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HBV Genotype May Predict Cirrhosis
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"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"
Journal of Hepatology
Sept 2005
Chia-Ming ChuCorresponding Author Informationemail address, Yun-Fan Liaw
Fig. 3. Cumulative probability of progression to cirrhosis in relation to (A) HBV genotype (P=0.0003) and (B) reactivation of hepatitis B (P<0.0001) in 133 patients with spontaneous HBeAg seroconversion.
INTRODUCTION
There are eight genotypes of hepatitis B virus (HBV) designated A to H based on greater than 8% nucleotide variation over the entire genome [1]. The eight genotypes of HBV show a distinct geographical distribution. The prevalent genotypes in Asia are genotypes B and C [2]. HBV genotypes may influence the course of disease. Studies of the Asian patients revealed that, compared to genotype B, genotype C is associated with a higher prevalence of hepatitis B e antigen (HBeAg), higher serum levels of HBV DNA, higher histological activities, more severe acute exacerbation, a lower rate of spontaneous HBeAg seroconversion, and a higher rate of cirrhosis and hepatocellular carcinoma [3-11]. However, other studies have shown controversial results: there was no significant difference in spontaneous HBeAg seroconversion rate between genotype B and genotype C [12,13]; the frequency of acute exacerbation showed no significant difference between genotype B and genotype C [12,14]; severe icteric acute exacerbation was associated with genotype B rather than genotype C [15,16]; and the distribution of genotype B and genotype C showed no significant difference between different stage of chronic liver disease [12,15]. The reason for these controversies remains unknown. Furthermore, it has been shown that reactivation of hepatitis B is a major risk factor for progression to cirrhosis [17,18]. However, the relationship between HBV genotypes and reactivation of hepatitis B and progression to cirrhosis has been rarely explored in longitudinal studies.
The natural history of chronic HBV infection can be divided into three phases: immune tolerance (HBeAg positive and normal alanine aminotransferase [ALT]), immune clearance (HBeAg positive and elevated ALT), and residual phases (hepatitis B e antibody [anti-HBe] positive and normal ALT) [19-21]. Previous studies on the natural course of chronic HBV infection usually included patients with chronic hepatitis B. Most of these studies were reported from tertiary medical centers and likely enrolled patients with more severe or protracted course. A longitudinal study beginning at the early phase of infection may minimize the referral bias inherent to many natural history studies [18]. In this study, the impact of HBV genotype on the natural course of chronic HBV infection was studied in 202 HBeAg-positive patients with normal ALT at baseline.
ABSTRACT
Background/Aims:
Longitudinal studies on the relationship between hepatitis B virus (HBV) genotypes and reactivation of hepatitis B and progression to cirrhosis were very rare.
Methods:
Liver biochemistry, virological markers and ultrasound were monitored in 202 hepatitis B e antigen (HBeAg)-positive patients with normal alanine aminotransferase (ALT) at baseline for 3-20 (average 10.8) years, and the outcome was correlated with HBV genotypes.
Results:
There were 150 genotype B and 52 genotype C patients. Hepatitis activity during the HBeAg-positive phase showed no significant difference. However, genotype B was associated with a significantly earlier and higher rate of HBeAg seroconversion. HBeAg seroconversion correlated with age at entry for genotype B and with ALT levels for genotype C. Reactivation of hepatitis B was significantly more common in genotype C patients. Five genotype B and 10 genotype C patients progressed to cirrhosis. Multivariate analysis revealed that genotype C (P=0.03) and reactivation of hepatitis B (P=0.0004) were independent factor predictive of cirrhosis.
Conclusions:
Rate and factors of HBeAg seroconversion, and rate of reactivation of hepatitis B differed between genotype B and genotype C patients. Genotype C and reactivation of hepatitis B were associated with increased risk of cirrhosis.
Discussion
The present study had two unique features. First, the subjects recruited in this study were HBeAg-positive patients with normal ALT at baseline. By the contrast, most previous studies have included patients with chronic hepatitis B and were reported from tertiary medical centers, where patients are likely to have a more severe or protracted course. Second, the followed up duration was long up to 20 years (mean 11 years) that enabled us to delineate the rate of reactivation of hepatitis B and the incidence of cirrhosis in relation to the HBV genotype.
In this cohort, only 23% of patients had maximal ALT levels >200U/l, 2.5% had bilirubin levels >34mol/l, and 4.5% had two or more episodes of ALT levels >200U/l during the HBeAg-positive phase. The clinical severity of chronic hepatitis B in this cohort was milder than in previous studies [11,14], but might close to in a recent population study [26]. Moreover, hepatitis activity during the HBeAg-positive phase showed no significant difference between genotype B and genotype C patients. The published data on the relationship between hepatitis activity and HBV genotypes remained much controversial [3,6,11,12,14-16]. The reason for these controversies is unknown but may be related to difference in selection criteria of the study patients.
Although ALT levels during the HBeAg-positive phase showed no significant difference between genotype B and genotype C patients, the probability of spontaneous HBeAg seroconversion is significantly higher in the former than in the latter. Previous studies in Asian patients have identified several factors significantly associated with spontaneous HBeAg seroconversion: older age at entry, higher ALT levels, and genotype B [11,14]. The present results showed that HBV genotype is the only factor significantly predictive of spontaneous HBeAg seroconversion. Because we did not test serum HBV DNA during the HBeAg-positive phase, whether serum levels of HBV DNA at baseline or during follow up may predict HBeAg seroconversion in this cohort of patients is unknown.
