intake of aflatoxin in Taiwan [81], the difference is probably the consequence of the different subgenotypes found in mainland Asia (Ba) and Japan (Bj) [12]. Further studies are required to resolve this issue. When matched HBV carriers were compared, HBeAg-positivity occurred in a significantly lower proportion of those infected with subgenotype Bj compared with Ba or genotype C (and loss of HBeAg occurs earlier in carriers of Bj) [13,47]. Subgenotype Ba occurred more frequently in acute than in chronic hepatitis patients [13].

Genotypes A and D were found to be prevalent in the Indian subcontinent. In one study genotype D was associated with more severe liver disease and with HCC in young patients [93], whereas in another study, where the majority of patients were infected with genotype D, it was concluded that genotype D did not influence the clinical outcome of infection [94].

There have been fewer studies on the effect of genotype on disease progression in western countries. The long-term outcome of HBV infection was found to be different in patients infected with different genotypes in Europe. Chronic infection with genotype A is more frequent than when individuals are infected with genotype D [95]. Genotype A was more prevalent in HBeAg-positive chronic hepatitis patients, whereas genotype D was more prevalent in those positive for anti-HBe [20,49,50,96]. HBeAg-positive and HBeAg-negative carriers infected with genotype D were found to have higher levels of HBV-DNA when compared with genotype A, B and C [20,41]. The prognosis of chronic hepatitis B may be better in patients infected with genotype A than in those infected with either genotypes D or F because concomitant sustained biochemical remission and decrease in HBV-DNA levels occurred at a higher rate in genotype A- than in genotype D- or genotype F-infected patients [96]. Genotype D was also found to be associated with severe recurrent disease post-transplantation [97]. In a single study, genotype F-infected individuals showed a higher mortality rate than those infected with genotype A or D [96]. However, this does not agree with other reports that showed a low pathogenicity of genotype F [22,98].

Very few isolates of genotype G have been characterized making it difficult to draw any conclusions regarding the influence of this genotype on disease progression. Nevertheless a trend is observable. Chronic hepatitis patients infected with genotype G are characterized by high HBV-DNA and HBeAg levels [20,24,99-101] and elevated ALT levels [102]. However, coinfection with genotype A may account for these attributes [101,102]. One patient infected with genotype G had cirrhosis [100] and two were found to lack an anti-HBc response [24,99].

Genotypes and response to antiviral therapy

Although mass vaccination programmes have begun to control the spread of HBV infection, therapeutic intervention is the only option for those with established chronic HBV-associated disease.

Interferon
One of the more effective therapies available is treatment with interferon (IFN)-alpha, a naturally occurring cytokine primarily produced by B lymphocytes, null lymphocytes and macrophages [103-105]. IFN has anti-viral, anti-proliferative and immunomodulatory effects [106]. The molecular virological factors that contribute to the responsiveness of HBV infection to IFN treatment and may play a significant role in predicting whether IFN can be used effectively for treatment are largely unknown. The ability to predict responsiveness is important in the clinical setting, considering the fact that IFN treatment is expensive, is administered by injection, and can have side-effects and be poorly tolerated.

To date, the most important viral factor that has convincingly been shown to determine the response to IFN is the pretreatment HBV-DNA titre, the lower the titre the better the response [107]. Other viral factors that may play a role include the presence of BCP and precore mutations. It has been proposed, although not proven, that the BCP mutations together with a low HBV-DNA level and elevated ALT may be favourable factors of response in IFN-induced anti-HBe seroconversion [108]. The data on the relevance of precore mutants and their influence on the long term response to IFN is also inconclusive. In some studies precore mutants were considered to be necessary for response to IFN [107,109,110]. These data differ from other studies that showed that the precore mutants do not have prognostic value for virus elimination following IFN therapy in HBeAg-positive or -negative patients [111-113]. These differences in responsiveness to IFN treatment may possibly be the result of different genotypes of the virus and therefore an analysis of how various mutations influence the therapeutic response to IFN also requires knowledge about the genotype [114].

