P- Reviewer: Borzio M, Marzuillo P S- Editor: Tian YL L- Editor: A E- Editor: Wu HL
Published online Mar 27, 2015. doi: 10.4254/wjh.v7.i3.289
Peer-review started: September 20, 2014
First decision: November 14, 2014
Revised: December 4, 2014
Accepted: December 29, 2014
Article in press: December 29, 2014
Published online: March 27, 2015
The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB.
Core tip: Chronic hepatitis B (CHB) is a major global cause of liver related morbidity and mortality. Genotypes of the Hepatitis B virus have distinct geographical distributions and are known to influence a number of clinical features of disease and response to treatment. Certain well recognised viral mutations are also known to influence clinical risk of cirrhosis and hepatocellular carcinoma but in addition may have implications for vaccination programs and screening of blood for donation. This review examines the current state of knowledge about genotype and viral variants of CHB and their utility in the management of this disease.
- Citation: Croagh CM, Desmond PV, Bell SJ. Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance. World J Hepatol 2015; 7(3): 289-303
- URL: https://www.wjgnet.com/1948-5182/full/v7/i3/289.htm
- DOI: https://dx.doi.org/10.4254/wjh.v7.i3.289
Chronic hepatitis B (CHB) is a global health problem and a leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. The Hepatitis B virus (HBV) is a hepatotropic virus of the family hepadnaviridae. It comprises a central icosahedral core protein (HBcAg) which contains the viral DNA and HBV viral polymerase. This core (also called the nucleocapsid) is surrounded by a lipid membrane studded with viral proteins which are the small, medium and large HBV surface proteins. The entire virion is 42 nmol/L and was originally referred to as the Dane particle following its discovery by an English pathologist DS Dane. In the past, HBV was divided into serotypes which were subgroups based on the antigenic determinants of the hepatitis B surface antigen (HBsAg) and 4 subtypes were known, adr, adw, ayr and ayw.
In 1988 it was first suggested by Okamoto et al that HBV could be divided into 4 genotypes based on a divergence of ≥ 8% in the complete genomic sequence and genotypes A,B,C and D were identified. The relationship between serotypes and genotypes is not clearly known and the same serotype may be classified into different genotypes. Genotyping may be performed by a number of different techniques including restriction fragment length polymorphism, line probe assay, the enzyme-linked immunosorbent assay or genotype specific polymerase chain reaction. Direct sequencing can also be used and for commercial purposes, genotype can usually be determined through a partial sequence especially of the S gene since it is usually more conserved than other parts of the HBV genome. Following the initial description of genotypes A-D, Norder et al also proposed genotypes E and F which differed by more than 4% in the S gene from the other genotype groups and this has become an alternative criterion for classification of distinct genotypes. Genotype G is the least common of the genotypes and was reported in 2000 from samples of French and American patients but its geographic origin is still unknown. The precore and core regions of genotype G are aberrant with a 36-nucleotide insertion within the core gene making it the longest of the HBV genotypes. Stop codons in the precore region are also present and some have suggested it is not able to produce hepatitis B e antigen (HBeAg) although others report high HBeAg levels in HIV/HBV coinfected patients with genotype G. However, this may be due to coinfection with genotype A. It is thought that genotype G requires the presence of another genotype, most commonly genotype A2 to enhance its viral replication. Although monoinfection has been reported, this was transient. Genotype H has been shown to be prevalent in central America and the Amazon region and is closely related to genotype F HBV. It is thought to perhaps have split off from genotype F within the “New World”. It is particularly common in Mexico.
GenotypeIdescribed in Vietnam may not meet the criteria for a novel genotype since the diversity in its complete genome sequence is only 7% from that of its closest neighbour, genotype C. Genotype J is a novel variant described in a Japanese patient who had previously travelled to Borneo. It is thought to be phylogenetically positioned between human and primate HBV variants being close to strains which had been previously found in orang-utans and gibbons.
This genetic variability in the HBV may come about through natural mutation or by recombination. Natural mutation rates are high in HBV. The HBV is error prone since its reverse transcriptase lacks proof reading ability and it is estimated that the rate of nucleotide substitutions per site per year is approximately 1.4-3.2 × 10-5 which is 10 times higher than other DNA viruses and 100 times higher than the human genome. Recombination, in which DNA exchange or cross over of parts of a gene sequence occurs between two different viruses, is thought to be another potential mechanism for the development of divergent strains of HBV and has been described between numerous different genotypes[21,22]. Recent evidence suggests that the core gene may be a preferred site for recombination to take place as noted in West African patients with A/E recombinant strains of HBV.
Subgenotypes are also described if there is a divergence of > 4% (but less than 7.5%) of the nucleotide sequence in the complete genomic sequence. There have been numerous (up to 40) subgenotypes reported amongst genotypes A-D and F. Geographic distribution varies for subgenotypes and certain clinical outcomes have also been attributed to some of them however confounding factors are difficult to control for in many of these studies. Divergence of < 4% between subgenotypes are referred to as “clades”. There has been concern raised by experts in the field about the accuracy of classification of some of the newly reported subgenotypes. Pourkarim et al suggest that applying phylogenetic analysis over a full length genome sequence rather than partial sequence only is critical to avoid misclassification. They also suggest that recombinant strains should not necessarily be introduced as independent subgenotypes and propose the term “recombino-subgenotype” to identify HBV strains that show strong evidence of recombination in their nucleotide divergence.
The geographical distribution of the different genotypes is quite varied and for most of the older known genotypes and many regions, is well documented. Many parts of the world have dominant genotypes although frequently there are at least 2 prevalent genotypes.
Patients may also be coinfected with more than one genotype since in many parts of the world 2 or more genotypes are commonly found eg B and C in Asia. Genotype G also, as mentioned, appears to require the presence of genotype A or H for chronic infection. The distribution of HBV genotypes in different continents are detailed in Table 1.
|Africa||Subsaharan Africa (Egypt, Algeria, Libya)||Genotype D|
|West Africa (Guinea Bissau, Ghana, Cameroon)||Genotype E and also A|
|Central Africa||Genotype E and also A|
|East Africa (Malawi, Tanzania)||Genotype A|
|South Africa||Genotype A|
|Europe||Mediterranean Basin (Greece, Italy, Spain)||Genotype D in majority. Gentype A also seen in Spain|
|Western Europe||Mixtures of A-D from various migrant groups|
|Eastern Europe||A (Czech republic, Poland) and D (Russia, Croatia, Romania)|
|Americas||North America||Mixtures of A-D from various migrant populations Genotype F and B in Alaskan natives|
|Central America||Genotype H (Mexico) Genotype F (Costa Rica)|
|South America||Genotype F predominant and Genotypes A and D in Brazil/Argentina|
|Asia||Western Asia ( Iran, Yemen, Saudi Arabia, Turkey)||Genotype D|
|Central Asia (Uzbekistan, Tajikistan, Afghanistan, Pakistan)||Genotype D|
|South Asia (India and Pakistan)||Genotype D in India but also Gentoype A|
In East Africa (including Malawi and Tanzania) genotype A is found in the vast majority (> 90%) of patients[28,29]. In South Africa also, the dominant genotype is A. In other parts of Africa, for example West Africa, Genotype E is prevalent[31,32] and this appears to stretch into parts of central Africa also. There has been some work suggesting that HBV genotype E introduction and expansion in West Africa has been a relatively recent phenomenon[34,35] . In sub-Saharan (or Northern) Africa including Egypt, Algeria and Libya) which forms part of the Mediterranean Basin, genotype D predominates in up to 80% of patients[36,37].
In the European countries of the Mediterranean basin, in particular Greece, Italy, and Spain, the predominant genotype is Genotype D. Genotype D is also found in about 50% of cases in Eastern Europe, with genotype A in approximately 30%. Although some countries have a higher proportion of genotype A, e.g., 86% in Poland and 67% in Czech republic, Genotype D is found in the majority of Russian (93%), Romanian (67%) and Croatian (80%) patients[41,42]. The proportions of genotypes A and D are similar at about 30%-40% in the remainder of Europe (the EU and northern Europe) with smaller contributions from other genotypes including B and C, most likely due to migration.
In Western Asia, e.g., Turkey and the Middle East including Iran, the prevalent genotype is D. Central Asian countries of Uzbekistan and Tajikistan also have a preponderance of genotype D infection of up to 88%[46,47]. Southern Asian countries similarly show predominantly genotype D infection, e.g., 95% of cases in Afghanistan and in a majority of Indian patients[49-51] and 65% of Pakistani patients. However genotype A is also seen in India and a recent study from Eastern India highlights a shift in the prevalences of genotypes with an increase in Genotypes A and C along with a decrease in that of genotype D in East India.
