Single-tablet regimens (STRs) of highly safe and effective combination antiretroviral therapy (cART) have had a significant beneficial impact on the clinical outcomes and lives of people living with HIV (PLHIV). As a consequence, healthcare professionals caring for PLHIV in high-income countries have increasingly focused on issues beyond those related to HIV itself, i.e. HIV-related neurological disease, or associated opportunistic infections, which include co-infections, and primarily age- and lifestyle-related comorbidities such as cardiovascular disease, diabetes mellitus, renal impairment, osteoporosis and frailty. This review considers drug side effects and comorbidities seen in PLHIV and evaluates the role of a recently licensed STR - bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) - in mitigating some of those challenges. Factors that need to be evaluated for initial cART regimens include: pretreatment CD4 cell count; plasma HIV RNA; HIV drug resistance; hepatitis B co-infection; HLA-B*5701 status; drug-drug interactions; pregnancy and pregnancy potential; psychiatric and physical comorbidities such as renal or bone disease, as well as simplicity and adherence-friendliness, all of which need to be considered in all lines of therapy. BIC/FTC/TAF constitutes a new STR that includes an unboosted integrase strand transfer inhibitor with a high barrier against resistance with TAF and FTC. Its virological efficacy was non-inferior to dolutegravir-based regimens previously recommended by most guidelines for treatment initiation in large double-blind, randomised clinical trials in treatment-naïve or switch patients over 96 weeks. Tolerability and pharmacological properties of the regimen make it a useful tool to address several of the clinical management issues raised above.