In a study of German patients a higher rate of HBeAg seroconversion following IFN treatment was found in those infected with genotype A than those with genotype D (37%vs 6%) [115]. The rate of HBeAg loss was also significantly higher in patients with genotype B compared with those with genotype C in a Taiwanese study (41%vs 15%) [60]. In the former study, additional factors besides genotype, including the number of BCP mutations and low DNA levels, were found to be related to a better response and in the latter study; young age was found to be an additional positive predictive factor. Because genotype B-infected patients have a high HBeAg seroconversion rate, Wai et al. [116] compared treated and untreated Chinese patients with chronic hepatitis B. They showed that, in addition to low pre-treatment HBV-DNA levels and elevated ALT levels, genotype B was associated with a higher antiviral response to IFN treatment. The response to IFN treatment of genotype A-infected Chinese patients was found to be better than those infected with genotype D/E (70%vs 40%) [117]. In contrast, in a study performed in Japan, IFN was given to seven patients with chronic HBV infection. Of the four responders, one was infected with HBV genotype B and three with genotype C. HBsAg persisted in the remaining three patients, all of whom were infected with genotype A, and HBeAg remained positive in one of them [118]. In a longitudinal study, no difference was reported in the rates of sustained seroconversion to anti-HBe in IFN-treated patients compared with those that were untreated, and this was not affected by the HBV genotype with which the patient was infected. However, the cumulative probability of HBsAg clearance was greater in patients infected with genotype A than those infected with genotype D [96]. These studies involved a small number of patients, which may be the reason for the conflicting observations.

Genotype switching has also been observed after IFN treatment indicating infection with a mixture of genotypes prior to treatment [65,119,120]. The minor populations, however, were not detected by either standard genotyping assays or direct sequencing and were detected using either a genotype-specific PCR plus RFLP or cloning.

Thus the results of studies from one geographical region cannot be extrapolated to other regions, without a thorough knowledge of the HBV strains circulating in each of the regions.

Lamivudine
Lamivudine, a nucleoside analogue, has been approved for the treatment of chronic hepatitis B. In addition to reducing inflammatory activity in liver, lamivudine reduces HBV-DNA levels in most patients. A drawback of this treatment, however, is the appearance of lamivudine-resistant mutants.

Genotype B has a better virological response to lamivudine than genotype C in Taiwan. However both genotypes have a similar risk of developing lamivudine resistance after 1 year of therapy [121]. On the contrary, adw has been shown to have a 20-fold higher risk of lamivudine resistance than ayw infections [122]. Emergence of resistance was also found to be more rapid in adw carriers. The appearance of the lamivudine-resistance mutations was predicted to result in a change in hydrophilicity in the S region of the ayw subtype but not in the adw subtype [122] and this could explain the reduced risk of developing resistance in ayw subtype. The genotypes can be deduced to be genotype A (adw) and genotype D (ayw) because these are the genotypes predominant in Germany and the serotypes associated with them. When comparing patients infected with genotype A and D isolates, it was found that although the risk of emergence of lamivudine resistance mutations was higher during the first year of treatment in genotype A-infected patients, there was no difference when the time of treatment was prolonged to 2 or 3 years. In other words, lamivudine resistance mutations took longer to develop in genotype D [123]. In a large-scale study in Japan, the emergence rate of lamivudine resistance was independent of genotype A, B and C. On the contrary, the emergence rate was significantly higher in subgenotype Ba than in Bj [124]. This study also suggested that the risk of HBeAg-positivity on the development of lamivudine resistance may differ between the genotypes and that the risk of severe breakthrough hepatitis may be higher in patients infected with genotype C [124].

Adefovir dipivoxil
Adefovir dipivoxil, an oral prodrug of adefovir, has been tested in phase III trials and was approved recently for the treatment of chronic hepatitis B in the USA [20]. There was no significant difference in the antiviral response between patients infected with the different genotypes of HBV [20].

Relationship of mutations
to genotypes

1896 stop codon mutation
The precore-core region of the HBV genome codes for the precore-core fusion protein that is post-translationally modified to give rise to hepatitis B e antigen (HBeAg) [27,28]. Although HBeAg is not required for viral replication or infectivity [29,30], its exact function is not known. It is thought to play a role in immune modulation and can alter the host response to core protein [31,32]. Thus, the emergence of the 1896 G to A stop-codon mutation [33,34] that prevents expression of HBeAg may be a means of immune evasion. The occurrence of the 1896 mutation is restricted by the secondary structure of the encapsidation signal (e) [26,35-37], which is transcribed from the same region of the HBV genome coding for HBeAg (Fig. 1). Destabilization of this structure by the disruption of the G-C base pair between positions 1858 and 1896 (that would result from a G-to-A mutation at 1896) would be detrimental to viral replication [26], as has been shown by transfection experiments [25,35]. Thus the development of the 1896 mutation depends on the presence or absence of C or T at position 1858 and shows geographic variation that is related to the distribution of the various genotypes [25]. Genotypes B, D and E have T1858, whereas A and H have C1858. Genotype C and F isolates can have either C1858 or T1858: genotype F strains in Central America have a T1858 [22] and Japanese genotype C strains have T1858 exclusively [38,39], whereas C1858 is confined to carriers of genotype C in South-east Asia [19,40-44]. Some studies found no difference in the prevalence of 1896 mutants between genotypes B and C [45,46]. This is to be expected because both these studies were carried out in Japan where genotype C with T1858 predominates. It is of interest that although both subgenotypes of genotype B, identified in Asia (Ba and Bj) have T1858, the 1896 mutation was found to occur more often in subgenotype Bj [47]. The 1896 mutation is found most frequently in anti-HBe positive patients infected with genotype D [25,26,48-51] and E [52] and is rarely found in genotype A [25,50,51], genotype H [8] and in a minority only of genotype C [19,41,42] and genotype F strains [6,17,19,22].

