ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Clinical significance of hepatitis B virus genotypes

Clinical significance of hepatitis B virus genotypes
Author:
Anna SF Lok, MD
Section Editor:
Rafael Esteban, MD
Deputy Editor:
Jennifer Mitty, MD, MPH
Literature review current through: May 2024.
This topic last updated: Oct 04, 2022.

INTRODUCTION — Hepatitis B virus (HBV), a member of the Hepadnaviridae family, replicates asymmetrically via reverse transcription of an RNA intermediate [1]. Because the viral polymerase lacks proofreading activity during reverse transcription of the pregenomic RNA, mutations are common accounting for genetic heterogeneity of HBV. The estimated mutation rate of the hepadnavirus genome is about 2 x 10(4) base substitutions/site/year, about 100 times higher than that of other DNA viruses but about 100 to 1000 times lower than that of other RNA viruses [2]. According to phylogenetic analyses, HBV can be classified into 10 genotypes (A to J) based upon an inter-group divergence of 8 percent or more in the complete nucleotide sequence [3-5]. There is growing evidence suggesting that HBV genotypes influence clinical outcomes, HBeAg seroconversion rates, mutational patterns in the precore and core promoter regions, and response to interferon therapy. This topic will provide a concise review on the clinical significance of HBV genotypes.

EPIDEMIOLOGY — The prevalence of specific genotypes varies geographically (figure 1) [4,6-8]:

Genotype A is found mainly in Northern Europe, North America, India, and Africa

Genotype B and C are prevalent in Asia

Genotype D is more common in Southern Europe, the Middle East, and India

Genotype E is restricted to West Africa

Genotype F is found in Central and South America

Genotype G has been reported in France, Germany, and the United States

Genotype H has been found in Central America

Genotype I is found in Vietnam and Laos

Genotype J was identified in the Ryukyu Islands in Japan

However, the existing information is still incomplete since data are not available from many parts of the world, and for genotypes G through J, data are based upon very small numbers of patients in a few countries only.

Several large population-based studies have evaluated the distribution of HBV genotypes in the United States, which are summarized below. Considered together, they suggest that genotypes B and C are most common among those with chronic HBV, while genotype A is most common among those with acute HBV. The preponderance of genotypes B and C among those with chronic HBV infection in the United States is largely due to migration of individuals who acquired HBV infection in Asian countries.

Two studies from the Hepatitis B Research Network described the distribution of HBV genotypes in children and adults in the United States and Canada [9,10].

Among the 343 children and adolescents with chronic HBV (age range of 1 to 18 years), the majority had HBV genotypes B or C (43 and 32 percent, respectively) [10]. The others had genotype A (5 percent), D (16 percent), or E (4 percent). Approximately 80 percent of the children were Asian, and about half of those children were adopted.

Among the 1615 adults with chronic HBV that were evaluated, the distribution of HBV genotypes were A (18 percent), B (39 percent), C (33 percent), D (8 percent), and E (3 percent) [9]. Only 18 percent of these adults were born in North America; of those who were born outside North America, most were from Asia (67 percent) and Africa (11 percent). In a separate report that compared United States-born and foreign-born African Americans, distribution of HBV genotypes varied by country of birth with 84 percent of US-born African Americans infected with genotype A subtype A2, 78 percent of East Africa-born African Americans infected with genotype A subtype A1, and 67 percent of West Africa-born African Americans infected with genotype E [11].

An earlier study (involving 694 patients with chronic HBV from 17 medical centers in the United States) identified seven genotypes (A to G) of which genotypes A and C were most common (representing 35 and 31 percent of the cohort, respectively) [12]. HBV genotypes B and C accounted for 75 percent of the patients on the west coast, whereas genotypes A and D accounted for 74 percent of the patients in the south. There was a strong correlation between genotype and ethnicity. Genotype A was more common among White persons and African Americans, and those with sexually acquired HBV infection while genotypes B and C were seen mostly in Asian persons, and those who acquired HBV through maternal-infant transmission. This study also underscored the impact of patient migration from Asia on the epidemiology of HBV genotypes in the United States.

One study evaluated 614 patients across six counties in the United States who developed acute HBV between 1999 and 2005 [13]. The majority (75 percent) were infected with HBV genotype A, while 18 percent were infected with genotype D. Genotype A infection was much more common among African American compared with Hispanic persons. Genotype A was less common among recent drug users than among non-injection drug users.

SUBGROUPS — HBV genotypes can be further subdivided based upon their distinct ethnic and geographic origins. Subgroups of genotypes have been reported for most genotypes including A [14], B [15,16], and C [17,18], although the most detailed findings have been published for genotype B:

Two subtypes of genotype B have been identified (Ba and Bj). Genotype Ba (B2) arises from a recombination between HBV genotype B and C and has been found in many Asian countries, while genotype Bj (B1) (which does not appear to have arisen from recombination with genotype C) is found mainly in Japan [15]. Genotype Ba is more commonly associated with the presence of HBeAg although the role of HBV subgroups in determining clinical outcome remains to be studied [15,16]. A cross-sectional study from Japan found that fulminant hepatitis was associated with genotype Bj, lack of HBeAg, and high replication due to precore mutants [19].

African subtype A1 is associated with a more rapid progression and a higher incidence of hepatocellular carcinoma than the European subtype A2 [20]. (See 'Hepatocellular carcinoma' below.)

RECOMBINATION AND COINFECTION — Recombinations between HBV genotypes have been reported [21-25].

Patients may be coinfected with more than one genotype. Although the clinical consequences are unclear, antiviral treatment in patients coinfected with more than one genotype may lead to a shift in the predominant genotype [26]. Other reports have demonstrated that infection with HBV genotype G appears to be always associated with genotype A infection [27,28].

