The role of pre-core hepatitis B virus mutants on the long-term outcome of chronic hepatitis B virus hepatitis. A longitudinal study

To define the relationship between pre-core hepatitis B virus mutants and the long-term outcome of chronic hepatitis B virus infection, we monitored the type of circulating pre-core hepatitis B virus-DNA by polymerase chain reaction and sequencing in 41 selected chronic HBsAg carriers with extensive follow up. They included 12 HBeAg-positive patients with chronic hepatitis, who seroconverted to anti-HBe during follow up and 29 anti-HBe positive patients, 23 of whom had chronic hepatitis and six acute severe exacerbation occurring spontaneously (three cases) or during antitumor chemotherapy (three cases). In the presence of HBeAg, all showed prevalence of the pre-core wild type along with high levels of viral replication and elevated alanine aminotransferase. Anti-HBe seroconversion was accompanied by a dramatic reduction of hepatitis B virus replication and normalization of alanine aminotransferase in all, except one, and by the emergence of mutated strains with a pre-core stop codon (point mutation G to A at nt 1896) that replaced the wild type in seven of the 12. Of the seven who harboured the pre-core mutant, three continued to show normal alanine aminotransferase during subsequent follow up, three had mild alanine aminotransferase elevation and one had an acute short-lived reactivation after 4.4 years of normal alanine aminotransferase. The five cases who continued to show prevalence of wild type in spite of anti-HBe seroconversion all revealed persistently normal alanine aminotransferase. Of the 29 anti-HBe positive patients, two (7%) were infected predominantly by wild type pre-core, two (7%) showed a mixed viral population consisting of pre-core stop codon and wild type strains, while 25 (86%), including the six with acute reactivation, revealed prevalence of pre-core defective strains. Since it was observed in 23 cases, the predominant pre-core defect was the stop codon reported above, associated with a mutation (also G to A) at nt 1899 in 12. A point mutation at nt 1814 (A to C) that eliminated the pre-core start codon was detected in two cases. Anti-HBe-positive patients with a prevalence of precore mutants had more severe or progressive liver disease compared with those who were predominantly infected with wild type or mixed viral populations. This study confirmed that, after seroconversion to anti-HBe and emergence of precore mutants, two outcomes are possible: either asymptomatic normal alanine aminotransferase/HBsAg carrier state or ongoing liver disease. However, anti-HBe-positive patients with the most severe form of chronic hepatitis are infected predominantly with pre-core hepatitis B virus mutants. (C) Journal of Hepatology.