Effet des antirétroviraux sur la pathogénèse du VIH : une étude par modélisation mathématique intégrant la cinétique du virus, de l’immunité, du médicament, et le comportement d’adhésion avec leurs variabilités interindividuelles

Tremendous progress was made in treating people living with HIV. Nowadays, antiretroviral therapy usually allows patients to suppress viral loads for several years, if not decades. Despite this scientific achievement, chronic drug intake is usually necessary as no treatment can completely eradicate the virus. Patients under these conditions may experience constant side effects. Further, patients’ tissues and organs may become damaged over time, as chronic immune activation is observed in most patients despite adequate drug intake and undetectable viremia. The number of treatment options can also become seriously limited over time if patients’ viruses develop and accumulate drug resistance. These issues motivate current scientific efforts. Hopefully, results from these efforts may lead to improvements in patient’s quality of life and lower the financial burden HIV imposes on society.  Using the most up-to-date knowledge in the field of HIV, this thesis addresses some of the above-mentioned issues through a quantitative systems pharmacology approach supported by clinical data. Our main objective was to inform the mechanisms underlying the development of resistance and the persistence of the virus in vivo. We used available information on the components involved in the virologic response to drugs. This allowed developing models that bridge multiple scales, going from molecular, to viral, then cellular and finally to the clinical level. By assessing the ensuing models’ ability to explain and reproduce empirical data, we studied the consistency of hypotheses regarding the causality of studied phenomena. First, we developed a model allowing to better understand the extent of drug resistance development in patients undergoing antiretrovial therapy. The model combines several components, including viral kinetics, immunity, pharmacokinetics and pharmacodynamics, drug adherence as well as their interindividual variability. Predictions originating from our in silico model are consistent with clinical observations of virologic failure for the three treatments that were considered consisting of efavirenz, emtricitabine, tenofovir, darunavir and ritonavir. Through this integrative approach, we have remedied previous models that largely underestimated the risk of resistance. Our results highlight the important role played by low lymph node drug penetration in the development of resistance. The model we developed is an added forward step toward the use of in silico methods in the prediction of virologic responses in HIV patients. We then investigated the causes underlying the increasingly slow phases of viral decline observed in patients initiating antiretroviral therapy. Opinions differ as to the role played by low drug penetration in tissues in the existence of these phases, leading to a fragmentation in research efforts. To shed light on this issue, we additionally considered, in our integrative model, different rates of tissue penetration.  Our results indicate that, if low drug penetration were the only cause of the decline in phases of the viral load, then the ensuing low drug exposure would put patients at a very high risk of developing drug resistance. Prediction of high risk quantitatively contradicts the observed reality (little to no resistance), leading us to conclude that low penetration is unlikely a fair explanation to the phases of viral decline. The last part of the thesis examines the ability of some patients to maintain low viral loads after interrupting prolonged antiretroviral therapy. We revisited a reported correlation between viral load values at interruption (also called residual viremia) and the duration of time patients maintained low viral loads afterwards. The interpretation of this correlation proved to be challenging since this duration includes both a time of complete control of viremia and a time during which viremia grows to a low-level threshold once control is lost. Using a mechanistic model and advanced statistical techniques, we were able to estimate the expected duration of complete viremia control along with its interindividual variability. Contrary to a direct interpretation of the correlation reported in the literature, our analysis reveals that the time of viremia control is unlikely associated with patients’ residual viremia. In summary, the in silico approach adopted in this thesis is part of an overall effort aiming to minimize patient recruitment and the financial costs involved in drug development. Our models suggest that better drug penetration in lymph nodes would likely lead to a decreased risk of drug resistance in non-adherent patients. However, our results also suggest that such an improvement would have little influence on the rate of decline of viral loads. Further, and regardless of the influence lymphatic tissue drug penetration may have on residual viremia, this improvement would not favour viremia control after antiretroviral discontinuation.

Keyphrases: drug adherence, drug distribution, drug efficacy, drug individualization, drug resistance, highly active antiretroviral therapy (HAART), HIV, HIV persistence, in vitro to in vivo extrapolation, interindividual variability, latent cells, mathematical modeling, post-treatment control, quantitative systems pharmacology (QSP), viral rebound, virologic failure