Moving further east into South East Asia and China, genotypes B and C start to predominate. The relative prevalences of genotypes in many countries of south east Asia and regions of China are set out in Table 2[55-79] . In brief however, genotype C is seen in the majority of patients of Cambodian, Thai, Laotian and Myanmar ethnicity. Genotype B is predominant in Vietnamese cohorts and some parts of Indonesia and Malaysia. In China, Genotype C is prevalent in most areas although in other parts, Genotype B is seen frequently. Japan has a predominance of genotype C (82% in a study of 1271 patients). This study also reported an increase in the prevalence of genotype A from 1.7% to 3.5% from the period 2001-2006 which is thought to be due to persistence of sexually acquired acute HBV in adulthood. In Korea genotype C2 predominates.
|Laos||386||42.2% B 55.4% C 2.4% not typable ? I||Cohort of patients from Vientiane city and central provinces. 19 patients did not group into genotype A-H ? genotype I|||
|Cambodia||12||67% C , 33% B (subtype 4)|||
|22||72% C 28% B|||
|Vietnam||76||51% B, 48.7% C||Chronic cohort|||
|40||75% B 18% C 2.5% B + C, 5% not determined||Based in Hanoi|||
|27||85% C 7.4% B 7.4% D||Papua|||
|Malaysia||86||60% B||Genotype B 80% in ethnic Chinese|||
|34% C||Genotypes B and C equal prevalence in Ethnic Malays|
|2% D||Gentoype D in Indian patients|
|51||56.9% B 31.4% C 7.8% B + C 2% each D and E|||
|Thailand||224||86.6% C (Subgeno C1) 11.2% B 0.44% each of A and D 3 suspected recombinations||Myanmar ethnicity 97.5% genotype C Laos ethnicity 71% C 26% B, Cambodia 84% C, 12% B|||
|216||89.3% C 7.4% B, 1.9% B + C, 0.5% A||Northern Thailand adult voluntary blood donors|||
|53||90.6% C 7.5% B 1.9% B + C||Children in Chiang Mai|||
|332||73.2% C 20.8% B 3.3% A 2.7% unclassified||Cohort included CHB and HCC patients and found that genotype B was not associated with HCC in younger patients|||
|Philippines||100||51% A 22% B 27% C|||
|50||28% A 12% B 26% C 6% Mixed A + C/A + B + C 28% Non typable|||
|China||101||36% B 64% C||Hong Kong 42% B Shnaghai 39% B Beijing 20% B|||
|121||33% B 63.6% C 1.7% B/C 1.7% D||From Beijing China|||
|126||38.1% B 54.8% C 0.8% D, 3.2% unknown 1.6% B/C, 1.6% A/C||Yunnan China|||
|142||9.2% B 88% C 2.8% D||Northern China (Harbin University China)|||
|142||4.2% A 14.1% B 78.9% C 1.4% D||Southern China (Nanning)|||
|786||63.23% B 34.99% C 0.89% A and D each||Southern China (Guizhou )|||
|220||1.4% A 17.2% B 81.4% C||Shanghai China|||
|China (Hong Kong)||776||1.5% A 32.5% B 62.6% C 3.4% Mixed||Hong Kong|||
|Tibet||26||96% C/D recombinant 4% C||Sequences based on surface Ag gene showed that 25 clustered with genotype D and 1 clustered with genotype C. However based on core gene all clustered with genotype C|| .|
Among Indigenous populations living in the Arctic, and northern Canada and Greenland genotype B (subgenotype B6) has been found to be prevalent. Genotype F has also been shown to be predominant in Alaskan native Inuit populations. Genotype F is also found in South and central America and is thought to be the most prevalent genotype in most of these countries although in Brazil, and Argentina genotypes (plural) A and D are also seen. In Central America, genotype H HBV is prevalent, being found in approximately 75% of patients in a small study in Mexico.
In the United States, CHB is found primarily in migrant populations where the mix of different genotypes reflects the various immigrant groups. A large study of 694 patients in the United States identified a strong correlation between ethnicity and genotype and found that in patients of Asian background, genotypes B and C were most common and in those of white or African American background who usually acquired hepatitis B in adulthood through sexual transmission, genotype A was most common.
In Australia, Bell et al showed in 2005 that in the cohort at St Vincent’s Hospital, Melbourne, 8% had genotype A, 29% B, 41% C and 22% D reflecting the multicultural nature of Australian Society and the patterns of migration from the Mediterranean region and more recently South East Asia. There are few studies from the Pacific Island nations however one from the Solomon Islands where Hepatitis B is hyperendemic (prevalence of 21%), found a predominance of genotypes C and D which appeared ethnicity specific.
There are a number of studies documenting the effect of genotype on various clinical outcomes. Many of these provide comparisons of 2 prevalent genotypes in a region, e.g., A vs D, or B vs C. Table 3 sets out some of what is known about the different genotypes and clinical associations. There is a paucity of information about genotype E and its associations with clinical outcome and more work is needed to further elucidate its impact on HBV related liver disease.
|Progression to chronicity||+++||++||+++||++|
|Association with advanced liver disease||+||++||+++||++||+/-|
|Association with HCC||+ (subgeno A1)||+||++||++||++ (subgeno F2)|
|Early HBeAg seroconversion||++||+++||+||+++||+++|
|Sustained remission after HBeAg Seroconversion||+++||+++||++||++||++|
|Response to IFN Tx||+++||++||+||+/-||+||+++|
|Association with PreCore mutations||-||++||+||+++||++||+++ (F1 but not F2)|
|Association with BCP mutation||++||++||++|
Genotype A appears to have the highest risk of progression to chronicity following acute adult acquired Hepatitis B and resolution of acute hepatitis B is often prolonged in genotype A. In a cohort of Asian patients, genotype C2 was independently associated with progression to chronicity, compared to genotype B. Acute infection with genotype D appears to be more commonly associated with acute liver failure than other genotypes.
Many Asian studies have documented the more prolonged HBeAg positive phase and delayed HBeAg seroclearance of genotype C in comparison to Genotype B[92,93] including Chu et al who showed that HBeAg seroconversion occurs about 10 years earlier in genotype B compared to genotype C. A study of 1158 Alaskan natives which also looked at timing of seroconversion found that HBeAg seroconversion in genotype C (Subgenotype C2) patients lagged behind that of other genotypes by approximately 3 decades. Age at HBeAg seroconversion of the 75th percentile of patients was 32 years in genotype A2, 27.5 years in B6, 27.3 years in D, 24.5 in F1 but 58.1 years in C2. Genotype C patients are more prone to repeated episodes of acute exacerbation with failure of HBeAg seroconversion and HBeAg sero-reversion after HBeAg loss. Rates of spontaneous HBsAg clearance are higher in genotype B compared to C. Sustained remission following HBeAg seroconversion has been reported to be more commonly seen in genotype A than D as was HBsAg clearance .
Genotype C has been reported to have a significantly higher viral load than genotype B. Viral load in genotype D has also been shown to be significantly higher than in Genotype A. Genotype E is reported as being more likely to be associated with HBeAg positive disease and higher HBV DNA levels than Genotype D thus perinatal infection of infants from infected mothers is likely be an important factor in transmission for African people infected with genotype E.
Genotype C patients are more prone to the complications of advanced fibrosis and cirrhosis[102-104] than Genotype B patients. Some small studies have shown that histological inflammation is more significant in genotype C than genotype B patients[71,105] . Genotype F, in studies of Arctic, South American and Spanish populations, also appears to be associated with worse liver disease[98,106,107]. Genotype A appears to have a more favourable prognosis than genotype D with one small Indian study of 52 patients (46% Genotype A and 48% genotype D) showing more severe histological disease in genotype D and others also attributing more severe liver disease to genotype D compared to A. Genotype D is associated with HBeAg negative CHB and reports from Mediterranean countries of high rates of cirrhosis associated with HBeAg negative disease are now thought to possibly be attributable to genotype D. Genotype H infection in Mexican patients is often adult acquired and thus is frequently associated with low viral loads and low risk of chronic liver disease and HCC. Occult HBV infection is reported to be commonly seen in genotype H patients however this may be partly due to the suboptimal sensitivity of HBsAg assays used. Furthermore the contribution of HBV genotype H to liver disease in Mexican populations is difficult to establish as alcohol, HCV coinfection and obesity are common cofactors.
Genotype C has been shown to carry an increased risk for the development of HCC in the REVEAL study cohort, with an adjusted hazard ratio of 2.35. In addition there is data to suggest that HCC in genotype C is associated with a higher tumour recurrence rate. Genotype B on the other hand may be more likely to be associated with HCC in non cirrhotic patients and has been reported to have higher rates of solitary tumour and more satellite nodules than genotype C. Genotype B has been reported to be more prevalent in patients with HCC developing at a younger age compared to age matched inactive carriers (80% vs 52% in those < 50 years and 90% in those < 35 years). Genotype A in Africans has also been shown to be associated with HCC and at a much younger age than in other groups. Subgenotype A1 which is the most prevalent type in sub-Saharan Africa appears to be the main factor associated with this increased risk. However the contribution of aflatoxin, human immunodeficiency virus (HIV) coinfection and dietary iron overload are also factors to be considered . Genotype F has also been shown to be a risk factor for HCC especially in young Alaskan natives in a case control study while the rates of HCC in genotype H affected populations in Mexico are low.
Response rates to treatment with Peg IFN differ by genotype. In HBeAg positive patients treated with 52 wk of Peg IFN α-2β, HBeAg loss varied with genotype, being 47% in genotype A, 44% in Genotype B, 28% in genotype C and 25% in D. A small study of Peg IFN treatment in Genotype E patients also showed poor responsiveness. Limited data currently available on genotype F patients response to IFN suggests similar response to genotype A. Genotype G in a small number of patients’ treated with standard IFN showed poor responsiveness. Based on pooled data of the 2 largest global trials of Peg IFN in HBeAg positive patients Buster et al recommend Peg IFN be used in all genotype A patients, and in genotype B and C patients with a high alanine aminotransferase (ALT) and a low HBV DNA. In HBeAg negative CHB also, genotypes B and C have been shown to have higher response rates to Peg IFN treatment compared to genotype D.
