The long-term toxicity (LTT) of chronic human immunodeficiency virus (HIV) antiretroviral therapy (ART) is an important clinical consideration. A recent study has demonstrated that the fear of LTT (encompassing cardiovascular disease, renal disease and bone fractures) may also impact patient utility. Reducing drug burden via a streamlined 2-drug regimen (2DR), could ameliorate ART-associated LTT and improve patients’ quality of life (QoL), which traditionally is not the main endpoint in clinical trials. This study sought to estimate the impact of treatment with a streamlined 2DR of dolutegravir and rilpivirine (DTG/RPV) on LTT vs current triple ART (cART), regarding total life years (LYs), quality-adjusted life years (QALYs) and other health outcomes in a European setting. A lifetime analysis of DTG/RPV was undertaken using a previously published Markov model with health states reflecting CD4 cell count, viral load and death. The model was populated with efficacy and safety data derived from two phase III SWORD trials and DEXA sub-study. Patients were initiated in the model according to SWORD baseline characteristics under two scenarios: [A] no LTT; [B] LTT, and disutility associated with LTT, and with the fear of LTT, applied to cART based on baseline ART regimens. Discounting was applied as per French recommendations (4% up to 30 years, 2% thereafter). Under scenario A, LYs and QALYs for DTG/RPV were 15.01 (undiscounted: 25.79) and 11.30 (19.10), respectively, and 15.02 (25.80) and 11.31 (19.12) for cART, respectively. Under scenario B, LYs and QALYs for DTG/RPV were 15.01 (25.79) and 10.73 (17.79), respectively and 15.02 (25.80) and 9.96 (16.67) for cART, respectively. Reducing drug burden through the introduction of a streamlined 2DR with DTG/RPV may provide improved quality of life for those receiving long term ART for chronic HIV infection, through a reduction in LTT incidence and fear of toxicity outcomes.