DETECTION OF PRECORE HEPATITIS-B VIRUS MUTANTS IN ASYMPTOMATIC HBSAG-POSITIVE FAMILY MEMBERS

Precore hepatitis B virus mutants have been detected mainly in HBeAg-n egative patients with active liver disease. We previously reported two novel mutations: M(1) (C-to-T change at nucleotide 1856 [proser at co don 15]) and M(3) (G-to-A change at nucleotide 1898 [gly-ser at codon 29]) in addition to two well-described mutations: M(2) (G-to A change at nucleotide 1896 [trp-stop at codon 28]); and M(4) (G-to-A change at nucleotide 1899 [gly-asp at codon 29]) in Chinese patients. The aims of this study were to determine (a) the prevalence of precore HBV muta tions in asymptomatic carriers and (b) whether family members share th e same mutated sequence as the index patients. Fifty-three index patie nts and 89 HBsAg-positive family members were studied by means of dire ct sequencing of polymerase chain reaction-amplified hepatitis B virus DNA. M(o), a conserved mutation (T-to-C at nucleotide 1858, codon 15) , was detected in 81% and 12% family members of index patients with an d without M(o), respectively (p < 0.0001). The clustering of M(o) indi cates that most subjects were infected through intrafamilial transmiss ion. M(1) was detected in ah the family members of patients with M(1) but in none of the family members of patients with wild-type or M(2) s equences (p < 0.0001). M(2) was detected in 25%, 0% and 15% of family members of patients with M(2), M(1), and WT sequences, respectively (p = 0.19). M(3) was detected in five and M(4) in four family members. M (1) was equally distributed among HBeAg-positive and HBeAg-negative fa mily members, 19.5% vs. 9% (p = 0.34), whereas M(2) was detected more frequently in HBeAg-negative family members: 45.5% vs. 4.5% in HBeAg-p ositive family members (p < 0.0001). Ten (77%) of 13 family members wi th M(2) and all 15 family members with M(1) had normal serum aminotran sferase levels. The family members with M(2) were significantly older than those with wild-type or M(1) sequences (mean ages, respectively, 37.9 +/- 5, 23 +/- 1.4 and 24.1 +/- 3 yr; p = 0.0005). In addition, M( 2) was more frequently detected in family members who were older than the index patients. Longitudinal studies documented progression from w ild-type sequence to M(2) in some family members, but progression from wild-type to M(1) or M(1) to M(2) was not observed. Our data showed t hat precore HBV mutants can be detected in 33% asymptomatic carriers. M(1) appears to be present at the onset of infection, whereas M(2) eme rges (from wild-type but not M(1)) during the course of infection. Ini tiation of infection with M(2) only seems to be rare.