Abstract
Most HIV-infected patients who initiate combination antiretroviral therapy experience a viral load decline in several phases. These phases are characterized by different rates of viral load decay that decrease when transitioning from one phase to the next. There is no consensus as to the origin of these phases. One hypothesis put forward is that short- and long-lived infected cells are responsible for the first and second phases of decay, respectively. However, significant differences in drug concentrations are observed in monocytes from various tissues, suggesting the first two phases of decay in viral loads could instead be attributed to short-lived cells being differently exposed to drugs. Compared to a well-exposed compartment, new cell infection can be expected in a compartment with limited drug exposure, thus leading to a slower viral load decay with potential virologic failure and drug resistance. In the current study, the latter hypothesis was investigated using a model of viral kinetics. Empirical datasets were involved in model elaboration and parameter estimation. In particular, susceptibility assay data was used for an in vitro to in vivo extrapolation based on the expected drug concentrations inside physiological compartments. Results from numerical experiments of the short-term evolution of viral loads can reproduce the first two phases of viral decay when allowing new short-lived cell infections in an unidentified drug-limited compartment. Model long-term predictions are however less consistent with clinical observations. For the hypothesis to hold, efavirenz, tenofovir and emtricitabine drug exposure in the drug-limited compartment would have to be very low compared to exposure in peripheral blood. This would lead to significant long-term viral growth and the frequent development of resistant strains, a prediction not supported by clinical observations. This suggests that the existence of a drug-limited anatomical compartment is unlikely, by itself, to explain the second phase of viral load decay.
Highlights
Viral loads in the plasma of patients initiating highly active antiretroviral therapy (HAART) generally decrease very rapidly during the first days of treatment before reaching a slower second phase of decay.[1, 2] up to four phases of decreasing viral load can be observed, each new phase being slower than the previous one.[3]
Viral loads during the first and second phases of viral decay mainly come from one infected cell population: CD4 cells having a half-life of virion production of about one day
The QSP approach adopted here has previously led to a model that serves as a basis for this study.[24]. This previous model, which only looked at infected CD4+ lymphocytes in active state as a source of virions, has been modified in order to simultaneously consider two Second phase of viral decay and drug-limited compartment physiological compartments differently exposed to antiretroviral drugs
Summary
Viral loads in the plasma of patients initiating highly active antiretroviral therapy (HAART) generally decrease very rapidly during the first days of treatment before reaching a slower second phase of decay.[1, 2] up to four phases of decreasing viral load can be observed, each new phase being slower than the previous one.[3]. Viral loads are proportional to the number of infected cells This assumption is partially supported by results suggesting rapid virion clearance in lymphoid tissue and plasma (no accumulation of virions).[5, 6] Under the third assumption, HAART has the capacity to fully inhibit all new cell infections. If all of these assumptions were true, there would be only one phase of viral decay, as depicted by Fig 1A. We will show how two of these assumptions have been revisited in order to give rise to two competing hypotheses, one of which is further studied
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