Variability in long-term hepatitis B virus dynamics under antiviral therapy.

Hepatitis B virus (HBV) dynamics in treated patients can be complex and differ considerably from other viral infections. We analyse dynamics of liver and serum levels of HBV DNA in 24 chronically HBV-infected individuals undergoing 1 year of combination therapy with pegylated interferon alpha and adefovir dipivoxil (ADV), followed by 2 years of ADV monotherapy. Serum viral dynamics differentiated the patients into four response groups dependent on how quickly viremia became undetectable: quickly suppressed (HBV DNA <100 copies/ml within 8 weeks and staying suppressed, GRP1); quickly suppressed but some rebound (<10,000 copies/ml, GRP2); slow decay (GRP3); virological failures (>10,000 copies/ml, GRP4). These groups did not differ before start of therapy by serum HBV DNA (p=0.2), HBsAg (p=0.1), ALT (p=0.4), total HBV DNA within the liver (p=0.08), or cccDNA (p=0.3). Despite very different serum HBV DNA levels after 3 years, there was no statistical difference in total HBV DNA within the liver (p=0.08), nor in cccDNA levels (p=0.1), but HBsAg levels in serum were significantly lower for GRP1 compared to GRP4 (p=0.02). Efficacy in terms of reduction over the 3 years of serum HBV DNA, liver HBV DNA, cccDNA, and ratios of liver HBV DNA to cccDNA were 99.98%, 99.5%, 98.4%, and 83.2% respectively, exhibiting larger antiviral effects in serum than in liver. Over the course of therapy, HBV DNA viremia exhibited large oscillations for some individuals. Mathematical modelling reproduced the dynamics of these diverse groups by assuming a number of viral clones arose that experienced delayed recognition by the antibody response. Large viremia oscillations under therapy suggest sequential outgrowth of viral clones with delayed recognition by the humoral response.