Increasing heterogeneity of the 'a' determinant of HBsAg found in the presumed late phase of chronic hepatitis B virus infection.

To investigate if the concomitant presence of hepatitis B virus (HBV) DNA and antibodies to hepatitis B surface antigen (anti-HBs) is associated with mutations in the HBV envelope gene, selected sequences of the HBV genome in 54 patients with chronic liver disease, collected from the Wuhan district of China, were amplified by polymerase chain reaction (PCR) and the DNA sequences of the products were determined. The part of the S gene coding for the 'a' determinant of HBsAg was found to be prone to diversity. A total of 19 aberations occurring at 11 of the 69 nucleotide positions of this part of the genome were found in sera from 15 HBsAg-negative but anti-HBs-positive patients. One of 13 HBsAg/HBeAg-positive and 8 of 17 HBsAg/anti-HBe-positive samples also showed point mutations in this gene sequence. Most prevalent was a point mutation from adenine to guanine at nucleotide 530 resulting in a change from threonine to alanine at amino acid position 126. This study highlights that the long time course of chronic HBV infection could favour a selection of escape mutants. The occurrence of such HBV variants in patients with chronic liver disease are not detected by conventional HBV serology, and the patients can therefore easily by be misdiagnosed. If viral mutants like those described here can be transmitted to other patients, there will be difficulties in identifying these infections, and conventional HBV vaccination will presumably not be protective against them.