Clinical significance of hepatitis B virus genotypes

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.