T1762 A1764 basic core-promoter mutations
An adenine (A) to thymine (T) transversion at position 1762 together with a guanine (G) to A transition at 1764 in the basic core promoter (BCP) were first described in HBV isolates from Japanese patients [53,54]. The presence of the mutations precedes seroconversion from HBeAg to anti-HBe in genotype A strains but not in genotype D [48,55]. Their presence results in reduced levels of precore mRNA and HBeAg expression in transfection studies [56-59]. The T1762A1764 mutations develop more frequently in genotypes A and H with C1858, but in a minority of genotype C with C1858 [39] and more often in subgenotype Ba than in Bj or genotype C [47]. However, in other analyses, they are equally distributed among the HBV genotypes [49,51]. Yet other studies show a higher frequency of the T1762A1764 in genotype C compared with genotype B [41,42,45,46,60,61], and this does not correlate with HBeAg status [45,46]. Only 25% of carriers infected with genotype E possess the T1762A1764 mutations and this finding is independent of HBeAg status [52]. These mutations are found to be significantly associated with more severe liver disease [liver cirrhosis with or without hepatocellular carcinoma (HCC)] and an older age (>35 years) [45,62,63].

Pre-S mutants
Various mutations in the pre-S region have been described. These range from point mutations and small deletions and insertions [64] to very large deletions [65,66] and deletions that prevent the expression of the pre-S2 protein [67]. A few studies have analyzed the relationship between genotypes and the occurrence of pre-S mutants. In two independent studies, pre-S deletion mutants were found to occur more frequently in genotype C than in genotype B isolates [68] and in adr (corresponding to genotype C) than in adw (corresponding to genotype B) isolates [69]. In contrast, in another study, although these mutants are found more frequently in genotypes B and C than in the other genotypes, no statistical difference was found between their incidence in genotypes B and C [70]. This discrepancy may be explained by the different geographic distributions of the isolates or the fact that the latter study was not a case-control study. Moreover, these deletion mutants are more frequently detected in isolates from patients with severe liver disease (liver cirrhosis and HCC) than other patients [68,70].

Deletions within the pre-S region can lead to impaired viral clearance without affecting HBV binding to hepatocytes and their subsequent penetration, and therefore could contribute to chronicity of infection [71]. In keeping with this possibility is the observation that pre-S deletion mutations are more frequently detected in isolates from patients with cirrhosis or HCC [68,70]. Mutation clustering regions within the core region
Ehata et al. [72] have identified mutation clustering regions (MCR) within the core region of HBV isolates from individuals with liver disease and speculated that these may be immunological targets for cytotoxic T lymphocytes [73]. MCRs have been mapped to different positions in the different genotypes. Genotypes B (most) and C (adr subtype) have mutations clustering at positions 84 to 99 of the core gene and genotypes A, B and D (adw subtype) at positions 48 to 60 [74]. The MCR of genotype F residues was mapped between positions 57 and 68 of the core protein [22].

Splice variants
These HBV variants arise from the encapsidation and reverse transcription of spliced pregenomic RNA [75]. Using in vitro tranfection studies, there is no difference in the dominant splice variant produced by genotypes D, C and E, whereas the minor splice variants synthesized by isolates belonging to the different genotypes vary [75]. Splicing in HBV may contribute to the pathogenicity and/or persistence of the virus [75-77].

The variation in the presence and the development of mutations in the different genotypes of HBV may be a contributing factor to the influence of genotypes in disease progression.

Conclusion
It is becoming increasingly evident that the genotype of HBV may have a role to play in predicting the response to various therapies and that this should be taken into account as a variable before initiating any treatment. However, differences in host and environmental factors make it difficult to extrapolate findings from one geographical region to another. Therefore larger, in-depth studies are necessary, in various regions of the world, especially in regions where HBV is hyperendemic such as South-east Asia and sub-Saharan Africa. Although some studies have shown that HBV serotypes may influence the efficacy of HBV vaccination [125], to our knowledge, no studies have been undertaken to find the relationship between genotypes of HBV in response to vaccination and/or the emergence of vaccine-escape mutants. This is another area that requires further research. As most studies to date have been cross-sectional, more longitudinal prospective studies could provide more information on the relationship of HBV genotypes to the severity of liver disease and therefore clinical outcome. Moreover, the advent of new molecular antivirals makes it paramount that the genotypes are well characterized, so that the drugs can be tailor-made to the sequence of the virus prevalent in the different regions of the world.

