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Viral dynamics during tenofovir therapy 195
η = effectiveness of tenofovir in blocking the de novo infection of uninfected cells. The
fi rst-phase decline refl ects the clearance rate of free virus from plasma; the secondphase
decline refl ects the death rate of productively infected cells.
We used two different approaches to describe viral decay: individual nonlinear fi tting
and mixed-effect group fi tting. Mixed modelling implies a group-wise analysis while
each patient retains his or her own subject-specifi c decline by introducing random
effects on all parameters. All variables as well as all patient data are related; based on
these data, group effects can be derived and compared. In the group fit approach, the
random effect of λ1 was set to zero, because of lack of variation between individuals.
This indicates that λ1 is stable and therefore justifi es the choice of a fi xed λ1.
The nonlinear modelling approach, which was used to fit the biphasic model, was conducted
in the NLINMIX macro in SAS 8.02.
Neumann et al. 18 assumed that η = 0 (there was no block of de novo infection of uninfected
cells), while Tsiang et al. 24 and Nowak et al. 25 assumed that η = 1 (there was a
complete block of infection of uninfected cells). If η = 1, then λ2 = δ, and A refl ects
antiviral effi cacy. We have explored both assumptions in both models (individual vs
group fit) as a possibility and we report the mathematical effi cacy for all four situations.
Models of viral dynamics during the fi rst 24 weeks of treatment
Validated models of HBV viral kinetics are available only for the fi rst 4 weeks of therapy
and are unavailable for later viral kinetics. The viral kinetics patterns have been classifi
ed according to the defi nitions used by Neumann et al. for describing HBV-DNA early
kinetics in chronic hepatitis B patients treated with adefovir dipivoxil. 26 We modifi ed
these existing defi nitions to describe the fi rst 24 weeks of kinetics, taking into account
the availability of frequent quantitative HBV-DNA measurements in the fi rst 4 weeks of
tenofovir treatment. First, we investigated viral decay in the fi rst week (fi rst-phase), then
we examined decay in the following 23 weeks (second-phase), which we further divided
into two periods (up to 4 weeks, days 8–28 and up to 24 weeks, days 29–168).
Defi nitions of viral kinetic patterns in the fi rst-phase (days 1–7):
1 Rapid (R): decline of =1 log
2 Slow (S): decline between 0.5 and 1 log
3 Flat (F): decline of 1 log/4 weeks