A 13‐year longitudinal study of the impact of double mutations in the core promoter region of hepatitis B virus on HBeAg seroconversion and disease progression in patients with genotype C chronic active hepatitis

Abstract

The pathogenic role of core promoter (CP) mutations (T1762/A1764) of hepatitis B virus (HBV) in hepatitis B e antigen (HBeAg) seroconversion or disease progression remains unclear. We investigated the clinical relevance of these mutants over a long-term follow-up period of up to 15 years. In this longitudinal cohort study, 29 HBeAg-positive patients with biopsy-proved chronic active hepatitis without cirrhosis were regularly monitored for >10 years. The viral isolates were characterized, using the frozen liver tissue obtained on the day of biopsy. Long-term outcomes were compared between patients with and without CP mutations of HBV at baseline. HBV genotyping showed that 100% of study subjects were infected with genotype C HBV. During a median follow-up period of 12.5 years, patients without double CP mutations of HBV at baseline showed a tendency towards achieving an earlier HBeAg seroconversion than those with (6.9 vs 9.4 years, P = 0.062) double CP mutations. Double CP mutations at baseline were also significantly associated with the eventual development of cirrhosis or hepatocellular carcinoma (P = 0.013), whereas the absence of double CP mutations predicted inactive carrier status at the last follow-up (P = 0.027). At 10 years, liver-related tests were also significantly better in patients without double CP mutations of HBV than in those with these mutations, as reflected by higher platelet counts and albumin levels (P = 0.036 and P = 0.044, respectively). Double T1762/A1764 mutations are significantly related to liver deterioration in HBeAg-positive genotype C active hepatitis patients. A longer period of immune clearance coupled with delayed HBeAg seroconversion appears to contribute to disease progression in patients harbouring these mutations in the CP region of HBV.

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

“…In Japan, the prevalence of HBV infection was estimated to be 0.8% in 2000, and the vast majority of individuals are infected with HBV genotype C [4][5][6]. Genotype C virus has been associated with high rates of progression to the complications of CHB, including cirrhosis and HCC [7][8][9][10][11]. In addition to genotype, the level of HBV DNA in the serum is strongly associated with liver disease progression [12,13].…”

Natural history of chronic hepatitis B: Special emphasis on disease progression and prognostic factors

“…Summary measure of cirrhosis incidence rates according to clinical status and geographic area is shown in Table 3 [17,28,30,[39][40][41][42][43][44][45][46][47][48]. Inactive Asian and Caucasian carriers have a very low risk of cirrhosis development, below 0.1 per 100 person years [17,30].…”

Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection

“…The vast majority of CHB patients in Japan are infected with hepatitis B virus (HBV) of genotype C [6,7]. Infection with genotype C virus has been associated with delayed HBe seroconversion, more advanced liver disease, and increased probability of HCC development [8][9][10][11].…”