Quantitative HBsAg (qHBsAg) levels are increasingly being used as predictors of response in Peg IFN therapy for CHB. In HBeAg positive disease, for patients with genotype A and D, absence of any decline in qHBsAg at week 12 has a negative predictive value (NPV) of 97-100% for poor response and in genotypes B and C, week 12 qHBsAg levels of >20000 IU/mL has a high NPV. In HBeAg negative patients treated with Peg IFN, a stopping rule in genotype D based on no decline in HBsAg and < 2 log10 drop in HBV DNA at week 12 of therapy has also become part of recent guidelines based on a very high negative predictive value for sustained response. In HBeAg negative patients treated with Peg IFN, the on treatment kinetics of HBsAg has been shown to vary between genotypes. Long term virological response to Peg IFN treatment has been shown to be predicted by end of treatment qHBsAg with varying threshold levels of qHBsAg identified for different genotypes. HBV genotype does not appear to influence response rates to nucleoside analogue therapy, however the patterns of drug resistant mutations that develop have been reported to be different in different genotypes.
HBV replicates at a high rate through the reverse transcription of an RNA intermediate and has a high spontaneous rate of error resulting in numerous mutations arising in the HBV genome. Thus HBV exists as a quasispecies, ie a heterogeneous viral population composed of closely related but non identical genomes. The predominant strain selected out is determined by factors such as host immune response, viral replication fitness and exogenous pressures such as antiviral therapy. The most frequently occurring natural HBV variants are the precore and the basal core promotor (BCP) mutations. They result in a reduction or abolition of HBeAg production. During the early course of perinatally acquired CHB , i.e., the immunotolerant phase, these mutations in the core or precore region are uncommonly seen, but they emerge during the immune clearance phase as a result of immune selective pressures.
A point mutation at nucleotide 1896 in the HBV with substitution of G for A results in a stop codon at this point thus preventing production of HBeAg although without affecting replication and HBcAg production. The formation of this “precore” mutation is essentially precluded in certain genotypes in particular A and H and it occurs most frequently in genotype D and to a lesser extent in Genotypes B, C and E. The reason for this relates to the fact that nucleotide 1896 is important in maintaining a stem loop structure (epsilon) which is necessary for encapsidation of the pregenomic RNA into the nucleocapsid. Nucleotide 1896 is opposite nucleotide 1858 in the stem loop structure and thus genotypes with a T at nucleotide position 1858 (e.g., genotype D) are more likely to predispose to the development of the G1896A mutation since T-A pairing is more stable than T-G pairing. Likewise genotypes with C at position 1858 (genotype A) are much less prone to development of the precore mutant virus since C-A pairing is weaker than than C-G pairing. Subgenotype F2 similarly codes for C at position 1858 but F1 does not , so precore mutation may occur in some but not other genotype F CHB patients.
It has been suggested that stabilisation of the epsilon encapsidation signal may increase the replicative fitness of HBV which may be one reason for it being selected out. Although HBV DNA levels are lower in HBeAg negative disease, this impairment in virion productivity is not thought to be related to Precore and BCP mutants but instead be the result of an independent process. The HBeAg and its relationship to the host immune response is complex. It has been shown to be able to tolerize T cells and cause immunomodulation of Toll-like receptor mediated signalling pathways to evade immune responses and thus is thought to contribute to viral persistence. However its presence in the cytosol also acts as a target for the inflammatory response. Thus it has been suggested that HBeAg may act as a tolerogen or an immunogen in different circumstances and that loss of HBeAg may be a favourable biological characteristic that renders the HBV less vulnerable to immune attack. Numerous other mutations have been described in the precore region including a point mutation at G1899A (commonly seen in association with G1896A). It has been shown that viral mutation rates increase in the immune clearance phase when compared to the immune tolerant phase and in fact there is significant viral sequence diversity present in the months/years leading up to HBeAg seroconversion. Furthermore, the high rates of nucleotide substitution continue post seroconversion, with ongoing immune selection pressure being applied in the immune control phase although at lower viral loads.
Clinically, the G1896A precore mutation is a major cause of HBeAg negative chronic hepatitis and it appears to be associated with reports of fulminant hepatitis, especially in acute adult acquired HBV although not in fulminant cases of CHB. It was shown to be associated with a slightly lower risk of HCC than wildtype virus in a subanalysis of the REVEAL study cohort. However, also recently published is a meta-analysis of 85 case control studies of 16745 patients with 5781 cases of HCC which reports that the precore mutations G1896A, G1899A as well as deletions in Pre-S region were associated with an increased risk of HCC.
Mutations in the core promoter region occur most commonly at nucleotides 1762 (adenine (A) to thymine (T)) and 1764 [guanine (G) to adenine (A)] and are usually found together[150,151]. Once again this is thought to possibly confer some compensatory advantage to the virus and Tacke et al showed that BCP mutations increased viral replication levels to above those of wildtype virus, including in strains with Lamivudine resistant mutations also present. Other mutations in the basal core promotor region have also been described, including at positions 1653, 1753-1757, 1766, 1768 and these are usually seen in addition to the A1762T and G1764A variants. Overall the association with HBeAg negativity is less strong in patients with BCP mutations than in those with precore mutations The double BCP reduces the production of HBeAg by approximately 70% and this may be even further reduced in HBV variants with the additional mutations in position 1753 and 1766. The BCP mutation has been found to occur more frequently in genotype C than B[78,154] and one possible reason for this may be because genotype C is more likely to have a C at nucleotide position 1858, which largely precludes formation of the precore mutation. The prevalence of the BCP mutation does appear to vary between genotypes being reported at 41%, 27%, 60% and 42% in genotypes A, B, C and D, thus the lower prevalence in genotype A compared to C suggests that other factors apart from the nucleotide at position 1858 are also important. The BCP mutations have been implicated quite strongly in more advanced liver disease and in the development of HCC. Yuen reported an association with higher ALT levels in patients with BCP mutations compared to those with wildtype. The authors also subsequently looked at 66 patients with liver biopsies, 71% of whom had the BCP mutations and found these patients had more severe necroinflammation than those without. Lin et al also showed that the BCP mutation was associated with the development of cirrhosis and HCC although this was restricted to males. Increasing prevalence of the BCP double mutation was reported by Kao et al in patients with more significant liver disease, being 3% in inactive carriers and 64% in patients with HCC. Orito et al also described a significant association between BCP and more advanced liver disease (OR = 4.1, 95%CI: 1.6-10.2). Recently a study by Tseng et al of 251 spontaneous seroconverters (Genotypes B and C) showed that a higher proportion of BCP mutation (> 45%) was associated with an OR of 2.81 for the risk of cirrhosis. However, whether the BCP mutant HBV is causative or simply a reflection of more significant immune pressure and thus immune mediated inflammation and fibrosis is not known. The association of the BCP mutation with HCC has been documented by a number of groups who reported the BCP mutation was significantly associated with HCC in both genotypes B and C[154,160], in cirrhotic and non cirrhotic HCC[161,162] and by Baptista who found a high prevalence of the mutations in black African patients with HCC.
More recently the REVEAL study group also reported an increased risk of HCC in patients with the BCP A1762T/G1764A double mutant compared to wildtype (HR = 1.73, 95%CI: 1.13-2.67). Genotype C also had a higher hazard ratio compared to genotype B (HR = 1.76, 95%CI: 1.19-2.61) and the highest risk was amongst those with the BCP mutations, Genotype C and wildtype virus at the 1896 precore variant site (adjusted HR = 2.99, 95%CI: 1.57-5.7). There is no strong evidence that the presence or absence of the precore or BCP mutations affects the response to Interferon or nucleos(t)ide analogue treatment. However some studies have shown that the proportion of pre-core and BCP mutant virus present prior to treatment correlates with the chance of HBeAg seroconversion with an approximately 2% increase in HBeAg seroconversion rates per 1% increase of PC and BCP mutant percentages.
Variations in the HBsAg protein can result in viral infection developing in a vaccinated subject. Anti-HBs is directed towards a highly conserved region of the surface protein (amino acids 99-160) which includes the major “a” determinant of this protein. HBsAg mutations resulting in amino acid substitutions in the region 137-147 of the surface protein can change the conformational epitope in the “a” determinant so that it is not recognized by the neutralizing anti-HBs antibodies. In particular the G145R vaccine escape mutant is known to be stable and replication competent[165,166]. The infectivity of HBsAg mutants is currently thought to be low, however another problem is their lack of detectability by serological tests as was reported in a recent case of HBV with a 4 amino acid repeat insertion at position 115 in the surface protein. The development of vaccine escape mutants has been thought in some parts to be related to the emergence of anti-viral drug resistant mutants because of the overlap of the polymerase gene (where nucleot(s)ide analogue associated resistant mutations occur) with the surface antigen domains recognized by anti-HBs. There is evidence however that emergence of the vaccine escape mutants predates mass vaccination programs. It is thought possible that immune pressure exerted on HBV by anti-HBV due to expanding vaccination programs will result in an increasing problem of vaccine escape mutants. The sG145R vaccine escape mutant has also been detected in 2 of 65 patients in an Australian indigenous cohort, despite wild type polymerase gene sequences in all. Graft infection with HBV following liver transplant in patients who received hepatitis B Immune globulin therapy post transplant has also been shown to be due to the development of S gene mutant HBV.