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HBV 基因型和变异, 疾病演化和抗病毒治疗反应的关系（ 2005.8.16 ）
对抗病毒的治疗对变化，疾病前进和回应的肝炎 B 病毒的基因型的关系

滤过性毒菌肝炎的日记
第 12 册议题 5 第 456 页 - 2005 年九月

A. Kramvis 和 M. C. Kew
分子的 Hepatology 研究单位，医学部， Witwatersrand 的大学，南非约翰尼斯堡的 MRC/ 大学

摘要。系统发育的分析已经导致肝炎 B 病毒的分类进八个基因型之内, 指定一到 H. 基因型有生物学的财产不同并且有他们的全球分配的表演异种。 基因型的这些属性可能解释不只有对于不同在各种不同的地理区域中的肝炎 B 病毒突变异种的传播中, 但是也负责对不同的人口团体的抗病毒的治疗在临床的结果和回应的不同。

介绍
肝炎 B 病毒 (HBV) ， DNA 病毒, 是家庭 Hepadnaviridae 的一个成员 [1] 滤过性毒菌的改为暗码 polymerase 的 encapsidated pregenomic RNA 的反面抄写的那统计实验 [2]. 滤过性毒菌的 polymerase 缺乏校正活动，而且序列异种因此是一个 HBV 的特征。

系统发育的分析已经导致 HBV 的分类进八个基因型之内, 被一种在团体之间分歧定义 > 完全的基因组序列的 8%[3,4] 和 > S 基因的 4%[5]. 因为 1988[4] 的 HBV 的四个基因型 (一-D) 的第一描述，另外四个已经被识别, 指定了 E 和 F[6], G[7] 和 H[6-8]. 而且, 在完全基因组中的和有特色的序列特性和一种分歧的次基因型 >4% 在基因型里面已经被发现一 [9-11], B[12-14], C[15] 和 F[16,17].

八个基因型表示有特色的地理分配。 基因型一是普遍的在欧洲西北方，美国北部和非洲 [18-20]. 基因型 B 和 C 是特性的亚洲 [4,19,20], 然而基因型 D 有全世界的分配但是在地中海的区域中掌握 [19,20]. 基因型 E 在非洲人身上被发现 [6,19,21], 南美洲的原始人口的基因型 F[18,22] 和基因型 H 盘据中美洲的 Amerindian 人口 [8,23]. 为了要约会,基因型 G 的隔绝对在法国和格鲁吉亚州中的 HBV 运送者已经被限制, 美国 [7] 英国 [20] 意大利 [20] 和德国 [24].

HBV 的生物学财产的基因型- 相关的不同第一个例证是观察，停止- codon 的突变异种普遍在基因型 D 在区域中采用而且缺席的区域中被发现的 precore 1896 是被发生的基因型一 [25]. 和基因型 D 的 1896 突变异种的协会理由是，这一个变化提高了允许回答的 encapsidation 信号 (e) 的安定, 然而在基因型一中它会导致它的扰动因此避免回答 [26]. 后来，它已经变得逐渐显然， HBV 基因型的全球分配的异种可能解释不只有为不同的人口 HBV 变化的传播不同但是也负责对抗病毒的治疗在 HBV 传染的临床结果和回应的不同。

基因型和疾病前进

因为疾病前进能被若干因素影响, 如此的如获得和传染的路径年龄 [41] ，主人的免疫胜任, 和环境因素的影响力如此的当做酒精摄取,烫对 aflatoxin 的超载和暴露,当解释基因型在疾病前进的角色时候，照料应该被练习。

在基因型对疾病前进的效果上的多数研究已经在 HBV 是 hyperendemic 和基因型 B 的亚洲东南部被接手，而且 C 采用哪里。一个较棒的频率和肝脏官能不良的严重在感染被与 adw( 主要地基因型 B) 相较的 serotype ayr( 主要地基因型 C) 的病人身上最初被报告 . 来自 HBeAg 的 Seroconversion- 超过基因型 C 运送者更加早地到反 HBe 确实在基因型 B 中发生 [42,45,46,61,78,81-85]. 比较高度的 HBV- DNA 的在感染被与感染一些研究的基因型 B 的那些相较的基因型 C 的病人身上已经被发现 [44,81,86], 但是不在其它里面 [45,46]. 不同可能被归因于病人的 HBeAg 状态。 基因型 C 被发现在 HBeAg- 积极的状态内有较低的 HBV DNA 水平胜于基因型 A ， B 和 D[20]. 在基因型 D 的日本西南方籍的运送者中是比较年轻的并且跟有基因型 C 的运送者比起来展现了早的反 HBe seroconversion[87].

