  Pilot studies of structured treatment interruptions (STI) in HIV therapy have
shown that patients can maintain low viral loads whilst benefiting from reduced
treatment toxicity. However, a recent STI clinical trial reported a high degree
of virologic failure. Here we present a novel hypothesis that could explain
virologic failure to STI and provides new insights of great clinical relevance.
We analyze a classic mathematical model of HIV within-host viral dynamics and
find that nonlinear parametric resonance occurs when STI are added to the
model; resonance is observed as virologic failure. We use the model to simulate
clinical trial data and to calculate patient-specific resonant spectra. We gain
two important insights. Firstly, within an STI trial, we determine that
patients who begin with similar viral loads can be expected to show extremely
different virologic responses as a result of resonance. Thus, high
heterogeneity of patient response within a STI clinical trial is to be
expected. Secondly and more importantly, we determine that virologic failure is
not simply due to STI or patient characteristics; rather it is the result of a
complex dynamic interaction between STI and patient viral dynamics. Hence, our
analyses demonstrate that no universal regimen with periodic interruptions will
be effective for all patients. On the basis of our results, we suggest that
immunologic and virologic parameters should be used to design patient-specific
STI regimens.