RELATIONSHIP OF GENOTYPES TO SEROTYPES — HBV was traditionally classified into four subtypes or serotypes (adr, adw, ayr, and ayw) based upon antigenic determinants of the hepatitis B surface antigen (HBsAg) [29]. The common determinant is "a" while "d/y" and "r/w" are mutually exclusive sub-determinants. HBV has been further classified into nine different serotypes (ayw1, ayw2, ayw3, ayw4, ayr, adw2, adw4, adrq+, and adrq-) [30]. While several studies have been conducted to investigate the relationship between HBV serotypes and genotypes [31-34], the results are incomplete because of the limited number of isolates analyzed. In addition, the same serotype may be classified into different genotypes (table 1) [31].

DETERMINATION OF GENOTYPES — Genotypic differences of HBV can be reflected in a partial sequence of the genome such as the pre-S or S gene [3]. Thus, genotyping can be accomplished without determining the entire genomic sequence. The sequence of the S gene is more conserved and thus more suitable for genotyping than the pre-S region [35]. Several methods have been used for HBV genotyping:

Direct sequencing — Samples are amplified by polymerase chain reaction (PCR) using primers in the pre-S or S regions, directly sequenced, and the sequences are then compared against published sequences to determine homology with known genotypes [4,32].

Restriction fragment length polymorphism (RFLP) — PCR products of HBV S gene containing type-specific regions are digested by restriction enzymes; HBV genotypes can be differentiated based upon difference in sizes of the digested fragments [7,35].

Line probe assay — Amplicons of HBV S gene are hybridized to strips pre-coated with type-specific oligonucleotide probes and HBV genotypes are determined based upon the pattern of reactive bands [36,37].

Enzyme-linked immunosorbent assay (ELISA) — ELISA uses monoclonal antibodies to genotype-specific epitopes of the preS2-region [38].

Genotype-specific PCR [39] or multiplex PCR [40] — Genotype-specific primers are used for PCR reaction. One study described quantification of HBV DNA and genotyping in a single reaction by real-time PCR and melting curve analysis [41].

Mass spectrometry — Amplicons of HBV S gene are subjected to base-specific cleavage and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF) [42]. The resulting mass peak patterns are used to identify the HBV genotype by automated comparison with the peak patterns simulated from reference sets of HBV sequences of known genotypes. This method has been shown to have a high concordance with sequencing and is amenable to high volume and automated data reporting.

GENOTYPES/SEROTYPES-DISEASE PROGRESSION AND HBEAG SEROCONVERSION — Most of the information on the clinical significance of HBV genotypes has been based upon studies of patients with chronic HBV infection in Asia. Because of the preponderance of genotypes B and C in Asian countries, the studies have generally been restricted to comparisons of patients with these two genotypes (table 2). Nevertheless, such comparisons provide important information on the relation between HBV genotype B and C and the rate of progression of liver disease, since the age at the onset of infection is presumed to be the same (perinatal period) in the vast majority of patients.

The earliest study done in Japan (involving 1744 patients) found that liver dysfunction (defined as abnormal aminotransferase levels) was observed less frequently in hepatitis B carriers with adw serotype (mainly genotype B) compared with those with adr serotype (mainly genotype C) [43]. Several subsequent studies confirmed that compared with genotype C, HBV genotype B is associated with less active liver disease and a slower rate of progression to cirrhosis [44-49].

Many cross-sectional studies, mostly in Asian patients, found that the prevalence of HBeAg was higher in patients with genotype C than those with genotype B [12,43,44,47,48,50]. In addition, several longitudinal follow-up studies showed that the cumulative rate of spontaneous HBeAg seroconversion was significantly higher in patients with genotype B compared with those with genotype C [47,50-54]. Taken together, these studies showed that spontaneous HBeAg seroconversion occurred earlier and possibly at a higher rate in patients with HBV genotype B than those with genotype C. One study also found that genotype B patients were less likely to have abortive ALT flares before HBeAg seroconversion and more sustained biochemical remission after HBeAg seroconversion [50]. A longer duration of high levels of HBV replication may contribute to more active liver disease and, in turn, a higher rate of progression to cirrhosis among patients with HBV genotype C.

There is a paucity of data on the clinical course of patients with genotypes other than B and C. Genotypes A and D are prevalent in the Indian subcontinent. In one study genotype D was associated with more severe liver disease [55]. However, this finding was not confirmed by another study from West India [56]. Another study on 258 Spanish patients with chronic HBV infection (52 percent A, 35 percent D, 7 percent F) found that HBeAg seroconversion rates were similar in patients with genotypes A and D, but sustained biochemical and virological remission was more common in patients with genotype A who had HBeAg seroconversion [57]. HBsAg clearance occurred more often in patients with genotype A compared with genotype D, while deaths related to liver disease occurred more often in patients with genotype F. There are several limitations with this study: the number of patients with genotype F was very small and some patients received interferon therapy during the study period. A study from Germany found that among children with chronic HBV infection, genotype D was associated with higher HBV DNA levels than genotype A [58].

There has been no published study comparing the rate of HBeAg seroconversion, activity of liver disease, and rate of progression to cirrhosis among patients with all known HBV genotypes. The lack of such studies is related to the preponderance of 1 or 2 HBV genotypes in most geographical regions. The finding of HBV genotypes A to G in the United States permits studies that compare the clinical course of HBV infection among patients with a wider spectrum of HBV genotypes. In one cross-sectional study of 694 patients in the United States, genotypes B and D were associated with a lower prevalence of HBeAg than genotype A, while genotype B was associated with a lower rate of hepatic decompensation compared with genotype A, C, or D [12]. However, other factors such as differences in ethnic/racial background, age at onset and duration of infection, and exposures to alcohol/environmental toxins rather than HBV genotypes may have contributed to the differences in clinical manifestations.