Other mutations in the S protein, eg due to missense mutations in the S gene have also been described and are a particular concern for screening of blood donors since they result in false negatives for HBsAg serological testing. The prevalence of 8 mutations associated with HBsAg diagnostic failure, including P120T, T126S, Q128H, G130N, S143L D144A and G145R was found to be approximately 1% in a study of 11,221 HBV sequences encompassing genotypes A-H.
A study of 4.4 million Dutch blood donations identified 23 HBsAg negative but HBV DNA positive persons and also reported the presence of multiple escape mutations in the S gene especially in Genotype D patients with occult HBV. Other reasons for HBsAg negativity in the setting of HBV DNA positivity in this study were early acute HBV infection (prior to development of HBsAg), occult HBV infection, genotype G HBV with decreased HBsAg production and suppressed infection after vaccination.
Mutations in the pre-S region, including Pre-S2 deletions, pre-S1-S2 deletions and Pre-S2 start codon mutations have been described[176,177]. Pre-S mutants have been shown to be associated with decreased synthesis and secretion of HBsAg. It has been also been shown that Pre-S2 deletions are associated with more advanced liver disease[179-181] and possibly with the development of HCC especially in younger patients[162,182].
HBV genotype and viral variants have clear implications for many clinical aspects of CHB and should become more routinely utilised to help predict likely clinic course, e.g., longer duration of HBeAg phase and higher risk of progression to cirrhosis in genotype C and increased HCC risk in genotypes C and F. It could be argued that formal testing of genotype should be done rather than it being assumed on the basis of ethnicity especially as populations worldwide become increasingly cosmopolitan and subtle shifts in HBV genotype prevalences are already reported (e.g., in Africa and India). Easy to use nomograms derived from the Taiwanese REVEAL study’s cohort for predicting HCC risk show further refinement in risk stratification with the addition of genotype to other parameters. Similarly nomograms that incorporate genotype into predictability of sustained response to Peg IFN therapy can assist with management decisions in CHB patients. Thus practical tools already exist for use in clinics which are based on existing knowledge about the impact of genotype in CHB. Further research into the genotypes E, F and H are required. International agreement amongst experts on issues related to genetic and phylogenetic classification of genotypes and subgenotypes are also important for the future in this evolving area.
With regard to viral variants, knowledge of variants harboured by patients should also be increasingly incorporated into clinical decision making. Revill and Locarnini recently argued that given the evidence that the BCP mutation is an important viral biomarker of the risk of cirrhosis in genotype B and C patients, detection and quantification of BCP mutants should be performed and used as triggers for treatment in Asian CHB patients. Further work on the significance of these mutations in other genotypes was also recommended.
Further elucidation of the clinical significance of other viral variants is warranted. Importantly from a population health perspective, ongoing monitoring of prevalences of vaccine escape and S escape mutants is necessary and further research into vaccines that remain efficacious against mutant forms of HBV will be needed.
|1.||Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet. 1970;1:695-698. [PubMed] [DOI]|
|2.||Mazzur S, Burgert S, Blumberg BS. Geographical distribution of Australia antigen determinants d, y and w. Nature. 1974;247:38-40. [PubMed] [DOI]|
|3.||Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988;69:2575-2583. [PubMed] [DOI]|
|4.||Guirgis BS, Abbas RO, Azzazy HM. Hepatitis B virus genotyping: current methods and clinical implications. Int J Infect Dis. 2010;14:e941-e953. [PubMed] [DOI]|
|5.||Norder H, Hammas B, Löfdahl S, Couroucé AM, Magnius LO. Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains. J Gen Virol. 1992;73:1201-1208. [PubMed]|
|6.||Stuyver L, De Gendt S, Van Geyt C, Zoulim F, Fried M, Schinazi RF, Rossau R. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol. 2000;81:67-74. [PubMed]|
|7.||Lindh M. HBV genotype G-an odd genotype of unknown origin. J Clin Virol. 2005;34:315-316. [PubMed] [DOI]|
|8.||Li K, Zoulim F, Pichoud C, Kwei K, Villet S, Wands J, Li J, Tong S. Critical role of the 36-nucleotide insertion in hepatitis B virus genotype G in core protein expression, genome replication, and virion secretion. J Virol. 2007;81:9202-9215. [PubMed] [DOI]|
|9.||Dao DY, Balko J, Attar N, Neak E, Yuan HJ, Lee WM, Jain MK. Hepatitis B virus genotype G: prevalence and impact in patients co-infected with human immunodeficiency virus. J Med Virol. 2011;83:1551-1558. [PubMed] [DOI]|
|10.||Kato H, Orito E, Gish RG, Bzowej N, Newsom M, Sugauchi F, Suzuki S, Ueda R, Miyakawa Y, Mizokami M. Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology. 2002;35:922-929. [PubMed] [DOI]|
|11.||Sakamoto T, Tanaka Y, Watanabe T, Iijima S, Kani S, Sugiyama M, Murakami S, Matsuura K, Kusakabe A, Shinkai N. Mechanism of the dependence of hepatitis B virus genotype G on co-infection with other genotypes for viral replication. J Viral Hepat. 2013;20:e27-e36. [PubMed] [DOI]|
|12.||Zaaijer HL, Boot HJ, van Swieten P, Koppelman MH, Cuypers HT. HBsAg-negative mono-infection with hepatitis B virus genotype G. J Viral Hepat. 2011;18:815-819. [PubMed] [DOI]|
|13.||Arauz-Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol. 2002;83:2059-2073. [PubMed]|
|14.||Panduro A, Maldonado-Gonzalez M, Fierro NA, Roman S. Distribution of HBV genotypes F and H in Mexico and Central America. Antivir Ther. 2013;18:475-484. [PubMed] [DOI]|
|15.||Tran TT, Trinh TN, Abe K. New complex recombinant genotype of hepatitis B virus identified in Vietnam. J Virol. 2008;82:5657-5663. [PubMed] [DOI]|
|16.||Kurbanov F, Tanaka Y, Kramvis A, Simmonds P, Mizokami M. When should “I” consider a new hepatitis B virus genotype? J Virol. 2008;82:8241-8242. [PubMed] [DOI]|
|17.||Tatematsu K, Tanaka Y, Kurbanov F, Sugauchi F, Mano S, Maeshiro T, Nakayoshi T, Wakuta M, Miyakawa Y, Mizokami M. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol. 2009;83:10538-10547. [PubMed] [DOI]|
|18.||Orito E, Mizokami M, Ina Y, Moriyama EN, Kameshima N, Yamamoto M, Gojobori T. Host-independent evolution and a genetic classification of the hepadnavirus family based on nucleotide sequences. Proc Natl Acad Sci USA. 1989;86:7059-7062. [PubMed] [DOI]|
|19.||Yuen MF, Lai CL. Hepatitis B virus genotypes: natural history and implications for treatment. Expert Rev Gastroenterol Hepatol. 2007;1:321-328. [PubMed] [DOI]|
|20.||Morozov V, Pisareva M, Groudinin M. Homologous recombination between different genotypes of hepatitis B virus. Gene. 2000;260:55-65. [PubMed] [DOI]|
|21.||Wang Z, Liu Z, Zeng G, Wen S, Qi Y, Ma S, Naoumov NV, Hou J. A new intertype recombinant between genotypes C and D of hepatitis B virus identified in China. J Gen Virol. 2005;86:985-990. [PubMed] [DOI]|
|22.||Kurbanov F, Tanaka Y, Fujiwara K, Sugauchi F, Mbanya D, Zekeng L, Ndembi N, Ngansop C, Kaptue L, Miura T. A new subtype (subgenotype) Ac (A3) of hepatitis B virus and recombination between genotypes A and E in Cameroon. J Gen Virol. 2005;86:2047-2056. [PubMed] [DOI]|
|23.||Garmiri P, Loua A, Haba N, Candotti D, Allain JP. Deletions and recombinations in the core region of hepatitis B virus genotype E strains from asymptomatic blood donors in Guinea, west Africa. J Gen Virol. 2009;90:2442-2451. [PubMed] [DOI]|
|24.||Kramvis A, Arakawa K, Yu MC, Nogueira R, Stram DO, Kew MC. Relationship of serological subtype, basic core promoter and precore mutations to genotypes/subgenotypes of hepatitis B virus. J Med Virol. 2008;80:27-46. [PubMed] [DOI]|
