Cohorte de patients vivant avec le VIH et ayant de la résistance prouvée ou présumée : analyse des changements de traitement pour une trithérapie contenant deux inhibiteurs nucléosidiques de la transcriptase inverse (INTI) avec du dolutégravir ou du ténofovir/abacavir avec un troisième agent

Significant progress has been made in treatment for people living with HIV (PLHIV) with the development of increasingly effective antiretroviral (ARV) therapy, safe with good tolerability. However, clinicians can sometimes face treatment challenges related to the monitoring of PLHIV whose HIV could carry genetic mutations conferring resistance to treatments either because of a history of virologic failure or because of previous exposure to mono/bitherapy to nucleoside reverse transcriptase inhibitors (NRTIs) (suboptimal therapy that was provided before the era of triple therapy).  In these patients, clinicians can sometimes try less studied combinations in the hopes to better control viral load or reduce side effects in these patients.  Therefore, this thesis by articles had three objectives aiming to evaluate less studied therapies that are used in these patients. The first objective (Paper 1) was to determine whether the efficacy of ARV regimen with dolutegravir in stable patients (whose viral load is controlled) varied in the presence of a history of virologic failure or with a previous exposure to suboptimal therapy regimen. The second objective (Paper 2) was to study virologic outcome after switching to dolutegravir compared to remaining on a boosted protease inhibitor (PI/r) regimen in stables PLHIV with prior documented virologic failure or exposure to mono/dual NRTI. Finally, the third objective (Paper 3) was to compare the risk of virologic failure for PLHIV who have previous documented virologic failure or prior exposure to suboptimal therapy taking an ARV therapy composed of abacavir/tenofovor (ABC/TDF) with a third agent of a different class, versus an ARV regimen composed of a standard backbone also with a non-NRTI third agent. We used data from the Quebec HIV cohort which brings together clinical information from 10,219 PLHIV followed in four clinical care centers in Montreal including the “Clinique de médecine urbaine du Quartier Latin (CMUQL)”, “Clinique médicale l’Actuel (CMA)”, the “Centre hospitalier de l'Université de Montréal (CHUM)” and the “McGill University Health Center (MUHC)”. A restriction to some patients in the cohort was made with regards to each objective of this thesis. Patients with an undetectable viral load who had received therapy with dolutegravir +2 NRTI from 2013 were selected for the objective 1. A Cox proportional hazard model with propensity score was used to compare the virologic outcome of patients on dolutegravir according to the exposure. For objective 2, patients with an undetectable viral load with an history of documented virologic failure or exposure to suboptimal therapy who were on PI/r + 2 NRTI from 2014 were selected. A marginal structural Cox model was used to measure the effect of switching to dolutegravir +2 NRTI compared to those who remained on PI/r + 2 NRTI therapy. For objective 3, patients with a documented virologic failure or exposure to suboptimal therapy in standard backbone (abacavir/lamivudine, tenofovir disoproxil/emtricitabine, tenofovir disoproxil/lamivudine) with another agent from January 01, 2006 were selected. A Cox proportional multivariate model was used to compare the virologic outcome of patients who switched to a non-standard regimen including ABC/TDF therapy versus those who remained on standard backbone. The article 1 suggested similar virologic efficacy of dolutegravir in stables patients with or without an history of documented virologic failure or exposure to suboptimal therapy (adjusted Hazard Ratio (aHR)=0,84 (95%CI: 0,35 - 2,01)). In article 2, no evidence of an increased risk of virologic failure was found in stables patients who had a regimen switched to dolutegravir compared to those who maintained their regimen with PI/r in patients who have had previous virologic failure or exposure to suboptimal therapy (aHR=0,57 (95%CI: 0,21 - 1,52)). In article 3, a non-significant reduction in the risk of virologic failure with the non-standard backbone including ABC/TDF was found compared to standard backbone (aHR=0,45 (95%CI: 0,06 - 3,36)).  In conclusion, the results of this thesis first suggested no effect of the presence of previous virologic failure or exposure to suboptimal therapy on the efficacy of dolutegravir in stables patients. In addition, the results showed that the switch to dolutegravir +2 NRTI for patients with an undetectable viral load on PI/r +2NRTI regimen can be considered despite the presence of proved or suspected NRTI resistance mutation. These results are of great importance as they should lead to changes the clinical guidelines for the use of dolutegravir in stable patients. On the other hand, our results failed to show a significant advantage to the use of the backbone ABC/TDF instead of standard backbones in patients with prior documented virologic failure or previous exposure to suboptimal therapy.

Keyphrases: Human immunodeficiency virus (HIV), antiretroviral (ARV) therapy, dolutegravir switch, protease inhibitor/ritonavir (PI/r), documented virologic failure and exposure documented to mono/dual NRTI, resistance mutation, non standard backbone, virologic outcome