A study of 1158 Alaska native persons with chronic HBV infection found that among 507 persons who were initially HBeAg positive, time to spontaneous HBeAg clearance was longest in those with genotype C compared with persons with genotypes A, B, D, or F. Furthermore, genotypes C and F were associated with a higher rate of HBeAg reversion after HBeAg clearance [59].

Hepatocellular carcinoma — Studies on the relationship between HBV genotypes and hepatocellular carcinoma (HCC) have yielded conflicting results.

Several observational studies in East Asia (Japan, China, Hong Kong) and a 2013 meta-analysis have suggested that patients infected with HBV genotype C were more likely to develop HCC [60-64]. An analysis of a large cohort in Taiwan demonstrated that HBV genotype C and core promoter mutations were independently associated with increased risk of HCC, regardless of HBV DNA levels. Similarly, a study from the United States found that genotype C was associated with HCC in patients awaiting liver transplantation [65]. Longitudinal follow-up studies confirmed that HBV genotype C and high serum HBV DNA were independent predictors of HCC [66-68]. However, some studies [47,51] found that the lifetime risk of cirrhosis and HCC may not differ between patients with genotype B and C but adverse clinical outcomes occur later in patients with genotype B.

The major discrepant findings came from studies in Taiwan demonstrating that genotype B was more common than genotype C in younger (<35 years old) non-cirrhotic patients with HCC [45,54,69]. The discrepancy cannot be explained by different geographic distribution of genotype B subgroups (Ba and Bj) because studies from China and Hong Kong where the predominant subgroup is also Ba found that patients with genotype B had lower risk of HCC than those with genotype C.

Genotype A1, the subtype of genotype A found in Africa, is associated with a higher incidence of HCC than genotype A2, the subtype that is more common in Europe and the United States [20]. HBV-related HCC presents at an earlier age among patients in West Africa than those in East Africa; whether this is related to differences in predominant HBV genotype, E versus A1, or other factors such as host genetics or exposure to environmental carcinogens is not clear. An association between birth country and age at the time of HCC diagnosis has also been observed among Africans living in the United States [70].

A study of 1185 Alaska Natives followed for a median of 35.1 years found that HCC incidence was highest for those infected with genotype F followed by C, A, and D [71]. The relative rates for genotypes F, C, and A were 12.7 (95% CI, 6.1, 26.4), 10.6 (95% CI, 4.2, 26.0), and 2.9 (95% CI, 1.0, 8.0), respectively, compared to genotypes B and D.

Chronicity of infection — Several reports raised suspicion that HBV genotypes vary in their ability to induce chronic infection. Two studies from Japan with 57 and 53 cases of acute hepatitis supported the hypothesis that genotype A more often progressed to chronicity than genotype C [72-74]. Similar finding from Switzerland suggested that progression from acute to chronic hepatitis B was more likely with genotype A compared with genotype D [75]. Larger-scaled studies are needed to confirm these findings.

Fulminant hepatitis — Due to the rarity of the illness and the frequent absence of detectable serum HBV DNA at presentation, it has been difficult to investigate the role of HBV genotypes in fulminant hepatitis. One study reported that an outbreak of fulminant hepatitis in the United States was associated with genotype D [76]. Unfortunately, this study lacked a proper control group to establish any causal link and other factors such as HCV coinfection, and heavy exposure to alcohol, acetaminophen, and injected methamphetamine or cocaine rather than viral factors may be responsible for the fulminant course. A more comprehensive study by the United States Acute Liver Failure Study Group comparing 34 patients with HBV-related acute liver failure with a cohort of 530 patients with chronic HBV infection showed a higher prevalence of genotype D in the acute liver failure group (32 versus 16 percent) even after matching for race and HBeAg status [77]. The above results indicated that HBV genotypes may have a role in the outcome of acute infection.

SERUM QUANTITATIVE HBV DNA LEVELS — Studies evaluating the relation between HBV genotypes and HBV DNA levels have yielded conflicting results. As examples:

A study of blood donors found that patients with genotype C had higher serum HBV DNA levels compared with those with genotype B [78]. In contrast, two retrospective studies reported that serum HBV DNA levels were comparable between patients with genotype B and C, regardless of HBeAg status [47,51].

The United States nationwide study found that serum HBV DNA levels were comparable among the major genotypes (A to D) [12]. However, HBV DNA levels were tested at one time point only. Thus, a relation between HBV genotypes and serum HBV DNA levels cannot be definitively excluded.

Another study that focused on 694 patients who had participated in phase III trials of adefovir dipivoxil found that among HBeAg-positive patients, those infected with genotype C had significantly lower HBV DNA levels while among HBeAg-negative patients, those infected with genotype D had significantly higher HBV DNA levels [79]. It should be emphasized that patients in this study were participants of a clinical trial on antiviral therapy and may not be representative of patients with chronic HBV infection.

One prospective study of Taiwanese male HBsAg carriers found that HBV viral load was higher in those with genotype C compared with those with genotype B [67].

PRECORE VARIANTS — Mutations in the precore region of the HBV genome have been described in many HBeAg-negative patients who have persistent viremia and active liver disease [80-82]. The predominant mutation involves a G to A change at nucleotide 1896 (G1896A), which creates a premature stop codon (eW28X). This mutation prevents translation of the precore protein and completely abolishes the production of HBeAg. Nucleotide 1896 is engaged in the formation of a stem-loop structure, epsilon, which is required for the encapsidation of the pregenomic RNA into the nucleocapsid for completion of the viral replication cycle [83]. (See "Characteristics of the hepatitis B virus and pathogenesis of infection".)

