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With prolonged life expectancy in HIV-positive patients on combination antiretroviral therapy, the quest for reducing lifelong drug exposure and minimizing or avoiding the toxicities of combination antiretroviral therapy while maintaining viral suppression has emerged when coformulations of antiretroviral agents with improved convenience, and better tolerability and efficacy became available. This review aims to update the current experience with the novel two-drug combination of dolutegravir (DTG) and rilpivirine (RPV) and elucidate the possible applications and limitations of coformulated DTG–RPV in the future.Five observational studies and two randomized, noninferiority trials (SWORD-1 and SWORD-2) evaluated the use of DTG and RPV in treatment-experienced patients. Despite variable inclusion criteria, 95–100% of the included patients maintained plasma HIV RNA load less than 50 copies/ml at the end of 24–48 weeks of observation. Overall, this regimen was well tolerated and only 0.8–7.9% of the patients discontinued the regimen due to adverse events.DTG and RPV is a novel two-drug antiretroviral combination regimen that can be effectively and safely used in patients with viral suppression for 6 months or longer. However, its use in patients with a previous history of virological failure and/or antiretroviral resistance warrants further investigation.