We analyze virological data from HIV patients treated during the very early, early and late phase of infection and compare them with computer simulations.
In Figure 1 clinical data of all three analyzed groups is shown altogether. In a point-by-point comparison we find no statistical difference in viral rebound between early and late-treated patients (P ≥ 0.05, Mann-Whitney U two-tailed test) confirming the results of [4]. In addition, we observe that a difference does exist for very early initiation of therapy (P < 0.05, Mann-Whitney U two-tailed test).
In the present work we extend the simulations of [4] to include the new clinical settings corresponding to a very early initiation of therapy. In particular, the very early simulation settings correspond to a beginning of the therapy within the first week whereas the late settings correspond to initiating therapy between week five and six from infection.
Figure 2 summarizes data of virological rebound (averages) after therapy interruption at different time points (4, 8 and 24 weeks) for very early and late patients for both clinical (empty boxes) and simulation data (filled boxes). Firstly, the figure shows that clinical and simulation data are in good agreement (differences are not statistically significant: P ≥ 0.05, Mann-Whitney U two-tailed test). Secondly, the difference in plasma HIV-1 RNA (copies/ml) between very early and late-treated patients decreases with increasing time from therapy interruption. Panel (a) shows a difference of about two logs with panel (b) for both clinical data and simulations. These differences vanish after 24 weeks from therapy interruption (cfr. panel (e) and (f)). The overall message is that a delay in the initiation of therapy reduces the chances of maintaining a therapy effect at discontinuation.
In order to provide a more precise estimate of the time "limit" beyond which the benefit of an early initiation of therapy vanishes, we use the simulation to investigate the influence of HAART initiation time (t
s
) on the viral rebound. The corresponding results are shown in Figure 3. The virological rebound at one week after therapy interruption as a function of t
s
is presented. We observe that there are two regimens, one for t
s
< 20 days and one for t
s
> 30 corresponding to what clinicians call respectively best controllers (with undetectable HIV RNA levels) and rebounders (whose HIV viremia load returns, approximately, to the pre-HAART level).
The points in Figure 3 fit pretty well a generalized logistic function (i.e., the Richards' curve, [15]) describing the growth of viremia as a function of t
s
,
where the parameter k is the carrying capacity or the upper asymptote, a is the lower asymptote, d is the growth rate, and is the time of maximum growth. By moving the time of the measurements beyond one week after therapy interruption, the resulting data still fit the same V (t
s
) but with a greater a, a smaller d and a greater . In particular the limit for d going to zero, of V (t
s
) is (a + k)/2 may lead to the deceiving conclusion that there is no window of opportunity because the viral rebound is independent from t
s
.
With respect to , the value of~ 23:5 days points to the early inflammation as a critical phase of the disease. To bring into focus this facet, we compare two simulated "markers" of the inflammation state in untreated (control case), very early and lately treated simulated patients (see Figure 4). These virtual markers are given by the cell counts of active macrophages (a) and dendritic cells presenting viral proteins on class II MHC molecules (b). We observe that the late-treated case is comparable to the control case (untreated) whereas the very early stands on its own. This observation suggests that it is the activation of the immune system through the set up of an in ammatory state that has to be blamed for the increased viral rebound for t
s
> .
Figure 4 shows with clarity that very early initiation of the treatment can down-regulate the immune activation, hence limiting viral replication and spread. Interestingly, this view is supported by the observation that HIV triggers the immune activation directly (e.g., HIV gene products can induce the activation of lymphocytes and macrophages as well as the production of pro-inflammatory cytokines and chemokines [2]) or indirectly (e.g., sustained antigen-mediated immune activation occurs in HIV-1-infected patients due also to other viruses like the cytomegalovirus or the Epstein-Barr virus [2]). In both case, the result is a high level of pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin 6 and interleukin 1 beta, right from the early stages of HIV-1 infection [2].