QUANTITATIVE HEPATITIS-B VIRUS-DNA ASSESSMENT BY THE LIMITING-DILUTION POLYMERASE-CHAIN-REACTION IN CHRONIC HEPATITIS-B PATIENTS - EVIDENCEOF CONTINUING VIRAL SUPPRESSION WITH LONGER DURATION AND HIGHER DOSE OF LAMIVUDINE THERAPY

Lamivudine, a novel cytosine analogue, exhibits potent antiviral activ ity against hepatitis B virus (HBV) in vitro and in vivo. The standard HBV DNA hybridization assay used in phase II clinical studies has a L ow sensitivity, the detection limit of HBV DNA levels being approximat e to 10(7) genome equivalents per mi (geq ml(-1)). In this work we use d a semiquantitative polymerase chain reaction (PCR) assay (detection limit approximate to 10(3) geq ml(-1)) to determine HBV DNA levels dur ing a 24-week study of lamivudine in 51 stable chronic hepatitis B pat ients who were positive for hepatitis B surface antigen (HBsAg) and he patitis B e antigen (HBeAg). Patients were randomly allocated to recei ve oral doses of 25, 100 or 300 mg lamivudine once daily, At week 24 t he median serum concentration of HBV DNA had fallen from 10(8) to 10(4 ) geq ml(-1), a 4-log median reduction. A trend towards more profound suppression of viral replication with an increased dose of lamivudine was observed, After 12 weeks of therapy, 12% of patients had an HBV DN A level that was undetectable in the PCR assay; this increased to 26% after 24 weeks, while in an additional 30% of patients, HBV DNA decrea sed to the level of detection of the PCR assay, We conclude that a 24- week course of lamivudine decreases serum HBV DNA to the level of PCR detection in 46% of patients, Such additional viral suppressive activi ty with higher doses and more protracted lamivudine may be of clinical utility prior to liver transplantation. Further studies are needed to define the degree of virus suppression required in clinical practice, and methods are required to increase the efficacy of virus suppressio n.