Guidelines for the management of HIV infection in adults and adolescents have recently been updated by the Department of Health and Human Services. The authors have switched to people-first language. In addition, terminology used to describe antiretrovirals’ (ARV) place in therapy has changed from “recommended regimen options” and “alternative regimen options” to “recommended initial regimens for most people with HIV” and “recommended initial regimens in certain clinical situations”, respectively. The most significant change that will impact patient care is the removal of boosted darunavir (DRV) from the “recommended initial regimens for most people with HIV” category due to its association with increased cardiovascular risk. All integrase strand transfer inhibitors (INSTI), including newly approved bictegravir (BIC) combined with tenofovir alafenamide/ emtricitabine (TAF/FTC), are recommended as initial regimens for most people with HIV infection due to their proven efficacy, safety, and high threshold for resistance development. This review article will discuss major modifications to the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV with a focus on pharmacotherapy recommendations for treatment-naïve, treatment-experienced, and co-infected patients, including clinical trial results that influenced the recommendations. Adverse effects and drug interactions will also be reviewed.