感染基因型 B 的病人更可能有一在自然的 HBeAg seroconversion 之后超过感染基因型 C 的病人维持生物化学的宽恕 [85], 更可能发展慢性的和先进的肝脏疾病 [44,86]. 基因型 C 以纤维症或硬化是更普遍的在病人中 [43,46,82] 而且超过基因型 B 与比较严格的 histological 肝脏损害有关 [88] 或基因型 D[87].感染基因型 C 的病人让与感染基因型 B 的那些相关的比较高度的 histological 活动和纤维症的得分 [41,42] 和较高的 alanine aminotransferase(中高音)[44,83] ，基因型一或 D[89].

多数的研究在国家中已经用对基因型 B 感到远比东方的基因型 C 显示 HCC 发展的较高危险 [43,68,90,91].然而，感染基因型 B 的病人超过感染基因型 C 的那些以较慢的比率展现对肝脏纤维症和 HCC 的较早 HBe seroconversion 和进步，而且它已经被建议先进的纤维症和 HCC 的发展前进的生活- 长危险不可能不一致在基因型 B 之中- 而且 C- 相关了慢性的肝脏疾病 [46,61]. 因为大多数的研究已经是代表性的,如果预期又纵观的研究被接手以长期口吻决定基因型是否影响疾病的影响之方式，它将会是有帮助的。

与基因型 B 在台湾发现相反 [82] 和中国 [83], 与在一个年轻的年龄 HCC 的发展有关, 在日本，重要地感染基因型 B 的 HCC 病人的低劣年龄是比感染基因型 C 的那些年长的 [46,81,92].虽然它已经被建议，华人和日本 HCC 病人之间的这一个相差, 在台湾可能是一个主人因素的结果和 aflatoxin 的摄取 [81], 不同或许是在大陆亚洲 (Ba) 和日本 (Bj) 被发现的不同次基因型的结果 . 更高深的研究是解决这一个议题所必要者。 当相配 HBV 运送者的时候被比较,HBeAg- 确实在感染被与 Ba 或基因型 C(而且 HBeAg 的损失早地在 Bj 的运送者中发生) 相较的次基因型 Bj 的那些重要比较低比例方面发生 . 次基因型 Ba 更时常发生在敏锐的超过在慢性的肝炎病人中 [13].

基因型一而且 D 被发现是普遍的在印度的次大陆中。 在一个研究基因型 D 中与比较严重的肝脏疾病有关和由于年轻的病人 HCC[93], 然而在另外的一项研究中, 在多数的病人感染基因型 D 的地方, 它被得出结论基因型 D 没有影响传染的临床结果 [94].

在国家西部中已经有在基因型对较少的研究效果上的疾病前进。 HBV 传染的长期结果被发现是不同的在欧洲感染不同的基因型的病人中。 当个体感染基因型 D 的时候，和基因型一的慢性传染时常发生 [95]. 基因型一是更普遍的在 HBeAg 中-积极的慢性肝炎病人, 然而基因型 D 对于反 HBe 是更普遍的在那些实在中 [20,49,50,96]. HBeAg-实在和感染基因型 D 的 HBeAg- 否定的运送者被发现有比较高度 HBV- DNA 当与基因型 A ， B 和 C 相较的时候 [20,41].因为附随物维持了生物化学的宽恕和在基因型一中被以较高的比率发生的 HBV- DNA 的水平减少，所以慢性肝炎 B 的预知可能在感染基因型一的病人中比在感染基因型 D 或 F 的那些中好- 超过在基因型 D 中- 或基因型 F- 受传染的病人 [96]. 基因型 D 也被发现与严重的再发生的疾病有关在移植之后的 [97]. 在一项单一研究中, F- 受传染的的基因型个体表示了一个较高的死亡率胜于感染基因型一或 D 的那些 [96]. 然而，这不同意其他的报告以表示了基因型 F 的低 pathogenicity[22,98].

少许的基因型 G 隔离已经被表示的特色使下关于这一个基因型对疾病前进的影响力的任何结论是困难的。 然而一个趋势是观察得出的。 感染基因型 G 的慢性肝炎病人被高的 HBV 表示的特色- DNA 和 HBeAg 水平 [20,24,99-101] 和提高的中高音水平 [102]. 然而，和基因型一的 coinfection 可能解释这些属性 [101,102].一位感染基因型 G 的病人有了硬化 [100] 和二被发现缺乏一个反 HBc 回应 [24,99].

