Hepatitis B virus genotype: A missing link in transmission risk and disease progression?


  • Potential conflict of interest: Nothing to report.

Livingston SE, Simonetti JP, Bulkow LR, Homan CE, Snowball MM, Cagle HH, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 2007;133:1452–1457. (Reprinted with permission.)


Background & Aims: Persistence of hepatitis B e antigen (HBeAg) in chronic hepatitis B has been associated with increased risk for development of cirrhosis and hepatocellular carcinoma. Five hepatitis B virus genotypes were identified in Alaska Native persons; we analyzed clearance of HBeAg by age and genotype. Methods: In this prospective cohort study, 1158 Alaska Native persons throughout Alaska were tested serially for HBeAg for a median of 20.5 years and were genotyped. Initial and final HBeAg-positive specimens, time to clearance, age at clearance, and subsequent HBeAg results were analyzed for persons initially HBeAg-positive. Subsequent HBeAg results were analyzed for persons initially negative. Results: Genotypes A, B, C, D, and F were identified. Genotype C persons initially HBeAg-positive were more likely than those with other genotypes to be positive on initial and final specimens (P < .001 for each) and time to HBeAg clearance was longer (P < .001). Age at which 50% of persons cleared HBeAg was <20 years for those infected with genotypes A, B, D, and F and 47.8 years in genotype C (P < .001). After losing HBeAg, those with genotypes C and F were more likely to revert to the HBeAg-positive state (P < .001). Conclusions: Genotype may have a strong effect on mode of transmission and outcome. Genotype C may have been responsible for most perinatal transmission, given that seroconversion from HBeAg occurs decades later than in other genotypes.


As new antiviral agents become available for the treatment of chronic hepatitis B virus (HBV) infection and strategies are developed to optimize virologic suppression while minimizing resistance, our knowledge of the natural history of HBV infection and risk factors for disease progression continues to expand. In light of these emerging data, a challenge lies in our ability to identify individuals with chronic hepatitis B who will benefit from earlier or more aggressive therapy.

It has become increasingly evident that certain populations with chronic HBV infection may be at greater risk of progressive liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Reports from long-term prospective cohort studies of hepatitis B surface antigen (HBsAg)-positive patients in Taiwan and China have identified virologic factors, notably the presence of hepatitis B e antigen (HBeAg) and elevated serum HBV DNA levels, which may be significantly associated with an increased risk of HBV-associated disease progression, development of HCC, and mortality.1–4 Although these studies have provided greater insight into how markers of viral activity may contribute to advanced liver disease in chronic HBV infection, other factors such as HBV genotype or mutational profiles were not assessed.

Hepatitis B virus genotype has been identified as a potentially important risk factor for adverse outcomes in chronically infected patients. Several studies, mostly in Asian populations predominantly infected with genotypes B and C, have suggested that infection with HBV genotype C is associated with more advanced hepatic histology, an increased prevalence of cirrhosis, and increased risk of HCC.5 Furthermore, HBV genotype C infection may be associated with lower treatment response rates, particularly during interferon-based therapy.6 The recent prospective cohort study by Livingston and colleagues7 adds to a growing body of evidence that has identified infection with HBV genotype C as a potential risk factor for progressive liver disease. Through longitudinal follow-up of a cohort of Alaska natives over a period greater than 20 years, these investigators provide additional insight into the natural history of chronic HBV infection in a population infected with several HBV genotypes.

The Alaska native population studied by Livingston et al. is one characterized by a very high prevalence of chronic HBV infection, ranging up to 8% in some areas.8 A large cohort of Alaska natives were identified and prospectively followed as part of an HBV screening program and vaccination campaign more than 20 years ago.7 The investigators identified 1158 untreated HBsAg-positive individuals with longitudinal measurements of virologic parameters, including HBeAg and antibody to HBeAg (anti-HBe), who had stored sera available for HBV genotype analysis. Five HBV genotypes (A, B, C, D, and F) were identified in this cohort and 44% were found to have detectable HBeAg at the time of initial detection of serum HBsAg.