|25.||Pourkarim MR, Amini-Bavil-Olyaee S, Kurbanov F, Van Ranst M, Tacke F. Molecular identification of hepatitis B virus genotypes/subgenotypes: revised classification hurdles and updated resolutions. World J Gastroenterol. 2014;20:7152-7168. [PubMed] [DOI]|
|26.||Kurbanov F, Tanaka Y, Mizokami M. Geographical and genetic diversity of the human hepatitis B virus. Hepatol Res. 2010;40:14-30. [PubMed] [DOI]|
|27.||Sánchez LV, Tanaka Y, Maldonado M, Mizokami M, Panduro A. Difference of hepatitis B virus genotype distribution in two groups of mexican patients with different risk factors. High prevalence of genotype H and G. Intervirology. 2007;50:9-15. [PubMed] [DOI]|
|28.||Hasegawa I, Tanaka Y, Kurbanov F, Yoshihara N, El-Gohary A, Lyamuya E, Matee M, Magessa P, Fujiwara K, Ozasa A. Molecular epidemiology of hepatitis B virus in the United Republic of Tanzania. J Med Virol. 2006;78:1035-1042. [PubMed] [DOI]|
|29.||Sugauchi F, Orito E, Kato H, Suzuki S, Kawakita S, Sakamoto Y, Fukushima K, Akiba T, Yoshihara N, Ueda R. Genotype, serotype, and phylogenetic characterization of the complete genome sequence of hepatitis B virus isolates from Malawian chronic carriers of the virus. J Med Virol. 2003;69:33-40. [PubMed] [DOI]|
|30.||Kimbi GC, Kramvis A, Kew MC. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa. J Gen Virol. 2004;85:1211-1220. [PubMed] [DOI]|
|31.||Huy TT, Ishikawa K, Ampofo W, Izumi T, Nakajima A, Ansah J, Tetteh JO, Nii-Trebi N, Aidoo S, Ofori-Adjei D. Characteristics of hepatitis B virus in Ghana: full length genome sequences indicate the endemicity of genotype E in West Africa. J Med Virol. 2006;78:178-184. [PubMed] [DOI]|
|32.||Suzuki S, Sugauchi F, Orito E, Kato H, Usuda S, Siransy L, Arita I, Sakamoto Y, Yoshihara N, El-Gohary A. Distribution of hepatitis B virus (HBV) genotypes among HBV carriers in the Cote d’Ivoire: complete genome sequence and phylogenetic relatedness of HBV genotype E. J Med Virol. 2003;69:459-465. [PubMed] [DOI]|
|33.||Bekondi C, Olinger CM, Boua N, Talarmin A, Muller CP, Le Faou A, Venard V. Central African Republic is part of the West-African hepatitis B virus genotype E crescent. J Clin Virol. 2007;40:31-37. [PubMed] [DOI]|
|34.||Forbi JC, Vaughan G, Purdy MA, Campo DS, Xia GL, Ganova-Raeva LM, Ramachandran S, Thai H, Khudyakov YE. Epidemic history and evolutionary dynamics of hepatitis B virus infection in two remote communities in rural Nigeria. PLoS One. 2010;5:e11615. [PubMed] [DOI]|
|35.||Andernach IE, Nolte C, Pape JW, Muller CP. Slave trade and hepatitis B virus genotypes and subgenotypes in Haiti and Africa. Emerg Infect Dis. 2009;15:1222-1228. [PubMed] [DOI]|
|36.||Ayed K, Gorgi Y, Ayed-Jendoubi S, Aouadi H, Sfar I, Najjar T, Ben Abdallah T. Hepatitis B virus genotypes and precore/core-promoter mutations in Tunisian patients with chronic hepatitis B virus infection. J Infect. 2007;54:291-297. [PubMed] [DOI]|
|37.||Saudy N, Sugauchi F, Tanaka Y, Suzuki S, Aal AA, Zaid MA, Agha S, Mizokami M. Genotypes and phylogenetic characterization of hepatitis B and delta viruses in Egypt. J Med Virol. 2003;70:529-536. [PubMed] [DOI]|
|38.||Hadziyannis SJ. Natural history of chronic hepatitis B in Euro-Mediterranean and African countries. J Hepatol. 2011;55:183-191. [PubMed] [DOI]|
|39.||Dal Molin G, Poli A, Crocè LS, D’Agaro P, Biagi C, Comar M, Tiribelli C, Campello C. Hepatitis B virus genotypes, core promoter variants, and precore stop codon variants in patients infected chronically in North-Eastern Italy. J Med Virol. 2006;78:734-740. [PubMed] [DOI]|
|40.||Basaras M, Arrese E, Blanco S, Sota M, de las Heras B, Cisterna R. Characterization of hepatitis B virus genotypes in chronically infected patients. Rev Esp Quimioter. 2007;20:442-445. [PubMed]|
|41.||Dzierzanowska-Fangrat K, Woynarowski M, Szczygielska I, Jozwiak P, Cielecka-Kuszyk J, Dzierzanowska D, Madalinski K. Hepatitis B virus genotypes in children with chronic hepatitis B in Poland. Eur J Gastroenterol Hepatol. 2006;18:655-658. [PubMed]|
|42.||Deterding K, Constantinescu I, Nedelcu FD, Gervain J, Nemecek V, Srtunecky O, Vince A, Grgurevic I, Bielawski KP, Zalewska M. Prevalence of HBV genotypes in Central and Eastern Europe. J Med Virol. 2008;80:1707-1711. [PubMed] [DOI]|
|43.||Halfon P, Bourlière M, Pol S, Benhamou Y, Ouzan D, Rotily M, Khiri H, Renou C, Pénaranda G, Saadoun D. Multicentre study of hepatitis B virus genotypes in France: correlation with liver fibrosis and hepatitis B e antigen status. J Viral Hepat. 2006;13:329-335. [PubMed]|
|44.||Sunbul M, Leblebicioglu H. Distribution of hepatitis B virus genotypes in patients with chronic hepatitis B in Turkey. World J Gastroenterol. 2005;11:1976-1980. [PubMed]|
|45.||Garmiri P, Rezvan H, Abolghasemi H, Allain JP. Full genome characterization of hepatitis B virus strains from blood donors in Iran. J Med Virol. 2011;83:948-952. [PubMed] [DOI]|
|46.||Khan A, Kurbanov F, Tanaka Y, Elkady A, Sugiyama M, Dustov A, Mizokami M. Epidemiological and clinical evaluation of hepatitis B, hepatitis C, and delta hepatitis viruses in Tajikistan. J Med Virol. 2008;80:268-276. [PubMed] [DOI]|
|47.||Kato H, Ruzibakiev R, Yuldasheva N, Hegay T, Kurbanov F, Achundjanov B, Tuichiev L, Usuda S, Ueda R, Mizokami M. Hepatitis B virus genotypes in Uzbekistan and validity of two different systems for genotyping. J Med Virol. 2002;67:477-483. [PubMed] [DOI]|
|48.||Amini-Bavil-Olyaee S, Alavian SM, Adeli A, Sarrami-Forooshani R, Sabahi F, Sabouri E, Tavangar HR, Azizi M, Mahboudi F. Hepatitis B virus genotyping, core promoter, and precore/core mutations among Afghan patients infected with hepatitis B: a preliminary report. J Med Virol. 2006;78:358-364. [PubMed] [DOI]|
|49.||Sharma S, Sharma B, Singla B, Chawla YK, Chakraborti A, Saini N, Duseja A, Das A, Dhiman RK. Clinical significance of genotypes and precore/basal core promoter mutations in HBV related chronic liver disease patients in North India. Dig Dis Sci. 2010;55:794-802. [PubMed] [DOI]|
|50.||Biswas A, Chandra PK, Datta S, Panigrahi R, Banerjee A, Chakrabarti S, Biswas K, Patra D, Bhattacharya P, Biswas K. Frequency and distribution of hepatitis B virus genotypes among eastern Indian voluntary blood donors: Association with precore and basal core promoter mutations. Hepatol Res. 2009;39:53-59. [PubMed] [DOI]|
|51.||Vivekanandan P, Abraham P, Sridharan G, Chandy G, Daniel D, Raghuraman S, Daniel HD, Subramaniam T. Distribution of hepatitis B virus genotypes in blood donors and chronically infected patients in a tertiary care hospital in southern India. Clin Infect Dis. 2004;38:e81-e86. [PubMed] [DOI]|
|52.||Alam MM, Zaidi SZ, Malik SA, Shaukat S, Naeem A, Sharif S, Angez M, Butt JA. Molecular epidemiology of Hepatitis B virus genotypes in Pakistan. BMC Infect Dis. 2007;7:115. [PubMed] [DOI]|
|53.||Kumar K, Kumar M, Rahaman SH, Singh TB, Patel SK, Nath G. Distribution of Hepatitis B virus genotypes among healthy blood donors in eastern part of North India. Asian J Transfus Sci. 2011;5:144-149. [PubMed] [DOI]|
|54.||Biswas A, Panigrahi R, Pal M, Chakraborty S, Bhattacharya P, Chakrabarti S, Chakravarty R. Shift in the hepatitis B virus genotype distribution in the last decade among the HBV carriers from eastern India: possible effects on the disease status and HBV epidemiology. J Med Virol. 2013;85:1340-1347. [PubMed] [DOI]|
|55.||Olinger CM, Jutavijittum P, Hübschen JM, Yousukh A, Samountry B, Thammavong T, Toriyama K, Muller CP. Possible new hepatitis B virus genotype, southeast Asia. Emerg Infect Dis. 2008;14:1777-1780. [PubMed] [DOI]|
|56.||Huy TT, Sall AA, Reynes JM, Abe K. Complete genomic sequence and phylogenetic relatedness of hepatitis B virus isolates in Cambodia. Virus Genes. 2008;36:299-305. [PubMed] [DOI]|
|57.||Srey CT, Ijaz S, Tedder RS, Monchy D. Characterization of hepatitis B surface antigen strains circulating in the Kingdom of Cambodia. J Viral Hepat. 2006;13:62-66. [PubMed] [DOI]|
|58.||Huy TT, Ushijima H, Quang VX, Ngoc TT, Hayashi S, Sata T, Abe K. Characteristics of core promoter and precore stop codon mutants of hepatitis B virus in Vietnam. J Med Virol. 2004;74:228-236. [PubMed] [DOI]|
