Integrase strand transfer inhibitor-based regimens have become the top drug class due to their excellent efficacy and tolerability profiles as well as their very high barriers to resistance. Both US and EU guidelines favor INSTI-based regimens as initial “recommended” regimens, which has driven a steady decline in the market share of protease inhibitor- and non-nucleoside reverse transcriptase-based regimens in the first-line setting. Protease inhibitors suffer from the requirement for co-administration with a pharmacokinetic boosting agent, which increases the risk of drug-drug interactions and adverse events, while non-nucleoside reverse transcriptase inhibitors suffer from low barriers to resistance. In the maintenance setting, launches of products such as ViiV Healthcare’s Dovato and Cabenuva have further driven consolidation to INSTI-based regimens by offering patients the opportunity to simplify their treatment regimens from three drugs to two. This will become particularly apparent when Merck and Gilead launch their two-drug regimen competitors.