Lamivudine is a nucleoside analogue with activity against hepatitis B virus (HBV) replication. The standard HBV DNA hybridization assay used in most clinical studies has a low sensitivity; the detection limit of HBV DNA levels is approximately 10⁷ genome equivalents per mL (genome Eq/mL) [1, 2]. We measured HBV DNA levels with the semiquantitative polymerase chain reaction (PCR) assay (detection limit, approximately 10³ genome Eq/mL, calibrated on the Eurohep HBV DNA standard) during a 24-week course of lamivudine therapy.

Fifty-one stable patients (hepatitis B e antigen-positive) with chronic hepatitis B were randomly allocated to receive oral lamivudine, 25, 100, or 300 mg once daily (16, 16, and 19 patients, respectively). All groups showed a statistically significant decrease in HBV DNA levels between weeks 0 and 12 (P < 0.001). Between weeks 12 and 24, HBV DNA levels decreased significantly only for the 300-mg/d group (P < 0.01). The median serum concentration of HBV DNA decreased from 10⁸ to 10⁴ genome Eq/mL, a 4-log median reduction (Figure 1). The percentages of patients who became negative for HBV DNA according to PCR are as follows: 25-mg/d group, 3% after 12 weeks of lamivudine therapy and 12% after 24 weeks; 100-mg/d group, 13% after 12 weeks and 29% after 24 weeks; 300-mg/d group, 19% after 12 weeks and 37% after 24 weeks. Lamivudine continued to potently suppress viral replication below the limit of detectability of traditional assays.

View larger version (29K): [in this window] [in a new window]   Figure 1. Serum hepatitis B virus (HBV) DNA levels according to the limiting-dilution polymerase chain reaction in patients receiving lamivudine once daily according to dosage (values are geometric means). Patients with negative results on the assay had levels of 101. Error bars represent SEs.

Prolongation of treatment is attractive first because lamivudine was well tolerated in clinical studies [1, 2] and second (but probably more important) because a correlation between persistent suppression of viral replication and subsequent improvement in liver histologic findings was found [3]. However, prolongation of lamivudine monotherapy beyond 6 months may result in the development of a lamivudine-resistant mutant virus [4, 5]. To prevent lamivudine resistance, an attractive goal is rapid and profound inhibition of HBV replication. We saw a trend toward more profound suppression of viral replication with increasing lamivudine dose.

In conclusion, lamivudine continues to potently suppress viral replication below the limit of detectability of traditional assays. Treatment lasting 24 weeks resulted in the loss of detectable HBV DNA by PCR in 33% of patients receiving 100 or 300 mg of lamivudine daily; in an additional 28% of patients, the HBV DNA level decreased to the level of detection of the assay. Further studies are needed to define the degree of virus suppression required in clinical practice, to examine the effect of suppression on survival, and to identify methods to increase the efficacy of virus suppression.