|59.||Thuy le TT, Ryo H, Van Phung L, Furitsu K, Nomura T. Distribution of genotype/subtype and mutational spectra of the surface gene of hepatitis B virus circulating in Hanoi, Vietnam. J Med Virol. 2005;76:161-169. [PubMed] [DOI]|
|60.||Nurainy N, Muljono DH, Sudoyo H, Marzuki S. Genetic study of hepatitis B virus in Indonesia reveals a new subgenotype of genotype B in east Nusa Tenggara. Arch Virol. 2008;153:1057-1065. [PubMed] [DOI]|
|61.||Lusida MI, Surayah H, Nagano-Fujii M, Soetjipto R, Boediwarsono PB, Nidom CA, Ohgimoto S, Hotta H. Genotype and subtype analyses of hepatitis B virus (HBV) and possible co-infection of HBV and hepatitis C virus (HCV) or hepatitis D virus (HDV) in blood donors, patients with chronic liver disease and patients on hemodialysis in Surabaya, Indonesia. Microbiol Immunol. 2003;47:969-975. [PubMed] [DOI]|
|62.||Lusida MI, Nugrahaputra VE, Soetjipto R, Nagano-Fujii M, Sasayama M, Utsumi T, Hotta H. Novel subgenotypes of hepatitis B virus genotypes C and D in Papua, Indonesia. J Clin Microbiol. 2008;46:2160-2166. [PubMed] [DOI]|
|63.||Meldal BH, Bon AH, Prati D, Ayob Y, Allain JP. Diversity of hepatitis B virus infecting Malaysian candidate blood donors is driven by viral and host factors. J Viral Hepat. 2011;18:91-101. [PubMed] [DOI]|
|64.||Lim CK, Tan JT, Khoo JB, Ravichandran A, Low HM, Chan YC, Ton SH. Correlations of HBV genotypes, mutations affecting HBeAg expression and HBeAg/ anti-HBe status in HBV carriers. Int J Med Sci. 2006;3:14-20. [PubMed] [DOI]|
|65.||Sa-Nguanmoo P, Tangkijvanich P, Thawornsuk N, Vichaiwattana P, Prianantathavorn K, Theamboonlers A, Tanaka Y, Poovorawan Y. Molecular epidemiological study of hepatitis B virus among migrant workers from Cambodia, Laos, and Myanmar to Thailand. J Med Virol. 2010;82:1341-1349. [PubMed] [DOI]|
|66.||Jutavijittum P, Jiviriyawat Y, Yousukh A, Kunachiwa W, Toriyama K. Genotypes of hepatitis B virus among voluntary blood donors in northern Thailand. Hepatol Res. 2006;35:263-266. [PubMed] [DOI]|
|67.||Jutavijittum P, Yousukh A, Jiviriyawat Y, Kunachiwa W, Toriyama K. Genotypes of hepatitis B virus among children in Chiang Mai, Thailand. Southeast Asian J Trop Med Public Health. 2008;39:394-397. [PubMed]|
|68.||Tangkijvanich P, Mahachai V, Komolmit P, Fongsarun J, Theamboonlers A, Poovorawan Y. Hepatitis B virus genotypes and hepatocellular carcinoma in Thailand. World J Gastroenterol. 2005;11:2238-2243. [PubMed]|
|69.||Sakamoto T, Tanaka Y, Orito E, Co J, Clavio J, Sugauchi F, Ito K, Ozasa A, Quino A, Ueda R. Novel subtypes (subgenotypes) of hepatitis B virus genotypes B and C among chronic liver disease patients in the Philippines. J Gen Virol. 2006;87:1873-1882. [PubMed] [DOI]|
|70.||Batoctoy KS, Tseng TC, Kao JH, Quiza FE, Garcia LH, Lao-Tan J. HBV/A and HBV/C genotype predominance among patients with chronic hepatitis B virus infection in Cebu City, Philippines. Hepatol Int. 2011;5:774-781. [PubMed] [DOI]|
|71.||Zhu L, Tse CH, Wong VW, Chim AM, Leung KS, Chan HL. A complete genomic analysis of hepatitis B virus genotypes and mutations in HBeAg-negative chronic hepatitis B in China. J Viral Hepat. 2008;15:449-458. [PubMed] [DOI]|
|72.||Du H, Li T, Zhang HY, He ZP, Dong QM, Duan XZ, Zhuang H. Correlation of hepatitis B virus (HBV) genotypes and mutations in basal core promoter/precore with clinical features of chronic HBV infection. Liver Int. 2007;27:240-246. [PubMed] [DOI]|
|73.||You J, Sriplung H, Chongsuvivatwong V, Geater A, Zhuang L, Huang JH, Chen HY, Yu L, Tang BZ. Profile, spectrum and significance of hepatitis B virus genotypes in chronic HBV-infected patients in Yunnan, China. Hepatobiliary Pancreat Dis Int. 2008;7:271-279. [PubMed]|
|74.||Li D, Gu HX, Zhang SY, Zhong ZH, Zhuang M, Hattori T. YMDD mutations and genotypes of hepatitis B virus in northern China. Jpn J Infect Dis. 2006;59:42-45. [PubMed]|
|75.||Ding X, Mizokami M, Ge X, Orito E, Iino S, Ueda R, Nakanishi M. Different hepatitis B virus genotype distributions among asymptomatic carriers and patients with liver diseases in Nanning, southern China. Hepatol Res. 2002;22:37-44. [PubMed] [DOI]|
|76.||Ding Jj, Zhang Q, Peng L, Liu YH, Li Z, Liu SD, Hu L. Investigation on virus genotype in patients infected with hepatitis B virus in four cities of Guizhou. Zhonghua Liuxingbingxue Zazhi. 2006;27:977-980. [PubMed]|
|77.||Ding X, Mizokami M, Yao G, Xu B, Orito E, Ueda R, Nakanishi M. Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. Intervirology. 2001;44:43-47. [PubMed]|
|78.||Yuen MF, Sablon E, Tanaka Y, Kato T, Mizokami M, Doutreloigne J, Yuan HJ, Wong DK, Sum SM, Lai CL. Epidemiological study of hepatitis B virus genotypes, core promoter and precore mutations of chronic hepatitis B infection in Hong Kong. J Hepatol. 2004;41:119-125. [PubMed] [DOI]|
|79.||Cui C, Shi J, Hui L, Xi H, Zhuoma G. The dominant hepatitis B virus genotype identified in Tibet is a C/D hybrid. J Gen Virol. 2002;83:2773-2777. [PubMed]|
|80.||Matsuura K, Tanaka Y, Hige S, Yamada G, Murawaki Y, Komatsu M, Kuramitsu T, Kawata S, Tanaka E, Izumi N. Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A. J Clin Microbiol. 2009;47:1476-1483. [PubMed] [DOI]|
|81.||Kim BJ. Hepatitis B virus mutations related to liver disease progression of Korean patients. World J Gastroenterol. 2014;20:460-467. [PubMed] [DOI]|
|82.||Osiowy C, Larke B, Giles E. Distinct geographical and demographic distribution of hepatitis B virus genotypes in the Canadian Arctic as revealed through an extensive molecular epidemiological survey. J Viral Hepat. 2011;18:e11-e19. [PubMed] [DOI]|
|83.||Alvarado-Mora MV, Pinho JR. Distribution of HBV genotypes in Latin America. Antivir Ther. 2013;18:459-465. [PubMed] [DOI]|
|84.||Alvarado-Mora MV, Pinho JR. Epidemiological update of hepatitis B, C and delta in Latin America. Antivir Ther. 2013;18:429-433. [PubMed] [DOI]|
|85.||Alvarado-Esquivel C, Sablon E, Conde-González CJ, Juárez-Figueroa L, Ruiz-Maya L, Aguilar-Benavides S. Molecular analysis of hepatitis B virus isolates in Mexico: predominant circulation of hepatitis B virus genotype H. World J Gastroenterol. 2006;12:6540-6545. [PubMed]|
|86.||Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS, Luketic VA, Terrault N. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125:444-451. [PubMed]|
|87.||Bell SJ, Lau A, Thompson A, Watson KJ, Demediuk B, Shaw G, Chen RY, Ayres A, Yuen L, Bartholomeusz A. Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients. J Clin Virol. 2005;32:122-127. [PubMed]|
|88.||Utsumi T, Yano Y, Truong BX, Tanaka Y, Mizokami M, Seo Y, Kasuga M, Kawabata M, Hayashi Y. Molecular epidemiological study of hepatitis B virus infection in two different ethnic populations from the Solomon Islands. J Med Virol. 2007;79:229-235. [PubMed] [DOI]|
|89.||Ito K, Yotsuyanagi H, Yatsuhashi H, Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T. Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults. Hepatology. 2014;59:89-97. [PubMed] [DOI]|
|90.||Zhang HW, Yin JH, Li YT, Li CZ, Ren H, Gu CY, Wu HY, Liang XS, Zhang P, Zhao JF. Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China. Gut. 2008;57:1713-1720. [PubMed] [DOI]|
|91.||Wai CT, Fontana RJ, Polson J, Hussain M, Shakil AO, Han SH, Davern TJ, Lee WM, Lok AS. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat. 2005;12:192-198. [PubMed] [DOI]|
|92.||Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol. 2004;72:363-369. [PubMed] [DOI]|
|93.||Ni YH, Chang MH, Wang KJ, Hsu HY, Chen HL, Kao JH, Yeh SH, Jeng YM, Tsai KS, Chen DS. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology. 2004;127:1733-1738. [PubMed] [DOI]|
|94.||Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology. 2002;122:1756-1762. [PubMed] [DOI]|
|95.||Livingston SE, Simonetti JP, Bulkow LR, Homan CE, Snowball MM, Cagle HH, Negus SE, McMahon BJ. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology. 2007;133:1452-1457. [PubMed] [DOI]|