Individuals infected with HBV genotype C were characterized by an increased likelihood of having persistently detectable serum HBeAg as well as a longer time to spontaneous HBeAg clearance.7 Overall, those infected with HBV genotypes C, D, and F were more likely to have detectable HBeAg on initial evaluation. At the end of follow-up, individuals infected with HBV genotype C had the largest overall proportion of detectable HBeAg (28%) compared with other genotypes and had an even greater proportion (50%) in analysis restricted to individuals who were initially HBeAg-positive. Similarly, patients infected with genotype C were more likely to have persistently detectable serum HBeAg in every test performed throughout the follow-up period (39%). In patients with genotype C who cleared HBeAg, the time to HBeAg clearance was longer compared with genotypes A, B, D, and F. The age at which 50% of individuals infected with HBV genotype C were cleared of HBeAg was 47.8 years, whereas it was less than 20 years of age in those with genotypes A, B, D, and F. These observations by Livingston et al. are consistent with previous retrospective studies conducted in Taiwan and China in which patients infected with genotype C had lower rates of spontaneous HBeAg seroconversion over time compared with genotype B patients.9, 10

Livingston and colleagues also found that reversion to HBeAg positivity following a period of HBeAg clearance occurred most frequently in patients with genotypes C and F, particularly in those who were initially positive for HBeAg.7 Reversion to detectable HBeAg was also observed in patients who were initially negative for HBeAg, which again occurred most frequently in genotype C infection. In a previous study using prospective data from this same cohort of Alaska natives,11 these investigators identified reversion to HBeAg positivity as a factor associated with an increased risk of HCC. Taken together, these data suggest that HBeAg persistence, whether continuous or in the setting of reversion to HBeAg positivity, may contribute to the increased risk of HCC associated with HBV genotype C infection. Whether HBeAg reversion coincided with detectable HBV DNA or elevations in alanine aminotransferase (ALT) levels is uncertain, because these parameters were not assessed in this study. Although data are limited, the effect of HBeAg persistence on HCC risk may also occur in HBV genotype F infection, which has also been associated with an increased frequency of HCC in this population.12

A recent prospective study by Chu and Liaw13 of asymptomatic patients who were positive for HBeAg in the immune tolerance phase who were followed through immune clearance and subsequent HBeAg seroconversion to inactive carriers also found that HBV reactivation occurred more frequently in patients with genotype C infection. Hepatitis B reactivation, defined by detectable HBV DNA and greater than a two-fold elevation in ALT levels, occurred over a mean follow-up of 5.8 years after HBeAg seroconversion. Using multivariate analysis, Chu and Liaw noted that genotype was the most significant predictor of reactivation, because individuals infected with genotype C had a 3.8 times greater risk of reactivation compared with individuals infected with genotype B. Although this study was limited to patients with genotypes B or C, these observations support those of Livingston et al., in which genotype C infection may be associated with a higher propensity toward recurrent viral activity following a period of HBeAg clearance.

An important implication pointed out by Livingston and colleagues relates to transmission risks associated with HBV genotype C infection and how the mode of transmission may ultimately affect disease progression. The observations from this study imply that women infected with genotype C are more likely to have detectable HBeAg during their childbearing years, at which time they may have elevated serum HBV DNA levels and therefore present a greater risk of perinatal transmission. Consistent with these observations by Livingston et al., a strong association between HBV genotype and mode of transmission has previously been reported through cross-sectional analysis in which genotype C was associated with vertical transmission.14 Acquisition of HBV through vertical transmission may play an important role in the increased risk of HCC observed in genotype C infection, because vertical transmission itself may be a risk factor for HCC-associated mortality,15 possibly through prolonged periods of HBeAg positivity, high serum HBV DNA levels, elevated ALT levels, and active histologic disease. As noted earlier, prospective data have revealed that elevated HBV DNA levels are indeed linked to a greater incidence of both cirrhosis and HCC.2–4

As our ability to characterize genomic profiles associated with HBV infection continues to improve, we may develop a better understanding of the risk factors involved in HBV-associated disease progression. Virologic factors such as HBV subgenotype classification and the presence of specific mutations have been implicated in advanced disease associated with genotype C infection; however, their clinical importance will need to be addressed prospectively. Although limited by the absence of serum HBV DNA and ALT measurements, the study by Livingston et al. provides further evidence that chronic infection with HBV genotype C may significantly affect disease progression compared with other genotypes. In addition, the study's prospective design allows for greater insight into how genotype status may influence both the mode of transmission of HBV and the subsequent natural history of chronic HBV infection.

These observations may be useful in identifying high-risk populations that will benefit from more aggressive strategies to minimize perinatal transmission of HBV, earlier initiation of antiviral therapy, or surveillance for HCC initiated at younger ages. Strategies such as these must be weighed against the added costs of more aggressive surveillance and early therapy as well as concerns for the development of antiviral drug resistance. Whether clinicians should include testing for HBV genotype as part of the baseline evaluation of all patients diagnosed with chronic HBV infection has yet to be determined; however, it will likely become an important consideration in high-risk individuals and is already being more widely utilized.