Selection of the G1896A mutation is genotype-dependent and is more likely to occur when the nucleotide at the opposite position of the stem (nucleotide 1858) in the stem-loop structure of epsilon, the pregenome encapsidation signal, is T rather than C [84-86]. This may explain why HBeAg-negative chronic hepatitis B and the common precore variant G1896A are less frequently encountered in the United States and Northern Europe where genotype A (which almost always has a C at nucleotide 1858) is more common [7,37,85,86]. In contrast, in other parts of the world with a higher prevalence of precore mutants (such as Asia and the Mediterranean basin), HBV genotypes B, C, and D (which frequently have a T nucleotide at 1858) predominate [7].

An analysis of data from the Hepatitis B Research Network cohort study in North America found the G1896A variant present as the dominant species in 11 of 92 and 9 of 84 participants infected with genotype A1 and A2, respectively [87]. This was likely possible due to the presence of a C1858T variant in 17 of 20 participants with genotype A and G1896A variant, thus restoring base pairing in the epsilon structure. This study also found that precore and basal core promoter (BCP) variants can be present at a very young age, with the prevalence increasing from 14.4 percent in the first two decades of life to 51 percent after 40 years of age, Among HBeAg-positive patients, the interval between detection of precore G1896A variant and BCP A1762T/G1764A variant was shorter, reflecting the differential effects of these variants in stopping versus decreasing HBeAg production.

Two studies from Spain [86] and France [37] involving 42 and 151 patients with chronic HBV infection, respectively, found that the precore variant was most common among patients with genotype D (65 to 75 percent) and least common among patients with genotype A (9 to 18 percent). Most studies showed precore variant is more commonly associated with genotype B than C [44,47,48,88]. The nationwide study in the United States found that precore variant was detected in 3, 46, 24, and 73 percent of patients with genotype A, B, C and D, respectively [12].

CORE PROMOTER VARIANTS — The basal core promoter region (nucleotides 1742 to 1849) and the core upstream regulatory sequences (nucleotides 1643 to 1742) are located upstream of the precore region (nucleotides 1814 to 1901), and have an important role in HBV replication and HBeAg production [89]. Mutations in these regions downregulate precore mRNA transcription and HBeAg synthesis [90,91]. The most common core promoter variant involves a 2-nucleotide substitution: A to T at nucleotide 1762 and G to A at nucleotide 1764 (A1762T, G1764A) [92-94]. These changes were initially thought to be related to an "HBeAg-negative phenotype" but subsequent studies showed that they can also be found in some HBeAg-positive patients, especially those with chronic hepatitis [92,95].

The clinical and virologic significance of the basal core promoter mutations are not yet fully understood. Some [90,96,97] but not all [98] in vitro studies suggested that these changes may increase HBV replication. The core promoter variant has been associated with more severe liver damage [44,48,93,99,100] and HCC [63,100-102].

The prevalence of the core promoter variant varies among different HBV genotypes. Several studies found that the core promoter variant is more often detected in patients with HBV genotypes that preclude the selection of the precore variant [103,104]. Studies from Asia suggested that the dual core promoter variant (A1762T, G1764A) was more common in patients with genotype C than those with genotype B [44,48]. The United States nationwide study reported that the prevalence of core promoter variant among patients with genotype A, B, C and D were 41, 27, 60, and 42 percent, respectively [12].

In the Hepatitis B Research Network Study, core promoter variants were present in 26.9 percent of HBeAg-positive and in 42.1 percent of HBeAg-negative participants [87]. Core promoter variants were most frequently associated with genotype C followed by genotype D and A in both HBeAg-positive and HBeAg-negative participants. HBeAg-positive participants with dominant core promoter variants were more likely to clear HBeAg during follow-up compared to those with wild type sequence (15 versus 6 per 100 person-years).

PRE-S DELETION VARIANTS — Pre-S deletion variants have been associated with progressive liver disease and hepatocellular carcinoma (HCC). As an example, one case-control study in Taiwan found that the frequency of pre-S deletion was significantly higher in patients with genotype C compared with those with genotype B infection [105]. In addition, the presence of pre-S deletion was an independent risk factor for disease progression as well as HCC. A subsequent meta-analysis found that the odds ratio (OR) of HCC development for patients with pre-S deletion was 3.77 (95% CI 2.57-5.52) with a higher OR in patients with genotype C compared with genotype B [106].

RESPONSES TO INTERFERON — A number of reports have suggested that the response rate to interferon (IFN) therapy may be different among HBV genotypes.

Genotype B versus C: One study involving 58 patients in Taiwan found that the rate of HBeAg loss was significantly higher in patients with genotype B compared with those with genotype C (41 versus 15 percent) [107]. Similar conclusions were reached in a report that included 109 Chinese patients from Hong Kong (HBeAg clearance of 39 versus 17 percent for genotypes B versus C, respectively) [108]. Multivariate analysis showed that genotype B and lower pretreatment HBV DNA levels were independent predictors of antiviral response. Genotype A versus D: A study of 144 German patients (99 of them were HBeAg positive) found that the response rate to standard IFN therapy was higher among patients with genotype A than in those with genotype D, in both HBeAg-positive (46 versus 24 percent) and HBeAg-negative (59 versus 29 percent) patients [109].

Four major genotypes (A to D): A multinational trial included 266 patients with HBeAg-positive HBV who were randomly assigned to peginterferon alfa-2b alone or in combination with lamivudine for 52 weeks [110]. HBeAg loss was significantly higher for genotype A versus D (47 versus 25 percent) and for genotype B versus C (44 versus 28 percent). Genotype was an independent predictor of HBeAg loss on multivariate analysis. The rate of HBsAg seroconversion also differed according to genotype being significantly higher with genotype A versus D (13 versus 2 percent) [111]. Follow-up of these patients up to 3.5 years after stopping treatment showed that initial responders (HBeAg loss 26 weeks after stopping treatment) with genotype A were more likely to have a sustained response compared with patients with other genotypes. Sustained HBeAg loss was seen in 96 versus 76 percent, HBV DNA <400 copies/mL (approximately 80 international units/mL) in 65 versus 27 percent, and HBsAg loss in 28 versus 3 percent of patients with genotype A versus non-A, respectively [112] (see "Pegylated interferon for treatment of chronic hepatitis B virus infection"). Another study enrolling 814 HBeAg-positive patients found there were no differences in response rates between four major genotypes treated with pegylated interferon alfa-2a, lamivudine, or combination therapy [113].

