ADV & HBV Viral Dynamics

aloha

HBV Viral Dynamics in Chronic Hepatitis B Patients Treated with Hepsera (adefovir dipivoxil): Effect of Dose and Pre-Treatment HBV Disease Characteristics HBV decline in chronic Hepatitis B (CHB) patients during therapy with HBV polymerase inhibitors has been shown to be biphasic. However, the factors that contribute to the slope of the first and second phase declines and the predictors of response to therapy are not yet understood. The aim of the current study was to characterize the parameters of HBV dynamics during Hepsera (adefovir dipivoxil) therapy and test their dependence on dose, baseline serum HBV DNA and ALT levels. 54 HBeAg+ CHB patients in two phase 2 studies were randomized to receive 5 mg (N=9), 10 mg (N=14), 30 mg (N=15) and 60 mg (N=16) of Hepsera daily. Serum HBV DNA was determined by Roche Amplicor PCR (LLQ <400 copies/ml) a month before therapy, at baseline, weekly for 4 weeks, and every 4 weeks, thereafter. For the 10 mg group, additional early samples were also taken every 0.5 hours during the first 3 hours, and at 4, 6, 8, 12, 24, 36 and 48 hours of therapy. Using non-linear fitting, a viral dynamics model (Neumann et al, Science 1998) was applied to the 10 mg group where very frequent sampling was conducted. In addition, the first phase (days 0-7) and second phase (days 14-84) slopes were estimated for all patients. Frequent sampling in the 10 mg group has revealed a mean delay of 9.9 hours (range 3.4-17.6) before the initiation of serum HBV DNA decline. Thereafter a homogenous rapid viral decline was observed during the first week, followed by a slower second phase. The mean efficacy of inhibition of virion production was 95.8% (range 91.0%-99.4%) for 10 mg Hepsera. The mean free virus half-life was 16.3 hours (range 7.1-27.7). Log viral decline after 1 week of treatment was 1.020.36, 1.510.31, 1.690.40 and 1.750.33 log10 copies/ml for 5, 10, 30 and 60 mg Hepsera, corresponding to efficacies of 90.5%, 96.9%, 98.0% and 98.2%, respectively. The efficacy of 5 mg Hepsera was significantly (p<0.003) lower than all other doses, but the 10 and 30 mg doses were not significantly different. First phase decline did not correlate with pre-treatment serum HBV DNA or ALT levels. The second phase slope showed large inter-patient variability with several patients displaying a steady second phase or complex multiphasic patterns. Among the patients with a second phase decline, the mean half-life was 13.2 days (range 5.3 to >70). The second phase decline did not correlate with Hepsera dose, but was positively correlated (R=0.44, p<0.007) with the baseline ALT levels. The second phase slope was strongly correlated (R=0.55, p<0.003) with the slope of viral decline during the month before treatment (between pre-treatment month -1 and baseline). Patients with pre-treatment viral decline faster than 0.1 log/month had a significantly (p<0.001) more rapid second phase (median half-life 9.9 days, range 5.3-23.1) compared to patients with no pre-treatment decline (median 23 days, range 9.9 to >70). All the patients with a second phase half-life of less than 8.7 days had pre-treatment viral decline faster than 0.1 log/month and ALT higher than 100 IU/ml. None of the patients with a steady second phase had pre-treatment viral decline or high ALT. Conclusions: The dependence of the first and second phases of HBV clearance on Hepsera dose and pre-treatment baseline HBV disease characteristics is distinct. The first phase is dose dependent although the efficacy of 10 mg Hepsera is not significantly different from 30 mg. For the 4 doses tested there was no effect of Hepsera dose on the second phase slope, which may be a more important determinant of response. The existence of pre-treatment viral decline, which is correlated with high pre-treatment ALT levels, is a necessary condition for rapid second phase decline during treatment. This finding indicates that ongoing rapid loss of infected cells immediately prior to therapy is strongly prognostic of an enhanced antiviral and clinical response. 01/22/03 Reference A Neumann and others. HBV VIRAL DYNAMICS IN CHRONIC HEPATITIS B PATIENTS TREATED WITH ADEFOVIR DIPIVOXIL: EFFECT OF DOSE AND PRE-TREATMENT HBV DISEASE CHRACTERISTICS. Abstract 849. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.