|96.||Kao JH, Chen PJ, Lai MY, Chen DS. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol. 2002;40:1207-1209. [PubMed]|
|97.||Yuen MF, Wong DK, Sablon E, Tse E, Ng IO, Yuan HJ, Siu CW, Sander TJ, Bourne EJ, Hall JG. HBsAg seroclearance in chronic hepatitis B in the Chinese: virological, histological, and clinical aspects. Hepatology. 2004;39:1694-1701. [PubMed] [DOI]|
|98.||Sánchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodés J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology. 2002;123:1848-1856. [PubMed] [DOI]|
|99.||Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, Shih WL, Kao JH, Chen DS, Chen CJ. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265-272. [PubMed]|
|100.||Oommen PT, Wirth S, Wintermeyer P, Gerner P. Relationship between viral load and genotypes of hepatitis B virus in children with chronic hepatitis B. J Pediatr Gastroenterol Nutr. 2006;43:342-347. [PubMed] [DOI]|
|101.||Yousif M, Mudawi H, Bakhiet S, Glebe D, Kramvis A. Molecular characterization of hepatitis B virus in liver disease patients and asymptomatic carriers of the virus in Sudan. BMC Infect Dis. 2013;13:328. [PubMed] [DOI]|
|102.||Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. J Hepatol. 2005;43:411-417. [PubMed] [DOI]|
|103.||Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, Kanda T, Fukai K, Kato M, Saisho H. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology. 2003;37:19-26. [PubMed] [DOI]|
|104.||Chan HL, Wong GL, Tse CH, Chim AM, Yiu KK, Chan HY, Sung JJ, Wong VW. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B. Clin Gastroenterol Hepatol. 2009;7:1361-1366. [PubMed]|
|105.||Chan HL, Tsang SW, Liew CT, Tse CH, Wong ML, Ching JY, Leung NW, Tam JS, Sung JJ. Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection. Am J Gastroenterol. 2002;97:406-412. [PubMed] [DOI]|
|106.||Kowalec K, Minuk GY, Børresen ML, Koch A, McMahon BJ, Simons B, Osiowy C. Genetic diversity of hepatitis B virus genotypes B6, D and F among circumpolar indigenous individuals. J Viral Hepat. 2013;20:122-130. [PubMed] [DOI]|
|107.||Marciano S, Galdame OA, Gadano AC. HBV genotype F: natural history and treatment. Antivir Ther. 2013;18:485-488. [PubMed] [DOI]|
|108.||Thakur V, Guptan RC, Kazim SN, Malhotra V, Sarin SK. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol. 2002;17:165-170. [PubMed] [DOI]|
|109.||Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48:335-352. [PubMed]|
|110.||Liaw YF, Brunetto MR, Hadziyannis S. The natural history of chronic HBV infection and geographical differences. Antivir Ther. 2010;15 Suppl 3:25-33. [PubMed] [DOI]|
|111.||Roman S, Panduro A. HBV endemicity in Mexico is associated with HBV genotypes H and G. World J Gastroenterol. 2013;19:5446-5453. [PubMed] [DOI]|
|112.||Roman S, Tanaka Y, Khan A, Kurbanov F, Kato H, Mizokami M, Panduro A. Occult hepatitis B in the genotype H-infected Nahuas and Huichol native Mexican population. J Med Virol. 2010;82:1527-1536. [PubMed] [DOI]|
|113.||Yang HI, Yeh SH, Chen PJ, Iloeje UH, Jen CL, Su J, Wang LY, Lu SN, You SL, Chen DS. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:1134-1143. [PubMed]|
|114.||Chen JD, Liu CJ, Lee PH, Chen PJ, Lai MY, Kao JH, Chen DS. Hepatitis B genotypes correlate with tumor recurrence after curative resection of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2004;2:64-71. [PubMed] [DOI]|
|115.||Lin CL, Chen JD, Liu CJ, Lee PH, Chen PJ, Lai MY, Kao JH, Chen DS. Clinicopathological differences between hepatitis B viral genotype B- and C-related resectable hepatocellular carcinoma. J Viral Hepat. 2007;14:64-69. [PubMed] [DOI]|
|116.||Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology. 2000;118:554-559. [PubMed]|
|117.||Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol. 2005;75:513-521. [PubMed] [DOI]|
|118.||Kew MC. Hepatocellular carcinoma in African Blacks: Recent progress in etiology and pathogenesis. World J Hepatol. 2010;2:65-73. [PubMed] [DOI]|
|119.||Livingston SE, Simonetti JP, McMahon BJ, Bulkow LR, Hurlburt KJ, Homan CE, Snowball MM, Cagle HH, Williams JL, Chulanov VP. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis. 2007;195:5-11. [PubMed] [DOI]|
|120.||Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TM, Gerken G, de Man RA, Niesters HG, Zondervan P, Hansen B, Schalm SW. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-129. [PubMed] [DOI]|
|121.||Boglione L, Cusato J, Cariti G, Di Perri G, D’Avolio A. The E genotype of hepatitis B: clinical and virological characteristics, and response to interferon. J Infect. 2014;69:81-87. [PubMed] [DOI]|
|122.||Erhardt A, Göbel T, Ludwig A, Lau GK, Marcellin P, van Bömmel F, Heinzel-Pleines U, Adams O, Häussinger D. Response to antiviral treatment in patients infected with hepatitis B virus genotypes E-H. J Med Virol. 2009;81:1716-1720. [PubMed] [DOI]|
|123.||Buster EH, Hansen BE, Lau GK, Piratvisuth T, Zeuzem S, Steyerberg EW, Janssen HL. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137:2002-2009. [PubMed] [DOI]|
|124.||Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, Germanidis G, Yurdaydin C, Diago M, Gurel S. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56:699-705. [PubMed] [DOI]|
|125.||Sonneveld MJ, Hansen BE, Piratvisuth T, Jia JD, Zeuzem S, Gane E, Liaw YF, Xie Q, Heathcote EJ, Chan HL. Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology. 2013;58:872-880. [PubMed] [DOI]|
|126.||European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167-185. [PubMed] [DOI]|
|127.||Rijckborst V, Hansen BE, Ferenci P, Brunetto MR, Tabak F, Cakaloglu Y, Lanza AG, Messina V, Iannacone C, Massetto B. Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a. J Hepatol. 2012;56:1006-1011. [PubMed] [DOI]|
|128.||Brunetto MR, Marcellin P, Cherubini B, Yurdaydin C, Farci P, Hadziyannis SJ, Rothe V, Regep L, Bonino F. Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: on-treatment kinetics of HBsAg serum levels vary by HBV genotype. J Hepatol. 2013;59:1153-1159. [PubMed] [DOI]|
|129.||Damerow H, Yuen L, Wiegand J, Walker C, Bock CT, Locarnini S, Tillmann HL. Mutation pattern of lamivudine resistance in relation to hepatitis B genotypes: hepatitis B genotypes differ in their lamivudine resistance associated mutation pattern. J Med Virol. 2010;82:1850-1858. [PubMed] [DOI]|
|130.||Nowak MA, Bonhoeffer S, Hill AM, Boehme R, Thomas HC, McDade H. Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci USA. 1996;93:4398-4402. [PubMed]|
|131.||Rodriguez-Frias F, Buti M, Tabernero D, Homs M. Quasispecies structure, cornerstone of hepatitis B virus infection: mass sequencing approach. World J Gastroenterol. 2013;19:6995-7023. [PubMed] [DOI]|
|132.||Locarnini S. Molecular virology and the development of resistant mutants: implications for therapy. Semin Liver Dis. 2005;25 Suppl 1:9-19. [PubMed] [DOI]|
|133.||Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis. 2006;26:130-141. [PubMed] [DOI]|
|134.||Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989;2:588-591. [PubMed]|
|135.||Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA. 1994;91:4077-4081. [PubMed]|
|136.||Li JS, Tong SP, Wen YM, Vitvitski L, Zhang Q, Trépo C. Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region. J Virol. 1993;67:5402-5410. [PubMed]|
|137.||McMahon BJ. The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B. Hepatol Int. 2009;3:334-342. [PubMed] [DOI]|
|138.||Volz T, Lutgehetmann M, Wachtler P, Jacob A, Quaas A, Murray JM, Dandri M, Petersen J. Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients. Gastroenterology. 2007;133:843-852. [PubMed] [DOI]|
|139.||Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci USA. 1990;87:6599-6603. [PubMed]|
|140.||Lang T, Lo C, Skinner N, Locarnini S, Visvanathan K, Mansell A. The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. J Hepatol. 2011;55:762-769. [PubMed] [DOI]|
|141.||Milich D, Liang TJ. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology. 2003;38:1075-1086. [PubMed] [DOI]|
|142.||Chotiyaputta W, Lok AS. Hepatitis B virus variants. Nat Rev Gastroenterol Hepatol. 2009;6:453-462. [PubMed] [DOI]|