对抗病毒的治疗基因型和回应

虽然大众的接种疫苗节目已经开始控制 HBV 传染的传布, 但是治疗的干涉是由于确定的慢性 HBV- 联合的疾病那些的唯一选项。

产生于受细菌侵犯之细胞的蛋白质
可得的比较有效的治疗之一是有产生于受细菌侵犯之细胞的蛋白质 (IFN) 的治疗-阿尔发, 一自然地发生被 B 淋巴球，无效力的淋巴球和 macrophages 主要地生产的 cytokine[103-105]. IFN 有反滤过性毒菌又反 proliferative 和 immunomodulatory 效果 [106]. 成为对 IFN 治疗的 HBV 传染的回答因素而且可能在预测 IFN 是否能有效地被用方面扮演重要角色的分子 virological 因素因为治疗相当未知。 能力预测回答是重要的在临床的设定中,考虑 IFN 治疗是贵的,被注入管理的事实, 而且能有副作用并且贫穷地被宽容。

为了约会，使人信服地已经被显示决定对 IFN 的回应最重要的滤过性毒菌的因素是处理前的 HBV- DNA 的浓度测定, 那降低浓度测定那更回应 [107]. 可能扮演一个角色的其他滤过性毒菌的因素包括 BCP 和 precore 变化的出现。资讯科技已经被计划, 虽然不证明, 那个 BCP 变化连同一个低度的 HBV- DNA 的一起而且提高的中高音可能是感应 IFN 的反 HBe seroconversion 的回应有用因素 [108]. 对 IFN 的在长期回应方面的 precore 突变异种的中肯和他们的影响力上的数据也是非决定性。 在一些研究 precore 突变异种中被考虑对对 IFN 的回应是必需的 [107,109,110].这些数据不同于表示 precore 突变异种在 HBeAg 的 IFN 治疗之后为病毒除去没有表示预兆的价值其他的研究- 实在或 - 否定的病人 [111-113]. 对 IFN 治疗的在回答中的这些不同可能是病毒的不同基因型的结果，而且因此一项各种不同的变化如何也影响对 IFN 的治疗回应的分析需要对基因型的了解 [114].

在一项德国病人的研究中 HBeAg seroconversion 的较高比率在 IFN 治疗之后在感染基因型一胜于有基因型 D(37% 相对 6%) 的那些那些中被发现 .HBeAg 损失的比率以被与有一项台湾研究 (41% 相对 15%) 的基因型 C 的那些相较的基因型 B 在病人中也是重要地更高地 . 在前研究 , 除了基因型以外的另外因素中,包括 BCP 变化和低的 DNA 水平的数字,被发现被对一个较好的回应和在后者研究中讲; 年轻的年龄被发现当另外的积极预言性的因素。 因为基因型 B- 受传染的病人有高的 HBeAg seroconversion 率， Wai et al 。 [116] 比较对待和未经处理的中国病人由于慢性的肝炎 B. 他们表示 , 除了低度的前治疗 HBV- DNA 的和提高的中高音水平之外 , 基因型 B 与一个比较高的抗病毒的回应有关和 IFN 治疗。 对基因型一的 IFN 治疗的回应- 受传染的中国病人被发现是比感染基因型 D/ E(70% 相对 40%) 的那些好的 . 在差别中,在一项研究中在日本运行,IFN 对七位病人以慢性的 HBV 传染有。在四个回应者中，一感染 HBV 基因型 B 和三由于被坚持剩余的三位病人的基因型 C. HBsAg ，全部都感染基因型一，而且 HBeAg 在他们的其中之一中保持积极 [118]. 在一项纵观的研究中，没有不同在维持的 seroconversion 的比率中被报告到反 HBe 在 IFN 对待的病人与那些相较以是未经处理的，而且这不是被病人感染的 HBV 基因型影响的。 然而， HBsAg 清除的累积可能性在感染基因型一的病人中是比那些以基因型 D 传染更更棒 [96]. 这些研究牵涉了少数的病人,可能是不一致的观察理由。

基因型转变也已经在 IFN 治疗之后被观察在～之前治疗用一个基因型的混合指出传染 [65,119,120]. 较小的人口,然而,加上 RFLP 或复制也不是被也标准基因型化验或直接的序列发现的并且被发现使用基因型- 特性的 PCR。

如此来自一个地理的区域研究的结果不能够被外推法到其他的区域,没有在每一个区域中流通的 HBV 紧张的完全知识。

Lamivudine
Lamivudine ，一个 nucleoside 类似物,已经被为慢性肝炎 B. 的治疗除了减少肝脏的激动活动之外核准,lamivudine 减少大多数的病人 HBV- DNA 的水平。 一个这治疗的不利点,然而,是 lamivudine- 反抗的突变异种的外表。

