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Viral dynamics during tenofovir therapy 197
of treatment. The decline in HBV-DNA was signifi cant at the time-points noted (P = 0.003
for the change from baseline to the transition between the fi rst-and the second-phase,
P = 0.005 for the change from baseline to 4 weeks and P = 0.005 for the change from
baseline to 24 weeks). In fi ve patients, treatment achieved HBV-DNA levels below the
level of 1000 copies/mL. One patient had loss of hepatitis B e antigen (HBeAg), without
seroconversion to anti-HBe.
Lamivudine resistance and transaminase levels
The HBV polymerase mutant analyses at day 28 showed the presence of baseline mutations
in nine patients; patient F showed a mixed population of YVDD and YMDD variants.
In one patient, the level of serum alanine aminotransferase (ALT) was >1.1 Upper
Limit Normal (ULN) after 24 weeks of treatment with tenofovir. In this patient, the ALT
level after 24 weeks of treatment was higher than pretreatment ALT levels.
Safety and tolerability
Tenofovir disoproxil fumarate was generally well-tolerated; none of the patients had
abnormal renal function (data available for 10 patients) or phosphorous levels (n = 8).
Models of viral dynamics
Estimates of the parameters of effi cacy, based on the biphasic model with individual
nonlinear fi tting and mixed-effect group fi tting, are shown in Table 2. The median
effective ness of blocking viral replication in the individual fit was 93% (range: 73–99) for
η = 0 and 93% (range: 59–99) for η = 1. The half-life of free virus was 21.18 h (median;
range: 16.23–47.34), the half-life of infected hepatocytes was 5.77 days (median; range:
3.06–33.24) when assessed by the individual fit. Similarly, with the group fit, the half-life
of free virus was 21.54 h and the half-life of infected hepatocytes was 5.24 days.
On treatment with tenofovir, distinct patterns of response were observed. All patients
showed a similar biphasic decline pattern in the fi rst 4 weeks of treatment (Fig. 1a–k).
The combined data for the group fit for the data set clearly demonstrates biphasic
decline pattern (Fig. 2).
In nine patients, the fi rst-phase response was rapid (Fig. 1a–k). Six of the nine patients
followed this rapid fi rst-phase by an initially rapid second-phase. However, in this study,
the rate of viral decay in the fi rst week of treatment did not appear to determine the rate
in the following phase (the next 3 weeks of treatment). Some patients had rapid decay