An interesting finding of our study is that factors associated with spontaneous HBeAg seroconversion differ between genotype B and genotype C patients. In genotype B patients, HBeAg seroconversion correlated significantly with age at entry (presumably duration of infection, P=0.03) but less with ALT levels (P=0.15). The rate of HBeAg seroconversion increased with the time of follow up without significant difference with the levels of ALT. Previous studies have revealed that HBeAg seroconversion is frequently preceded by ALT flares >300U/l [27,28]. The present findings suggest that HBeAg seroconversion can occur in the absence of significant ALT flare >200U/l in the majority of genotype B patients, though the possibility of failure to detect asymptomatic ALT flare cannot be excluded. On the contrary, HBeAg seroconversion in genotype C patients did not correlate with age at entry (P=0.61). This finding may suggest that genotype C patients have slow HBeAg seroconversion and tend to be persistently HBeAg positive at older age. The HBeAg prevalence rate in HBsAg carriers in Taiwan decreased remarkably after age 40: 9.8% at the age of 41-50 and 6.2% after age 50 [29]. The present results revealed that genotype C is predominant (69% or 11/16) among patients with persistent HBeAg after age 45. Furthermore, in genotype C patients, HBeAg seroconversion correlated significantly with ALT levels (P=0.03). HBeAg seroconversion was enhanced in patients with ALT >200U/l but much slow in those without.
Results
Clinical characteristics at baseline and during follow up
Of the 206 study patients, 150 had genotype B and 52 had genotype C, while four had HBV genotypes unclassified and were excluded from analysis. Table 1 compares the clinical characteristics at baseline and during follow up between genotype B and genotype C patients.
ALT levels returned to normal in all patients after HBeAg seroconversion. During a median follow up of 5-6 years, reactivation of hepatitis B, defined as elevation of ALT accompanied by reappearance of HBV DNA [median (range) levels=78pg/ml (11-1800pg/ml)], was noted in 26 patients. No patents had serological evidence of superinfection with HCV or HDV. ALT levels were persistently or intermittently abnormal in 22 patients (85%). Maximal ALT levels ranged from 92 to 649U/l (median 224U/l).
Factors associated with HBeAg seroconversion
The relevant variables that may be associated with spontaneous HBeAg seroconversion, such as age at entry, gender, HBV genotype, and hepatitis activity during the HBeAg-positive phase, including maximal ALT levels, ≥2 episodes of ALT >200U/l, and bilirubin >34mol/l, were analyzed by using Cox proportional hazards regression models. HBV genotype was the only factor significantly associated spontaneous HBeAg seroconversion (Table 2). The cumulative probability of HBeAg seroconversion in relation to HBV genotypes is shown in Fig. 1. HBeAg seroconversion correlated significantly with age at entry among genotype B patients and with ALT levels among genotype C patients (Table 2). The cumulative probability of HBeAg seroconversion in relation to ALT levels for genotype B patients is shown in Fig. 2(A), and for genotype C patients in Fig. 2(B).
Final outcome: cirrhosis and hepatocellular carcinoma
Clinical and ultrasound evidence of cirrhosis was identified in five genotype B and 10 genotype C patients during the mean follow up of 10.8±4.3 (range 3-20) years. Of these, four patients received liver biopsy and all had histological evidence of cirrhosis. Three patients were detected to have cirrhosis during the HBeAg-positive phase and the other 12 patients progressed to cirrhosis after HBeAg seroconversion. In other words, three (4.3%) of 69 patients with persistent HBeAg and 12 (9.0%) of 133 patients with HBeAg seroconversion progressed to cirrhosis (P=0.36).
Among 69 patients with persistent HBeAg, the age at last follow up or diagnosis of cirrhosis was ≦45 years in 53 and >45 years in 16. Genotype C was significantly more frequent in the latter (68.8% or 11/16) than in the former (28.3% or 15/53, P=0.008). None of the 42 genotype B patients progressed to cirrhosis during the mean follow up of 9.8±3.2 (range 3-19) years, while three (11.1%) of 27 genotype C patients progressed to cirrhosis during the mean follow up of 11.1±4.2 (range 3-19) years (P=0.056). Factors predictive of cirrhosis cannot be evaluated due to small number of patients progressed to cirrhosis, but genotype C patients with persistent HBeAg after age 45 years tended to have increased risk of cirrhosis (Table 3).
Among 133 patients with HBeAg seroconversion, 12 progressed to cirrhosis during the mean follow up of 11.2±4.2 (range 3-20) years. In univariate analysis, age at entry, age at HBeAg seroconversion, genotype C, and reactivation of hepatitis B were factors significantly predictive of cirrhosis, whereas gender, maximal ALT, ≥2 episodes of ALT >200U/l, and total bilirubin >34mol/l did not contribute to development of cirrhosis. In multivariate analysis, genotype C and reactivation of hepatitis B were two independent factors significantly predictive of cirrhosis (Table 3). In patients with reactivation of hepatitis B, the frequency of progression to cirrhosis showed no significant difference between patients with HBV DNA >100pg/ml (33.3% or 4/12) and those with HBV DNA ≦100pg/ml (35.7% or 5/14, P=1.0) or between patients with maximal ALT >200U/l (28.6% or 4/14) and those with maximal ALT ≦200U/l (41.6% or 5/12, P=0.68). The cumulative probability of progression to cirrhosis in relation to HBV genotype and reactivation of hepatitis B is shown in Fig. 3(A) and (B), respectively.
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