Regarding the impact of HBV genotypes on sustained response in HBeAg-negative patients, retrospective analysis of 518 patients in a trial comparing 48 weeks of peginterferon alfa-2a alone, lamivudine alone, or combination of peginterferon alfa-2a and lamivudine found that, compared with genotype D, patients with genotype B (odds ratio: 3.69, P = 0.003) or genotype C (odds ratio: 5.46, P<0.001) were more likely to achieve ALT normalization and HBV DNA <2x10(4) copies/mL (approximately 400 international units/mL) one year after completion of treatment [114].

RESPONSES TO LAMIVUDINE — The correlation between HBV genotype and response to lamivudine has not been well-established.

Genotype B versus C: Several studies in Asia, all involving small numbers of patients and varying duration of lamivudine treatment, showed that HBeAg seroconversion occurred in similar proportions of patients with genotypes B and C [115,116]. The incidence of virological breakthrough and the patterns of mutations in the YMDD locus seemed unrelated to HBV genotypes [115-118]. However, two studies, one in HBeAg-positive and one in HBeAg-negative patients found that patients with genotype B were more likely to sustain their response than genotype C when treatment was discontinued [119,120].

Genotype A versus D: One study found that patients with adw serotype (mainly genotype A) were more likely to develop resistance to lamivudine than those with ayw serotype (mainly genotype D) [121]. However, this study was based upon only 26 patients. Studies from Italy and Germany found lamivudine-resistant mutants may emerge more rapidly in those with genotype A versus D, but a correlation with response was not reported [122,123]. A study involving 76 Indian patients showed genotype D achieved higher rate of sustained virological response than genotype A (29 versus 4 percent) [124]. However, the result was based upon a 12-month duration of therapy and heterogeneous (45 HBeAg-positive and 31 HBeAg-negative) study population.

RESPONSE TO ADEFOVIR DIPIVOXIL — The relation between HBV genotype and response to adefovir dipivoxil was studied in 694 patients who participated in the phase III trials [79]. HBV DNA reduction and HBeAg seroconversion occurred in similar proportions of patients with genotypes A to D at the end of 48-week treatment. However, this study combined HBeAg-positive and HBeAg-negative patients and did not provide data on durability of treatment response. In addition, the number of patients with HBeAg seroconversion was too small for a definitive conclusion on the relation between HBV genotype and adefovir-related HBeAg seroconversion. In another report, development of adefovir resistance was associated with genotype D [125].

RESPONSE TO ENTECAVIR OR TELBIVUDINE — The impact of HBV genotypes on drug resistance to entecavir has been evaluated in lamivudine-refractory patients [126]. The HBV genotype was not an independent factor of virological breakthrough. A clinical trial enrolling 458 HBeAg-positive and 222 HBeAg-negative patients [127] who received two years of telbivudine showed that HBeAg seroconversion, ALT normalization, and HBV DNA negativity by PCR were comparable among the four major genotypes.

RESPONSE TO TENOFOVIR WITH OR WITHOUT PEGINTERFERON — The combination of pegylated interferon (PegIFN) and tenofovir disoproxil fumarate may enhance the rate of HBsAg, particularly in those with genotype A infection. This was demonstrated in a randomized trial of 751 patients (58 percent HBeAg-positive), where all major genotypes were represented (approximately 9, 28, 42, and 21 percent had genotypes A, B, C, and D, respectively) [128]. Individuals received one of four regimens: tenofovir (300 mg daily) plus PegIFN alfa2a (180 mcg weekly) for 48 weeks; tenofovir plus PegIFN for 16 weeks followed by tenofovir alone for 32 weeks; tenofovir monotherapy for 120 weeks; or PegIFN monotherapy for 48 weeks. A significantly greater proportion of patients receiving combination therapy for 48 weeks had HBsAg loss at 72 weeks compared with those receiving monotherapy with tenofovir or PegIFN. Among patients receiving combination therapy for 48 weeks, HBsAg loss occurred in patients with all viral genotypes. However, HBsAg loss was most likely to occur in those with genotype A infection (38 and 33 percent for HBeAg-positive and HBeAg-negative patients, respectively, versus ≤11 percent for all others).

RECURRENCE AFTER TRANSPLANTATION — A pilot study suggested that patients infected with genotype D may be at increased risk for the development of HBV recurrence following liver transplantation [129]. Different conclusions were reached in a second report, which found no association between genotypes A or D and recurrence or any other clinical outcomes [130].

SUMMARY — Growing evidence suggests that hepatitis B virus (HBV) genotypes may influence HBeAg seroconversion rates, mutational patterns in the precore and core promoter regions, severity of liver disease, and response to interferon treatment. However, the role of HBV genotyping in guiding clinical decisions requires further study before it can be recommended routinely.

Because different HBV genotypes predominate in various parts of the world, the heterogeneity in disease manifestations and response to antiviral treatment among patients with chronic hepatitis B in different parts of the world may, at least in part, be attributed to differences in HBV genotypes. Despite increasing knowledge on the clinical relevance of HBV genotypes, routine testing for HBV genotypes in clinical practice is not warranted except for HBeAg-positive patients who are contemplating interferon therapy because of a much higher rate of HBeAg and HBsAg loss in those with genotype A, particularly subgenotype A2.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Chi-Jen Chu, who contributed to an earlier version of this topic review.