|143.||Nordin M, Ingman M, Lindqvist B, Kidd-Ljunggren K. Variability in the precore and core promoter region of the hepatitis B virus genome. J Med Virol. 2014;86:437-445. [PubMed] [DOI]|
|144.||Bozkaya H, Ayola B, Lok AS. High rate of mutations in the hepatitis B core gene during the immune clearance phase of chronic hepatitis B virus infection. Hepatology. 1996;24:32-37. [PubMed] [DOI]|
|145.||Lim SG, Cheng Y, Guindon S, Seet BL, Lee LY, Hu P, Wasser S, Peter FJ, Tan T, Goode M. Viral quasi-species evolution during hepatitis Be antigen seroconversion. Gastroenterology. 2007;133:951-958. [PubMed] [DOI]|
|146.||Thompson A, Locarnini S, Visvanathan K. The natural history and the staging of chronic hepatitis B: time for reevaluation of the virus-host relationship based on molecular virology and immunopathogenesis considerations? Gastroenterology. 2007;133:1031-1035. [PubMed] [DOI]|
|147.||Ozasa A, Tanaka Y, Orito E, Sugiyama M, Kang JH, Hige S, Kuramitsu T, Suzuki K, Tanaka E, Okada S. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology. 2006;44:326-334. [PubMed] [DOI]|
|148.||Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS. Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol. 2004;72:545-550. [PubMed] [DOI]|
|149.||Liao Y, Hu X, Chen J, Cai B, Tang J, Ying B, Wang H, Wang L. Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. PLoS One. 2012;7:e38394. [PubMed] [DOI]|
|150.||Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, Tanaka T, Miyakawa Y, Mayumi M. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol. 1994;68:8102-8110. [PubMed]|
|151.||Günther S, Piwon N, Will H. Wild-type levels of pregenomic RNA and replication but reduced pre-C RNA and e-antigen synthesis of hepatitis B virus with C(1653) --& gt; T, A(1762) --& gt; T and G(1764) --& gt; A mutations in the core promoter. J Gen Virol. 1998;79:375-380. [PubMed]|
|152.||Tacke F, Gehrke C, Luedde T, Heim A, Manns MP, Trautwein C. Basal core promoter and precore mutations in the hepatitis B virus genome enhance replication efficacy of Lamivudine-resistant mutants. J Virol. 2004;78:8524-8535. [PubMed] [DOI]|
|153.||Parekh S, Zoulim F, Ahn SH, Tsai A, Li J, Kawai S, Khan N, Trépo C, Wands J, Tong S. Genome replication, virion secretion, and e antigen expression of naturally occurring hepatitis B virus core promoter mutants. J Virol. 2003;77:6601-6612. [PubMed] [DOI]|
|154.||Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology. 2003;124:327-334. [PubMed] [DOI]|
|155.||Chan HL, Hussain M, Lok AS. Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology. 1999;29:976-984. [PubMed] [DOI]|
|156.||Yuen MF, Tanaka Y, Ng IO, Mizokami M, Yuen JC, Wong DK, Yuan HJ, Sum SM, Chan AO, Lai CL. Hepatic necroinflammation and fibrosis in patients with genotypes Ba and C, core-promoter and precore mutations. J Viral Hepat. 2005;12:513-518. [PubMed]|
|157.||Lin CL, Liao LY, Wang CS, Chen PJ, Lai MY, Chen DS, Kao JH. Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B. Liver Int. 2005;25:564-570. [PubMed] [DOI]|
|158.||Orito E, Mizokami M, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, Okanoue T, Yotsuyanagi H, Iino S. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group. Hepatology. 2001;33:218-223. [PubMed]|
|159.||Tseng TC, Liu CJ, Yang HC, Chen CL, Yang WT, Tsai CS, Kuo SF, Verbree FC, Su TH, Wang CC. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut. 2015;64:292-302. [PubMed] [DOI]|
|160.||Yuen MF, Tanaka Y, Mizokami M, Yuen JC, Wong DK, Yuan HJ, Sum SM, Chan AO, Wong BC, Lai CL. Role of hepatitis B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study. Carcinogenesis. 2004;25:1593-1598. [PubMed] [DOI]|
|161.||Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, Chen DS. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis. 2006;194:594-599. [PubMed] [DOI]|
|162.||Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst. 2009;101:1066-1082. [PubMed] [DOI]|
|163.||Baptista M, Kramvis A, Kew MC. High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers. Hepatology. 1999;29:946-953. [PubMed] [DOI]|
|164.||Yang HC, Chen CL, Shen YC, Peng CY, Liu CJ, Tseng TC, Su TH, Chuang WL, Yu ML, Dai CY. Distinct evolution and predictive value of hepatitis B virus precore and basal core promoter mutations in interferon-induced hepatitis B e antigen seroconversion. Hepatology. 2013;57:934-943. [PubMed] [DOI]|
|165.||Carman WF, Zanetti AR, Karayiannis P, Waters J, Manzillo G, Tanzi E, Zuckerman AJ, Thomas HC. Vaccine-induced escape mutant of hepatitis B virus. Lancet. 1990;336:325-329. [PubMed] [DOI]|
|166.||Zuckerman JN, Zuckerman AJ. Mutations of the surface protein of hepatitis B virus. Antiviral Res. 2003;60:75-78. [PubMed] [DOI]|
|167.||Teo CG, Locarnini SA. Potential threat of drug-resistant and vaccine-escape HBV mutants to public health. Antivir Ther. 2010;15:445-449. [PubMed] [DOI]|
|168.||Flanagan E, Thompson AJ, Colledge D, Edwards R, Littlejohn M, Walsh R, Warner N, Bowden DS, Iser DM. A novel hepatitis B virus S gene insertion associated with reduced humoral immunity and diagnostic escape. Intern Med J. 2014;44:709-710. [PubMed] [DOI]|
|169.||Locarnini SA, Yuen L. Molecular genesis of drug-resistant and vaccine-escape HBV mutants. Antivir Ther. 2010;15:451-461. [PubMed] [DOI]|
|170.||Oon CJ, Chen WN. Current aspects of hepatitis B surface antigen mutants in Singapore. J Viral Hepat. 1998;5 Suppl 2:17-23. [PubMed] [DOI]|
|171.||Davies J, Littlejohn M, Locarnini SA, Whiting S, Hajkowicz K, Cowie BC, Bowden DS, Tong SY, Davis JS. Molecular epidemiology of hepatitis B in the Indigenous people of northern Australia. J Gastroenterol Hepatol. 2013;28:1234-1241. [PubMed] [DOI]|
|172.||Carman WF, Trautwein C, van Deursen FJ, Colman K, Dornan E, McIntyre G, Waters J, Kliem V, Müller R, Thomas HC. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology. 1996;24:489-493. [PubMed] [DOI]|
|173.||Larralde O, Dow B, Jarvis L, Davidson F, Petrik J. Hepatitis B escape mutants in Scottish blood donors. Med Microbiol Immunol. 2013;202:207-214. [PubMed] [DOI]|
|174.||Ma Q, Wang Y. Comprehensive analysis of the prevalence of hepatitis B virus escape mutations in the major hydrophilic region of surface antigen. J Med Virol. 2012;84:198-206. [PubMed] [DOI]|
|175.||Lieshout-Krikke RW, Molenaar-de Backer MW, van Swieten P, Zaaijer HL. Surface antigen-negative hepatitis B virus infection in Dutch blood donors. Eur J Clin Microbiol Infect Dis. 2014;33:69-77. [PubMed] [DOI]|
|176.||Gerken G, Kremsdorf D, Petit MA, Manns M, Meyer zum Büschenfelde KH, Bréchot C. Hepatitis B defective virus with rearrangements in the preS gene during HBV chronic infection. J Hepatol. 1991;13 Suppl 4:S93-S96. [PubMed] [DOI]|
|177.||Fernholz D, Stemler M, Brunetto M, Bonino F, Will H. Replicating and virion secreting hepatitis B mutant virus unable to produce preS2 protein. J Hepatol. 1991;13 Suppl 4:S102-S104. [PubMed] [DOI]|
|178.||Fan YF, Lu CC, Chen WC, Yao WJ, Wang HC, Chang TT, Lei HY, Shiau AL, Su IJ. Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection. Hepatology. 2001;33:277-286. [PubMed] [DOI]|
|179.||Choi MS, Kim DY, Lee DH, Lee JH, Koh KC, Paik SW, Rhee JC, Yoo BC. Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection. J Viral Hepat. 2007;14:161-168. [PubMed] [DOI]|
|180.||Sugauchi F, Ohno T, Orito E, Sakugawa H, Ichida T, Komatsu M, Kuramitsu T, Ueda R, Miyakawa Y, Mizokami M. Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease. J Med Virol. 2003;70:537-544. [PubMed] [DOI]|
|181.||Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS. High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology. 2006;130:1153-1168. [PubMed] [DOI]|
|182.||Yeung P, Wong DK, Lai CL, Fung J, Seto WK, Yuen MF. Association of hepatitis B virus pre-S deletions with the development of hepatocellular carcinoma in chronic hepatitis B. J Infect Dis. 2011;203:646-654. [PubMed] [DOI]|
|183.||Yang HI, Sherman M, Su J, Chen PJ, Liaw YF, Iloeje UH, Chen CJ. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Clin Oncol. 2010;28:2437-2444. [PubMed] [DOI]|