基因型 B 在台湾有对 lamivudine 的一个较好的 virological 回应胜于基因型 C 。 然而两者的基因型有在 1 年的治疗后的发展中 lamivudine 抵抗的相似危险 [121]. 在相反者身上， adw 已经被显示有 20- 折层较高危险的 lamivudine 抵抗胜于 ayw 传染 [122]. 抵抗的出现也被发现是更迅速的在 adw 运送者中。 lamivudine- 抵抗的变化外表被预测在 ayw 次类型的 S 区域中造成在 hydrophilicity 方面的改变但是不在 adw 次类型中 [122] 而且这可以解释 ayw 次类型的发展中抵抗的被减少的危险。 因为这些是优越的在德国和与他们有关的 serotypes 中的基因型，所以基因型能被推论是基因型一 (adw) 和基因型 D(ayw) 。 当比较病人以基因型一传染，而且 D 隔离的时候, 一般发现虽然 lamivudine 抵抗变化的出现危险在基因型一的第一年的治疗期间是比较高的-当治疗的时候被延长到 2 或 3 年的时候，受传染的病人, 没有不同。 换句话说， lamivudine 抵抗变化轮流更久在基因型 D 中发展 [123]. 在日本的一项大规模的研究， lamivudine 抵抗的出现率与在相反者上的基因型 A ， B 和 C. 无关, 出现率重要地在次基因型 Ba 中比在 Bj 中高 [124]. 这一项研究也建议 HBeAg 的危险- 在 lamivudine 抵抗的发展上的确实可能在基因型之间不一致而且严格突破性的发展肝炎的危险可能是比较高的在感染基因型 C 的病人中 [124].

Adefovir dipivoxil
Adefovir dipivoxil ， adefovir 的口头 prodrug, 已经在 3 阶段中被测试试验而且最近在美国被为慢性肝炎 B 的治疗核准 [20]. 没有在感染 HBV 的不同基因型的病人之间的抗病毒的回应重要的不同 [20].

变化的关系
到基因型

1896个停止 codon 变化
HBV 基因组的 precore- 核心区域为 precore- 核心的融合物编码被修正引起肝炎 B e 抗原 (HBeAg) 的后平移地的蛋白质 . 虽然 HBeAg 为滤过性毒菌的回答或 infectivity 没被需要 [29,30],它的精确功能不为人所知。 资讯科技被认为扮演免疫的调音一个角色而且能改变对核心的主人回应蛋白质 [31,32]. 因此, 一个停止- codon 的变化 1896 G 的出现 [避免 HBeAg 的表达 33,34] 可能是一个免疫逃避的方法。 1896 变化的发生被 encapsidation 信号 (e) 的中级结构限制 , 从为 HBeAg(图 1) 编码的 HBV 基因组的相同区域被抄写. G 的分裂这结构的扰动- C 基础在位置 1858 和 1896(那会起因于 a G-到- 一个变化在 1896) 之间成对会对滤过性毒菌的回答是有害的 [26], 如同已经被 transfection 显示实验 [25,35]. 如此 1896 变化的发展在位置 1858 仰赖出现或缺少 C 或 T 并且表示对各种不同的基因型的分配被讲的地理变化 [25]. 基因型 B ， D 和 E 有 T1858, 然而一而且 H 有 C1858 。 基因型 C 和 F 隔离能有 C1858 或 T1858: 基因型 F 紧张在中美洲有 T1858[22] 和日本基因型 C 紧张独家地有 T1858[38,39], 然而 C1858 在亚洲东南部盘据基因型 C 的运送者 [19,40-44]. 一些研究没发现在基因型 B 和 C 之间的 1896个突变异种的传播不同 [45,46]. 这是预期的因为两者的这些研究在和 T1858 的基因型 C 掌握的日本被实行。 资讯科技是兴趣，虽然两者基因型 B 的次基因型, 在亚洲 (Ba 和 Bj) 识别有 T1858,1896 变化被发现在次基因型 Bj 中更时常发生 [47].1896 变化被最时常发现在反 HBe 中积极的病人以基因型 D 传染 [25,26,48-51] 和 E[52] 而且很少地在基因型一中被发现 [25,50,51], 基因型 H[8] 和在少数中只有基因型 C[19,41,42] 和基因型 F 劳累 [6,17,19,22].