  1. Summers J, Mason WS. Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell 1982; 29:403.
  2. Girones R, Miller RH. Mutation rate of the hepadnavirus genome. Virology 1989; 170:595.
  3. Norder H, Couroucé AM, Magnius LO. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes. Virology 1994; 198:489.
  4. Stuyver L, De Gendt S, Van Geyt C, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol 2000; 81:67.
  5. 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.
  6. Norder H, Hammas B, Lee SD, et al. Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary structure of the surface antigen. J Gen Virol 1993; 74 ( Pt 7):1341.
  7. Lindh M, Andersson AS, Gusdal A. Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus--large-scale analysis using a new genotyping method. J Infect Dis 1997; 175:1285.
  8. Liu CJ, Kao JH. Global perspective on the natural history of chronic hepatitis B: role of hepatitis B virus genotypes A to J. Semin Liver Dis 2013; 33:97.
  9. Ghany MG, Perrillo R, Li R, et al. Characteristics of adults in the hepatitis B research network in North America reflect their country of origin and hepatitis B virus genotype. Clin Gastroenterol Hepatol 2015; 13:183.
  10. Schwarz KB, Cloonan YK, Ling SC, et al. Children with Chronic Hepatitis B in the United States and Canada. J Pediatr 2015; 167:1287.
  11. Hassan MA, Kim WR, Li R, et al. Characteristics of US-Born Versus Foreign-Born Americans of African Descent With Chronic Hepatitis B. Am J Epidemiol 2017; 186:356.
  12. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology 2003; 125:444.
  13. Teshale EH, Ramachandran S, Xia GL, et al. Genotypic distribution of hepatitis B virus (HBV) among acute cases of HBV infection, selected United States counties, 1999-2005. Clin Infect Dis 2011; 53:751.
  14. Sugauchi F, Kumada H, Acharya SA, et al. Epidemiological and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A. J Gen Virol 2004; 85:811.
  15. Sugauchi F, Orito E, Ichida T, et al. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C. Gastroenterology 2003; 124:925.
  16. Kobayashi M, Suzuki F, Akuta N, et al. Virological differences between patients infected with subtypes Ba and Bj of hepatitis B virus genotype B. J Gastroenterol Hepatol 2005; 20:570.
  17. Huy TT, Ushijima H, Quang VX, et al. Genotype C of hepatitis B virus can be classified into at least two subgroups. J Gen Virol 2004; 85:283.
  18. Chan HL, Tsui SK, Tse CH, et al. Epidemiological and virological characteristics of 2 subgroups of hepatitis B virus genotype C. J Infect Dis 2005; 191:2022.
  19. Ozasa A, Tanaka Y, Orito E, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology 2006; 44:326.
  20. Kew MC, Kramvis A, Yu MC, et al. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol 2005; 75:513.
  21. Bollyky PL, Rambaut A, Harvey PH, Holmes EC. Recombination between sequences of hepatitis B virus from different genotypes. J Mol Evol 1996; 42:97.
  22. Morozov V, Pisareva M, Groudinin M. Homologous recombination between different genotypes of hepatitis B virus. Gene 2000; 260:55.
  23. Bowyer SM, Sim JG. Relationships within and between genotypes of hepatitis B virus at points across the genome: footprints of recombination in certain isolates. J Gen Virol 2000; 81:379.
  24. Wang Z, Liu Z, Zeng G, et al. A new intertype recombinant between genotypes C and D of hepatitis B virus identified in China. J Gen Virol 2005; 86:985.
  25. Kurbanov F, Tanaka Y, Fujiwara K, et al. 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.
  26. Hannoun C, Krogsgaard K, Horal P, et al. Genotype mixtures of hepatitis B virus in patients treated with interferon. J Infect Dis 2002; 186:752.
  27. Kato H, Orito E, Gish RG, et al. Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology 2002; 35:922.
  28. Kremsdorf D, Garreau F, Capel F, et al. In vivo selection of a hepatitis B virus mutant with abnormal viral protein expression. J Gen Virol 1996; 77 ( Pt 5):929.
  29. Mazzur S, Burgert S, Blumberg BS. Geographical distribution of Australia antigen determinants d, y and w. Nature 1974; 247:38.
  30. Couroucé-Pauty AM, Lemaire JM, Roux JF. New hepatitis B surface antigen subtypes inside the ad category. Vox Sang 1978; 35:304.
  31. Okamoto H, Tsuda F, Sakugawa H, et al. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol 1988; 69 ( Pt 10):2575.
  32. Norder H, Hammas B, Löfdahl S, et al. 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 ( Pt 5):1201.
  33. Norder H, Couroucé AM, Magnius LO. Molecular basis of hepatitis B virus serotype variations within the four major subtypes. J Gen Virol 1992; 73 ( Pt 12):3141.
  34. Norder H, Couroucé AM, Coursaget P, et al. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology 2004; 47:289.
  35. Mizokami M, Nakano T, Orito E, et al. Hepatitis B virus genotype assignment using restriction fragment length polymorphism patterns. FEBS Lett 1999; 450:66.
  36. Grandjacques C, Pradat P, Stuyver L, et al. Rapid detection of genotypes and mutations in the pre-core promoter and the pre-core region of hepatitis B virus genome: correlation with viral persistence and disease severity. J Hepatol 2000; 33:430.
  37. Hussain M, Chu CJ, Sablon E, Lok AS. Rapid and sensitive assays for determination of hepatitis B virus (HBV) genotypes and detection of HBV precore and core promoter variants. J Clin Microbiol 2003; 41:3699.
  38. Usuda S, Okamoto H, Iwanari H, et al. Serological detection of hepatitis B virus genotypes by ELISA with monoclonal antibodies to type-specific epitopes in the preS2-region product. J Virol Methods 1999; 80:97.
  39. Naito H, Hayashi S, Abe K. Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers. J Clin Microbiol 2001; 39:362.
  40. Kirschberg O, Schüttler C, Repp R, Schaefer S. A multiplex-PCR to identify hepatitis B virus--enotypes A-F. J Clin Virol 2004; 29:39.
