Of 165 patients investigated, 47.3% were infected with HBV genotype A, 40.0% with HBV genotype D, 6.7% with HBV genotype C, 3.6% with HBV genotype B, 1.8% with genotype E, and 0.6% with genotype G. HBV genotypes H and F were not encountered. HBV genotype D was found significantly more often in HBeAg negative hepatitis B than in HBeAg positive hepatitis B (p<0.01) (table 1). HBV genotype A was the predominant HBV genotype in HBeAg positive hepatitis B (table 1). Due to insufficient power, HBV genotypes B, C, E, and G were not included in further statistical analysis.
Table 1 Hepatitis B virus (HBV) genotype distribution according to hepatitis B e antigen (HBeAg) status
Baseline HBV-DNA, cumulative IFN dose, and cirrhosis prevalence did not differ significantly between HBV genotypes (table 2). Infection with HBV genotype B or C was characterised by a longer disease duration and a higher rate of females compared with other HBV genotypes. ALT levels were significantly lower in patients with HBV genotype B compared with HBV genotype A, C, or D. Disease duration was not different between patients with HBV genotype A compared with HBV genotype D (78 (10) v 74 (15) months) despite a higher frequency of perinatal infections in genotype D. Disease duration was determined in 74% of patients. Neither frequency of liver cirrhosis (table 2) nor mean stage of liver fibrosis (2.2 v 2.1) or mean grade of inflammatory activity (2.3 v 2.0) differed significantly between HBV genotypes A and D.
Table 2 Characteristics of patients with chronic hepatitis B according to hepatitis B virus (HBV) genotype*
Mean treatment duration and cumulative IFN dose were not different between patients with HBV genotype A and HBV genotype D (table 3). Treatment duration and cumulative IFN dose were slightly higher among patients with HBeAg negative hepatitis compared with HBeAg positive hepatitis (7.0 v 6.1 months (p<0.03); 473 v 413 MU IFN (p<0.06)). In HBeAg positive hepatitis, 16.9% of patients compared with 37% of HBeAg negative patients were treated for longer than six months. For HBeAg positive hepatitis B, treatment duration and cumulative IFN dose were slightly in favour of HBV genotype D whereas in HBeAg negative hepatitis B, treatment duration and cumulative IFN dose were slightly in favour of HBV genotype A (table 3).
Table 3 Response rates (SR-6) to interferon alfa (IFN) therapy in patients with chronic hepatitis B according to hepatitis B virus (HBV) genotype
Overall sustained response to IFN six months post treatment (SR-6) was 35%. SR-6 rates to IFN therapy varied greatly between the different HBV genotypes (table 3). Despite administration of slightly lower cumulative IFN doses compared with other HBV genotypes, patients with HBV genotype A showed the best end of treatment response (ETR) and SR-6 rates. Among patients with HBV genotype B (n
6), HBV genotype C (n
11), and HBV genotype E (n
3), SR was 0%, 18% and 0%, respectively. ETR was 50%, 46%, and 0% among patients with HBV genotypes B, C, and E. The only patient with HBV genotype G achieved a sustained IFN response.
A significantly better SR-6 rate was observed in patients with HBV genotype A (49%) compared with patients with HBV genotype D (26%; p<0.005). This was also the case for the subgroups of HBeAg positive (46 v 24%; p<0.03) and negative (59 v 29%; p<0.05) patients with HBV genotype A or D. The higher SR-6 in patients with HBV genotype A compared with HBV genotype D was the result of both a higher primary IFN response rate and a lower relapse rate in HBV genotype A hepatitis patients. In HBeAg positive hepatitis, relapse rates were comparably low in both HBV genotypes (13% for HBV genotype A v 18% for HBV genotype D; NS) but ETR differed significantly (53% for HBV genotype A v 29% for HBV genotype D; p<0.02). HBeAg negative hepatitis was characterised by higher and more divergent relapse rates between HBV genotype A and D (29% v 58%; p<0.09) and by higher but less different ETR (82% v 68%; NS) compared with HBeAg positive hepatitis B.
Data on sustained response 12 months post treatment (SR-12) were available in 142 patients with HBV genotype A or D. SR-12 was 47% for HBV genotype A compared with 23% in HBV genotype D (p<0.002). Among HBeAg positive patients, SR-12 was 44% compared with 24% (p<0.04) and among HBeAg negative patients SR-12 was 59% versus 21% (p<0.01) for HBV genotype A and HBV genotype D, respectively.
Univariate regression analysis revealed no effect of sex, cirrhosis, HBeAg status, or HBV-DNA titre on response rate to IFN (table 4). HBV genotype A and ALT levels were relevant predictive parameters of IFN response and were further included in the multivariate analysis. SR-6 was 45% among patients with ALT levels >2×upper limit of normal (ULN) but only 20% in patients with ALT levels
2×ULN (p<0.001). SR-6 for patients with HBV genotype A and ALT>2 ULN was 56% compared with 26% for ALT
2×ULN (p<0.03), and 31% and 14%, respectively, in patients with HBV genotype D.
Table 4 Univariate logistic regression analysis of factors associated with sustained response (SR-6) among patients with hepatitis B virus (HBV) genotype A and D
Multivariate logistic regression analysis identified HBV genotype A (odds ratio (OR) 2.7 (95% confidence interval (CI) 1.3–5.8); p<0.009) and elevated pretreatment ALT level (
>2×ULN; OR 3.0 (95% CI 1.2–7.5); p<0.02) as independent parameters for sustained response. Low pretreatment HBV-DNA level (
200 pg/ml v
>200 pg/ml), sex, or cirrhosis were not found to be independent factors associated with sustained response (table 4).