核心- 促进者的变化 T1762 A1764 基本
在位置 1762 的对 thymine(T) transversion 的一个腺嘌呤 (一) 连同 guanine(G) 一起到一个转变在 1764 在基本的核心促进者 (BCP) 中首先被描述在 HBV 从日本病人隔离 [53,54]. 变化的出现从 HBeAg 到反 HBe 在基因型一中在 seroconversion 之前紧张但是不在基因型 D 中 [48,55]. 他们的出现造成减少 transfection 的 precore mRNA 和 HBeAg 表达的程度研究 [56-59]. T1762A1764 变化更时常在基因型中发展一和和 C1858 的 H, 但是在和 C1858 的基因型 C 的少数中 [39] 和更时常在次基因型 Ba 中超过在 Bj 或基因型 C 中 [47]. 然而,在其它里面分析, 他们在 HBV 基因型之中相等地被分配 [49,51]. 然而其他的研究表示被与基因型 B 相较的基因型 C 的 T1762A1764 的较高频率 [41,42,45,46,60,61], 而且这不与 HBeAg 状态互有关连 [45,46].感染基因型 E 的只有 25% 的运送者持有 T1762A1764 变化，而且这一个发现与 HBeAg 状态无关 [52]. 这些变化被发现重要地与比较严重的肝脏疾病有关 [ 肝脏硬化由于或没有 hepatocellular 癌 (HCC)] 和一个较年长的年龄 (>35 年)[45,62,63].

前 S 突变异种
各种不同的变化在前 S 区域中已经被描述。 这些范围从点变化和小的划除和插入 [64] 排到非常大的划除 [65,66] 和避免前 S2 的表达蛋白质的划除 [67]. 一些研究已经分析在基因型和前 S 突变异种的发生之间的关系。在二项独立的研究中，前 S 划除突变异种比在基因型 B 中隔离被发现更时常在基因型 C 中发生 [68] 和在 adr(符合到基因型 C) 中比较在 adw(符合到基因型 B) 中隔离 [69].在差别中，在另外的一项研究中，虽然这些突变异种在基因型 B 中被更时常发现而且发现 C 比较在其他基因型中，没有统计的不同在基因型 B 和 C 的他们影响之方式之间被发现 [70].这一个相差可能被不同地理分配解释那隔离或后者研究不是一项情形- 控制的研究事实。 而且，这些划除突变异种更时常被发现在超过其他的病人从患有严重的肝脏疾病 (肝脏硬化和 HCC) 的病人隔离 [68,70].

在前 S 区域里面的划除能带领不需要影响绑到 hepatocytes 和他们的后来渗透的 HBV 就损害滤过性毒菌的清除, 因此可以成为传染的慢性因素 [71]. 在以这一种可能性保存方面是前 S 划除变化更时常被发现的观察在以硬化或 HCC 从病人隔离 [68,70]. 变化在核心区域里面聚集区域
Ehata et al。 [72] 已经识别在 HBV 的核心区域里面聚集区域 (MCR) 的变化从患有肝脏疾病的个体隔离而且深思了这些可能是 cytotoxic T 淋巴球的免疫学的目标 [73]. MCRs 已经被映射到不同的位置在不同的基因型中。 基因型 B(大部分) 和 C(adr 次类型) 有变化在位置在位置聚集核心基因和基因型 A ， B 和 D(adw 次类型) 中的 84 到 99个 48 到 60[74]. 基因型 F 残留物的 MCR 被映射在核心的位置 57 和 68 之间蛋白质 [22].

接合变体
这些 HBV 变体从 encapsidation 和相反出现接合的 pregenomic RNA 的抄写 [75]. 在 vitro tranfection 中使用学习, 没有在占优势的接合不同不同的被基因型 D ， C 和 E 生产, 然而较小的接合被综合的变体被隔离属于不同的基因型改变 [75]. 在 HBV 中接合可能成为 pathogenicity 及[或] 病毒的持续因素 [75-77].

HBV 的不同基因型的出现和变化的发展变化可能是疾病前进的基因型的影响力的有助于因素。

结论
资讯科技正在变成逐渐显然， HBV 的基因型可能有一个角色在预测对各种不同的治疗回应方面玩而且这在开始任何的治疗之前应该进入如一个变数的帐户之内被轮流。 然而，主人和环境的因素不同对从一个地理的区域到另外的外推法调查结果使它困难。 在世界的各种不同区域中因此比较大又深入的研究是必需的, 尤其在 HBV 是 hyperendemic, 像是亚洲东南部和次撒哈拉的非洲区域中。 虽然一些研究已经显示， HBV serotypes 可能影响 HBV 接种疫苗的效能 [125],到我们的知识，没有研究被接手回应接种疫苗及[或] 疫苗- 逃亡突变异种的出现找在 HBV 的基因型之间的关系。 这是需要较进一步的研究另外的一个区域。就如约会的大多数的研究已经是代表性的,更纵观的预期研究可以提供关于 HBV 基因型的关系较多的资讯给肝脏疾病因此临床的结果严重。 而且, 来到新的分子抗病毒的使它最重要基因型很好地被表示的特色,所以药对普遍的在世界的不同区域中的病毒序列可能是量身订做。

乙肝杀手

thank you very much!