  41. Yeh SH, Tsai CY, Kao JH, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol 2004; 41:659.
  42. Ganova-Raeva L, Ramachandran S, Honisch C, et al. Robust hepatitis B virus genotyping by mass spectrometry. J Clin Microbiol 2010; 48:4161.
  43. Shiina S, Fujino H, Uta Y, et al. Relationship of HBsAg subtypes with HBeAg/anti-HBe status and chronic liver disease. Part I: Analysis of 1744 HBsAg carriers. Am J Gastroenterol 1991; 86:866.
  44. Lindh M, Hannoun C, Dhillon AP, et al. Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis 1999; 179:775.
  45. 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.
  46. 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.
  47. Sumi H, Yokosuka O, Seki N, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003; 37:19.
  48. Orito E, Mizokami M, Sakugawa H, et al. 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.
  49. Chan HL, Wong GL, Tse CH, et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B. Clin Gastroenterol Hepatol 2009; 7:1361.
  50. 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.
  51. Yuen MF, Sablon E, Yuan HJ, et al. Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma. Hepatology 2003; 37:562.
  52. Nakayoshi T, Maeshiro T, Nakayoshi T, et al. Difference in prognosis between patients infected with hepatitis B virus with genotype B and those with genotype C in the Okinawa Islands: a prospective study. J Med Virol 2003; 70:350.
  53. 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.
  54. Ni YH, Chang MH, Wang KJ, et al. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology 2004; 127:1733.
  55. Thakur V, Guptan RC, Kazim SN, et al. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol 2002; 17:165.
  56. Gandhe SS, Chadha MS, Arankalle VA. Hepatitis B virus genotypes and serotypes in western India: lack of clinical significance. J Med Virol 2003; 69:324.
  57. Sánchez-Tapias JM, Costa J, Mas A, et al. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002; 123:1848.
  58. 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.
  59. Livingston SE, Simonetti JP, Bulkow LR, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007; 133:1452.
  60. Orito E, Ichida T, Sakugawa H, et al. Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology 2001; 34:590.
  61. Fujie H, Moriya K, Shintani Y, et al. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan. Gastroenterology 2001; 120:1564.
  62. Ding X, Mizokami M, Yao G, et al. Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. Intervirology 2001; 44:43.
  63. Yang HI, Yeh SH, Chen PJ, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 2008; 100:1134.
  64. Wong GL, Chan HL, Yiu KK, et al. Meta-analysis: The association of hepatitis B virus genotypes and hepatocellular carcinoma. Aliment Pharmacol Ther 2013; 37:517.
  65. Gaglio P, Singh S, Degertekin B, et al. Impact of the hepatitis B virus genotype on pre- and post-liver transplantation outcomes. Liver Transpl 2008; 14:1420.
  66. Chan HL, Hui AY, Wong ML, et al. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 2004; 53:1494.
  67. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005; 97:265.
  68. Mahmood S, Niiyama G, Kamei A, et al. Influence of viral load and genotype in the progression of Hepatitis B-associated liver cirrhosis to hepatocellular carcinoma. Liver Int 2005; 25:220.
  69. Chen CH, Eng HL, Lee CM, et al. Correlations between hepatitis B virus genotype and cirrhotic or non-cirrhotic hepatoma. Hepatogastroenterology 2004; 51:552.
  70. Yang JD, Altekruse SF, Nguyen MH, et al. Impact of country of birth on age at the time of diagnosis of hepatocellular carcinoma in the United States. Cancer 2017; 123:81.
  71. McMahon BJ, Nolen LD, Snowball M, et al. HBV Genotype: A Significant Risk Factor in Determining Which Patients With Chronic HBV Infection Should Undergo Surveillance for HCC: The Hepatitis B Alaska Study. Hepatology 2021; 74:2965.
  72. Kobayashi M, Arase Y, Ikeda K, et al. Clinical characteristics of patients infected with hepatitis B virus genotypes A, B, and C. J Gastroenterol 2002; 37:35.
  73. Kobayashi M, Arase Y, Ikeda K, et al. Clinical features of hepatitis B virus genotype A in Japanese patients. J Gastroenterol 2003; 38:656.
  74. Suzuki Y, Kobayashi M, Ikeda K, et al. Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan. J Med Virol 2005; 76:33.
  75. Mayerat C, Mantegani A, Frei PC. Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection? J Viral Hepat 1999; 6:299.
  76. Garfein RS, Bower WA, Loney CM, et al. Factors associated with fulminant liver failure during an outbreak among injection drug users with acute hepatitis B. Hepatology 2004; 40:865.
  77. Wai CT, Fontana RJ, Polson J, et al. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat 2005; 12:192.
  78. Kao JH, Chen PJ, Lai MY, Chen DS. Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C. J Clin Microbiol 2002; 40:22.
  79. Westland C, Delaney W 4th, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology 2003; 125:107.
  80. Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989; 2:588.
  81. Akahane Y, Yamanaka T, Suzuki H, et al. Chronic active hepatitis with hepatitis B virus DNA and antibody against e antigen in the serum. Disturbed synthesis and secretion of e antigen from hepatocytes due to a point mutation in the precore region. Gastroenterology 1990; 99:1113.
  82. Brunetto MR, Giarin MM, Oliveri F, et al. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A 1991; 88:4186.
  83. Junker-Niepmann M, Bartenschlager R, Schaller H. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J 1990; 9:3389.
  84. 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 U S A 1994; 91:4077.
  85. Li JS, Tong SP, Wen YM, et al. 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.
  86. Rodriguez-Frias F, Buti M, Jardi R, et al. Hepatitis B virus infection: precore mutants and its relation to viral genotypes and core mutations. Hepatology 1995; 22:1641.
  87. Lau DTY, Ganova-Raeva L, Wang J, et al. Precore and Basal Core Promoter Hepatitis B Virus (HBV) Variants Are Present From a Young Age and Differ Across HBV Genotypes. Hepatology 2021; 73:1637.
  88. Watanabe K, Takahashi T, Takahashi S, et al. Comparative study of genotype B and C hepatitis B virus-induced chronic hepatitis in relation to the basic core promoter and precore mutations. J Gastroenterol Hepatol 2005; 20:441.
  89. Yuh CH, Chang YL, Ting LP. Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol 1992; 66:4073.
  90. Buckwold VE, Xu Z, Chen M, et al. Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 1996; 70:5845.
  91. Scaglioni PP, Melegari M, Wands JR. Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame. Virology 1997; 233:374.
  92. Okamoto H, Tsuda F, Akahane Y, et al. 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.
  93. Takahashi K, Aoyama K, Ohno N, et al. The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. J Gen Virol 1995; 76 ( Pt 12):3159.
  94. Kurosaki M, Enomoto N, Asahina Y, et al. Mutations in the core promoter region of hepatitis B virus in patients with chronic hepatitis B. J Med Virol 1996; 49:115.
  95. Kidd-Ljunggren K, Oberg M, Kidd AH. Hepatitis B virus X gene 1751 to 1764 mutations: implications for HBeAg status and disease. J Gen Virol 1997; 78 ( Pt 6):1469.
  96. Moriyama K, Okamoto H, Tsuda F, Mayumi M. Reduced precore transcription and enhanced core-pregenome transcription of hepatitis B virus DNA after replacement of the precore-core promoter with sequences associated with e antigen-seronegative persistent infections. Virology 1996; 226:269.
  97. Buckwold VE, Xu Z, Yen TS, Ou JH. Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication. J Gen Virol 1997; 78 ( Pt 8):2055.
  98. 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) --> T, A(1762) --> T and G(1764) --> A mutations in the core promoter. J Gen Virol 1998; 79 ( Pt 2):375.
  99. Sato S, Suzuki K, Akahane Y, et al. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995; 122:241.
  100. 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.
  101. Fang ZL, Ling R, Wang SS, et al. HBV core promoter mutations prevail in patients with hepatocellular carcinoma from Guangxi, China. J Med Virol 1998; 56:18.
  102. 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.
  103. 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.
  104. Chan HL, Leung NW, Hussain M, et al. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology 2000; 31:763.
  105. Lin CL, Liu CH, Chen W, et al. Association of pre-S deletion mutant of hepatitis B virus with risk of hepatocellular carcinoma. J Gastroenterol Hepatol 2007; 22:1098.
  106. Liu S, Zhang H, Gu C, et al. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 2009; 101:1066.
  107. Kao JH, Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J Hepatol 2000; 33:998.
  108. Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 2002; 36:1425.
  109. Erhardt A, Blondin D, Hauck K, et al. Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut 2005; 54:1009.
  110. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005; 365:123.
  111. Flink HJ, van Zonneveld M, Hansen BE, et al. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006; 101:297.
  112. Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology 2008; 135:459.
  113. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352:2682.
  114. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007; 56:699.
  115. Kao JH, Liu CJ, Chen DS. Hepatitis B viral genotypes and lamivudine resistance. J Hepatol 2002; 36:303.
  116. Yuen MF, Wong DK, Sablon E, et al. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther 2003; 8:531.
  117. Akuta N, Suzuki F, Kobayashi M, et al. The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment. J Hepatol 2003; 38:315.
  118. Yuen MF, Yuan HJ, Sablon E, et al. Long-term follow-up study of Chinese patients with YMDD mutations: significance of hepatitis B virus genotypes and characteristics of biochemical flares. J Clin Microbiol 2004; 42:3932.
  119. Chien RN, Yeh CT, Tsai SL, et al. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003; 38:1267.
  120. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2004; 11:432.
  121. Zöllner B, Petersen J, Schröter M, et al. 20-fold increase in risk of lamivudine resistance in hepatitis B virus subtype adw. Lancet 2001; 357:934.
  122. Buti M, Cotrina M, Valdes A, et al. Is hepatitis B virus subtype testing useful in predicting virological response and resistance to lamivudine? J Hepatol 2002; 36:445.
  123. Zöllner B, Petersen J, Puchhammer-Stöckl E, et al. Viral features of lamivudine resistant hepatitis B genotypes A and D. Hepatology 2004; 39:42.
  124. Thakur V, Sarin SK, Rehman S, et al. Role of HBV genotype in predicting response to lamivudine therapy in patients with chronic hepatitis B. Indian J Gastroenterol 2005; 24:12.
  125. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006; 44:283.
  126. Sherman M, Yurdaydin C, Simsek H, et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 2008; 48:99.
  127. Zeuzem S, Gane E, Liaw YF, et al. Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B. J Hepatol 2009; 51:11.
  128. Marcellin P, Ahn SH, Ma X, et al. Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B. Gastroenterology 2016; 150:134.
  129. Devarbhavi HC, Cohen AJ, Patel R, et al. Preliminary results: outcome of liver transplantation for hepatitis B virus varies by hepatitis B virus genotype. Liver Transpl 2002; 8:550.
  130. Girlanda R, Mohsen AH, Smith H, et al. Hepatitis B virus genotype A and D and clinical outcomes of liver transplantation for HBV-related disease. Liver Transpl 2004; 10:58.
Topic 3644 Version 19.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